CHAP TER 1 
Cardiovascular System
Wayne F. Robinson  •  Nicholas A. Robinson
DISEASES OF THE HEART 2
GENERAL CONSIDERATIONS 2
Normal structure and function 2
Morphologic patterns of heart disease 4
The mural and valvular endocardium and the heart
valves proper 4
The myocardium 4
The pericardium 5
Pathophysiologic patterns of heart disease 5
Disturbances of impulse formation or impulse conduction 5
Depressed myocardial contractile strength 5
Impeded blood flow 5
Regurgitant blood flow 5
Abnormal pattern of blood flow (shunted blood flow) 6
Restricted atrial/ventricular filling 6
HEART FAILURE 6
Intrinsic cardiac responses in heart failure 7
Cardiac dilation 7
Cardiac hypertrophy 7
Systemic responses in heart failure 9
Syndromes of circulatory failure 10
Cardiac syncope 10
Peripheral circulatory failure 10
Congestive heart failure 10
EXAMINATION OF THE HEART 12
CONGENITAL ABNORMALITIES OF THE HEART AND
LARGE VESSELS 14
Malformations causing systemic to pulmonary
(left-to-right) shunting 16
Atrial septal defect 16
Atrioventricular (AV) septal defect 17
Ventricular septal defect 17
Patent ductus arteriosus 17
Malformation of semilunar or atrioventricular valves 19
Pulmonic stenosis 19
Tetralogy of Fallot 20
Aortic and subaortic stenosis 20
Dysplasia of the right atrioventricular valve 21
Left atrioventricular valvular insufficiency or stenosis 22
Transposition complexes 22
Miscellaneous cardiac anomalies 22
Vascular anomalies 23
PERICARDIAL DISEASE 24
Noninflammatory lesions of the pericardium 24
Hydropericardium 24
Hemopericardium 25
Serous atrophy of pericardial fat 25
Pericarditis 25
ENDOCARDIAL DISEASE 27
Degenerative lesions 27
Myxomatous valvular degeneration (“endocardiosis”) in dogs 27
Valvular cysts 30
Subendocardial fibrosis 30
Subendocardial mineralization 30
Endocarditis 30
MYOCARDIAL DISEASE 33
Hemorrhage of the heart and its membranes 33
Myocardial degeneration 34
Myocardial necrosis 34
Fluoroacetate poisoning 37
Gousiekte 38
Avocado poisoning 38
Taurine deficiency in cats 38
Myocardial necrosis secondary to neural injury 39
Doxorubicin (Adriamycin) cardiotoxicity 39
Porcine stress syndrome (pale, soft, and exudative [PSE] pork) 39
Mulberry heart disease of swine 39
Myocarditis 41
Encephalomyocarditis virus infection 43
Parasitic myocarditis 43
Cardiomyopathies 44
Feline cardiomyopathies 46
Canine cardiomyopathies 48
Bovine cardiomyopathies 50
DISEASES OF THE CONDUCTION SYSTEM 51
NEOPLASMS OF THE HEART 52
DISEASES OF THE VASCULAR SYSTEM 54
GENERAL CONSIDERATIONS 54
ARTERIES 56
Congenital anomalies 56
Degeneration of arteries 56
Arteriosclerosis 56
Atherosclerosis 57
Arteriolosclerosis 59
Mineralization 60
Arterial rupture, aneurysms 62
Arterial thrombosis and embolism 63
Aortic-iliac thrombosis in horses 64
Disseminated intravascular coagulation 64
Arterial hypertrophy 66
“High-altitude disease” of cattle 66
Congenital and acquired cardiac disease and pulmonary
arterial hypertension 66
Medial hypertrophy of the pulmonary arteries of cats 67
Vasculitis 67
Polyarteritis nodosa (panarteritis or periarteritis nodosa) 71
Viral vasculitides 71
Rickettsial vasculitides 80
Verminous arteritis 83
VEINS 88
Phlebothrombosis and thrombophlebitis 89
Parasitic thrombophlebitis 91
Schistosomiasis (bilharziasis) 91
LYMPHATICS 94
Congenital anomalies 94
Dilation and rupture of lymphatics 95
Lymphangitis 96
Ulcerative lymphangitis 97
Epizootic lymphangitis 97
Parasitic lymphangitis 98
VASCULAR NEOPLASMS 98
Angioma 99
Angiosarcoma 99
1
2 CHAPTER 1  •  Cardiovascular System
ACKNOWLEDGMENTS
This update of the Cardiovascular System chapter is based on
previous editions by Drs. Ken Jubb, Peter Kennedy, Nigel Palmer,
Wayne Robinson, and Grant Maxie, and their contributions are
gratefully acknowledged.
DISEASES OF THE HEART
GENERAL CONSIDERATIONS
The heart is structured and functions to fulfill a singular role,
which is to move sufficient volumes of blood to all organs in
the body to meet the varying metabolic needs of the organism.
For this purpose, the heart can be described as an in-series,
2-stage, rate-variable, one-way pump. From this characteriza-
tion, the heart must provide sufficient force to eject the blood
it receives, respond to the host’s needs by varying the amount
of blood ejected per unit time, and finally, ensure one-way
flow without impediment of forward flow as well as prevent
backflow. As befits a biological pump, the heart is a physically
active organ that rhythmically contracts and relaxes which,
over an average 10-year lifetime of a dog, beats in the vicinity
of 400 million times and receives and ejects ten million  and ventricular walls.
liters of blood—by any measure, a remarkable and sustained
performance.
If the structure or function of any of the components of
the pump are compromised or fail, it will result in either
diminution, or at worst, complete cessation of function. Addi-
tionally, if each component of the heart as a pump is examined
and understood, it then facilitates the understanding and cat-
egorization of the causes and effects of component dysfunc-
tion. We are concerned predominantly with the diseases that
interfere with the heart’s rate and rhythm, its strength of con-
traction, and the flow of blood through the heart. Heart disease
may be clinically detectable and, when sufficiently severe,  base of the aorta. The left coronary artery gives rise to the left
may give rise to heart failure, or may be only evident on  descending and the left circumflex coronary arteries. The epi-
postmortem (eFig. 1-1).
Under the anatomic units of the pericardium, endocardium,
and myocardium, we will first consider the normal form and
function of the heart, the morphologic patterns of disease, its
pathophysiology, and finally, its reaction to injury and its spe-
cific diseases.
Normal structure and function
Located within the mediastinum, the heart is enclosed in the
fibroserous pericardial sac, which is lined by a serosal mem-
brane and contains several milliliters of clear serous fluid that
acts as a lubricant.
The heart consists of a right and left side; each side consists
of an atrium and a ventricle. The ventricles function as 2
pumps in series. Venous blood from the body enters the right
atrium, passes into the right ventricle, and is pumped through
the pulmonary artery into the lungs to be oxygenated and to
give up its carbon dioxide. Oxygenated blood returns via the
pulmonary veins to the left atrium, enters the left ventricle,
and is then pumped to the body via the aorta. Heart weight
varies with species, age, sex, nutritional status, and fitness level
of the animal; averages about 1% of body weight in newborns;
and decreases to 0.3-0.8% in juveniles and adults.
Ventricular thickness varies greatly. Left ventricular free
wall and interventricular septum are normally 2-4 times
thicker than the right ventricular free wall. An increase in
General Considerations
myocardial mass is termed hypertrophy; an increase in chamber
volume is termed dilation. An overall increase in the external
dimensions of the heart is termed cardiomegaly.
The 4 cardiac valves are structured to allow unimpeded
unidirectional blood flow, to prevent backflow, and to withstand
pressure, especially those of the left side of the heart. The atrio-
ventricular (AV) valves, supported by tendinous cords
(chordae tendineae) and papillary muscles of the ventricles,
allow flow from the atria into the ventricles and prevent
backflow into the atria. The right AV (RAV, tricuspid) valve
has 3 valve cusps (2 cusps in the dog). The left AV (LAV,
bicuspid, mitral) valve in most species consists of 2 cusps. The
pulmonic and aortic semilunar (crescent moon-shaped) valves
each have 3 cusps, and they allow flow into the pulmonary
artery and aorta, respectively, and prevent backflow into the
ventricles. The nodules (nodules of Arantius) in the center of
the free edges of the semilunar valve cusps are normal struc-
tures. Valve cusps are normally thin and translucent. The free
edges of the valve cusps (coaptation region) normally overlap
during closure, and therefore fenestrations of the valve edges
are usually insignificant. Normal valve function depends on
coordinated actions of the respective annulus and leaflets, and
in the case of AV valves, the tendinous cords, papillary muscles,
The cardiac muscle and valves are supported at the base
of the heart by the cardiac skeleton, which consists of 4 fibrous
rings, the fibrous triangle, and the fibrous or membranous part of
the ventricular septum. The fibrous triangle fills the space
between the AV openings and the base of the aorta; it consists
of dense fibrous connective tissue in pigs and cats, fibrocarti-
lage in dogs, hyaline cartilage in horses, and bone (os cordis)
in large ruminants.
The blood supply to the heart is primarily via 2 major coro-
nary arteries. The left and right coronary arteries arise, respec-
tively, behind the left and right cusps of the aortic valve at the
cardial coronary arteries give rise to the intramural arteries that
penetrate the myocardium. Most coronary arterial blood flow
occurs during ventricular diastole, when the coronary microcir-
culation is not compressed by myocardial contraction.
The myocardial conduction system consists of modified
cardiac myocytes that initiate and conduct an electrical
impulse (Fig. 1-1). The sinus node (sinoatrial node, SA node)
is located subepicardially at the junction of the cranial vena
cava and the right auricle. Because cells in the sinus node are
not capable of remaining in a depolarized state, after each
repolarization, their membranes permit leakage of sodium and
potassium until they reach a stage of depolarization (the criti-
cal threshold), when they rapidly depolarize. The impulse
from this pacemaker (the dominant pacemaker) in turn causes
atrial depolarization and contraction, and travels through
internodal bundles to the AV node located in the interatrial
septum just cranial to the coronary sinus. The impulse slows
while traversing the AV node before traveling via the AV
bundle (bundle of His) to the left and right bundle branches,
or crura, through the Purkinje fibers. These modified myocar-
dial cells ramify within the myocardium and transmit the
depolarizing impulse to ventricular myocytes.
Although each component of the conduction system has
different rates of diastolic depolarization, the sinus node has
the most frequent rate and is therefore dominant. The fre-
quency of depolarization of the sinus node is in turn modified
 2.e1

Clinically detectable
No clinical disease,
disease (murmur,
lesion detected
arrhythmia) but no
at autopsy
evidence of failure

Heart disease

May give
rise to

Heart failure

Congestive heart failure Acute heart failure

(fluid accumulation, edema) (collapse, weakness)

Both may be present

eFigure 1-1  Relationship between heart disease and heart

failure. Heart disease may be present without attendant clinical
signs or may give rise to either acute or congestive heart failure.
(Modified from Robinson WF, Huxtable CRR, eds. Clinicopatho-
logic Principles for Veterinary Medicine. Cambridge, UK: 
Cambridge University Press, 1988. Reprinted with permission.)
Diseases of the Heart
Cranial vena cava
SA node
RA
LA AV node
Internodal Left bundle
pathways branch
AV trunk
(bundle of His)
LV
Right bundle RV
branch
Cardiac
conducting fibers
Figure 1-1  The myocardial conduction system. Major species
differences include ramification of the cardiac conduction fibers,
which can reach the subepicardium in some species (not shown).
AV, atrioventricular; LA, left atrium; RA, right atrium; LV, left
ventricle; RV, right ventricle; SA, sinoatrial. (Modified from
Robinson WF, Huxtable CRR, eds. Clinicopathologic Principles
for Veterinary Medicine. Cambridge, UK: Cambridge University
Press, 1988. Reprinted with permission.)
by the autonomic nervous system. Atrial and ventricular myo-
cytes do not normally exhibit the property of automaticity.
However, when atrial or ventricular myocytes are injured,
they may repeatedly depolarize independent of a stimulus
from the conduction system and may become dominant pace-
makers. There are diseases that specifically affect the conduc-
tion system producing dysrhythmias (abnormalities of rate and
rhythm), but it is the dysrhythmias resulting from disease
injuring the atrial and ventricular myocytes that are most
common. The cardiac wall has 3 layers:
1. The epicardium, the outermost layer
2. The myocardium, the thick muscular middle layer
3. The endocardium, the innermost layer, which is continu-
ous with the tunica intima of the great vessels entering and
leaving the heart
The epicardium, or visceral pericardium, consists of a thin
layer of mesothelium resting on elastic fiber-rich connective
tissue that merges with that of the myocardium. The epicar-
dium is continuous with the parietal pericardium, which con-
sists of an inner mesothelial layer and a thick layer of collagen
and elastic fibers. The cavity between the visceral and parietal
pericardium contains serous fluid that lubricates the surfaces
and reduces friction between the epicardium and pericardium
during cardiac motion. Although the pericardial sac is not a
vital organ, its proper function includes prevention of sudden
cardiac dilation, assurance of equal end-diastolic transmural
pressures throughout the ventricles, limitation of right ven-
tricular stroke work, hydrostatic compensation for gravita-
tional or inertial forces, reduction of friction, and maintenance
of cardiac alignment and streamlined cardiac flow.
General Considerations 3
The myocardium, the generator of the force required to
eject blood from the atria and ventricles, consists of striated
muscle cells—cardiac myocytes—embedded in a well-
vascularized connective tissue framework. Individual myo-
cytes, which account for about 2 3 of the myocardial volume,
are intimately joined at intercalated discs to function as a unit.
Each cardiac myocyte consists of a single, central nucleus;
mitochondria; abundant contractile elements (myofibrils),
predominantly composed of actin, myosin, tropomyosin, and
troponin; sarcoplasmic reticulum that stores calcium needed
for the initiation of contraction; and the cell membrane (sar-
colemma) and T tubules needed for impulse conduction.
Myocytes may be binucleate in some species, for instance,
dogs, and are commonly multinucleate in pigs (4-16 nuclei
per cell). The actin and myosin filaments comprise contractile
units called sarcomeres, which are demarcated by Z lines.
Mitochondria occupy about 20-30% of the volume of cardiac
myocytes versus 2% in skeletal muscle, reflective of the great
dependence of cardiac muscle on aerobic metabolism. Sarco-
mere length varies from 1.6-2.2 µm; ventricular dilation
increases sarcomere length, which enhances contractility (Frank-
Starling relationship). Atrial cardiac myocytes are typically
smaller than ventricular cardiac myocytes, predominantly
because they operate in a low-pressure system where less
force is required to eject blood. There are consequently many
fewer myofibrils and mitochondria per cell, but they contain
specific granules encasing the hormone atrial natriuretic factor
(ANF) which is released on dilation or stretching of the atria.
The cardiac interstitium contains blood vessels and fibro-
blasts in a diverse extracellular matrix that consists of colla-
gens, proteoglycans, noncollagenous glycoproteins, growth
factors and cytokines, and extracellular proteases. The collagen
network of the heart is arranged into 3 interconnected regions:
the collagenous weave of the endomysium around individual
fibers, the perimysium around groups of fibers, and the epimy-
sium around the whole muscle. This fibrillar collagenous
network of the myocardium prevents overstretching of myo-
fibers, transmits myofiber-generated force to the chamber, and
provides tensile strength and stiffness to the chamber. The
collagenous struts that connect adjacent myofibers provide
proper alignment during contraction. Struts that connect
myocytes to capillaries help to maintain capillary patency
during high intraventricular pressure.
The endocardium lines the heart and consists of a mono-
layer of endothelium on a continuous basement membrane,
covering the inner subendothelial layer of dense collagen, and
the outer subendothelial layer composed of collagen, elastin,
and blood and lymph vessels. The atrioventricular (AV) valves
are endocardial infoldings with a layer rich in elastin on the
atrial side (atrialis); a central layer (fibrosa) of dense irregular
connective tissue covered by layers of elastic fibers; and, on
the ventricular side, loose connective tissue (spongiosa). The
central collagen of the AV valves is continuous with the dense
collagen of the chordae tendineae, which are attached to the
ventricular papillary muscles. The aortic and pulmonic semi-
lunar valves consist of a ventricularis layer of collagen and
radially aligned elastin on the ventricular side, a central spon-
giosa layer of water and glycosaminoglycans, and a fibrosa layer
of collagen and elastin arranged in a circumferential direction
on the great vessel side of the valves to resist back-pressure of
blood. Valve cusps are predominantly avascular.
The coronary arteries feed a dense capillary network that
supplies the myocardium, endocardium, epicardium, cardiac
4 CHAPTER 1  •  Cardiovascular System
skeleton, and bases of the cardiac valves. Blood collected by
venules and veins is drained into the right atrium via the coro-
nary sinus. Lymphatic capillaries draining the cardiac connec-
tive tissue are continuous with larger lymph vessels in the
endocardium and epicardium. Sympathetic and parasympa-
thetic innervation is extensive in the atria, and particularly
around the SA and AV nodes.
Morphologic patterns of heart disease
The 3 broad anatomic divisions of the heart—the mural and
valvular endocardium, the myocardium, and the pericardium—
exhibit differing features in the face of disease. It is not that
the usual suspects that affect all organs are not in play. Inher-
ited disease, infectious agents, toxins, nutritional deficiencies,
and neoplasia all affect the heart, but it is the combination of
the structure of the heart, the biological characteristics of the
cells comprising the heart, and their response to injury, in
concert with the host’s general response to injury, that results
in the display of the particular features of heart disease. It
should be remembered that the heart may also show evidence
of disease as an integral part of diseases of another organ
system or systemic disease.
The mural and valvular endocardium and
the heart valves proper
Valvular abnormality from any cause can lead to disturbances
of blood flow through the heart either by altering the normal
unidirectional pattern of flow, or by impeding blood flow into
or out of the chambers. Alterations in hemodynamics reflect
changes in systolic workloads characterized by changed pres-
sure loading during contraction (afterload), or changed volume
loading during diastole (preload). Most valvular disorders
impose only a single preload or afterload on the heart. This
encompasses those valvular disorders that cause either insuf-
ficiency (failure to close) or stenosis (narrowing, failure to open).
Some of the congenital heart abnormalities, such as patent
ductus arteriosus and tetralogy of Fallot, have multiple preload
and afterload effects. The general rules are (eFig. 1-2):
1. Valvular insufficiency increases the preload on the
ventricle.
2. Semilunar valvular stenosis, outflow tract stenosis, and
hypertension increase the afterload on the ventricle.
3. AV valvular stenoses and pericardial disorders decrease the
preload on the ventricles.
Subendocardial hemorrhage is a frequent accompaniment
to a myriad of diseases of the heart, but more particularly,
with systemic disease, where the heart is just another surface
where hemorrhage can be observed. Subendocardial mineral-
ization occurs as either a dystrophic or metastatic phenome-
non. Additions to valves and/or the mural endocardium result
from disturbances to the health of the endothelial lining of
the mural and valvular endocardium, and because of the loca-
tion, can have wide-ranging consequences. The most severe
and extensive occurs with microorganisms, particularly bacte-
ria, that arrive via the systemic circulation that adhere to
endothelium and/or subendocardium after the endothelium
has been damaged or eroded. The cascade of events that
follow, especially the incitement of thrombosis, results in a
mass of platelets, fibrin, and inflammatory cells (vegetations)
accumulating on the exposed surfaces, impeding blood flow
through the heart and predisposing to thrombotic emboli
lodging in end-arteries in organs throughout the host. Although
healing may occur, the healed valve is rarely returned to its
General Considerations
original state and is often left thickened, shrunken, and dis-
torted. Affected valves may be either insufficient or stenotic
or both, but one or the other usually predominates. Distor-
tions of the structure of heart valves in the absence of vegeta-
tions and with an intact valvular endothelium are commonly
encountered. Valves can be effaced, displaced, shrunken,
thickened, or, in the case of the AV valves, no longer firmly
anchored to the papillary muscles. All result, to a greater or
lesser extent, in a diminution of effective unidirectional blood
flow. Probably the best examples of distortions in architecture
are those seen in congenital heart disease, such as valvular
aortic and pulmonic stenosis, left and right AV valvular steno-
sis or insufficiency. Similar lesions can be seen in acute or
healed valvular endocarditis and degenerative diseases of the
AV valves, such as endocardiosis in dogs. Abnormal chamber
or great vessel communication is of special interest because
of the altered hemodynamics that ensue in the transition from
fetal to postnatal life. Predominantly congenital in origin, it is
often the result of incomplete closure of fetal communications
between the atria, ventricles, and great vessels following birth.
Acquired arteriovenous communication can also occur.
The myocardium
The myocardium may be primarily and specifically affected
by a particular disease, but it may also be just another organ
involved in systemic disease. The morphologic manifestations
of myocardial disease reflect some of the characteristics of the
myocardium, such as the predominance of contractile proteins
in each cardiac myocyte; the exquisite compartmentalization
of calcium required for regular and orderly contraction; its
high requirement for energy for regular contraction; its end-
arterial blood supply, predisposing the myocardium to infarc-
tion; and the very limited capacity of cardiac myocytes for
regeneration. Cardiac myocytes, however, have a remarkable
capacity to increase in mass (hypertrophy) in response to an
increase in either physiologic or pathologic workload.
As do all tissues, the myocardium has a limited set of reac-
tions to injury, but the pattern and distribution of lesions may
aid in arriving at a morphologic and etiologic diagnosis. The
stage of irreversible damage to a myocyte, at least in ischemia,
is determined by structural and functional changes in the
mitochondria. Irreversible damage occurs after only 30
minutes of ischemia, whether or not flow is restored.
Shortly after birth, most cardiac myocytes lose their ability
to regenerate. Once the neonatal period passes and a particular
myocyte or group of myocytes is lost, there is usually no
replacement. There is, however, recent evidence to show that
there is a low level of cardiac myocyte turnover throughout
life. On the death of myocytes, there is progressive scavenging
of the necrotic or apoptotic remnants of the myocytes and
replacement by fibrosis. Remaining myocytes do have the
capacity for compensatory hypertrophy.
Myocardial injury may be functionally manifest as either
irregularities in the rate or rhythm of impulse formation and
conduction (dysrhythmias), or as depression in the force of
myocardial contraction. Dysrhythmias are usually associated
with acute, nonlethal, often focal injury to cardiac myocytes.
Contractility disturbances occur when there are either insuf-
ficient numbers of ventricular myocytes for effective contrac-
tion, as occurs in massive ischemic necrosis of ventricular
myocytes following blockage of a major coronary artery, or
when there is generalized ineffective contraction of normal
numbers of myocytes. Generalized, ineffective myocardial
 4.e1

Semilunar Stenoses
Supra/subvalvular and
valvular stenosis
Increased ventricular
afterload
Concentric hypertrophy

Hemodynamic
effects of
valvular
abnormalities

Insufficiencies AV stenoses
[Both AV and SL valves] Decreased ventricular
Increased ventricular preload
preload Increased atrial afterload
Eccentric hypertrophy

eFigure 1-2  Hemodynamic effects of valvular abnormalities. AV, atrioventricular; SL, semilunar.
(Courtesy Vasileios Psychas.)
Diseases of the Heart
contraction is most commonly seen as a feature of dilated
cardiomyopathies. The basis of generalized ineffective con-
traction is complex and reflects the many contributing factors
to the normal functioning of cardiac myocytes. For example,
with the cardiomyopathies, there are a number of disorders
that have as their origin inherited defects in either contractile
proteins, cytoskeletal proteins, or mitochondrial proteins, all
leading to a lowering of the effectiveness of contraction.
A number of grossly observable permutations and combi-
nations assist in arriving at a diagnosis that involves the myo-
cardium. An increase in ventricular wall thickness or mass
should lead the investigator to search for a cause of increased
workload performed by the heart, such as a stenotic valve, or
a shunt between chambers or great vessels, which produce an
increased afterload on the heart. If no obvious cause for the
increased mass can be discerned, a primary myocardial disease,
such as hypertrophic cardiomyopathy, should be considered.
A dilated ventricular lumen accompanied by a normal to thin
ventricular wall leads toward consideration of an increased
preload on the heart, such as AV or semilunar valvular insuf-
ficiency or a vascular shunt. In the absence of an inciting cause,
dilated cardiomyopathy should be considered. Focal pale
areas in an otherwise normally appearing myocardium suggest
destruction of cardiac myocytes alone, cellular infiltration
alone, or a combination of the two. The most common causes
include bacterial and viral infections as well as nutritional
deficiencies and toxins that induce necrosis of cardiac  cardiac output. Disturbances of both impulse formation and
myocytes. Metastatic neoplasms should also be considered.
Although rare in domestic animals, a special type of focal,
well-circumscribed area of paleness with a reddened periph-
ery is indicative of a recent infarct following thrombosis of a
coronary artery. Focal scarring/fibrosis of the ventricular wall
is characteristic of a healed infarct or replacement fibrosis of
necrotic cardiac myocytes. Discrete nodules in the chamber
walls, especially of the ventricles, are typical of bacterial/
fungal/parasitic infections. Frank abscessation is more typical
of bacterial infection, whereas nodules with caseous centers
ringed by well-demarcated fibrous tissue suggest intermediate
stage parasitic infection.
The pericardium
The inability of the pericardium to stretch rapidly to accom-
modate additional fluid in the pericardial sac leads to clinically
significant disease. Fluid accumulation prevents adequate
filling of the chambers during diastole, lowering stroke volume
and cardiac output. This is also central feature of a resolving
or resolved pericarditis.
• Blood, often clotted blood, within the pericardial sac is
often the result of a ruptured atrium, ventricle, great vessel,
or coronary artery. Unclotted blood in the pericardial sac,
of unknown cause, occurs in dogs.
• Clear fluid in the pericardial sac should lead to an inves-
tigation of causes of hypoproteinemia and as part of a
number of infectious diseases.
• Fibrinous/purulent exudates in the pericardial sac usually
indicate acute bacterial/mycoplasmal infection. The pres-
ence of pericardial and epicardial fibrosis often indicates a
prolonged and ineffective attempt at repairing acute fibrin-
ous and purulent pericarditis.
Pathophysiologic patterns of heart disease
When the heart is diseased, there is a restricted array of altera-
tions in function that can be categorized as follows.
General Considerations 5
Disturbances of impulse formation or
impulse conduction
Diseases affecting the sinus node of the heart’s specialized
conduction system can lead to an increase, decrease, or absence
of impulse formation. Any disease affecting the conducting
fibers—the intra-atrial conduction pathways, the AV node, the
common bundle, right and left bundle branches, or Purkinje
fibers—can result in a decrease or an absence of impulse con-
duction. These are manifest as various forms of bradyarrhyth-
mias (heart block), such as sinoatrial arrest; first-, second-,
and third-degree heart block; and left and right bundle 
branch block.
By far and away the most significant and most common
disturbances of impulse formation are those that arise from
injury to atrial and ventricular myocytes. Common causes
include electrolyte disturbances, coronary arterial thrombosis
or embolism, nutritional deficiencies, bacterial and viral infec-
tions, and toxins, especially plant toxins. The predominant
alterations in heart rate and rhythm are an increased rate and
an erratic rhythm (tachyarrhythmias). It should be noted that
arrhythmias arise from the inappropriate depolarization of
injured components of the conduction system or cardiac myo-
cytes (ectopic pacemakers) that are often in close proximity
to necrotic/apoptotic myocytes. The major pathophysiologic
effect of disturbances of the heart’s rate rhythm or conduction
is erratic filling and contraction, leading to a depression in
impulse conduction can be readily classified through the use
of electrocardiography.
Depressed myocardial contractile strength
This category is essentially one of either a decrease in ventricu-
lar myocardial contractile critical mass, such as in massive myo-
cardial necrosis, or, in a heart that has sufficient ventricular
myocardial mass, but where there is a disturbance in the effec-
tiveness of contraction. The latter occurs in a number of dilated
cardiomyopathies, especially in dogs and cats.
Impeded blood flow
This occurs with stenosis (narrowing) of the AV or semilunar
valves, resulting in either a restriction of blood flow from one
chamber to another (atrium to ventricle), or from a ventricle
to the major arteries. This places an increased systolic work-
load (afterload) on the affected chamber. The lesion is not
invariably pure in nature. Stenotic valves can also be mildly
regurgitant, but it is the stenosis that predominates. Stenosis
can either be congenital or acquired. More common forms of
acquired impedance of blood flow include acute valvular
endocarditis with thrombosis or healed endocarditis with
resultant distorting fibrosis of the valves.
Regurgitant blood flow
This is associated with lesions of the AV and semilunar valves
in which the valve structure is so effaced that it becomes
insufficient and cannot prevent backflow of blood from ven-
tricle to atrium or from a great vessel back to its ventricle.
With regurgitation, the heart responds by increasing its stroke
volume, which places an increased diastolic load (preload) on
the heart. The lesion can be congenital, such as congenital
mitral insufficiency, or acquired, such as healed endocarditis
or the degenerative AV valvular condition endocardiosis, in
dogs. Again, some primarily insufficient valves can be mildly
stenotic, but in these cases, the insufficiency predominates.
6 CHAPTER 1  •  Cardiovascular System
Abnormal pattern of blood flow
(shunted blood flow)
Although these can be acquired, they are much more com-
monly congenital in origin. They can be simple communica-
tions between the great vessels (patent ductus arteriosus), the
atria (patent foramen ovale/atrial septal defect), or the ven-
tricles (ventricular septal defect). The pathophysiology can be
complicated where the defect results in increases in both
preload and afterload on particular chambers. A special case
of shunted blood flow occurs with the transposition of the
great vessels.
Restricted atrial/ventricular filling
Pericardial disease, either acute or chronic, can restrict chamber
filling during diastole, as can some of the hypertrophic cardio-
myopathies. In essence, the compliance of either the pericar-
dium or the myocardium is reduced, which prevents full
diastolic relaxation of the ventricles. The major pathologic
effect is one of increased central venous pressure leading to
congestive heart failure, which can be predominantly right-
sided or left-sided, depending on which chamber is most
affected.
Further reading
Bergmann O, et al. Evidence for cardiomyocytes renewal in humans.
Science 2009;324:98-102.
Bonow RO, et al., editors. Braunwald’s Heart Disease. A Textbook of
Cardiovascular Medicine. 9th ed. Philadelphia: Elsevier Saunders;
2012.
Ettinger SJ, Feldman EC, editors. Textbook of Internal Veterinary Med-
icine: Diseases of the Dog and Cat. 7th ed. Philadelphia: Saunders
Elsevier; 2010.
Hurst JW, et al. The Heart. 13th ed. New York: McGraw-Hill; 2011.
Miller LM, et al. Cardiovascular System and Lymphatics. In: Zachary JF,
McGavin MD, editors. Pathologic Basis of Veterinary Disease.
5th ed. St Louis: Elsevier; 2012.
Orton EC. The Heart. In: Bojrab MJ, Monnet E, editors. Mechanisms of
Disease in Small Animal Surgery. Boca Raton, Fla: CRC Press; 2010.
Plendl J. Cardiovascular System. In: Eurell JO, Frappier BL, editors. Dell-
man’s Textbook of Veterinary Histology. 6th ed. Ames, Iowa: Wiley
Blackwell; 2007. p. 117-133.
Schoen FJ, Mitchell RN. The heart. In: Kumar V, et al., editors. Robbins
and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia:
Saunders; 2010. p. 529-587.
HEART FAILURE
Heart failure is the end point of a number of causes, rather than
a specific disease, and denotes a situation in which all compen-
satory mechanisms have been exhausted, and the heart is
unable to meet the demands of the animal. The syndrome is
characterized by diminished cardiac output (“forward failure”),
or damming back of blood in the venous system (“backward
failure”), or both. The heart can fail because of impaired pump
function or because of increased cardiac work demands; both
mechanisms may be operative in some cases. The heart can
fail as a pump because of
1. Decreased myocardial contractility, or loss or replacement
of myofibers, or
2. Decreased distensibility (compliance), or
3. Dysrhythmia (abnormal heart rate and/or rhythm)
Heart Failure
Increased cardiac work demands on one or both ventricles
result from disturbed hemodynamics, in the form of sustained
pressure overload (e.g., obstructed flow in aortic valvular
stenosis) or volume overload (e.g., regurgitant flow in mitral
valvular regurgitation).
Congestive heart failure is characterized by vascular conges-
tion and edema fluid within the interstitium of tissues and body
cavities. Not all cases of heart failure are of the congestive type.
Although in congestive heart failure the clinical manifesta-
tions are more or less constant, in acute heart failure, there
may be intermittent weakness and syncope caused by a sub-
stantial change in heart rate or rhythm, resulting in a precipi-
tous drop in cardiac output. The effect of acute heart failure
is often sudden unexpected death, often with minimal lesions.
Circulatory failure, or shock, denotes a state of inadequate
peripheral vascular perfusion and is used to describe a state that
may or may not be the result of heart failure. It is character-
ized by a drop in effective circulating blood volume. Common
causes are acute internal or external hemorrhage, dehydration,
or endotoxic shock. Shock can of course lead to acute heart
failure.
Based on clinical manifestations, heart failure may be pre-
dominantly either left-sided failure or right-sided failure. Left-
sided failure results in left atrial dilation, pulmonary congestion
and edema, and clinical signs of dyspnea and cough. A promi-
nent feature of chronic left-sided heart failure is the presence
of hemosiderin-laden macrophages (“heart failure cells”) in
pulmonary alveoli, the result of diapedesis of red cells into 
the alveoli. Right-sided failure results in excessive right atrial
pressure and systemic venous congestion, expressed as jugular
distension, hepatic and splenic enlargement, ascites, and
peripheral edema. Cor pulmonale is defined as right heart
failure secondary to pulmonary disease, such as chronic obstruc-
tive pulmonary disease, dirofilariasis, or pulmonary thrombo-
embolism. Because the cardiovascular system is closed, failure
of one ventricle will ultimately lead to failure of the other,
culminating in global or biventricular failure.
Although there are many causes that lead to intermittent
or permanent lowering of effective cardiac output, there is a
limited set of responses to this by the animal. The major
compensatory mechanisms include the intrinsic cardiac
responses of dilation and hypertrophy, and the systemic
responses, which include increased heart rate and peripheral
resistance, redistribution of blood flow, venular constriction, and
increased blood volume. In each case, the compensatory
responses are at least temporarily beneficial and are directed
toward increasing cardiac output to meet the metabolic needs
of the animal. The range within which the compensatory
mechanisms result in an increase in cardiac output is wide.
Indeed, the increase may be up to 5 times the basal rate. As
cardiac output falls below the requirements of the animal,
signs of congestive heart failure appear. These may be inter-
mittent or prolonged, depending on the nature of the defect.
An untoward side effect of the systemic responses is
increased capillary hydrostatic pressure that leads to the accu-
mulation of edema fluid. This can involve the systemic or
pulmonary veins. Right-sided lesions, such as right atrioven-
tricular (AV) valvular insufficiency, pulmonic stenosis, or pul-
monary hypertension, result in peripheral-dependent edema
(e.g., submandibular edema [“bottle-jaw”], brisket edema),
ascites, hydrothorax, and hydropericardium. Left-sided defects,
such as left AV or aortic valvular insufficiency, cause pulmo-
nary edema as the predominant finding.
 6.e1

Further reading
Borg TK, et al. The cell biology of the cardiac interstitium. Trends Car-
diovasc Med 1996;6:65-70.
Darke PGG, et al. Color Atlas of Veterinary Cardiology. London: Mosby-
Wolfe; 1996.
Fox PR, et al. Textbook of Canine and Feline Cardiology. Principles and
Clinical Practice. 2nd ed. Philadelphia: WB Saunders; 1999.
Robinson TF, et al. Skeletal framework of mammalian heart muscle.
Arrangement of inter- and pericellular connective tissue structures.
Lab Invest 1983;49:482-498.
Tilley LP, Goodwin J-K. Manual of Canine and Feline Cardiology.
Philadelphia: WB Saunders; 2001.
Ware WA. Cardiovascular Disease in Small Animal Medicine. London:
Manson Publishing; 2011.
Diseases of the Heart
Figure 1-2  Cardiac dilation in a lamb. Left ventricular dilation
with effacement of papillary muscles and severe subendocardial
fibrosis. (Courtesy Vasileios Psychas.)
Intrinsic cardiac responses in heart failure
Cardiac dilation
Dilation is a response to an increased workload in both physio-
logic and pathologic states. Increasing the end-diastolic volume,
and hence stretching the myofibers, can increase the contrac-
tile force of the heart and increase the stroke volume and
cardiac output. This is known as the Frank-Starling relation-
ship, or heterometric autoregulation. Transient cardiac dila-
tion is an acute response to increased demands, for instance,
increased exercise. Continued stretch increases contractile
force to a limit, after which increased stretch will result in a
decrease in tension developed. The limit of stretch in most
species appears to be a sarcomere length of 2.2-2.4 µm.
Chronic dilation of a ventricle can occur through addition of
sarcomeres and hence lengthening of myocytes.
Various disease conditions can cause an increased diastolic
workload (preload) and hence dilation of the heart, such as
arteriovenous shunts, and AV and semilunar valvular insuffi-
ciencies (Fig. 1-2). Acute volume overload of a chamber is
expected to lead to dilation, whereas chronic volume overload is
one stimulus to the development of cardiac hypertrophy.
Cardiac hypertrophy
Cardiac hypertrophy is a reversible increase in the mass and a
minimal increase in the number of myocardial cells, and is a
compensatory response to an increase in mechanical work or to
trophic signals. In general, chronic pressure overload leads to
myocardial hypertrophy, whereas chronic volume overload
leads to combined ventricular dilation and hypertrophy. Hyper-
plasia, or increase in the number of cells, has recently been
shown to occur in response to workload, although the capacity
of the myocyte to divide decreases rapidly prior to birth, and
little mitotic activity is observed after the first few weeks  chondria, altered protein synthesis and degradation, and cyto-
of life.
At this juncture, it is important to distinguish between hyper-
trophy that is physiologic and hypertrophy that is pathologic in
nature. Physiologic hypertrophy is a response to exercise or
pregnancy and results in a mild increase in heart weight, not
>10-20% normalized to body weight. It is an extension of the
normal growth process, is without deleterious effect and
occurs without the induction of the molecular stress fetal gene
program that is associated with the development of pathologic
Heart Failure 7
hypertrophy. Physiologic hypertrophy is initiated by ligands
that include thyroid hormone, insulin, insulin growth factor
1, and growth hormone. Additionally, cardiac function is
maintained or enhanced and is reversible. On the other hand,
with pathologic hypertrophy, there may be up to a 4-fold
increase in mass, depressed cardiac function, and the induction
of a molecular fetal stress cardiac gene program. Of particular
note is the initiation of hypertrophy by mechanical work
through the activation of stretch-sensing transducing proteins
located in the plasma membrane, within the cardiac Z line, or
by adhesion complexes. The following discussion will be con-
cerned only with the process of hypertrophy following a
defined change in workload or stimulation. The presence of
hypertrophy in the absence of an observable increase in work-
load will be considered to be primary and is discussed under
the cardiomyopathies.
In pathologic hypertrophy, the mass and size of the heart
are increased through a restricted number of hypertrophic
stimuli resulting in the activation of a limited number of
intracellular signal transduction pathways that alter gene
expression. The initiating actions include mechanical stimuli
(stretch) or trophic stimuli (polypeptide growth factors; vaso-
active agents, such as angiotensin II and α-adrenergic agonists),
all of which increase the rate of protein synthesis; the amount
of protein, especially contractile proteins; the size of myo-
cytes; and the number of sarcomeres and mitochondria. The
hypertrophic response is accompanied by selective upregula-
tion of several immediate early-response genes and embryonic
forms of contractile and other proteins. The phenotype of the
hypertrophic myocyte may be changed by this expression of
embryonic genes, for instance, induction of atrial natriuretic
factor occurs in ventricular myocytes, and late response genes,
such as β-myosin heavy chain and skeletal α-actin, may be
expressed (a switch from adult to fetal/neonatal forms). Other
genes are also activated and selectively regulated in hypertro-
phy, including immediate early genes or proto-oncogenes 
that encode early regulatory factors (c-jun, c-fos, egr-1),
growth factors (transforming growth factor-β, insulin-like
growth factor, fibroblast growth factor), vasoactive agents
(α-adrenergic agonists, endothelin-1, angiotensin II), and com-
ponents involved in receptor-mediated signaling pathways,
such as protein kinase C.
In pathologic states, hypertrophy is an adaptive response of
limited benefit, where myocytes have impaired intrinsic con-
tractility, impaired ventricular relaxation, and decreased 
compliance, which cause increased end-diastolic pressure and
limited exercise performance. Once further muscle mass
cannot meet the demands posed by increased workload, heart
failure ensues. Degenerative changes occur in myofibers,
including loss of myocardial contractile elements. Limitations
to continued hypertrophy and the reasons for eventual myo-
cardial failure include inadequacy of the vascular supply to
the enlarged fibers, diminished oxidative capacity of mito-
skeletal alterations. The capillary density in hypertrophic
myocardium typically does not keep pace with myofiber size,
intercapillary distances increase, and fibrous tissue is deposited
in the interstitium (“reactive interstitial fibrosis”). Also, the
altered isoforms of proteins produced by expression of fetal
genes may be less functional than adult forms. Myocyte hyper-
trophy occurs only if increased protein synthesis exceeds the
rate of degradation. Similarly, hypertrophy of the ventricle
occurs only if growth of individual myocytes exceeds the
8 CHAPTER 1  •  Cardiovascular System Heart Failure

apoptotic loss of myocytes; excessive apoptosis can contribute
to failure of a hypertrophic heart. This postulate is supported
by experimental work with receptor-mediated Gαq signaling
of cultured rat cardiac myocytes (Gαq is the α subunit of the
Gq family of G proteins, guanine nucleotide–binding proteins,
which transduce signals); moderate levels of Gq signaling
stimulate cardiac hypertrophy, whereas high-level Gq activa-
tion results in cardiac myocyte apoptosis.
There are distinctive anatomic patterns of hypertrophy that
accompany the increase in workload. Concentric cardiac
hypertrophy, that is, an increase in mass of the ventricle without
accompanying increase in end-diastolic volume, characterizes
increased systolic loads (increased afterloads), such as aortic
stenosis, pulmonic stenosis, and pulmonary hypertension in
patent ductus arteriosus. There is often a decrease in the
volume of the ventricular lumen (Fig. 1-3). An increase in
diastolic load (increased preload), typically produced by AV or
semilunar valvular insufficiencies or by arteriovenous shunts,
results in eccentric cardiac hypertrophy, which is an increase
in myocardial mass accompanied by increased end-diastolic
volume (dilated chamber). Because of dilation, the thickness of
the involved ventricular wall is usually no more than normal
and may be less (Fig. 1-4).
In relation to altered hemodynamic loads placed on the
heart, AV valvular stenosis or pericardial fibrosis restrict ven-
tricular filling, leading to a decrease of the load on the myo-
cardium (Fig. 1-5).
The gross appearance of the hypertrophic heart depends
on the chamber affected and the nature of the insult. In
general, hypertrophy of the right side of the heart makes the
heart broader at its base; hypertrophy of the left side increases
the organ length; bilateral hypertrophy produces a more
rounded shape than normal.
In concentric hypertrophy, there is increased thickness of the
wall of the affected chamber, and a marked increase in the
size of the papillary muscles and the trabeculae carneae (Fig.
1-6). Although the hypertrophy may emphasize one or other
chamber, the whole heart is involved. When the right ventricle
is involved, the moderator band (trabecula septomarginalis)
may be much thickened. Extreme hypertrophy of one chamber
Increased ventricular afterload (Pressure overload)
Increased
ventricular
systolic
Increased resistance pressure
to ventricular ejection
Ventricle undergoes
compensatory
hypertrophy
(concentric)
Figure 1-3  Increased ventricular afterload. The involved ventri-
cle undergoes concentric hypertrophy following increased resis-
tance to ventricular ejection. End-diastolic volume may be
reduced. The shaded area shows the outline of a normal ventricle.
(Modified from Robinson WF, Huxtable CRR, eds. Clinicopatho-
logic Principles for Veterinary Medicine. Cambridge, UK: 
Cambridge University Press, 1988. Reprinted with permission.)

Increased ventricular preload (volume overload)

Increased venous
return from AV
shunt such as PDA

Either bidirectional flow or

increased volume of
blood received by ventricle

Increased end
diastolic volume

Ventricle undergoes
Increased ventricular compensatory
contractility following hypertrophy (eccentric)
stretching of myofibers
Figure 1-4  Increased ventricular preload. Increased ventricular preload may result from (1) bidi-
rectional flow from insufficient atrioventricular (AV) or semilunar valves, or (2) increased volume
of blood from intracardiac or extracardiac arteriovenous shunts. The ventricle dilates and under-
goes eccentric hypertrophy. The shaded area shows the outline of a normal ventricle. PDA, patent
ductus arteriosus. (Modified from Robinson WF, Huxtable CRR, eds. Clinicopathologic Principles
for Veterinary Medicine. Cambridge, UK: Cambridge University Press, 1988. Reprinted with
permission.)
Diseases of the Heart Heart Failure 9

Decreased preload

AV valve
stenosis or
pericardial
disease

Decreased
cardiac output

Decreased end
diastolic volume
Restriction of blood flow
into the ventricle
Figure 1-5  Decreased ventricular preload. Decreased ventricular
preload follows atrioventricular (AV) valvular stenosis or myocar-
dial restriction, such as pericardial fibrosis. End-diastolic volume
decreases because of restricted inflow. (Modified from Robinson
WF, Huxtable CRR, eds. Clinicopathologic Principles for Veteri-
nary Medicine. Cambridge, UK: Cambridge University Press,
1988. Reprinted with permission.)
Figure 1-6  Concentric left ventricular hypertrophy. The ven-
tricular free wall and interventricular septum are thickened, and
the lumen of the ventricle is reduced, in this cross-section of
ventricles from a dog.
may encroach on the diastolic capacity of its opposite number.
Microscopically, the myocytes are enlarged, but the increase
in the size of fibers is not uniform and is not always easy to
discern on routine microscopy.
In eccentric hypertrophy and dilation, the heart tends to be
globose, and even though the mass is increased, the wall is
usually thin. The papillary muscles may also be attenuated
(Fig. 1-7).
Figure 1-7  Eccentric left ventricular hypertrophy in dilated car-
diomyopathy in a dog. The lumen of the left ventricle is increased
relative to the thickness of the walls of the ventricle.
In both types of hypertrophy, the endocardium may be
diffusely opaque as a result of subendocardial fibrosis, and 
this alteration may be the best indication of dilation in the
atria, in which dilation and hypertrophy can be difficult 
to assess.
An example of concentric cardiac hypertrophy occurs 
in cats with hyperthyroidism (thyrotoxicosis), a condition
usually resulting from the presence of thyroid hyperplasia or
adenoma. The thyroid glands in these cases are unilaterally or
bilaterally enlarged, nodular, pink to dark brown, and may
contain cysts. Microscopically, the thyroids usually exhibit a
mixture of hyperplastic areas, adenomatous nodules, and
normal follicles (see also disorders of the thyroid gland in Vol.
3, Endocrine glands). The pathogenesis of ventricular hyper-
trophy in this disease is not clear, but may involve the direct
action of thyroid hormones on myocardium, enhanced myo-
cardial adrenergic receptor number or affinity, peripheral 
vasodilation, and work hypertrophy in response to increased
peripheral tissue demands for oxygen and dissipation of heat.
The hearts in most cases are symmetrically hypertrophied;
however, some exhibit asymmetric hypertrophy. The left 
ventricular lumen is usually reduced in size. Affected myofi-
bers are enlarged, but are not in disarray in the great 
majority of cases. The hypertrophy is reversible on return 
to euthyroidism.
Systemic responses in heart failure
The extracardiac features of heart failure stem from 2 basic
pathophysiologic changes: fluid accumulation and tissue or
organ ischemia. Depending on the cause of the heart failure,
both effects may be present, but it is more usual for one to
predominate.
Fluid accumulation results from the retention of sodium
and water, which primarily involves the kidneys, and also
involves atrial natriuretic factor released from the heart (eFig.
1-3A). The influence of the failing heart on the kidneys stems
from its inability to supply them with an adequate flow of
blood. Blood flow through different parts of the kidneys
depends on the vasomotor tone of blood vessels within the
 9.e1

Depression in
cardiac output

Redistributed/decreased
Increased ADH
renal blood flow

Increased retention
of water
Increased filtration fraction:
Increased renin/
Proportionally more sodium
angiotensin/aldosterone
delivered to tubules
Increase in
blood volume

Increased retention
of sodium
A
Pathologic features of CHF

Left-sided failure Right-sided failure

Gross features Gross features

Pulmonary edema [heavy, wet Subcutaneous edema, ascites,
lungs exude fluid on pressure. hydrothorax, hydropericardium.
White froth in airways] Enlarged congested liver

Histopathology Histopathology
Pulmonary venous congestion; Dilated congested hepatic sinusiods;
alveolar edema; alveolar macrophages parenchymal atrophy
contain RBCs/hemosiderin
B
eFigure 1-3  Congestive heart failure. A. Pathogenesis of heart failure. This involves sodium and
water retention by the kidney following reduced blood flow/redistribution of blood flow to the
kidney. Increased antidiuretic hormone (ADH) activity also contributes to the retention of water.
All lead to an increase in blood volume. (Modified from Robinson WF, Huxtable CRR, eds. Clini-
copathologic Principles for Veterinary Medicine. Cambridge, UK: Cambridge University Press,
1988. Reprinted with permission.) B. Pathologic features of congestive heart failure (CHF).
RBCs, red blood cells.
10 CHAPTER 1  •  Cardiovascular System
parenchyma. It is considered that many, if not all, of the intra-
renal blood flow changes in heart failure follow increased
activity of the sympathetic nervous system.
The kidneys receive approximately 20% of the output of
the left ventricle, almost all of which flows through the renal
cortices. One of the earliest changes following a drop in
cardiac output is redistribution of blood flow within the
kidney. There is reduced flow through the outer renal cortex
and increased flow within the outer renal medulla. This results
in readjustment of the filtration fraction, which is the ratio of
glomerular filtration rate (GFR) to renal blood flow. Contrary
to expectations, there is a less than proportionate drop in GFR
compared with renal blood flow, resulting in an increased
filtration fraction. As a consequence, proportionally more
sodium moves through the glomerular filter, leading to pro-
portionally more sodium being delivered into the proximal
convoluted tubule. Because the rate of sodium resorption
remains constant, a greater number of sodium ions are
resorbed. Also, because of the increased filtration fraction,
local plasma osmotic pressure in the efferent arteriole increases,
causing greater resorption of sodium and water.
The alteration in renal blood flow in heart failure also
increases the activity of the renin-angiotensin-aldosterone
system, producing more sodium resorption from the distal
convoluted tubule. There is also increased water-retaining
activity by antidiuretic hormone.
A mechanism within the heart also regulates blood volume,
blunting the activity of aldosterone and the renin-angiotensin
system. Atrial natriuretic factor (ANF), with natriuretic and
diuretic properties, is present in granules in some of the atrial
myocytes. If the atrial pressure is elevated or the atria are
distended, ANF is released and causes natriuresis, vasodilation,
suppression of the renin-angiotensin-aldosterone axis, and
decreased arterial blood pressure. In terms of homeostasis, ANF
has effects opposite to those of aldosterone, thus providing a
balance to fluid regulation. Although plasma ANF is signifi-
cantly increased in dogs with chronic left AV valvular insuf-
ficiency, it is not clear whether the metabolic effects of
aldosterone or ANF predominate, but it would appear that
the effects of aldosterone over-ride those of ANF.
It should be noted that none of the hormones mentioned
produce the edema of congestive heart failure if administered
alone. In addition, once a new steady state has been reached,
the hormonal state returns to relatively normal limits. Last,
the mechanisms that are brought into play are not exclusive to
the syndrome of heart failure. Any situation that leads to a
drop in effective circulating blood volume will activate the
sodium- and water-retaining mechanism. The fundamental
difference between these states and congestive heart failure is
that the total blood volume in heart failure is already more
than adequate, but the effective blood volume is much dimin-
ished because of the poor cardiac output. The volume
changes in heart failure should be viewed as an integrated
response by the body to compensate for the inability of the
heart to respond to the normal hemodynamic needs of  the lungs and the diminution in cardiac output. The pulmo-
the body.
The expansion of blood volume has both a beneficial and
a detrimental effect. By increasing blood volume, venous
return is enhanced and, in turn, cardiac output and tissue
perfusion are improved. However, this is to the detriment of
the balance between capillary hydrostatic pressure and plasma
osmotic pressure. This leads to an increase in the amount of
fluid in the interstitial spaces and body cavities.
Heart Failure
Syndromes of circulatory failure
Circulatory failure, the term implying severe systemic conse-
quences, falls into 3 general categories: cardiac syncope, periph-
eral circulatory failure, and congestive heart failure.
Cardiac syncope
Cardiac syncope is characterized clinically by profound
changes in blood pressure and heart rate with bradycardia or
tachycardia, either of which may result in inadequate output
of blood. Both may occur in the presence or absence of organic
heart disease.
In one form of cardiac syncope, hypersensitive or hyperac-
tive reflexes, for which the vagus nerve is the efferent limb,
may result in reflex inhibition of the heart rate, manifest as
extreme bradycardia or as asystole. The sudden deaths that
result from acute pleural irritation or the tracheal irritation of
aspirated vomitus fall into this group, and obviously there may
be no organic heart lesion.
In a second form of cardiac syncope, the heart rate is
extremely rapid, and the cardiac output severely reduced.
Such may occur in paroxysmal tachycardia, atrial flutter or
fibrillation, and ventricular fibrillation.
Third, in organic heart disease with complete obstruction
of impulse conduction from the atrium to the ventricle 
(complete heart block), syncope may occur if there is suffi-
cient delay before the ventricle assumes an independent
rhythm.
Finally, cardiac syncope may terminate a syndrome of con-
gestive cardiac failure when the cardiac reserve is depleted
and the heart cannot increase its output sufficiently to meet
sudden increases in peripheral needs.
Peripheral circulatory failure
Peripheral circulatory failure is characterized by reduction in
the effective circulating blood volume with insufficient venous
return and reduced cardiac output. Acute hemorrhage and
shock are examples of this form of circulatory failure.
Congestive heart failure
The combination of compensatory mechanisms, brought into
play to maintain cardiac output, is in general successful.
However, there is also the planting of the seeds of destruction.
Both the local increase in venous hydrostatic pressure and the
increased sodium and water retention by the kidneys tend to
promote the development of interstitial edema. Depending on
the inciting abnormality, it is usual for one side of the heart
to fail before the other, but it must be remembered that the
cardiovascular system is a closed circuit and that failure of one
side will eventually embarrass the other (eFig. 1-3B).
Left-sided heart failure is ushered in by progressive dilation
of the left ventricle and atrium, although this progression may
be marked by exacerbations and remissions if hypertrophy is
given time to develop. The major extracardiac manifestations
of left-sided failure arise from the damming back of blood in
nary venous congestion is transmitted back to the capillaries of
the alveolar wall, and edema fluid accumulates in the inter-
stitial tissue and the alveolar spaces. The consequent reduction
in pulmonary vital capacity and impaired gaseous exchange
of cardiogenic pulmonary edema result in hypoxic stimulation
of the carotid sinus and medullary respiratory centers so that
reflex dyspnea occurs. A wheezing bronchial cough is common
and is presumed to be due to irritation of the respiratory
Diseases of the Heart Heart Failure 11

A B

C
Figure 1-8  Congestive heart failure. A. Left-sided congestive heart failure in a dog. Pulmonary
alveolar capillaries are congested, and there is hemorrhage into alveoli that contain hemosiderin-
laden macrophages (“heart-failure cells”). H&E. B. Same section as (A) stained with Prussian blue
to highlight the abundance of iron derived from hemosiderin in alveolar macrophages. C. Chronic
passive congestion of the liver, leading to zonal hepatocyte atrophy, in right-sided congestive heart
failure in a dog. H&E.

mucosae by the edema fluid. Cyanosis may be present but is
more often the rule in right ventricular failure.
At postmortem, the lungs are usually of normal color, but
may be light brown, and are heavy and wet. Stable, white froth
is present in the airways, and fluid exudes from the cut surface.
Because of its low protein content, there is little evidence of
the abundant fluid on microscopic examination. The alveoli
contain erythrocytes and a scattering of macrophages, some of
which contain hemosiderin. It may be necessary to use a dif-
ferential stain for iron to confirm the presence of these
so-called “heart-failure cells” or siderophages (Fig. 1-8A, B).
They are more numerous in chronic disease, and hemosiderin
within their cytoplasm may be sufficient to produce tawny
discoloration of the lungs.
In right-sided heart failure, the major extracardiac mani-
festations depend on increased hydrostatic pressure in the
systemic and portal venous systems, and the reduction of flow
from the lungs to the left ventricle. Renal complications occur
more frequently in right-sided than in left-sided heart failure,
leading to increased blood volume, peripheral edema, and
more marked azotemia.
There is some species difference in the distribution of
edema in congestive heart failure. In ruminants and horses,
dependent subcutaneous edema is expected; in the other species,
excess subcutaneous fluid is scant or absent. In dogs, the pre-
dominant accumulation of fluid is in the peritoneal cavity. In
cats, it is in the thorax.
Grossly, the liver is enlarged and congested and has a
“nutmeg” appearance on section because of chronic passive
congestion (Fig. 1-8C). Microscopically, the sinusoids are
dilated, with atrophy of the parenchyma about the central
veins. In more severe or acute cases, the parenchyma in this
location may undergo degeneration or necrosis. It is excep-
tional for an animal with congestive failure to live long enough
for severe fibrosis and nodularity to occur. Impaired hepatic
function is not usually a significant part of the clinical course,
although jaundice may be observed.
Congestion of the stomach and intestines is evident, and
this may impair their function, which is manifest usually as
diarrhea. In horses, the subserosal lymphatics, particularly of
the large bowel, are often readily discernible, dilated, and filled
with edema fluid. The systemic and portal veins are distended,
12 CHAPTER 1  •  Cardiovascular System Examination of the Heart

and the spleen is enlarged and congested. However, this latter
finding is masked if the animal in question has been eutha-
nized using barbiturates.
EXAMINATION OF THE HEART
In a gross postmortem examination of the heart, it is impor-
tant to examine 4 major areas: pericardium, myocardium,
mural and valvular endocardium, and the great vessels. A
useful system is to follow the route of blood flow through the
heart, that is, an inflow-outflow method of dissection (Fig.
1-9A, eFig. 1-4). This technique may require modification in
the case of cardiac anomalies. Examination of the heart in the
planes used for echocardiographic examination could be
beneficial.
• The initial examination of the heart and great vessels is
best made with the organs in situ to assess abnormalities
of size and position.

i ii iii iv

A v vi vii viii
Caudal
AV node vena cava 1 Sinus
node
2
Septum

Coronary sinus
AV node
AV bundle RV
Bundle branches free wall

3 Ventricular septum
B
Figure 1-9  Examination of the heart. A. Gross examination. (i) Heart oriented to show right
atrium/ventricle facing. (ii) Incision made transversely from caudal vena cava to right auricular
appendage. (iii) Incision commenced in right atrium into junction between right ventricle and
interventricular septum. (iv) Right ventricle opened to display right atrioventricular valve. (v)
Incision continued to display right ventricular outflow tract and pulmonic valve. (vi) Heart oriented
to display left atrium (transversely incised from pulmonary vein to left auricular appendage) and
left ventricular free wall. (vii) Left ventricle free wall incised from base to apex displaying the left
atrioventricular valve. (viii) Left ventricular outflow tract and aortic valve displayed by incision
through left atrioventricular valve. Goat. B. Microscopic examination of the heart. The cardiac
conduction system can be assessed via block 1, in which the sinus node is located subepicardially
in the terminal groove at the junction of the cranial vena cava and right auricular appendage, and
block 2, in which the atrioventricular (AV) node is located subendocardially on the right side of
the interatrial septum, just cranial to the coronary sinus: Serial sections through this block will
reveal the AV node, the common bundle, and the origins of the bundle branches. A block through
the left ventricular free wall, including papillary muscle, or block 3, through the ventricular septum,
is the minimal representative sample to take from a grossly normal heart. RV, right ventricle.
 12.e1

1 Amputate apex 2 Open right atrium 3 Open right side

of right ventricle

4 Open left side of right 5 Right ventricle opened

ventricle and pulmonary trunk

6 Open left atrium 7 Open right side 8 Left ventricle open,

of left ventricle may open aorta (arrow)
eFigure 1-4  Gross examination of the heart (see text for details).
(1) Transect apex of heart and examine ventricular walls. (2)
Open right atrium from caudal vena cava to the tip of the right
atrial appendage. (3) Follow blood flow through right ventricle.
(4) Cut right ventricular free wall adjacent to septum and out
pulmonic valve. (5) Right ventricle and pulmonary trunk opened;
moderator band transected. (6) Open left atrium. (7) Open left
ventricle toward the apex. (8) Left ventricle opened and left
atrioventricular valve exposed; aorta may be opened as indicated
by arrow.
Diseases of the Heart Examination of the Heart 13

• Incise the pericardial sac and examine the pericardial fluid

before the thoracic viscera are removed; note the volume
Table • 1-1 
and color of the fluid, the presence of fibrin, and so forth.
• Remove the thoracic viscera and examine the external
Heart weight:body weight (HW/BW) ratios and
surfaces of pericardium, epicardium, and great vessels. left ventricular free wall plus septum:right
• Open the abdominal aorta in situ to the iliac bifurcation ventricular free wall [(LV + S)/RV] ratios in
and examine for such abnormalities as thrombi and ver- postmortem accessions of cattle without
minous arteritis; remove the aorta with the abdominal significant cardiovascular disease
viscera in a horse to better examine the cranial mesenteric
Age HW/BW (%) (n) (LV + S)/RV (n)
artery and its branches.
• The heart may be detached from the lungs if anomalies are <7 days 0.91 (5) 1.69 (5)
absent, but it is usually better left attached to allow careful 7-30 days 0.90 (6) 2.13 (6)
examination of vessels, for instance, pulmonary artery for
30-365 days 0.48 (9) 2.78 (10)
thrombi.
• Examine the atria, ventricles, and coronary arteries exter- >1 year 0.48 (11) 2.78 (15)
nally, and confirm normal relationships.
• When opening the heart, always inspect structures before
cutting, and try to preserve a stenotic or dilated valve or vessel. Table • 1-2 
• Open the right atrium, from the caudal vena cava to the
tip of the auricular appendage. Note any thrombus, and Reference values for heart weight:body weight
check the right AV valve and the foramen ovale/fossa (HW/BW) ratio and ventricular ratio [(LV + S)/
ovalis. Leave the cranial vena cava unopened, as a block of RV] in normal mature animals at postmortem
tissue to include the sinus node may be taken at the junc-
tion of the cranial vena cava and the right auricle. Examine Species N HW/BW (%) (LV + S)/RV
the right AV valve before cutting.
• Open the lateral side of the right ventricle adjacent to the X X ± 2 SD X X ± 2 SD
ventricular septum. Examine the right AV valve and Dog 21 0.71 0.43-0.99 3.26 2.39-5.12
chordae tendineae. The septal leaflet of the right AV valve
Horse 12 0.69 0.41-0.97 3.12 2.43-4.34
is normally thicker than the free leaflets. Transect the mod-
erator band (trabecula septomarginalis). Cat 9 0.58 0.28-0.88 3.45 2.94-4.17
• Cut through the rostral wall of the right ventricle, and open Cow 15 0.48 0.30-0.66 2.78 2.43-4.00
the pulmonic valve if there is no stenosis. Check the pul- Goat 11 0.46 0.26-0.66 3.12 2.50-4.17
monary arteries for thrombi, especially in animals with Sheep 8 0.41 0.17-0.65 3.33 2.63-4.54
indwelling jugular catheters. Note the patency or closure
Pig 8 0.40 0.32-0.48 2.94 2.38-3.84
of the ductus arteriosus (bear to the right when opening
the pulmonary artery in neonates to avoid cutting through BW, body weight; HW, heart weight; LV + S, left ventricular free wall
a patent ductus arteriosus and creating a false anomaly). + septum; RV, right ventricular free wall; x , mean; SD, standard devia-
tion; x, mean.
• Open the left atrium by cutting into the auricular append-
age and then parallel to the ventricular groove. Examine
the interatrial septum, foramen ovale/fossa ovalis, and the weigh the whole heart, right ventricular free wall, and left
left AV valve. ventricular free wall plus septum.
• Open the left ventricle by cutting longitudinally through the • The ratio of normal heart weight to body weight (HW : BW)
free wall (from base to apex), examining the left AV valve is 0.5-1.0%, depending on age and species (Tables 1-1, 1-2).
before cutting it. Chordae tendineae should be carefully • The HW : BW ratio is higher in neonates than in adults, the
examined before cutting the left AV valve to ensure that more athletic species (horses, dogs) have higher HW : BW
pre-existing ruptures of the chordae are detected. ratios, HW : BW ratio is increased by training or exercise,
• Continue to follow the blood flow by cutting through the and males typically have greater HW : BW ratios than do
left ventricular outflow tract and into the aorta. Note that females of the same species.
the pulmonary artery will be transected by this action. • The ratio of the weight of the left ventricle plus septum
• The circumference of the 4 cardiac valves may be mea- divided by the weight of right ventricular free wall [(LV 
sured at this time with a flexible ruler or string. Normal + S)/RV] is 2.8-4.0 in mature animals; (LV + S)/RV >4.0
right AV/left AV valve circumference ratio for dogs is 2:1. indicates left ventricular hypertrophy; (LV + S)/RV <2.8 is
The right ventricle is responsible for systemic circulation consistent with right ventricular hypertrophy.
in the fetus. Hence, in neonatal hearts, the wall thickness of The usual tissue block taken for routine histology is of left
the left and right ventricles is approximately equal; it is not ventricular papillary muscle, as this area is one of the most
until a month or more after birth that the mature proportions susceptible to damage and most representative in cases of
are attained. Ventricular wall thickness is poorly correlated generalized disease. Detailed examination of the heart, includ-
with ventricular mass, and heart weights provide more valid ing the conduction system, requires collection of tissue blocks
information about ventricular hypertrophy than do thickness (Fig. 1-9B) from the junction of the cranial vena cava and right
measurements, especially in cases of dilation and eccentric auricle (sinus node), both atria, the interatrial septum/dorsum
hypertrophy. To accurately assess cardiac mass, the heart should of the ventricular septum at the base of the heart just cranial
be weighed and the weight compared to body weight. After to the coronary sinus (atrioventricular node), right ventricular
removing the pericardial sac and postmortem blood clots, free wall and AV valve, ventricular septum, left ventricular
14 CHAPTER 1  •  Cardiovascular System
free wall/papillary muscle and AV valve, great vessels, plus any
grossly evident lesions.
The selection of sections to study the specialized conduc-
tion system should include the sinus node, the AV node, the
common bundle (bundle of His), left and right crura (bundle
branches), and conducting fibers. The sinus node lies subepi-
cardially in the terminal groove (sulcus terminalis) at the
junction of the cranial vena cava and the right atrium. Sections
should include either side of that site, to incorporate tissue in
the sulcus terminalis region. The AV node is obtained by
removing a block of tissue from the coronary sinus to the
cranial edge of the septal leaflet of the right AV valve. The
block includes interatrial septum and dorsal ventricular
septum, and will then contain the AV node, which is located
subendocardially on the right side of the interatrial septum,
the common bundle, and the left and right crura. The speci-
men should be serially sectioned into samples 3 mm thick,
and all samples should be processed.
In routine cases, there are no special requirements for fixa-
tion. Stains of particular use are hematoxylin and eosin,
Masson trichrome, phosphotungstic acid hematoxylin, Luxol
fast blue, and Gomori aldehyde fuchsin.
Note that rigor mortis begins earlier in myocardial than in
skeletal musculature, and reaches greater development in the
more powerful left ventricle. Rigor should completely express
the blood from the left ventricle; rigor of the right ventricle
is less efficient, and emptying is incomplete. The presence of
some clotted blood in the right ventricle is normal, whereas
if present in the left ventricle, it is indicative of incomplete
rigor and therefore perhaps of severe myocardial degenera-
tion. The presence of unclotted blood in the left ventricle
some hours after death is more difficult to interpret. Unclot-
ted blood, the result of fibrinolysis, may flow back into the
ventricle when rigor passes.
Blood usually clots slowly after death and permits eryth-
rocytes to sediment. Where blood is present in volume, as in
the heart and arterial trunks, sedimentation and subsequent
clotting leads to the formation of “currant jelly” and “chicken
fat” clots, the former containing erythrocytes, and the latter
largely devoid of them. Chicken fat clots are to be expected
in horses, which normally have a rapid erythrocyte sedimenta-
tion rate, and are in relative excess in anemia. Postmortem
clots are to be distinguished from thrombi; clots are not
attached to the endocardium.
Biopsy of the heart in not commonly undertaken in vivo,
but is possible via transvenous endomyocardial biopsy. Mul-
tiple biopsy samples of the right ventricular myocardium may
be obtained by this means, and may be used, for example, to
monitor the cardiotoxic effects of anthracycline therapy.
Further reading
Abel ED, Doenst T. Mitochondrial adaptations to physiological versus
pathological hypertrophy. Cardiovasc Res 2011;90:234-242.
Bernardo B, et al. Molecular distinction between physiological and
pathological cardiac hypertrophy: experimental findings and thera-
peutic strategies. Pharmacol Ther 2010;128:191-227.
Bourlaug BA, Redfield MM. Are systolic and diastolic heart failure
overlapping or distinct phenotypes within the heart failure spec-
trum? Circulation 2011;123:2006-2014.
Falk T, et al. Associations between cardiac pathology and clinical, echo-
cardiographic and electrocardiographic findings in dogs with con-
gestive heart failure. Vet J 2010;185:68-74.
Congenital Abnormalities of the Heart and Large Vessels
Jacob M, Wilson Tang WH. Pathophysiology of congestive heart failure.
In: Griffen BP, et al., editors. The Cleveland Clinic Cardiology
Board Review. Philadelphia: Lippincott Williams & Wilkins.; 2013.
p. 155-163.
Kemp CD, Conte JV. The pathophysiology of heart failure. Cardiovasc
Pathol 2012;21:365-371.
King JM, et al. The Necropsy Book. Gurnee, Ill: CL Davis DVM Founda-
tion; 1999.
Lymperopoulos A, et al. Adrenergic nervous system in heart failure:
pathophysiology and therapy. Circ Res 2013;113:739-753.
Maillet M, et al. Molecular basis of physiologic heart growth: funda-
mental concepts and new players. Nature Rev Mol Cell Biol
2013;14:38-48.
Schoning P, et al. Body weight, heart weight, and heart-to-body weight
ratio in greyhounds. Am J Vet Res 1995;56:420-422.
Souders CA, et al. Pressure overload induces early morphological
changes in the heart. Am J Pathol 2012;181:1226-1235.
Towbin JA. Molecular genetic basis of sudden cardiac death. Cardio-
vasc Pathol 2001;10:283-295.
CONGENITAL ABNORMALITIES OF
THE HEART AND LARGE VESSELS
In the transition from fetal to neonatal life, substantial adjust-
ments occur within the cardiovascular system. There are altera-
tions in the pressures in cardiac chambers and great vessels, the
pattern of blood flow, and the volume of blood flow. Because
of these changes, the retention postnatally of fetal vascular
communications, such as the ductus arteriosus, may place an
excessive load on the heart in the postnatal period and beyond.
There are also congenital heart defects, such as pulmonic ste-
nosis, which compromise the fetus, the newborn, and the adult.
It is typically only those defects that allow adequate in utero
development and a reasonably successful perinatal life that are
recognized; anomalies sufficiently severe to cause death in
utero, or in the neonatal period, often are not.
As with most diseases, there is a spectrum of change. The
variation in severity of a particular lesion may be wide and will
necessarily influence whether clinical signs are observed. As such,
there is a higher incidence of congenital heart disease than is
recognized clinically. There is also a group of congenital heart
diseases that do not produce clinical signs of heart failure, but
which are manifested by upper alimentary dysfunction.
Although little is known of the causes of many cardiac mal-
formations in domestic mammals, there is no doubt that,
especially in dogs, some are genetically determined. The dem-
onstration that some congenital heart diseases are genetically
determined arose from the observation that the incidence of
defects was higher in purebred populations. It has been
thought that both patent ductus arteriosus (PDA) and
conotruncal defects have a polygenic inheritance pattern,
where the full expression of these diseases depends on the
inheritance of a number of genes from different loci. However,
studies on Keeshonds with conotruncal defects indicate that
the inheritance pattern is most compatible with a single auto-
somal locus. The data suggest the presence of a mutant allele
that is partially penetrant in heterozygotes and fully penetrant
in homozygotes. Congenital subaortic stenosis in the New-
foundland dog is also genetically determined; it may either be
polygenic or a single dominant gene that is variably expressed.
Table 1-3 outlines the breed-specific predisposition to con-
genital heart disease in the dog.
 14.e1

Further reading
Adams JW, et al. Enhanced Gαq signaling: a common pathway medi-
ates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad
Sci U S A 1998;95:10140-10145.
Brand T, et al. Expression of nuclear proto-oncogenes in isoproterenol-
induced cardiac hypertrophy. J Mol Cell Cardiol 1993;25:1325-
1337.
Edwards WD. Cardiovascular system. In: Ludwig J, editor. Handbook
of Autopsy Practice. 3rd ed. New Jersey: Humana Press; 2002.
p. 21-43.
Gerdes AM, Capasso JM. Structural remodeling and mechanical dys-
function of cardiac myocytes in heart failure. J Mol Cell Cardiol
1995;27:849-856.
Hardt SE, Sadoshima J. Negative regulators of cardiac hypertrophy.
Cardiovasc Res 2004;63:500-509.
Hill JA, Olson EN. Cardiac plasticity. N Engl J Med 2008;358:1370-
1380.
Horban A, et al. Correlation between function and proto-oncogene
expression in isolated working rat hearts under various overload
conditions. J Mol Cell Cardiol 1997;29:2903-2914.
Keene BW, et al. Modified transvenous endomyocardial biopsy tech-
nique in dogs. Am J Vet Res 1990;51:1769-1772.
Matsuo T, et al. Mechanisms of cardiac hypertrophy in canine volume
overload. Am J Physiol 1998;275:H65-H74.
McMullen JR, et al. Phosphoinositide 3-kinase (p110α) plays a critical
role for the induction of physiological, but not pathological, cardiac
hypertrophy. Proc Natl Acad Sci U S A 2003;100:12355-12360.
Miller PJ, Holmes JR. Observations on structure and functions of the
equine mitral valve. Equine Vet J 1984;16:457-460.
Parmley WW. Neuroendocrine changes in heart failure and their clinical
relevance. Clin Cardiol 1995;18:440-445.
Sheaff MT, Hopster DJ. Post Mortem Technique Handbook. London:
Springer; 2001. p. 87-116.
Sugden PH, Clerk A. Cellular mechanisms of cardiac hypertrophy. J Mol
Med 1998;76:725-746.
Takemura N, et al. Atrial natriuretic peptide in the dog with mitral
regurgitation. Res Vet Sci 1991;50:86-88.
Tamamori M, et al. Endotheün-3 induces hypertrophy of cardiomyo-
cytes by the endogenous endothelin-1-mediated mechanism. J Clin
Invest 1996;97:366-372.
Woeber KA. Thyrotoxicosis and the heart. N Engl J Med 1992;327:94-
98.
Yamazaki T, et al. Molecular mechanism of cardiac cellular hypertrophy
by mechanical stress. J Mol Cell Cardiol 1995;27:133-140.
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels 15

Table • 1-3 
Breed-specific predispositions to congenital heart disease in dogs
Defect Breed

Patent ductus arteriosus
Pulmonic stenosis
Subaortic stenosis
Persistent right aortic arch
Tetralogy of Fallot
Atrial septal defect
Ventricular septal defect
Tricuspid insufficiency or dysplasia
Mitral insufficiency or dysplasia
Bichon Frise, Chihuahua, Cocker Spaniel, Collie, English Springer Spaniel, German Shepherd, Keeshond,
Kerry Blue Terrier, Maltese Terrier, Pomeranian, Poodle, Shetland Sheepdog, Yorkshire Terrier
Airedale Terrier, Beagle, Chihuahua, English Bulldog, Fox Terrier, Mastiff, Miniature Schnauzer,
Samoyed, Scottish Terrier, West Highland White Terrier
Boxer, English Bulldog, German Shepherd, German Shorthaired Pointer, Golden Retriever, Great
Dane, Newfoundland, Rottweiler, Samoyed
German Shepherd, Great Dane, Irish Setter
English Bulldog, Keeshond
Doberman Pinscher, Samoyed
English Bulldog
German Shepherd, Golden Retriever, Great Dane, Labrador Retriever, Weimaraner
Bull Terrier English Bulldog, Chihuahua, German Shepherd, Great Dane

Table • 1-4 
Proportions (%) of canine congenital cardiac anomalies in 4 surveys
Patterson Mulvihill, Priester Hunt et al. Tidholm
Anomaly* (1953-1965), n = 248 (1964-1971), n = 700 (1977-1989), n = 100 (1989-1996), n = 151

Patent ductus arteriosus 30 36 34 11

Atrioventricular valve dysplasia 4 9 18 15
Pulmonic stenosis 21 11 18 20
Aortic stenosis 15 6 10 35
Persistent right aortic arch 8 12 7 —
Ventricular septal defect 7 10† 7 12
Tetralogy of Fallot 4 — 3 0.6
Atrial septal defect 4 3 0 3
Other 7 13 3 3
Total (%) 100 100 100 100
*~7-9% of dogs had more than one anomaly.
†
Includes tetralogy of Fallot.

In humans, increasing attention has been focused on muta-
tions in transcription modulators, signal transduction, and
structural protein genes as causes of inherited congenital  and subaortic stenosis are common (Table 1-4). In cattle, atrial
heart disease. This includes the transcription factors Nkx2-5,
GATA4, and TBX-5, and the NOTCH pathway genes
JAGGED1, NOTCH1, and NOTCH2. The NOTCH pathway
genes have been associated with valvular defects and tetralogy
of Fallot. Further insights into the normal and abnormal devel-
opment of the heart and great vessels have come from the
effects of targeted gene mutations and deletions using the
zebrafish, Danio rerio, as an experimental model.
There may be other as yet undefined factors that contrib-
ute to the development of congenital heart disease in domestic
animals. In humans, cardiac and vascular anomalies are
common features of several syndromes produced by chromo-
somal abnormalities and viral infections such as rubella. There
is little evidence to suggest the presence of similar abnormali-
ties or infections associated with congenital heart disease in
domestic animals.
The pattern and incidence of congenital cardiac disease varies
with the species examined. In dogs, PDA, pulmonic stenosis,
and ventricular septal defects (VSDs) and transpositions of
the main vessels are most frequently diagnosed. Subaortic
stenosis and endocardial cushion defects are the most frequent
anomalies in pigs. In cats, endocardial cushion defects and
congenital left AV valve insufficiency appear to be common.
Congenital cardiovascular disease is quite uncommon in
horses.
In cases of suspected cardiac abnormality, it is essential to
examine the heart and large vessels in situ because relations
are difficult to trace once the organ is removed. Some animals
are born with hearts that, although of normal arrangement,
are very small. In the majority of cases of cardiac abnormality,
the anomaly is reflected in gross enlargement of the organ and
in alteration of the size or disposition of the large vessels.
Cardiac malformations are extremely variable, and their analy-
sis can be perplexing if it is not remembered that they do
16 CHAPTER 1  •  Cardiovascular System Congenital Abnormalities of the Heart and Large Vessels

follow fairly simple basic patterns. The recognition of the The consequence of an ASD in the neonate is excessive flow
primary abnormality is an essential first step. This then assists from the left to right atrium, with resultant volume overload on
in the recognition of secondary abnormalities, which develop the right ventricle and elevated central venous pressure (Figs.
as adjustments to allow blood to circulate through the heart. 1-10, 1-11). In some cases, following the development of
An understanding of the mechanics of abnormal development pulmonary hypertension, the flow through the defect is
is necessarily based on an understanding of the normal devel- reversed, leading to cyanosis.
opment of the organ, for which reference should be made to
a standard text of embryology. Aorta
There is no completely satisfactory system for classifying
congenital heart defects, as they may be complex or may
Cranial vena cava PA
overlap as part of a spectrum. Based on a combination of ana-
tomic defects and functional effects, they may be classified as
PV
• Malformations causing systemic to pulmonary (left-to-
right) shunting PV
• Malformations of cardiac valves RA
• Transposition complexes LA
• Miscellaneous cardiac anomalies
• Vascular anomalies Caudal
vena cava
Malformations causing systemic to pulmonary
(left-to-right) shunting
In the development of the heart, there are 3 major arteriove-
nous communications: between the atria, the ventricles, and RV
LV
the great vessels. These connections are necessary for shunting
of blood in the fetus. The atrial and ventricular septa close in
utero; the foramen ovale and the ductus arteriosus close early
in the neonatal period. Failure of closure results in atrial septal
defect (ASD), VSD, or PDA, 3 of the more common congenital
cardiac defects in domestic animals. Less common defects in Figure 1-10  Atrial septal defect (ASD). An ASD usually results
this group include AV septal defect, persistent truncus arteriosus, in increased blood flow from the left (LA) to the right (RA)
aorticopulmonary window, and anomalous pulmonary venous atrium. The right ventricle (RV) dilates under this increased
return. volume load. Also, a mild increase in afterload develops from the
increased volume load within the right ventricle. LV, left ventricle;
Atrial septal defect PA, pulmonary artery; PV, pulmonary vein. (Modified from Rob-
In the fetus, separation of the left and right atria commences inson WF, Huxtable CRR, eds. Clinicopathologic Principles for
with the downgrowth of the septum primum, which grows Veterinary Medicine. Cambridge, UK: Cambridge University
toward the AV junction, where the developing endocardial Press, 1988. Reprinted with permission.)
cushions begin to form the AV valves and separate the ven-
tricles. The septum fuses with the endocardial cushions, oblit-
erating the ostium primum, and then begins to fenestrate in its
middle. The fenestration is destined to become the ostium
secundum. A second septum (septum secundum) develops
downward and to the right of the septum primum. With its
semilunar edge, the septum secundum and the remains of the
septum primum form the foramen ovale. Within the left
atrium, the septum primum forms the flap valve of the
foramen ovale that allows blood flow from right atrium to left
atrium in the fetus. In the majority of animals, anatomic
closure of the foramen ovale follows functional closure post-
natally. A probe-patent foramen ovale postnatally is not an ASD, *
for although the foramen ovale may not be anatomically
closed, it is functionally closed (valvular competent) because
left atrial pressure exceeds right atrial pressure.
An ASD can result from
• Defects of the septum between the right upper pulmonary
veins and the cranial vena cava (sinus venosus defect)
• Failure of fusion of septum primum with the endocardial
cushions (ostium primum defect, low in the atrial septum
adjacent to the AV valves, a form of AV septal defect)
• An excessively large ostium secundum or inadequate
development of the septum secundum (ostium secundum Figure 1-11  Atrial septal defect (arrow) in a 3-week-old lamb. A
defect, in mid-septum at the site of the fossa ovalis, the high ventricular septal defect is also evident (asterisk). (Courtesy
most common type) M.J.M. Sula.)
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels 17

A B
Figure 1-12  Ventricular septal defect. A. High ventricular septal defect (arrow) in a dog, involving
the pars membranacea. The chamber of the left ventricle is enlarged (volume overload) and is
accompanied by mild subendocardial fibrosis following chronic dilation. (Courtesy D. Hayden.)
B. Large ventricular septal defect of the muscular part of the interventricular septum in a calf.

Atrioventricular (AV) septal defect
Also known as endocardial cushion defects or AV canal defects,
these malformations arise from deficiency of the AV septum
that separates the left ventricular inlet from the right atrium.
The atrial septum primum must fuse with the endocardial
cushions, which in turn contribute to the development of the
atrial and ventricular septa, and to the medial leaflets of the
left and right AV valves. Anomalous development may result
in a range of anatomic defects, including ostium primum defect
(partial AV canal), VSD with a cleft in the right AV valve, or
common AV canal. The common or complete AV septal defect
consists of an ostium primum defect, a VSD, and a common
AV orifice.
Defects of the AV canal are among the most common defects
in the pig. In the largest series examined, 40% of pigs with
congenital heart disease had this defect. It is also a frequent
finding in cats.
Ventricular septal defect
Ventricular septal defect is one of the most common defects
encountered in domestic animals. The separation of the left and
right ventricles is completed by 3 parts of the embryonic
heart: the muscular portion of the septum, the downward
growth of the conotruncal ridges, and the membranous portion
of the septum derived from the endocardial cushions. Defects
can be related to defective development of any of the 3 parts.
VSDs are usually single but may be multiple, and most com-
monly involve the membranous septum (Fig. 1-12A). This type
of VSD is termed paramembranous or perimembranous, as they
exceed the bounds of the membranous septum and involve a
muscular defect at their periphery; they may also be referred
to as subaortic or infracristal. Less common sites of VSD are
subpulmonary (infundibular, conal, supracristal), below the
septal leaflet of the right AV valve, or in the muscular portion of
the ventricular septum toward the apex of the heart (Fig.
1-12B). Although occurring most commonly as an isolated
defect, VSD is also seen as part of a number of other defects,
such as tetralogy of Fallot or persistent truncus arteriosus.
There appears to be a high incidence of spontaneous postnatal
closure of small VSDs in humans, and a similar phenomenon
has been reported in dogs.
The presence of a VSD has no deleterious effect on the
fetus because left and right ventricular pressures are equal,
and there is therefore little flow across the defect. Postnatally,
the effects of VSDs are related to the size of the defect and the
level of pulmonic vascular resistance relative to the systemic resis-
tance. Pulmonary vascular resistance normally drops postna-
tally, leading to a left-to-right shunt. Left ventricular output is
maintained by an increase in end-diastolic volume and aug-
mentation of contractility by the Frank-Starling mechanism.
Because right ventricular pressure equals left ventricular pres-
sure, the right ventricle is confronted with a large systolic and
diastolic load. Both ventricles undergo hypertrophy, the left
being more obviously eccentric in nature (Fig. 1-13).
Eventually, pulmonary hypertension can lead to shunt
reversal (right-to-left), cyanosis, and death. The term Eisen-
menger complex is applied to VSD cases in which, instead
of the usual left-to-right shunt, flow has been reversed to a
right-to-left shunt through the VSD as a consequence of
severe pulmonary hypertension that is, in turn, due to high
pulmonary vascular resistance. The more general term 
of Eisenmenger syndrome is applied to any anomalous
circulatory communication (e.g., ASD, VSD, PDA) that leads
to obliterative pulmonary vascular disease, with resulting
reversal of the left-to-right shunt across the pulmonary-
systemic communication.
Patent ductus arteriosus
Patent ductus arteriosus (PDA) is one of the more common
defects, and it is recorded in all species (Fig. 1-14). In the dog
18 CHAPTER 1  •  Cardiovascular System
Aorta
Cranial vena cava
PA
PV
PV
RA
LA
Caudal
vena cava
LV
RV
Figure 1-13  Ventricular septal defect (VSD). Blood flow in a
VSD is usually left to right, creating both an increased preload
and afterload on the right ventricle. The increased volume of
blood returning through the pulmonary circuit places an
increased preload on the left atrium and ventricle, which can
cause left ventricular dilation and hypertrophy. For abbreviations,
see Figure 1-10. (Modified from Robinson WF, Huxtable CRR,
eds. Clinicopathologic Principles for Veterinary Medicine.  the left ventricle and pressure overload of the right ventricle,
Cambridge, UK: Cambridge University Press, 1988. Reprinted
with permission.)
Figure 1-14  Patent ductus arteriosus (PDA) in a pig, with a
probe through the PDA connecting pulmonary artery (bottom)
with aorta. (Courtesy A. Rovira.)
it has a polygenic inheritance pattern, and PDA may result
from hypoplasia or asymmetry of ductal smooth muscle plus
aorta-like elastic tissue in the ductus wall. The ductus devel-
ops from the sixth left branchial arch, and functions in the
fetus to divert a major portion of blood from the pulmonary
Congenital Abnormalities of the Heart and Large Vessels
artery to the aorta. The flow from venous to arterial side is a
consequence of the presence of the high vascular resistance
of the fetal pulmonary bed. The structure of the normal
ductus differs from the adjacent pulmonary artery or aorta. In
contrast to the large elastic arteries, the media of the ductus
has a dense layer of smooth muscle, which is responsive to a
number of compounds. Among the most powerful are epi-
nephrine, norepinephrine, and angiotensin; less effective ones
include oxygen, acetylcholine, bradykinin, and indomethacin,
a prostaglandin inhibitor. Prostaglandin E2 keeps the ductus in
a dilated state. Of the compounds mentioned, oxygen and
acetylcholine are probably the most important in vivo in
causing constriction.
With contraction of the medial smooth muscle, the ductus
becomes functionally closed in the first few hours after birth.
There are exceptions. The ductus in some foals may remain
patent for up to 5 days, and a continuous murmur is detect-
able up to that time. A ductus arteriosus that remains patent
beyond this time is considered to be abnormal. They are
minimally responsive, or nonresponsive, to oxygen and other
compounds that constrict the normal ductus.
Continued patency results in a number of sequelae that are
dependent on the size of the PDA and the relationship
between the pulmonary and systemic vascular resistance. In
uncomplicated cases, the blood flow is from the aorta to the
pulmonary artery (left-to-right shunt) during both systole and
diastole. Depending upon the ensuing rise of pulmonary arte-
rial pressure, there may be left-to-right flow only during
systole. In severe cases, the shunt is reversed and flow from
the pulmonary artery to the aorta (right-to-left shunt) occurs.
If the ductus is of sufficient size, there is volume overload of
resulting in compensatory hypertrophy of both ventricles.
There is also left atrial dilation resulting from increased 
pulmonary blood flow (Fig. 1-15). The ascending aorta and
pulmonary artery are dilated, probably resulting from a com-
bination of turbulent flow and altered pressure relationships.
The development of congestive heart failure with a large PDA
is not only related to pulmonary vascular resistance, but also
to the ability of the left ventricle to handle volume overload.
In dogs where aorticopulmonary shunts were created experi-
mentally, a communication of 3 mm or less in diameter may
lead to the slow development of left ventricular hypertrophy,
but it is otherwise well tolerated. A window of 5 mm in
diameter may lead to pulmonary hypertension, with degen-
erative changes in pulmonary vessels and congestive heart
failure.
As a consequence of turbulent flow, a PDA is predisposed
to thrombosis, which is referred to as endocarditis of the
ductus. The anatomic appearance of the PDA ranges from a
ductus diverticulum, which is a blind funnel-shaped out-
pouching of the aorta at the site of the ductus, to a ductus
that approaches the diameter of the aorta. The length of the
patent ductus may also vary. In some cases, there is virtually
no ductus, but, instead, an opening between the aorta and
pulmonary artery, which are closely approximated. Hypopla-
sia and asymmetry of ductus-specific smooth muscle and the
presence of aorta-like elastic tissue in the ductus wall, as 
has been observed in some cases, may cause patency. In 
dogs, as the number of genes that determine its presence
increases, the histologic appearance of the PDA more closely
resembles the aorta, and the clinical severity of the defect
increases.
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels 19

Aorta

PDA
Cranial vena cava

PV

PV

RA
PA LA Left atrial
dilation
Caudal
vena cava

Increased RV
afterload LV Figure 1-16  Pulmonic stenosis in a dog. The pulmonary artery
has been opened showing the poststenotic dilation and the thick-
ened, distorted pulmonary valves fixed in a closed position.
(Courtesy A. G. Armien.)

Increased
preload
Aorta
Figure 1-15  Patent ductus arteriosus (PDA). In most cases,
blood flow through a PDA occurs during both systole and diastole
from the aorta into the pulmonary artery. The right ventricle Cranial vena cava PA
hypertrophies concentrically because of the increased afterload
(pulmonary arterial hypertension). The left atrium and ventricle PV
hypertrophy eccentrically because of the increased preload
(increased volume of blood returning from the pulmonary circuit). PV
For abbreviations, see Figure 1-10. (Modified from Robinson WF,
RA
Huxtable CRR, eds. Clinicopathologic Principles for Veterinary LA
Medicine. Cambridge, UK: Cambridge University Press, 1988.
Reprinted with permission.) Caudal
vena cava

Malformation of semilunar or
atrioventricular valves
Failure of adequate development of the semilunar valves
RV
usually results in valvular or subvalvular stenosis. Anomalous LV
AV valves may be insufficient or stenotic or both.

Pulmonic stenosis
Pulmonic stenosis is a relatively common congenital anomaly in
dogs, but an unusual finding in other domestic species. It is
inherited in Beagles, and is suspected to be so in English Bull-
dogs, Bull Mastiffs, Chihuahuas, and terrier types. The term
pulmonic stenosis encompasses 3 anatomic variations: supraval-
vular, valvular, and subvalvular or infundibular stenosis. Valvu-
lar stenosis, the most common form in dogs, is probably due
to disordered fusion of the valve cushions and their failure to
hollow out properly. The valve, which is then more or less
dome shaped with an irregular central perforation, is sur-
rounded by 3 recognizable sinuses of Valsalva that are small
and irregular in form (Fig. 1-16). Subvalvular or infundibular
stenosis is produced by a ring of connective tissue that encir-
cles the upper portion of the outflow tract of the right ven-
tricle, or by hypertrophy of the crista supraventricularis
muscle ridge. With each form, the pulmonary trunk is dilated
and thin walled. This is probably due to a combination of
turbulent flow and a drop in pressure, creating a venturi  be malformation of the left aortic sinus of Valsalva and inver-
effect in the pulmonary artery. Concentric right ventricular
Figure 1-17  Pulmonic stenosis is usually valvular and places an
increased afterload on the right ventricle which undergoes con-
centric hypertrophy. There is poststenotic dilation of the pulmo-
nary artery. For abbreviations, see Figure 1-10. (Modified from
Robinson WF, Huxtable CRR, eds. Clinicopathologic Principles
for Veterinary Medicine. Cambridge, UK: Cambridge University
Press, 1988. Reprinted with permission.)
hypertrophy is always present because of the increased afterload
placed on the right ventricle (Fig. 1-17).
In English Bulldogs, the breed most commonly affected by
pulmonic stenosis, the stenosis is frequently caused by a cir-
cumpulmonary left coronary artery that originates from a single
right coronary artery. The cause of this syndrome appears to
sion of the proximal segment of the left main coronary artery.
20 CHAPTER 1  •  Cardiovascular System Congenital Abnormalities of the Heart and Large Vessels

Aorta
PA
Aorta

RV
tal
LV ep
l a rs
t
icu ec
e ntr def
V
A

B
Aorta PA

LV

RV

C
Figure 1-18  Tetralogy of Fallot. A. Over-riding aorta and right ventricular hypertrophy can be
seen. B. High ventricular septal defect and over-riding aorta evident. C. Pulmonic stenosis and
right ventricular hypertrophy are evident. (Arrows—red for left side and blue for right side—on
white plastic tubes show direction of blood flow). LV, left ventricle; PA, pulmonary artery;
RV, right ventricle. (Courtesy V. Psychas.)

Tetralogy of Fallot
The primary lesion in tetralogy of Fallot is obstruction to right
ventricular outflow, either through pulmonic stenosis or infun-
dibular stenosis that results from abnormal conotruncal par-
titioning. The other lesions in the tetrad are ventricular septal
defect (VSD), overriding aorta, and secondary right ventricular
hypertrophy (Fig. 1-18A-C). Tetralogy is one of the congenital
heart diseases that invariably results in clinical signs. Affected
animals fatigue easily and are usually cyanotic and polycythemic.
The latter is a response to hypoxia. Growth rate is usually
retarded. At least in Keeshonds, the condition is inherited as a
defect at a single autosomal locus, in which there is partial
penetrance in heterozygotes and complete penetrance in
homozygotes. Analysis of affected Keeshonds has revealed
various grades of malformation. The spectrum of anomalies
included subclinical defects of the crista supraventricularis,
VSD, pulmonic stenosis with abnormal nonpatent interven-
tricular septum, and tetralogy of Fallot. Closure of the inter-
ventricular septum is contributed to by the conotruncal
septum. The flow of blood from the right ventricle into the
dextroposed aorta does not depend on the degree of overrid-
ing, but on the severity of the pulmonic stenosis (Fig. 1-19).
Aortic and subaortic stenosis
Isolated congenital aortic valvular stenosis is distinctly uncom-
mon. Subvalvular aortic (subaortic) stenosis is, in contrast, a
common defect in pigs and often occurs in conjunction with
what has been termed endocardiosis of the left AV valve. In one
study of 321 pigs that had left AV valvular abnormalities
(endocardiosis), 258 had accompanying subaortic stenosis.
Subaortic stenosis is among the more frequently encountered
anomalies in dogs, and often occurs in association with left
AV valvular disease. Dog breeds commonly affected include
the German Shepherd dog, Weimaraner, Golden Retriever,
German Shorthaired Pointer, Saint Bernard, Newfoundland,
Dogue de Bordeaux, and English Bull Terrier.
The anatomic appearance of the subvalvular lesion ranges
from a number of small fibrous plaques on the endocardial
surface of the left ventricular outflow tract on the interven-
tricular septal aspect, to a completely encircling fibrous band
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels
Aorta
PA
Cranial vena cava
PV
PV
RA
LA
Caudal
vena cava
RV
LV
Figure 1-19  Tetralogy of Fallot. The severity of the pulmonic
stenosis determines the predominant direction of flow. If severe
pulmonic stenosis is present, the flow is into the aorta via the
ventricular septal defect. The right ventricle hypertrophies con-
centrically because of the increased afterload placed on it. For
abbreviations see Figure 1-10. (Modified from Robinson WF,
Huxtable CRR, eds. Clinicopathologic Principles for Veterinary
Medicine. Cambridge, UK: Cambridge University Press, 1988.
Reprinted with permission.)
Figure 1-20  Aortic and subaortic stenosis. Note thickened aortic
valves and ridge of fibrous tissue in the aortic outflow tract. Dog.
(Courtesy A. Wuenschmann.)
just below the aortic valve (Fig. 1-20). There may also be
involvement of the aortic valve. The subendocardial thicken-
ings are composed of connective tissue in irregular arrange-
ments, intermixed with abundant mucinous ground substance.
The change is sometimes fibrocartilaginous in nature. Where
there is an accompanying left AV valvular defect, it is com-
posed of a thickened, ridged, and larger cranial leaflet, which
21
Aorta
PA
Cranial vena cava
PV
PV
RA
LA
Caudal
vena cava
RV LV
Figure 1-21  Aortic and subaortic stenosis place an increased
afterload on the left ventricle, which hypertrophies concentrically.
There is poststenotic dilation of the aorta. For abbreviations 
see Figure 1-10. (Modified from Robinson WF, Huxtable CRR,
eds. Clinicopathologic Principles for Veterinary Medicine. 
Cambridge, UK: Cambridge University Press, 1988. Reprinted
with permission.)
forms part of the left ventricular outflow tract. The cranial
leaflet forms about 13 of the cylinder that is the left ventricu-
lar outflow tract and, when abnormal, completes the stenosing
subaortic ring.
As with pulmonary outflow tract obstruction, increased
afterload on the left ventricle and turbulent poststenotic flow
produce compensatory concentric hypertrophy of the involved ven-
tricle and poststenotic dilation of the aorta (Fig. 1-21). Intimal
proliferation of collagen and deposition of glycosaminoglycans
in the intramural coronary arteries is common. This may well
explain the presence of multifocal myocardial necrosis and
fibrosis, and the relatively common clinical finding of sudden
death, presumably resulting from the generation of ventricular
dysrhythmias following myocardial necrosis.
The heritability of this anomaly in dogs is either polygenic
or involves a major dominant gene with modifiers. There is
some question as to whether it is a true congenital lesion. In
one experimental study, no dog exhibited the typical lesion
before 25 days of age. There is also some evidence that the
severity of the condition increases with age.
Dysplasia of the right atrioventricular valve
Dysplasia of the right AV valve appears to be one of the more
common defects observed in the cat, but is uncommon in other
domestic species. Affected dog breeds include Dogue de 
Bordeaux and Labrador Retriever. The anatomic characteris-
tics of right AV dysplasia are focal or diffuse thickening of the
leaflets, some of which may be absent, or short chordae ten-
dineae and papillary muscles, and direct fusion of portions of
22 CHAPTER 1  •  Cardiovascular System
the affected valve with the ventricular wall. In right AV dys-
plasia, the valve is insufficient, the right atrium is enlarged, and
the right ventricle is eccentrically hypertrophied. The anomaly
may be associated with malformation of the left AV valve
complex or VSD. In Ebstein’s anomaly of the right AV valve,
there is downward displacement of the basal portions of the
valve into the right ventricle. The morphologically similar
canine right AV valve malformation has been mapped to a
susceptibility locus on chromosome 9 in several kindreds of
purebred Labrador Retriever dogs. Right AV atresia—absence
of the right AV orifice—is accompanied by an interatrial com-
munication, right ventricular hypoplasia, and usually a VSD.
Left atrioventricular valvular insufficiency or stenosis
A mixed-frequency holosystolic murmur, with its point of
maximum intensity on the left caudal sternal border, is indica-
tive of left AV valve insufficiency. Commonly heard in old
dogs with endocardiosis, it may also be associated with moder-
ate to severe left-sided failure in young dogs and cats. Malfor-
mation of the left AV valve complex is probably the most common
congenital cardiac anomaly in the cat. The lesion has a relatively
wide spectrum of severity, and may result in either an insuffi-
cient or a stenotic valve. Anatomically, there is an enlarged
annulus, short thick leaflets, short thickened chordae tendin-
eae, upward malposition of atrophic or hypertrophic papillary
muscles, and enlargement of the left atrium and ventricle.
There is also diffuse endocardial fibrosis. In dogs, the lesion
has been most commonly seen in Cavalier King Charles  tissue, and Purkinje cells. False tendons are of debatable sig-
Spaniels, Great Danes, English Bull Terriers, and, to a lesser
extent, German Shepherd dogs.
Transposition complexes
Some of the more severe cardiac anomalies are a combination
of defects of the aorta and pulmonary artery. Malposition or
transposition of arterial trunks is a condition in which the
aorta lies in relation to the pulmonary artery such that it
receives blood from the right ventricle, the basic defect being
dextroposition of the aorta. There are 4 degrees, or types, of this
anomaly:
• Overriding aorta—(the most common type), the aorta
straddles the interventricular septum, which is defective,
and receives blood from both ventricles, and the pulmo-
nary artery leaves the right ventricle;
• Partial transposition—both vessels leave the right ventricle;
• Overriding pulmonary artery—the pulmonary artery strad-
dles a defective ventricular septum and the aorta emerges
from the right ventricle;
• Complete transposition—the aorta emerges from the right
ventricle and the pulmonary artery emerges from the left
(eFig. 1-5).
It is usual in these transposition complexes for either the
pulmonary artery or the aorta to be hypoplastic.
Miscellaneous cardiac anomalies
Congenital hematomas (hemocysts) on the margins of the AV
valves are common, especially in calves, but appear to be of little
consequence. These are usually blood-filled cysts lined by
endothelium; they originate in the clefts normally present in
the substance of the valves in intrauterine life. The cysts may
measure up to 1.0 cm in diameter and be multiple. There is
some question as to whether the cysts involute within a few
months of birth, or whether they persist for a year or more,
by which time the content is changed to serous fluid. A similar
Congenital Abnormalities of the Heart and Large Vessels
process, termed valvular telangiectasis in the septal cusp of the
right AV valve in Beagles, has been reported to progress from
telangiectasis through scarring and osseous metaplasia.
Primary endocardial fibroelastosis is characterized by
diffuse endocardial thickening by collagen and elastic fibers,
and left ventricular hypertrophy and dilation in the absence
of any associated cardiac malformation. The fact that diffuse
endocardial thickening occurs when any chamber of the heart
remains dilated for a prolonged period has probably led to the
confusion that exists about endocardial fibroelastosis. There
have been reports in the literature describing the existence of
this condition in a number of species, but the primary disease
has only been well documented in cats and, to a lesser extent,
dogs. The disease in affected Burmese kittens commences with
localized endocardial lymphedema. This is detectable micro-
scopically, but not grossly, at 1 day of age. Progressive deposi-
tion of endocardial collagen and elastin follows and allows
macroscopic detection from 20 days of age. The left atrium is
dilated, and the left ventricle is hypertrophied and dilated.
The endocardial fibrosis progressively involves cardiac con-
ducting fibers, which exhibit some degenerative change.
Although not definitely established, there appears to be little
doubt of the inherited nature of the disease.
False tendons are thin, often branching, structures that
traverse the cavity of the left ventricle and are not connected
to the valve cusps; they are common in domestic mammals.
They are composed of cardiac muscle, blood vessels, fibrous
nificance, but may play a role in innocent murmurs and 
cardiac dysrhythmia.
Cor triatriatum (triple atria) is a rare lesion in cats and dogs
resulting from failure of incorporation of the common pulmo-
nary vein into the left atrium. A membrane separates the left
atrium into 2 compartments, which can impede pulmonary
drainage and lead to pulmonary edema. Cor triatriatum dexter
(right atrium) can cause ascites.
Epithelial inclusions are found occasionally in ventricular
myocardium in well-defined areas of discoloration or spongi-
ness. The inclusions are present as acinar or ductular structures
lined by a simple layer of cuboidal epithelial cells on a base-
ment membrane. The inclusions are possibly of endodermal
origin from the foregut and represent displacements arising
very early in embryogenesis, when the heart rudiment is adja-
cent to the developing foregut.
Myocardial bridges are anatomic variants that are superfi-
cial myocardial bands that run across short segments of a
coronary artery located epicardially in the dog, cat, goat,
sheep, and human. The bridges appear to be of little functional
significance.
Congenital absence of the pericardium occurs in dogs.
Affected animals are usually asymptomatic.
Double-chambered right ventricle is a rare cardiac anomaly
in cats and dogs.
Variations in the position of the heart are not cardiac mal-
formations but, instead, malformations of adjacent structures:
• In ectopia cordis, the heart may lie in extrathoracic, prester-
nal, or intra-abdominal positions (Fig. 1-22). Dislocations
within the thorax are the result of asymmetrical pressure,
as for example, in congenital diaphragmatic hernia or
pleural effusion.
• In peritoneopericardial diaphragmatic hernia, which
occurs in dogs and cats, intestine and/or liver are present
in the pericardial sac.
 22.e1

eFigure 1-5  Complete transposition of aorta and pulmonary

artery in a foal. Coronary arteries arise from a common trunk
(arrowhead).
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels
Figure 1-22  Ectopia cordis in a calf. Extrathoracic ventral loca-
tion of the heart through a sternal and skin defect. (Courtesy 
R.W. Cook.)
Figure 1-23  The persistent right aortic arch traverses the esopha-
gus and the trachea, resulting in marked dilation of the esophagus
cranial to the persistent arch. (Courtesy P. Nation.)
• Dextrocardia is a rare condition in dogs in which the apex
of the heart, which normally points to the left (levocardia),
points to the right. Dextrocardia may be part of situs inver-
sus, in which the heart and other internal organs are trans-
posed in a mirror-image fashion. Kartagener’s syndrome, a
rare condition in dogs, includes dextrocardia, sinusitis, and
bronchiectasis, the last 2 features as a result of ciliary
dyskinesia.
Vascular anomalies
Persistence of the right aortic arch is a well-known anomaly
in dogs and has been observed in cattle. It is due to persistence
of the right fourth aortic arch instead of, as is normal, the left
fourth aortic arch. A right aorta descends to the right of the
midline, arches over the origin of the right bronchus, and
descends either to the left or right of the vertebral column.
With the aorta in this position, the ductus arteriosus (ligamen-
tum arteriosum), passing from the aorta to the pulmonary
artery, encloses the esophagus and compresses it against the
trachea. Obstruction of the esophagus at this point leads to
dysphagia and, shortly, to dilation of the cervical portion of
the esophagus (Fig. 1-23).
A double aortic arch is a variation of the foregoing in
which the left arch persists as well as the right. Both arches arise
23
Figure 1-24  Aortic coarctation (hypoplasia) with right atrioven-
tricular (AV) stenosis in a dog. Hypoplastic aorta (arrowhead),
pulmonary artery (arrow), right AV valvular stenosis (asterisk).
(Courtesy A. G. Armien.)
from the ascending aorta. The right arch, which is usually the
larger of the 2, follows the course given above. It is joined
above the esophagus by the small left arch. The significant end
result is constriction of the esophagus.
Aorticopulmonary septal defect, or window, is a rare defect
in dogs that results from incomplete division of the truncus
arteriosus. Pulmonary hypertension develops, leading to right-
to-left shunting of blood.
Coarctation of the aorta is another rare defect in dogs, and
is seen as narrowing of the aorta adjacent to the ductus
arteriosus/ligamentum arteriosum. Left ventricular pressure
overload can result in left heart failure. Additional malforma-
tions of the aorta reported in dogs include interruption of the
aorta and tubular hypoplasia of the ascending aorta (Fig. 1-24).
Congenital aneurysm of the aorta or of the pulmonary
artery, involves, for either vessel, the trunk and arch, but may
not extend beyond the insertion of the ligamentum arterio-
sum. Aortic aneurysm may be associated with aneurysm of
one or more of the aortic sinuses of Valsalva.
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Clark KL, et al. Transcription factors and congenital heart defects. Ann
Rev Physiol 2006;68:97-121.
French AT, et al. Genome-wide analysis of mitral valve disease in cava-
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Fukushima R, et al. Epidemiological and morphological studies of
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2011;73:1287-1293.
Granados-Riveron JT, et al. Combined mutation screening of NKX2-5,
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23.e1
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24 CHAPTER 1  •  Cardiovascular System
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PERICARDIAL DISEASE
Primary disease confined to the pericardium is rare, but the
close anatomic relationship of the pericardium to the heart,
lungs, and pleura sometimes results in the extension of disease
processes from the latter organs to the pericardium. It is also
often a site for the location of infectious agents as part of
systemic infections, particularly in the neonate. Somewhat
paradoxically, the pericardium is not needed for normal  rupture and result in a bloodstained effusion. Neoplastic
life, but pericardial disease can be life threatening. The peri-
cardial sac may be removed surgically for relief of pericardial
constriction.
The pericardial cavity may communicate with the perito-
neal cavity through clefts in the diaphragm; hence herniated
intestine may be found surrounding the heart as a result of
congenital peritoneopericardial diaphragmatic hernia. Partial or
complete congenital absence of the pericardial sac is without
clinical effect. Pericardial cysts are rare congenital anomalies
that occur in one of the costophrenic angles.
Epicardial fibrous fronds occur on the atria of Beagle dogs
as an occasional incidental finding at postmortem.
Noninflammatory lesions of the pericardium
Hydropericardium
The pericardial sac normally contains a very small quantity of
clear, serous fluid. Any excess in the volume of clear fluid is
referred to as hydropericardium. A small increase in volume
occurs by transudation after death, and it is soon reddened by
postmortem hemolysis.
Hydropericardium is often part of generalized anasarca and
is thus seen in many cachectic illnesses, perhaps as the result
of hypoalbuminemia, and in congestive heart failure (Fig. 1-25).
It may also be the product of local events such as implanted
metastases of neoplasms on the pericardium, and lymphoma-
tous infiltrations of the myocardium; primary tumors about
Pericardial Disease
Figure 1-25  Hydropericardium in a cat as the result of hypopro-
teinemia associated with the cachexia of neoplasia. The outline
of the heart is just visible through the fluid-filled pericardial sac.
the base of the heart and in the cranial mediastinum are rather
common causes of hydropericardium. Hydropericardium may
also accompany congenital and acquired peritoneopericardial
hernias and uremia. Infectious processes of the pleura, especially
granulomatous inflammations, may cause irritation of the peri-
cardium sufficient to provoke a sterile serous effusion; the
infection may eventually extend to the pericardial sac. If drain-
age of the thoracic duct is disrupted, for example, by a cardiac
neoplasm, then the fluid may be chylous (chylopericardium).
In hydropericardium, the serosal surfaces remain smooth
and glistening, but if the fluid persists for a long time, it may
produce slight fibrous thickening and opacity of the pericar-
dial and epicardial surfaces. It is usually about the base of the
ventricles, and small villus proliferations of the serosa may
involvement of the pericardium characteristically has this
result.
The pericardial fluid is clear or light yellow, without floc-
cules, and with low content of protein. Fluid rich in protein,
including fibrinogen, is often found in acute toxemias of clos-
tridial (gas gangrene group) origin. Clotting occurs soon after
exposure to air. In such cases, exudation is due to direct injury
to the endothelium by circulating toxins. Fluid that is copious
and gels on exposure also is characteristic of African horse
sickness and of heartwater. In pigs with edema disease or
mulberry heart disease, fibrin is often formed antemortem.
The presence of protein, especially fibrin, in pericardial fluid
is only an index of the degree of endothelial injury and
increased permeability and is not a precise point of distinction
between an exudate and a transudate. Inflammatory exudates
can be differentiated from transudates on the basis of the
higher content of protein and cells in exudates and histologic
evidence of inflammation involving the pericardium and
epicardium.
The volume of fluid that accumulates is quite variable and
of lesser significance than the rate at which it accumulates.
When fluid accumulates rapidly, the pericardium is put under
tension, the heart is compressed, and venous blood pools in
the splanchnic and systemic circulations because of impaired
atrial and ventricular filling (cardiac tamponade). When the
fluid accumulates slowly, there is time for stretching and adap-
tation of the pericardium so that very large amounts of fluid
Diseases of the Heart
Figure 1-26  Acute, severe, hemopericardium in a dog, following
rupture of a right atrial hemangiosarcoma. (Courtesy A. G.
Armien.)
can accumulate before there is significant impairment of dia-
stolic filling of the heart.
Hemopericardium
The term hemopericardium is limited to accumulations of pure
blood in the pericardial cavity, and should not apply to mix-
tures of blood and serous fluid. If the blood is clotted, it can
be assumed that the process is a true hemopericardium. Death
usually supervenes rapidly. It is an unusual lesion, except fol-
lowing cardiac rupture, puncture or other direct trauma. It is
seen in horses in which rupture of the intrapericardial aorta
or atria occurs. In dogs, hemopericardium occurs in atrial
rupture in endocardiosis, hemorrhage from atrial hemangio-
sarcoma, in ulcerative atrial endocarditis of renal failure, and
rarely, following rupture of a coronary artery or from hemor-
rhage from a heart base thymic remnant (Fig. 1-26). In young,
growing swine, rupture of the heart, particularly of an atrium,
a coronary artery, or the aorta occurs on rare occasions. These
deaths have not been examined specifically with deficiency of
copper in mind, but attention is drawn to the remarkable
cardiovascular lesions of experimental deficiency, which is
discussed with diseases of the arteries.
Idiopathic pericardial hemorrhagic effusion occurs pre-
dominantly in large-breed dogs, and is characterized by the
presence of both clotted and unclotted blood in the pericar-
dial sac without obvious cause. The clinical presentation is
that of slowly developing right-sided heart failure, with some
having accompanying left-sided heart failure. The heart sounds
are muffled or inaudible on initial presentation, with no evi-
dence of dysrhythmias. However, some subsequently develop
atrial fibrillation. The clinical course can be prolonged. The
slow onset of clinical signs suggests either slow or intermittent
bleeding, allowing distension without tamponade. Indeed,
some dogs may make a full clinical recovery following aspira-
tion of the pericardial fluid.
Serous atrophy of pericardial fat
In cachexia of any cause, and paralleling fairly closely the
reduction in body weight, there is progressive mobilization of
depot fat, including that beneath the epicardium. As the lipid
vacuoles are reduced in size, they are replaced by protein-
aceous fluid, and with a concomitant increase in interstitial
Pericardial Disease 25
Figure 1-27  Serous atrophy of epicardial fat, which is gelatinous
and translucent around the coronary groove in a cachectic alpaca.
fluid, the depots are converted to gray, gelatinous masses that
may be flecked by small white foci of fat necrosis (Fig. 1-27).
Further reading
Alleman AR. Abdominal, thoracic, and pericardial effusions. Vet Clin
North Am Small Anim Pract 2003;33:89-118.
Aronson LR, Gregory CR. Infectious pericardial effusion in five dogs.
Vet Surg 1995;24:402-407.
Dempsey SM, et al. A review of the pathophysiology, classification, and
analysis of canine and feline cavitary effusions. J Am Anim Hosp
Assoc 2011;47:1-11.
Hall DJ, et al. Pericardial effusion in cats: a retrospective study of
clinical findings and outcome in 146 cats. J Vet Intern Med
2007;21:1002-1007.
Vogtli T, et al. Hemorrhagic pericardial effusion in dogs. A retrospective
study of 10 cases (1989-1994) with a review of the literature.
Schweiz Arch Tierheilkd 1997;139:217-224.
Pericarditis
It is seldom possible by examination of the lesion itself to
decide the cause of pericardial inflammation, although 
a decision on the cause is often possible when the total 
pathologic picture in the cadaver is noted. For this reason and
for descriptive purposes, we use a morphologic classification
of pericarditis.
Fibrinous pericarditis is usually the result of hematogenous
microbial infections, but it may arise by lymphatic permeation
from an inflammatory process in adjacent tissue. In cattle,
fibrinous pericarditis, with or without some hemorrhage, is
commonly part of pasteurellosis, blackleg, sporadic bovine
encephalomyelitis, contagious bovine pleuropneumonia, clos-
tridial hemoglobinuria, and some of the neonatal coliform
infections that enter via the umbilicus. In swine, it is frequently
part of the morbid picture of Glasser’s disease and past­
eurellosis, is a common complication of porcine enzootic
 25.e1

Further reading
Aronsohn MG, Carpenter JL. Surgical treatment of idiopathic pericar-
dial effusion in the dog: 25 cases (1978-1993). J Am Anim Hosp
Assoc 1999;35:521-525.
Bouvy BM, Bjorling DE. Pericardial effusion in dogs and cats: 1. Normal
pericardium and cause and pathophysiology of pericardial effusion.
Compend Contin Educ Pract Vet 1991;13:417-424.
Bradley GA, et al. Hemopericardium in a dog due to hemorrhage
originating in a heart base thymic remnant. J Vet Diagn Invest
1992;4:211-212.
Gwatkin R, Moynihan W. Valvular lesion in swine: rupture of heart in
two cases. Can J Comp Med Vet Sci 1942;6:213-214.
Mansfield CS, et al. Intra-atrial rhabdomyoma causing chylopericar-
dium and right-sided congestive heart failure in a dog. Vet Rec
2000;147:264-267.
Mesfin GM. Spontaneous epicardial fibrous fronds on the atria of
Beagle dogs. Vet Pathol 1990;27:458-461.
Petrus DJ, Henik RA. Pericardial effusion and cardiac tamponade sec-
ondary to brodifacoum toxicosis in a dog. J Am Vet Med Assoc
1999;215:647-648.
26 CHAPTER 1  •  Cardiovascular System
pneumonia (infection with Mycoplasma hyopneumoniae and
other agents), and is occasionally observed in salmonellosis
and in streptococcal infection of piglets. Fibrinous pericarditis
in adult sheep is usually part of pasteurellosis; in lambs, it is
usually part of pasteurellosis or caused by streptococci. In
horses, Mycoplasma felis causes pericarditis and pleuritis; strep-
tococcal pericarditis may coexist with polyarthritis. Fibrinous
pericarditis in horses may also be associated with the mare
reproductive loss syndrome. Pericarditis is rare in cats, but it
is seen as part of feline infectious peritonitis.
In fibrinous pericarditis, there is seldom significant exuda-
tion of fluid, so distension of the pericardial sac is not to be
expected. The exudation of fibrin usually begins about the
base of the heart and extends from there to cover, more or
less completely, both the pericardium and epicardium. The
fibrin is gray-white, but it may be flecked with blood, or
yellow if a large number of leukocytes are added to the
exudate. Except for small pools of serum or serous exudate,
the pericardium and epicardium are in apposition. When the
leaves are drawn apart, the exudate is drawn out into villus-
like projections to give an appearance responsible for the
names “cor villosum,” “shaggy heart,” and “bread-and-butter
pericarditis” (Fig. 1-28).
The completeness of resolution depends upon how quickly
the fibrinous exudate can be removed, which is a function of
the amount of fibrin, and how quickly the mesothelium can
be regenerated, which is a function of the amount of meso-
thelium that has been destroyed. Restorative processes compete
with the processes of organization. Within a week or so, there
will be well-formed fibrous tissue in the deepest parts. Imme-
diately superficial to this, there will be young granulation
tissue and then a stratum of fibroblasts mixed with leukocytes,
and on the surface, there remains the fibrin clot infiltrated
with numerous leukocytes. If the course is prolonged,
Figure 1-28  Fibrinous pericarditis in a foal. Greatly thickened
pericardial sac and extensive fibrinous exudate loosely attached
to the epicardium, accompanied by epicardial hemorrhage.
Pericardial Disease
organization and scarring will result in focal or diffuse fibrous
adhesions between the pericardial surfaces, with partial or
complete obliteration of the sac.
The residual lesions of fibrinous pericarditis occur as more
or less distinct variants. Focal, patchy thickenings of the epi-
cardium without adhesions form minimal residue and are
usually more distinct on the ventricles than on the atria, where
they may be obscured by normal fat. The original scar tissue
may undergo fatty metaplasia or be edematous. (The same
lesion also occurs covering healed foci of superficial myocar-
ditis.) Focal or diffuse adhesive pericarditis varies in extent
from a few “violin strings” across the sac to complete oblitera-
tion of the sac. Inclusion cysts lined by mesothelium are often
present in fibrous adhesions, and there tends to be excess fluid
present in non-obliterated portions of the sac. The pericar-
dium is separable from the epicardium by blunt dissection. As
the connective tissue is not dense, there is usually no embar-
rassment of cardiac function.
Purulent pericarditis almost invariably denotes the presence
of pyogenic bacteria, either as primary pathogens or as oppor-
tunists in fibrinous pericarditis. It occurs almost solely in cattle
as a result of traumatic perforation by a foreign body originat-
ing in the reticulum, but it is observed in cats and horses in
association with empyema (pyothorax). Migrating grass awns
(“foxtail,” Hordeum glaucum, and H. leparinum) have been
identified as causes of suppurative pericarditis in dogs in the
western United States.
The suppurative pericardial fluid may appear as thin,
cloudy exudate; as frank, creamy pus; or as a mixture of pus
and masses of fibrin. The color depends on the organisms
present, but usually varies from yellow to green, being irregu-
larly dirty gray when putrefactive bacteria are present. The
exudate is usually foul smelling. The volume of exudate varies
from a thin layer on the serosal surface to 4 L or more. In the
early stages, it can be wiped or washed off to reveal the vas-
cular injection and granularity of the membranes. Soon, the
whole of the epicardium is covered with coagulum; the pari-
etal layer of the pericardium is less severely affected, and
separation of the 2 reveals a shaggy appearance of the heart
(cor villosum).
Microscopically, the subjacent tissues are densely infiltrated
with leukocytes, the reaction extending more deeply than in
fibrinous pericarditis, the formation of new blood vessels and
connective tissue is prominent, and the overlying coagulated
exudate is densely infiltrated with leukocytes.
Resolution probably never occurs. Because of the severity of
the inflammatory reaction, healing is by organization, as is
characteristic of all suppurative inflammations. Although the
course of suppurative pericarditis may be prolonged, the per-
sistence of the inciting agent, or more usually agents, prevents
complete organization.
Constrictive pericarditis resulting from progressive organi-
zation can be so severe and diffuse that it leads to impaired
diastolic filling and the development of right-sided heart
failure (Fig. 1-29). The adhesions cannot be broken down by
blunt dissection and may be mineralized. They obliterate the
pericardial cavity, but they may also extend beyond it to
involve the mediastinum. The heart, which is confined by scar
tissue, may be smaller than normal, or it may be greatly
enlarged and hypertrophic, especially when there are also
extrapericardial adhesions present. There is always severe
cardiac dysfunction, and death occurs from congestive heart
failure.
Diseases of the Heart
Figure 1-29  Chronic constrictive pericarditis in a cow, typical of
traumatic reticulopericarditis. Note the wide band of fibrosis on
the surface of the epicardium (arrow). (Courtesy A. P. Loretti.)
Further reading
Bolin DC, et al. Microbiologic and pathologic findings in an epidemic
of equine pericarditis. J Vet Diagn Invest 2005;17:38-44.
Braun U. Traumatic pericarditis in cattle: clinical, radiographic and
ultrasonographic findings. Vet J 2009;182:176-186.
Perkins SL, et al. Pericarditis and pleuritis caused by Corynebacterium
pseudotuberculosis in a horse. J Am Vet Med Assoc 2004;224:1133-
1138.
Shubitz LF, et al. Constrictive pericarditis secondary to Coccidioides
immitis infection in a dog. J Am Vet Med Assoc 2001;218:
537-540.
Veloso GF, et al. Septic pericarditis and myocardial abscess in an English
Springer spaniel. J Vet Cardiol 2014;16:39-44.
ENDOCARDIAL DISEASE
The most clinically significant endocardial lesions affect the
heart valves rather than the mural endocardium. Lesions may
cause valvular stenosis, or valvular insufficiency, or both. Ste-
nosis of a valve, or failure to open completely, impedes the forward
flow of blood. Valvular insufficiency, alternatively termed regur-
gitation, or incompetence results in reversed flow of blood. Valvu-
lar dysfunction may produce abnormal heart sounds that are
detectable clinically as murmurs. The consequences of valvular
disease depend upon the rapidity of onset, type, and duration
of the lesion, and may be ameliorated by cardiac compensa-
tory mechanisms.
The propensity of thrombi to form on the free margins of
valves is well known, but the factors leading to it are not. It
may be related to the continual movement and the resulting
apposition of the surfaces of the free margins of the valves.
There are also ill-defined factors, such as intercurrent disease
or increased workload, which promote the development of
thrombi. The lack of an internal blood supply to the valve may
also be a contributing factor, and in common with other vas-
cular structures, injured endothelial cells release inflammatory
mediators, such as prostaglandins, and other substances, such
as adenosine diphosphate, which are potent stimulators of
platelet aggregation. Once the endothelium is removed, the
exposed collagen also stimulates the aggregation of platelets.
The presence of the initial thrombus leads to further clotting.
In contrast to cardiac myocytes, endothelial cells have a great
capacity for regeneration and for covering any breach in their
Endocardial Disease 27
continuity. If the original insult is removed, which without
appropriate treatment is not often, the valve heals by fibrosis,
but a shrunken, distorted, insufficient, or stenotic valve may
remain.
Little is known of the process leading to the abnormal
development of valves in the embryo, or the progressive accu-
mulation of glycosaminoglycans in the degenerative disease
endocardiosis. The various theories are discussed under the
appropriate heading. However, both lead to deficiencies of
valve function.
Acute rupture of chordae tendineae can occur spontane-
ously or in association with chronic valvular degeneration or
valvular endocarditis. As well, acute rupture of chordae ten-
dineae or papillary muscles, and resultant acute valvular insuf-
ficiency and heart failure, can also be caused by blunt trauma
to the chest.
Degenerative lesions
Myxomatous valvular degeneration
(“endocardiosis”) in dogs
Myxomatous valvular degeneration, commonly termed endo-
cardiosis, is the most common cardiovascular lesion in dogs. It is
a significant cause of clinically apparent left-sided heart failure,
but is also frequently encountered as an incidental finding at
postmortem. Advanced endocardiosis of the left atrioventricu-
lar (AV) (mitral) valve leads to mitral insufficiency and regur-
gitant flow into the left atrium, noted clinically as a systolic
murmur, and culminates in left-sided heart failure. The
shrunken, distorted AV valves are seen with greatest frequency
in toy, small, and medium breeds of dogs, especially in 
males of breeds such as the Poodle, Pomeranian, Schnauzer,
Chihuahua, Doberman Pinscher, Whippet, Fox Terrier, Boston
Terrier, Cavalier King Charles Spaniel, Dachshund, and the
English Cocker Spaniel. There are significant negative associa-
tions for the Labrador Retriever and the German Shepherd
dog. The prevalence of the disease increases with age, from 5%
at <1 year of age to >75% at 16 years of age. Endocardiosis is
also reported in the left AV valves of normal market-weight
pigs, but appears to be clinically inconsequential.
Endocardiosis affects chiefly the left AV valve (Fig. 1-30A-C).
The right AV valve is less severely and less frequently affected.
The aortic and pulmonic semilunar cusps are only occasionally
involved. Grossly, the affected AV cusps are shortened and
thickened. The thickening of the leaflet may be more or less
uniform with a rounded edge, or with prominent nodular
thickenings on the free margin. The valves are opaque and
white, but the surface is smooth and glistening, without any evi-
dence of inflammation. The chordae tendineae may also be
thickened and occasionally are ruptured, allowing eversion of
the leaflet into the atrium and leading to acute ventricular
failure. The left AV valvular annulus may be enlarged.
The least severe gross change consists of a few small, dis-
crete nodules at the line of closure of the valve. These progress
to multiple larger nodules that tend to coalesce in the area of
contact. There may be irregular areas of opacity in the proxi-
mal portions of the leaflet. The nodules may coalesce to form
plaque-like deformities in the area of cusp contact. The
chordae tendineae are thickened at their points of insertion
into the valve, and there are clearly defined areas of opacity
on the basal portions of the leaflet. The most severe change is
characterized by a gross distortion of the valve by gray-white
nodules and elevated plaques. The cusps are contracted,
 27.e1

Further reading
Buttenschon J, et al. Microbiology and pathology of fibrinous pericar-
ditis in Danish slaughter pigs. J Vet Med A 1997;44:271-280.
Day MJ, Martin MW. Immunohistochemical characterisation of the
lesions of canine idiopathic pericarditis. J Small Anim Pract
2002;43:382-387.
Seahorn JL, et al. Case-control study of factors associated with fibrin-
ous pericarditis among horses in central Kentucky during spring
2001. J Am Vet Med Assoc 2003;223:832-838.
Stafford Johnson JM, et al. Septic fibrinous pericarditis in a cocker
spaniel. J Small Anim Pract 2003;44:117-120.
Wood JLN, Chanter N. Mycoplasma infections in horses: a fresh look
using modern methods may reveal an elusive “virus.” Equine Vet J
1996;28:177-179.
Worth LT, Reef VB. Pericarditis in horses: 18 cases (1986-1995). J Am
Vet Med Assoc 1998;212:248-253.
28 CHAPTER 1  •  Cardiovascular System Endocardial Disease

C
Figure 1-30  Endocardiosis in a dog. A. Smooth, glistening, nodular thickening of the left atrio-
ventricular (AV) valve. The left atrium also shows the presence of “jet lesions,” which are irregular
raised areas of subendocardial fibrosis. B. Close-up endocardiosis left AV valve. Cusps are thickened
and shrunken. (Courtesy E. Olson.) C. Dilated left atrium resulting from volume overload of the
atrium. There are also tears of the atrial wall, which led to hemopericardium.

thickened, and irregular. There may also be fixed upward
displacement of the free margin of the valve. Enlargement and
redundancy of the valve may be seen as doming or hooding
of the body of the valve toward the atrium; this prolapse of
the body of the redundant left AV valve into the atrium
(“mitral valve prolapse”) may be seen both echocardiographi-
cally and at postmortem. Chordae tendineae may be ruptured,
in which case the free edge of the valve may prolapse as a flail
leaflet. Care should be taken in the assessment of the valves,
because both the left and right AV valve leaflets thicken with
increasing age, and the free margin of the septal leaflet of the
right AV valve is normally distinctly thicker than the free
leaflets.
Changes secondary to AV valvular insufficiency are dilation
of the atria, particularly the left atrium, and dilation of the
ventricles. The ventricles may be eccentrically hypertrophied.
The left atrial and ventricular subendocardium may be
diffusely thickened by fibrosis following prolonged dilation.
There may also be evidence of regurgitation in the form of
focal elevated streaks and plaques of subendocardial fibrosis
in the atria (“jet lesions”). Left atrial tears may also be seen in
advanced cases, and these tears may rupture and lead to hemo-
pericardium. Mural thrombi can form in the dilated left
atrium; dislodgement of the thrombi can result in thrombo-
embolism, for instance, of coronary arteries leading to myo-
cardial infarction.
Microscopically, the earliest changes are present on the
atrial side of the valves. There is proliferation of the endothe-
lium, increased numbers of subendothelial fibroblasts and
macrophages, and splitting and separation of elastic fibers
between the atrialis and spongiosa. However, it is the thickening
of the spongiosa and degeneration of the fibrosa that are the most
prominent features of endocardiosis. The spongiosa is greatly
thickened by the proliferation of loose fibroblastic tissue and
Diseases of the Heart Endocardial Disease 29

A B

C
Figure 1-31  Microscopy of endocardiosis in a dog. A. Normal valve leaflet. H&E. (Courtesy C.
Foutz.) B. Affected leaflet. Myxomatous degeneration of the stratum spongiosum of the atrioven-
tricular valve. H&E. C. The increase in glycosaminoglycans in the affected valve leaflet is high-
lighted by staining with Alcian blue.

the deposition of the proteoglycans, hyaluronic acid, and
chondroitin sulfate (Fig. 1-31A-C). In a few cases, amyloid
may be deposited. There is no increase in collagen or elastic
tissue in the spongiosa. The changes in the fibrosa are also
marked. Collagen bundles become swollen and hyalinized,
fragment, and disappear. In advanced cases, only scattered
remnants of the fibrosa remain. Similar changes are seen in
chordae tendineae. Intramural coronary arteriosclerosis and
focal myocardial necrosis and fibrosis are commonly seen in
the left ventricular myocardium, especially the papillary
muscle, if the ventricle is hypertrophic.
The cause of endocardiosis is not known, but there is clearly
a genetically influenced degeneration of connective tissue at its
center. This suggestion is supported by the observation that the
most frequently affected breeds are of the chondrodystro-
phoid type. Endocardiosis is inherited in Dachshunds and
Cavalier King Charles Spaniels; a polygenic mode of inheri-
tance is suggested.
Recent research suggests that alteration in tensile strain on
the valves is involved in the initial phases of the disease. Given
the genetic nature in some breeds and the familial nature  intolerance, poor performance, or congestive heart failure
in others, the origin of the increased tensile strain on the  result. Dilation of the pulmonary artery may also ensue, indi-
valves may be the result of abnormal architecture of the AV
valvular complex and possibly abnormal conformation of the
ventricles themselves. This increased tensile strain leads to
increased serotonin levels in the valve itself, in turn activating
the transforming growth factor-β (TGF-β) group of pro-
teins. TGF-β proteins in turn promote the activation of
myofibroblasts/mesenchymal cell phenotypes. Whether the
increased production of proteoglycans is initiated by the same
mechanism remains to be seen. Activation of matrix metal-
loproteinases also appears to contribute to the destruction of
collagen and other fibrillar proteins in the valve.
There is a striking similarity of endocardiosis to the pro-
lapsed mitral valve syndrome of humans, in which there is
deposition of glycosaminoglycans in the spongiosa secondary
to an as yet undefined abnormality of collagen metabolism.
Mitral valve prolapse also occurs in humans in association
with connective-tissue disorders, such as Marfan syndrome,
Ehlers-Danlos syndrome, osteogenesis imperfecta, and a
variety of muscular dystrophies.
Mitral insufficiency in the horse can result from endocardio-
sis, endocarditis, flail valve leaflets, rupture of chordae tendin-
eae, and left AV valve prolapse. Clinical signs of exercise
cating pulmonary hypertension, and may presage pulmonary
artery rupture.
30 CHAPTER 1  •  Cardiovascular System Endocardial Disease

Valvular cysts
Congenital hematomas (hemocysts) on the margins of the AV
valves are common, especially in calves (see previously, Mis-
cellaneous cardiac anomalies). Blood cysts and serous cysts have
been reported in the AV valves in 11% of the hearts in a series
of 30,000 slaughter cattle, with a higher incidence in cows
than calves. Blood-filled cysts were often present on both AV
valves, whereas serous cysts occurred more frequently on the
left AV valve. This suggests that cysts do not regress with age;
indeed their incidence and size may increase with age. The
endothelium lining the blood-filled cysts was positive for
factor VIII–related antigen. The cysts may represent ectasias
of blood vessels and lymphatics.

Subendocardial fibrosis
Subendocardial fibrosis may be diffuse or focal, congenital, or
acquired. The congenital lesions are discussed under Congeni-
tal abnormalities of the heart and large vessels. Diffuse suben-
docardial fibrosis is seen whenever a ventricle or atrium is dilated
for a prolonged period. It is probably best exemplified by the
dilated cardiomyopathy of large-breed dogs.
Subendocardial fibrosis in localized areas is observed
chiefly in the atria and is regarded as a reaction of the endo- Figure 1-32  Extensive subendocardial mineralization in the left
cardium to abnormal jets of blood or to turbulence following atrium and ventricle of a horse following ingestion of Solanum
congenital or acquired valvular disorders (see Fig. 1-30A). glaucophyllum (vitamin D analogue toxicosis). (Courtesy A. P.
They are loosely termed jet lesions, but are probably areas Loretti.)
subject to increased static pressure in turbulent flow.

Subendocardial mineralization
Subendocardial mineralization is associated with a variety of
disorders. It occurs commonly in opaque plaques or as small
grains in the left atrium, and occasionally in the trunk of the
aorta in dogs that have recovered from ulcerative endocarditis
of renal insufficiency (see Mineralization, later). Prominent
white plaques of mineralization also occur beneath the endo-
cardium of the right ventricle in nutritional myopathy of lambs.
Subendocardial mineralization in the atria and left ventricle
may accompany endocardial fibrosis when these cavities are
acutely dilated, either as congenital or acquired defects, and
in a variety of prolonged debilitating diseases in cattle (Fig. 1-32).
Calcium and phosphorus are deposited in degenerate suben-
docardial muscle, but more commonly in fibroelastic tissue.
The fibroelastic tissue is modified either by chronic disease  primary on the valves, from which there may be some encroach-
or elevated serum levels of calcium and phosphorus, as in
vitamin D intoxication, or following the ingestion of plants
containing vitamin D analogues (see Vol. 3, Endocrine glands).
Proprietary rodenticides based on calciferols cause this lesion
in dogs.
Further reading
Aupperle H, et al. N-linked glycans of proteins from mitral valves of
normal pigs and pigs affected by endocardiosis. Eur J Biochem
2000;267:1299-1306.
Aupperle H, et al. Immunohistochemical characterization of the extra-
cellular matrix in normal mitral valves and in chronic valve disease
(endocardiosis) in dogs. Res Vet Sci 2009;87:277-283.
Disatian S, Orton EC. Autocrine serotonin and transforming growth
factor beta 1 signaling mediates spontaneous myxomatous mitral
valve disease. J Heart Valve Dis 2009;18:44-51.
Fox PR. Pathology of myxomatous mitral valve disease in the dog. J Vet
Cardiol. 2012;14:103-126.
Lacerda CM, et al. Static and cyclic tensile strain induce myxomatous
effector proteins and serotonin in canine mitral valves. J Vet Cardiol.
2012;14:223-230.
Marcato PS, et al. Blood and serous cysts in the atrioventricular valves
of the bovine heart. Vet Pathol 1996;33:14-21.
Orton EC, et al. Signaling pathways in mitral valve degeneration. J Vet
Cardiol 2012;14:7-17.
Endocarditis
Endocarditis is one of the more significant of the endocardial
alterations. It is usually bacterial in cause, the exceptions being
occasional parasitic or mycotic lesions. Any portion of the
endocardium may become inflamed, but the lesions are usually
ment on the adjacent mural endocardium (Fig. 1-33A, B). The
left AV valve is most commonly affected in most species, fol-
lowed by aortic, right AV valve, and pulmonic, except in cattle,
in which the right AV valve is more commonly affected.
Many bacterial species are capable of causing acute valvu-
lar endocarditis, and the larger the number of cases examined,
the wider the variety of pathogens recognized. In cattle, True-
perella pyogenes is probably the most common pathogen, and
a primary focus of infection can often be found in some other
site, such as a traumatic peritoneal abscess, hepatic abscess,
metritis, or mastitis. Streptococci of enteric origin are also of
some importance in cattle, although the manner of their sys-
temic invasion is not clear. Erysipelothrix rhusiopathiae causes
endocarditis in a variety of animals, most commonly in the
pig; however, streptococci are more commonly isolated from
cases of acute bacterial endocarditis of swine. Mature horses
seldom develop bacterial endocarditis, but the lesion has been
observed in association with Streptococcus equi, Actinobacillus
equuli, Escherichia coli, Pseudomonas aeruginosa, and Candida
parapsilosis. A number of cases in horses have originated from
 30.e1

Further reading
Aupperle H, et al. Expression of transforming growth factor-beta1,
-beta2 and -beta3 in normal and diseased canine mitral valves.
J Comp Pathol 2008;139:97-107.
Castagnaro M, et al. Morphological and biochemical investigations of
mitral valve endocardiosis in pigs. Res Vet Sci 1997;62:121-125.
Corcoran BM, et al. Identification of surface morphologic changes in
the mitral valve leaflets and chordae tendineae of dogs with myxo-
matous degeneration. Am J Vet Res 2004;65:198-206.
Gagna C, et al. Pathology of mitral valve in regularly slaughtered pigs:
an abattoir survey on the occurrence of myxoid degeneration
(endocardiosis), fibrosis and valvulitis. Zentralbl Veterinarmed A
1998;45:383-395.
Lester WM. Myxomatous mitral valve disease and related entities: the
role of matrix in valvular heart disease. Cardiovasc Pathol
1995;4:257-264.
McCarthy KP, et al. Anatomy of the mitral valve: understanding the
mitral valve complex in mitral regurgitation. Eur J Echocardiogr
2010;11:13-19.
Olsen LH, et al. Epidemiology and inheritance of mitral valve prolapse
in Dachshunds. J Vet Intern Med 1999;13:448-456.
Reef VB, et al. Severe mitral regurgitation in horses: clinical, echocar-
diographic, and pathological findings. Equine Vet J 1998;30:18-27.
Seki Y, et al. Transmural myocardial infarction caused by thromboem-
bolism associated with mitral insufficiency in a dog. J Vet Med Sci
1998;60:741-743.
Diseases of the Heart Endocardial Disease 31

A B
Figure 1-33  Endocarditis. A. Vegetative endocarditis of the right atrioventricular valve of a cow,
caused by Trueperella pyogenes. (Courtesy J. Schefers.) B. Ulcerative, destructive endocarditis of
the aortic valve of a dog. (Courtesy M. Bouljihad.)

septic jugular vein thrombophlebitis. Minor outbreaks of

endocarditis occur in lambs and are usually caused by Strep-
tococcus spp., particularly enterococci; there may be associated
polyarthritis. Endocarditis is seldom observed in dogs, but can
be associated with a variety of organisms, especially Streptococ-
cus spp., Staphylococcus aureus, and Escherichia coli, and less
frequently with Bartonella spp., Erysipelothrix rhusiopathiae,
Erysipelothrix tonsillarum, Pseudomonas aeruginosa, Pasteurella
multocida, or various Aspergillus spp. (Fig. 1-34A, B). Endocar-
ditis is unusual in cats, but has been caused by Bartonella spp.
and Streptococcus spp. In general, neonatal animals are more
prone to develop endocarditis in association with septicemias
of bacterial origin. The major features of endocarditis are
shown in eFigure 1-6.
The manner by which bacteria localize on a valve is not A
clear, and there is seldom detectable evidence of some sepa-
rate underlying disease of the leaflet. In active thrombotic
valvular endocarditis, bacteria are invariably present in the
lesion. Two factors that must be included in any concept of
pathogenesis are
1. The tendency for lesions to occur at the lines of apposition
of the valve surfaces exposed to the forward flow of blood
2. The necessity for sustained or recurrent bacteremia
It is possible that simple debilitation of endothelial cells in
recurrent bacteremia and aggravated locally on the valves by
the trauma of apposition may alter the adhesiveness of the
leaflet endothelium sufficiently for bacterial adhesion to occur.
It is of significance that valvular endocarditis can be produced
in normal animals by a single intravenous injection of bacteria
of suitable type and virulence; the incidence of endocarditis
is increased if the hearts of such animals are subjected to
increased workloads or the valves are traumatized during the
experiments. There is also the possibility that bacterial endo-
carditis can begin within the valve during septicemia, as has
been demonstrated by isolation of bacteria from the spongiosa
of pig valves.
Particular strains of Erysipelothrix rhusiopathiae can selec- B
tively adhere to the valvular endothelium of porcine heart
valves in vitro, with greatest numbers at the base of chordae Figure 1-34  Vegetative endocarditis in a dog. A. The valve leaflet
tendineae. The phenomenon of selective adherence has been is expanded by fibrin, inflammatory cells, and numerous bacterial
demonstrated for pathogens associated with other organ colonies. H&E. B. Gram’s stain highlighting numerous colonies in
system disease, notably staphylococci and streptococci in the vegetation (Erysipelothrix rhusiopathiae).
 31.e1

Begins at Valvular vegetations

lines of mostly composed
apposition of fibrin, few platelets
of valves and neutrophils

Some bacteria Bacterial colonies

selctively adhere embedded in the thrombi.
to valvular These may detach
endothelium to produce emboli

Infectious in origin
Valvular
Sustained or intermittent Healing of the
endocarditis
lesion occurs from
Bacteremia/fungemia the base by fibrosis
Parasitic [rarely]

eFigure 1-6  Major features of endocarditis.

32 CHAPTER 1  •  Cardiovascular System
mastitis and enterotoxigenic coliforms in colibacillosis. There
is also an immunologic cross-reaction between E. rhusiopath-
iae antigens and valvular and myocardial antigens. Various
Streptococcus spp. have been shown to adhere to exposed base-
ment membrane of porcine valves.
The lesion of acute bacterial endocarditis is usually
observed as irregular vegetations on the affected valve. It is
quite exceptional to find the earliest lesion, which consists of
irregular ulcerations on the swollen leaflet. The composition of
vegetations is similar to that of thrombi with, however, few
platelets. Numerous bacterial colonies are present in the vegeta-
tions, almost always in pure populations. It is wise to make
preliminary identification of the organisms by smears, because
although they persist in colonies buried in the vegetations,
they may not be cultivable. With the current techniques of
molecular biology, such as PCR, it should be possible to iden-
tify at least the genus of the noncultivable organisms embed-
ded in the thrombus. The bacteria that initiate the lesion are
enmeshed in the early layers of thrombi and are buried deeply
as new layers are formed on the surface. With continued
multiplication, many microscopic colonies are formed, and
without appropriate antimicrobial treatment, it is their per-
sistence in the protected environment that is the reason
healed bacterial endocarditis is seldom seen. Even though the
bacteria in the thrombi may lose their vitality, as indicated by
lack of cultivability, they are persistently antigenic.
Grossly, the vegetations are yellow-red or yellow-gray and
usually covered by a thin clot of blood, which can be easily
peeled off. The surface of the vegetation is friable, and small
vegetations can be easily removed to leave a granular, eroded
surface on the valve. The ulcerations are especially common
in the commissures and at the free margins of the valves,
imparting to them a rough, serrated appearance. The primary
valvular lesion frequently extends to the adjacent mural endo-
cardium and, in the cases of aortic valvular endocarditis, to
the adjacent aortic intima in the sinuses of Valsalva, which
may involve an orifice of a coronary artery, predisposing to
myocardial embolism. Endocarditis of the AV valves tends to
spread along the chordae tendineae, causing some of them  sion of aortic valvulitis into the right coronary artery and fis-
to rupture. Acute swelling and inflammatory change take
place in the substance of the valve itself, often with necrosis,
which obscures the line of partition between the valve and its
surface vegetation.
Organization of the thrombus proceeds from the base  fistula between the left ventricular outflow tract and the left
by the usual process of granulation, which is likely to be
impeded or destroyed by bacterial growth. Early scarification
in the deepest layers separates the thrombus from the  One of the more common forms of mural endocarditis
underlying myocardium and is frequently accompanied  occurs in renal failure in dogs. The lesion is confined, within
by mineralization.
Valvular endocarditis is commonly fatal, although resolution
may be complete if lesions are only minor. Clinical signs in
animals with endocarditis may only be detected late in the
disease, with the most common being pyrexia, lameness, and
cardiac murmurs. The frequency with which clinical signs are
observed is dependent on the husbandry conditions under
which the animal is kept. Other sequelae are those resulting
from valvular damage or embolism. Portions of the vegetations
may become detached and carried as emboli, to become
impacted in the vessels of other organs. Such emboli may be
either bland, that is, consist of thrombotic material only, or
septic, consisting of thrombotic material together with the enmeshed
infectious agent. Emboli arising in the right heart may produce
pulmonary abscesses or pulmonary thrombosis. These latter
Endocardial Disease
do not produce pulmonary infarcts in the absence of pre-
existing pulmonary congestion. Emboli arising in the left heart
produce their most obvious effects in the kidney and spleen
as septic or aseptic infarcts and embolic glomerulitis, and in
the myocardium as myocardial abscesses or interstitial myo-
carditis. Arthritis is commonly observed in association with
endocarditis in the dog. Cerebral embolism is rare in animals.
Unless the valvular lesions are very slight, there is, with
healing, some degree of permanent damage, especially if the
inflammation is recurrent. Shrinkage or adhesion of leaflets
may cause narrowing of the orifice (stenosis), or insufficiency
as a result of failure of the distorted valves to close the orifice.
Stenosis and insufficiency may coexist. The usual outcome is
congestive heart failure.
Mural endocarditis may be merely an extension to the
walls of the cardiac chambers of a process originating on the
valves. This is almost invariably true of endocarditis caused by
Trueperella pyogenes. Small foci of mural endocarditis may be
found adjacent to foci of myocarditis, especially myocardial
abscesses. Right or biventricular thrombosis in alpacas has
been associated with mural endocarditis and inconsistent iso-
lation of a causative agent. This suggests the possibility of a
fastidious organism as the cause, such as Bartonella spp. or the
possibility of an underlying cardiomyopathy.
Parasitic endocarditis caused by the larvae of Strongylus
vulgaris occurs in horses acutely in the form of vegetative
valvular endocarditis and chronically as caseous and calcare-
ous nodules attached to the endocardium at various sites,
including the apex of the left ventricle and protruding into
the cavity. There is, in the same cases, parasitic aortitis of the
bulb. With the advent of effective anthelmintics, parasitic
endocarditis in horses is rare.
An acute form of ulcerative mural endocarditis occurs in
cattle dying from blackleg, as red thrombotic masses attached
to the free wall of the right ventricle and, less often and less
extensively, on the right atrial and valvular endocardium.
Various unique intracardiac fistulae or shunts have been
reported as sequelae to endocarditis in dogs, including exten-
tulation into the right atrium; perforation of the membranous
interventricular septum, leading to a left ventricular outflow
tract–right atrial shunt (Gerbode defect) in a dog with severe
mural endocarditis caused by a Bordetella-like organism; and a
atrium adjacent to the mitral valve annulus in a dog with
Staphylococcus intermedius endocarditis.
the heart, to the left atrium, but similar lesions occur in the
large elastic arteries, being more frequent in the pulmonary
and aortic trunks immediately proximal to the valves, and less
frequently in the descending aorta and its major branches.
(The vascular lesions associated with renal failure are dis-
cussed under Diseases of the vascular system.) The endocar-
dial and major-arterial lesions are more common in acute 
than in chronic renal failure, insofar as these syndromes are
distinguishable.
The ulcerative atrial lesion, which is identical to the arterial
lesion, begins as a swelling of the interstitial spaces of the
subendocardium or intima of the arteries, with deposition of
glycosaminoglycans. Initially, the endothelium is intact and,
when viewed grossly in this stage, the endothelial surface is
seen to be raised slightly, finely wrinkled, and slightly opaque
Diseases of the Heart
Figure 1-35  Ulcerative atrial mural endocarditis of uremia in a
dog. (Courtesy Vasileios Psychas.)
but still shiny. The lesion may not progress farther than this
but, instead, heals with some fibrosis, which leaves areas of
uneven opacity. More usually, however, there is progression to
necrosis involving the cellular elements as well as collagen,
elastic, and reticulin fibers. The necrotic tissue ulcerates, and
the margin is densely infiltrated by leukocytes (Fig. 1-35). The
ulcerations may perforate the wall of the atrium. Thrombi, in
greater or lesser amounts, form on the ulcerated surface.
Heavy deposits of calcium salts often form in the degenerate
tissue. If renal sufficiency is re-established, the endocardial
lesion may heal leaving irregular patches of fibrosis with an
intact endothelium, often covering persistent white plaques
of mineralization. Other extrarenal lesions of uremia are con-
sidered in Vol. 2, Urinary system.
Further reading
Erol E, et al. Bartonella bovis isolated from a cow with endocarditis.
J Vet Diagn Invest 2013;25:288-290.
Firshman AM, et al. Thrombotic endocarditis in 10 alpacas. J Vet Intern
Med 2008;22:456-461.
Jarplid B, et al. Observations of apparent early valvular endocarditis in
swine. J Vet Diagn Invest 1997;9:449-451.
Malik R, et al. Vegetative endocarditis in six cats. J Feline Med Surg
1999;1:171-180.
Ohad DG, et al. Molecular detection of Bartonella henselae and Bar-
tonella koehlerae from aortic valves of Boxer dogs with infective
endocarditis. Vet Microbiol 2010;141:182-185.
Porter SR, et al. Vegetative endocarditis in equids (1994-2006). J Vet
Intern Med 2008;22:1411-1416.
Sykes JE, et al. Evaluation of the relationship between causative organ-
isms and clinical characteristics of infective endocarditis in dogs: 71
cases (1992-2005). J Am Vet Med Assoc 2006;228:1723-1734.
MYOCARDIAL DISEASE
Myocardial dysfunction can be the product of a wide variety
of agents and conditions (Table 1-5). This section deals with
the range of myocardial disease, from the more-or-less specific
myocardial conditions of degeneration, necrosis, hemorrhage,
Myocardial Disease 33
Table • 1-5 
Causes of myocardial dysfunction in
domestic animals
Infectious Viruses, chlamydiae, rickettsiae, bacteria, fungi,
protozoa, helminths
Toxic Ionophores (monensin, salinomycin,
maduramicin), catecholamines, antineoplastics
(cyclophosphamide, doxorubicin,
daunorubicin), doxycycline, gossypol,
saccharated iron, thallium, toxic plants
(many), insects (blister beetle [Epicauta])
Metabolic Hyperthyroidism, hypocalcemia
Nutritional Vitamin E-selenium, taurine (cats), copper,
deficiency thiamine
Genetic Porcine stress syndrome
Neuromuscular Muscular dystrophy
Storage Glycogen storage disease, amyloidosis
disorders,
other
depositions
Infiltrative Neoplasia (lymphoma, hemangiosarcoma)
Idiopathic Cardiomyopathy
and myocarditis, through idiopathic myocardial disease (cardio-
myopathy). The reaction of myocardium to insults is limited, and
includes the usual expressions of degeneration, necrosis,
inflammation, and healing. Acute changes, such as necrosis and
hemorrhage, will be discussed first. Given time to adapt to an
insult, a diseased myocardium may grossly take one of 2 con-
formations: dilated or hypertrophic. This classification is useful
conceptually, but is somewhat arbitrary, and individual cases
will often have features of more than one form, for instance,
the heart in a cat with hyperthyroidism will hypertrophy, but
it may eventually dilate and fail.
Hemorrhage of the heart and its membranes
Petechial and larger subepicardial hemorrhages are so common
in horses that die naturally that they are almost to be regarded
as normal. The incidence of hemorrhages in sheep and cattle
is somewhat lower; they are seldom seen in dogs and cats.
Subepicardial hemorrhages are common in instances of asphyxia
or death in anoxia, and in many acute infectious fevers. Larger
ecchymotic hemorrhages that may involve most of the epicar-
dium occur in the hemorrhagic diatheses.
Subendocardial hemorrhages have the same pathogenesis
but are considerably less common. Ecchymotic hemorrhages
beneath the endocardium of the left ventricle occur in
instances of acute cerebral injury and are useful as a diagnostic
indication of clostridial enterotoxemia in lambs and calves,
being present in a considerable proportion of cases.
Small interstitial capillary hemorrhages within the myocar-
dium accompany those within the subserosa. Deep myocardial
hemorrhages that do not extend to the serosa are commonly
present in pigs that die of asphyxia; they are distributed in the
wall of the right ventricle in the vicinity of the descending
coronary grooves. A remarkable degree of myocardial hemor-
rhage occurs in mulberry heart disease of swine (see Mulberry
heart disease of swine, later).
 33.e1

Further reading
Allen BL, et al. Streptococcus anginosus adheres to vascular endothe-
lium basement membrane and purified extracellular matrix pro-
teins. Microb Pathog 2002;32:191-204.
Bennett D, Taylor DJ. Bacterial endocarditis and inflammatory joint
disease in the dog. J Small Anim Pract 1987;29:347-365.
Bratberg AM. Immunological cross reactions of antigens of E. rhusio-
pathiae and heart tissue from swine. Acta Vet Scand 1981;22:46-
54.
Chomel BB, et al. Fatal case of endocarditis associated with Bartonella
henselae type I infection in a domestic cat. J Clin Microbiol
2003;41:5337-5339.
MacDonald KA, et al. A prospective study of canine infective endocar-
ditis in northern California (1999-2001): emergence of Bartonella
as a prevalent etiologic agent. J Vet Intern Med 2004;18:56-64.
Maxson AD, Reef VB. Bacterial endocarditis in horses: ten cases (1984-
1995). Equine Vet J 1997;29:394-399.
Pesavento PA, et al. Pathology of Bartonella endocarditis in six dogs.
Vet Pathol 2005;42:370-373.
Ramirez GA, et al. Left ventricular outflow tract-right atrial communi-
cation (Gerbode type defect) associated with bacterial endocarditis
in a dog. Vet Pathol 2003;40:579-582.
Smith AN, et al. Left ventricular outflow tract to left atrial fistula asso-
ciated with endocarditis in a dog. J Am Anim Hosp Assoc
2000;36:133-136.
Takahasi T, et al. Taxonomic evidence that serovar 7 of Erysipelothrix
strains isolated from dogs with endocarditis are Erysipelothrix ton-
sillarum. J Vet Med B Infect Dis Vet Public Health 2000;47:311-313.
Vasconcelos D, et al. Lesions caused by natural infection with Strepto-
coccus suis type 9 in weaned pigs. J Vet Diagn Invest 1994;6:
335-341.
34 CHAPTER 1  •  Cardiovascular System
Myocardial degeneration
Cardiac muscle is structurally similar to skeletal muscle and
is subject to the same anatomic types of degeneration. There
is, however, a greater liability for cardiac muscle to undergo
degeneration as a response to many nonspecific causes, prob-
ably related to its continuous activity. Diffuse nonspecific myo-
cardial degeneration occurs secondarily in a variety of systemic
diseases, especially infectious fevers, anemia, and toxemia.
Hydropic change, or vacuolar degeneration, of the myocar-
dium is characterized grossly by a dull gray appearance and
increased friability so that the myocardium is easily torn. On
cut surface, the muscle is smoother than normal, the outlines
of individual muscle bundles obscured.
Fatty change—the appearance of lipid vacuoles in myocyte
cytoplasm—is a more severe event than hydropic change, and
may be recognized grossly as uneven patches of pale yellow
myocardium. The process of fatty change is not uniform, and
it is sometimes possible to recognize, beneath the endocar-
dium, alternating bundles of fibers or strips of myocardium
more yellow than the remainder (“thrush-breast heart”). Both
hydropic change and fatty change are reversible forms of cel-
lular injury.
Atrophy of the heart occurs in chronic wasting diseases and
malnutrition. In some cases, the atrophy is accompanied by
dark pigmentation, and it is then called “brown atrophy.” It
should be recognized, however, that atrophy can occur without
pigmentation, and pigmentation can occur without atrophy.
Ruminants are principally affected by atrophy, brown or not,
and rarely does the atrophic heart produce clinical distur-
bance. The epicardial fat may be gelatinous, the endocardium
wrinkled, and myocardium brown and friable. Histologically,
the muscle fibers are thin, the nuclei small and dark, and
masses of brown pigment granules are present within second-
ary lysosomes at the nuclear poles. The pigment is lipofuscin
(“wear-and-tear pigment”), an oxidation product of unsatu-
rated lipids.
Xanthosis (xanthomatosis) refers to the abnormal lipofuscin
pigmentation of the myocardium and skeletal muscles seen in
cattle, particularly mature Ayrshire cows (see Vol. 1, Muscle
and tendon). Microscopically, lipofuscin is commonly seen at
the nuclear poles of cardiac myocytes in aged dogs and cats.
Mineralization occurs quite commonly in the myocardium,
and is to be expected whenever there is necrosis of fibers.
Calcium salts are selectively deposited in the Purkinje network
in organomercurial poisoning in cattle, in which the mineral-
ization is preceded by hyaline necrosis of the Purkinje fibers
and is followed by surrounding fibrosis.
Osteocartilaginous metaplasia of the right atrial myocar-
dium in sheep is a common incidental finding in adults, and
has been reported at a prevalence of ~10%. The foci of meta-
plasia are often palpable grossly, but may only be detectable
by radiography or microscopy. Histologically, the myocardium
of the atrial free wall contains trabeculae of lamellar bone that
are bordered by cartilage and chondroid matrix (Fig. 1-36).
The metaplastic regions are not associated with the os cordis
at the heart base.
Myocardial necrosis*
Focal to massive myocardial necrosis, or residual scars thereof,
is a common lesion in postmortem material. The causes are
*Contribution to the Myocardial necrosis section by Dr. R. McKenzie
is gratefully acknowledged.
Myocardial Disease
Figure 1-36  Osteocartilaginous metaplasia of the right atrium in
a sheep. The central aspect of the atrial free wall contains large
areas of mature lamellar bone and cartilage. H&E.
quite varied and part of a number of disease syndromes
described elsewhere in these volumes.
In infectious disease, the distinction between myocardial
necrosis and myocarditis with myofiber necrosis is somewhat
arbitrary—inflammatory cells will invade necrotic myocar-
dium; in acute myocarditis, inflammatory cells should be inti-
mately associated with necrotic myocardial cells, and adjacent
myocytes may appear normal. Necrosis predominates in
highly fatal foot-and-mouth disease in neonatal lambs, piglets,
and calves, whereas the residual lesions in older cattle qualify
as myocarditis with a significant inflammatory response. Ful-
minating infection by canine distemper virus in young puppies
is purely degenerative, whereas parvoviral and herpesviral
infections in the same age group contain elements of an
inflammatory response. Of the bacterial diseases, and except-
ing blackleg, Histophilus somni appears to be responsible for a
residual syndrome of sudden death in cattle with myocardial
necrosis or infarction, although in some cases myocardial
abscesses may be present.
Severe, often fatal, myocardial necrosis is typically part of
the important vitamin E and selenium-responsive syndromes
of nutritional myopathy of lambs, calves (Fig. 1-37A, B),
swine, and horses, and in mulberry heart disease of swine. 
It may also be seen as part of equine rhabdomyolysis and 
of capture myopathy and other exertional syndromes (see 
Vol. 1, Muscle and tendon).
Deficiency disease, additional to those that respond to
vitamin E and selenium, may include myocardial necrosis. It
occurs, although not invariably, in thiamine deficiency in car-
nivores, always as a single acute episode. Falling disease of
cattle in Australia and Florida is a syndrome of sudden death
believed to result from prolonged copper deficiency. Myocar-
dial scars accompany acute lesions, suggesting repetitive epi-
sodes and resembling the lesions of fluoroacetate poisoning in
cattle eating the gidgee plant, Acacia georginae, which is to be
distinguished from the nontoxic Acacia cambadgei (gidyea,
gidgee). In cats, taurine deficiency causes myocardial failure.
Toxic myocardial degeneration is common, and although
some examples are accompanied by degeneration of skeletal
muscle, they are described here. Injectable saccharated iron
compounds, by virtue of the capacity of iron to generate free
radicals in ferric/ferrous translations, cause fatal myocardial
Diseases of the Heart Myocardial Disease 35

B
A
Figure 1-37  Nutritional myopathy. A. Pale areas of myocardial necrosis in a lamb. (Courtesy
Vasileios Psychas.) B. Myocardial necrosis and mineralization of necrotic myocytes in a calf. H&E.

necrosis in piglets. Monensin, an ionophore that is widely used

as a coccidiostat and growth promotant in ruminants, may
contaminate compounded feeds for simple-stomached animals
and is cardiotoxic for horses and pigs (see Vol. 1, Muscle and
tendon for details of poisoning in other species). Also, rumi-
nants fed dried poultry litter containing the ionophores 
maduramicin or salinomycin develop severe cardiac myocyte
atrophy and interstitial fibrosis sufficient to result in clinical
signs of congestive heart failure. Myocardial necrosis occurs in
dogs ingesting rodenticides that contain thallium; these have
been widely replaced by warfarin analogues and calciferols.
Galenia africana (yellow bush or kraalbos) is a bushy
plant that is toxic to sheep and goats in South Africa, causing
a syndrome known as waterpens or waterbelly as ascites is a
prominent feature of this toxicosis. The toxin has not been
identified. Hepatotoxicosis appears to develop first, advancing
from dilation of central veins and sinusoids to centrilobular
and bridging fibrosis, with areas of coagulative necrosis. Myo-
cardial changes begin with myocyte hypertrophy and progress Figure 1-38  Extensive subendocardial hemorrhage in left ven-
to patchy degeneration and necrosis of myofibers and light tricle in oleander poisoning in a horse. (Courtesy S. Diab.)
fibrosis.
Plants that contain cardiac glycosides of both the bufadi- the observed clinical syndrome, and the presence of recogniz-
enolide and cardenolide types are of worldwide distribution. able plant parts in the ingesta. The cardiac glycosides are
Poisoning by bufadienolide cardiac glycoside–containing inhibitors of the sodium-potassium ATPase pump, which is
plants is the most important plant-associated poisoning of responsible for maintaining membrane ion concentrations and
livestock in southern Africa, and may be acute or chronic. the membrane potential of cardiac muscle fibers.
Acute poisoning is caused by plants of the family Iridaceae Chronic cardiac glycoside poisoning (“krimpsiekte”) is a
(“tulip”), for instance, Homeria pallida (the cape tulip), H. botulism-like, paretic condition of small stock that is caused by
miniata, Moraea polystachya, M. bipartita; family Liliaceae members of the family Crassulaceae (“plakkies”) that contain
(“slangkop”), for instance, Urginea sanguinea; and family San- cumulative bufadienolides, for instance, Tylecodon wallichii, T.
talaceae, for instance, Thesium lineatum (“witstorm”). As well, ventricosus, Cotyledon orbiculata, Kalanchoe lanceolata.
several species of Bryophyllum (synonym Kalanchoe) that Cardenolide cardiac glycoside—containing plants, for
occur in Madagascar and have been introduced to southern instance, Nerium oleander (common pink oleander), Cascabela
and eastern Africa, and Australia, for instance, B. tubiflorum thevetia (Thevetia peruviana, yellow oleander), of the family
and B. pinnatum, contain bufadienolides (bryotoxins A, B, C, Apocynaceae, are seldom eaten by livestock and are usually of
or bryophyllins). little veterinary importance. However, when ingested, typi-
In acute poisoning, death occurs within a few hours of cally as plant clippings mixed with other garden waste, their
ingesting the plant. Affected animals have cardiovascular positive inotropic effects on the heart can cause tachycardia,
(tachycardia, arrhythmia, heart block), gastrointestinal, respi- arrhythmias, and sudden death. Long-term exposure to olean-
ratory, and neuromuscular signs. Some cases may live for a few der can result in degeneration, fibrosis, and mononuclear cell
days and have scattered foci of myocardial necrosis, but usually infiltration of the myocardium (Fig. 1-38). Oleandrin, the
a diagnosis must be based on demonstrated access to the plant, responsible cardenolide, can be detected in blood or urine by
36 CHAPTER 1  •  Cardiovascular System
thin-layer chromatography or by high-performance liquid
chromatography/mass spectrometry (LC/MS). Summer
pheasant’s eye (Adonis aestivalis or Adonis microcarpa), which
contains cardenolides similar to oleander and foxglove (Digi-
talis spp.), causes endocardial and epicardial hemorrhage and
mild multifocal myocardial necrosis; strophanthidin, the agly-
cone of several cardenolides in Adonis, can be detected by LC/
MS in gastrointestinal contents from affected horses.
Not all acute cardiotoxicoses of botanical origin can be
ascribed to glycosides. Whereas chronic Phalaris spp. toxicosis
does produce interesting changes in the central nervous
system, the acute toxicosis is of much greater economic
importance as the cause of quick death in animals first exposed
to grazing on this pasture species. The acute toxicant in
Phalaris appears to be a tryptamine alkaloid, which may inter-
fere with the metabolism and action of serotonin and other
catecholamines. In sheep and cattle, Lantana camara causes
myocardial necrosis that might have an entirely different
pathogenesis, possibly dependent on reduced myocardial per-
fusion as a result of chronic reduction in circulating blood
volume. Poisoning by Cassia spp., including Cassia occiden-
talis (coffee senna), Karwinskia humboldtiana (coyotillo),
and Cicuta douglasii (western water hemlock), causes mus-
cular and myocardial necrosis in livestock. Vicia villosa (hairy
vetch) and V. benghalensis poisoning involves many organs,
including the heart. The lesions are unusual for a poisoning in
that there is a substantial chronic eosinophilic granulomatous
inflammatory response associated with the necrosis. Young
ruminants (before the rumen has developed), pigs, and dogs
are susceptible to the cardiotoxic effects of gossypol, a toxic
alcohol, when cottonseed meal is incorporated in their feed
as a protein supplement. Eupatorium rugosum (white snake-
root) causes myocardial and skeletal muscle damage through
the action of tremetol, another toxic alcohol. High erucic acid
rapeseed oil can cause myocardial degeneration and necrosis
in a variety of species; this effect has been mitigated by the
development of canola, which has low erucic acid content.
Acute selenium toxicosis resulting from the ingestion
of various selenium-accumulating plants, including certain
species of locoweed (Astragalus and Oxytropis), and western
aster (Symphyotrichum ascendens, formerly Aster ascendens),
occurs in horses, cattle, sheep, and pigs in China and western
North America. Cattle dying acutely had severe myocardial
necrosis, with some survivors developing severe myocardial
fibrosis and congestive heart failure. Selenium toxicity is
covered in detail in Vol.1 Integumentary system.
Cantharidin, the toxic principle in blister beetles (Epicauta
spp.), is thought to be the cause of gastric lesions, hemorrhagic
cystitis, enterocolitis, and myocardial necrosis in horses that
ingest the beetles in baled alfalfa hay.
Focal myocardial necrosis is also frequently observed as an
incidental finding on microscopic examination in many dis-
eases, and its immediate pathogenesis can seldom be ascer-
tained, but the lesions are thought to have an ischemic basis.
Ischemic myocardial necrosis occurs in thrombotic disease,
such as disseminated intravascular coagulation in the micro-
angiopathy of vitamin E/selenium deficiency, and in inflam-
matory vascular disease, such as periarteritis nodosa. Poor
myocardial perfusion may be the cause of the multifocal myo-
cardial necrosis seen occasionally in hypocalcemic parturient
dairy cows. The subendocardial necrosis seen following  Figure 1-39  Locally extensive infarct (pale areas) in apex of left
acute brain injury (“brain-heart syndrome”) may result from
coronary arterial spasm and/or catecholamine excess. Another
Myocardial Disease
example of catecholamine-induced myocardial necrosis is
that seen in cases of functional pheochromocytoma. The exact
mechanism(s) of catecholamine toxicosis is unknown, but
may involve a direct toxic effect, such as free radical damage
of myocyte membranes.
Coronary embolism is a relatively common cause of focal
myocardial necrosis, the emboli originating from vegetations
of left-sided endocarditis; septic emboli may result in myocar-
dial abscesses. In granulocytopenic diseases, bacterial embo-
lism may result in multiple minute myocardial infarcts, the
best examples being seen worldwide in bracken fern (Pterid-
ium spp.) poisoning in cattle. Myocardial infarction may occur
in polyarteritis (periarteritis nodosa and allied lesions).
Arteriosclerosis, although common in animals, is very
seldom severe enough to be responsible for ischemia of the
myocardium. In aged dogs, some degree of hyalinosis of the
intramural coronary arteries is frequently seen and may be
associated with, and presumably the cause of, myocardial
infarcts. This condition is called multifocal intramural myocar-
dial infarction (discussed later with Arteriolosclerosis). Hearts
that are dilated or hypertrophic are susceptible to focal necro-
sis of apparently random distribution, although larger lesions
are more obvious in the subendocardium of the left ventricle
and papillary muscles.
The gross and microscopic appearance of myocardial
necrosis is dependent on the interval between the initial insult
and death. Gross changes of necrosis are not readily apparent
until 12 hours after injury. By 18 to 24 hours, the affected
area, in which calcium salts may be deposited, is paler and
gray-brown (Fig. 1-39). The overlying serous membrane is
usually normal. Myocardial degeneration, mineralization, and
necrosis are most common in the subendocardial myocardium.
This area undergoes the greatest intramyocardial tension
during systole and is the most likely to be ischemic. However,
proliferative or thrombotic lesions completely occluding
vessels in these areas are rarely observed even with careful
technique. The common small foci of myocardial necrosis may
not be visible from the serous surface, and perhaps may be
recognizable only microscopically. The necrosis resulting 
from infarction will, if sufficiently large, involve the serosal
surfaces and produce fibrinohemorrhagic thickening of the
pericardium that may neatly overlie and indicate the infarcted
ventricle of a dog. (Courtesy University of Minnesota Veterinary
Diagnostic Laboratory.)
Diseases of the Heart
area. In cases dying within 24 hours, the pericardial reaction
may be the only indication grossly of infarction, the necrotic
muscle at this stage not being clearly altered or merely pale.
The necrotic area becomes more sharply defined by hyper-
emia by the second to fourth days. By the tenth day, there is
beginning replacement of the necrotic zone by fibrous
ingrowth. Replacement fibrosis is well established by the end
of the sixth week. A substantial, often transmural loss of myo-
cardium and replacement by fibrous tissue may lead to the
development of aneurysms of the ventricular wall.
Microscopically, lesions are not usually detectable for the
first 6-12 hours. However, ultrastructural changes are observed
within 1 hour. Recognition as early as 2 hours may be possible
using special stains, such as hematoxylin-basic fuchsin-picric
acid. Necrosis becomes apparent by routine stains after 12
hours (Figs. 1-40, 1-41). Subsequently, neutrophils infiltrate
Figure 1-40  Myocardial necrosis in a calf. Focal necrosis of
cardiac myocytes showing eosinophilia, loss of cross striations, and
absence of nuclei (arrowhead). Extensively mineralized necrotic
cardiac myocytes (arrow). Some normal cardiac myocytes remain
in lower portion. H&E.
Figure 1-41  Myocardial necrosis in a calf. Phosphotungstic acid
hematoxylin (PTAH) stain emphasizes the contraction bands
(collapsed sarcomeres) in the necrotic cardiac myocytes (arrow).
Normal cardiac myocytes (above and below arrow) have fine cross
striations of normal sarcomeres.
Myocardial Disease 37
the affected area, and the nuclei of the myocytes become
pyknotic. At this stage, macrophages are evident. Granulation
tissue appears at the periphery of the lesion toward the end
of the first week and usually predominates by the end of the
sixth week.
There are variations in the microscopic appearance of
myocyte necrosis, and some attempt has been made to associ-
ate the differing microscopic patterns with particular causes,
but these associations are not definitive. The first variant is
coagulative necrosis characterized by cellular swelling, nuclear
hyperchromasia, early loss of striations, and a “granular”
appearance of the myocyte. This type of change is observed
primarily in ischemic states. Coagulative myocytolysis is typi-
fied by the presence of thick, irregular, eosinophilic bands,
with an accompanying loss of striations and lightly staining
granular areas in myocytes. The bands are hypercontracted
sarcomeres (“contraction bands”) (see Fig. 1-41) and the light
granular areas are mitochondria. Evidence from experimental
models suggests that the alteration is the result of the excessive
release of endogenous catecholamines. However, this change
may be observed in normal myocardium if it is fixed imme-
diately after death. Colliquative myocytolysis appears as a loss
of striations, and homogeneous, weakly eosinophilic cyto-
plasm. The ultrastructural appearance is characterized by
intracellular edema, with disintegration of fibrils and other
organelles. Waviness of myocardial fibers is claimed by some to
be one of the earliest changes observed in myocardial infarc-
tion in humans. The affected fibers are not necrotic, but are
thinner and undulating in appearance. It is thought that the
waviness is due to irreversible stretching followed by compres-
sion of ischemic fibers by the surrounding viable myocardium.
Attenuated wavy fibers (<6 µm diameter, wavy appearance)
have been noted to be common in the myocardium of dogs
with dilated cardiomyopathy.
Anichkov (Anitschkow) cells, also known as “caterpillar
cells,” have been observed in myocarditis and a variety of natu-
rally occurring and experimentally induced myocardial necro-
ses. They are also seen in rheumatic fever in humans in
association with Aschoff bodies. Anichkov cells appear as large
mononuclear cells in which the nuclear chromatin is present
in an undulating wavy ribbon with slender processes radiating
from it (Fig. 1-42). The origin of these cells is in dispute. Sug-
gestions include a fibroblastic, pericytic, endothelial, or myo-
cytic origin. Depending on the theory accepted, the function
is either that of a macrophage or an abortive attempt at
cardiac myocyte regeneration.
A few of the more interesting examples of myocardial
degeneration and necrosis follow.
Fluoroacetate poisoning
Sodium fluoroacetate (compound 1080) is used extensively
in some parts of the world as a vertebrate pesticide, and espe-
cially as a rodenticide. It is also highly toxic for most domestic
mammals. The median lethal dose for most species is ~0.25-
1.00 mg/kg of body weight. Fluoroacetate is not directly toxic,
but becomes so when converted to fluoroacetyl–coenzyme A.
This compound is then combined with oxaloacetic acid to
form fluorocitrate. The citric acid cycle enzymes cis-aconitase
and succinic dehydrogenase are inhibited by fluorocitrate,
effectively inhibiting the production of adequate amounts of
adenosine triphosphate (ATP). Accidental poisoning by fluo-
roacetate occurs either by direct ingestion of the poison, or
indirectly, as when dogs eat poisoned rabbits.
38 CHAPTER 1  •  Cardiovascular System
Figure 1-42  Focal myocarditis (Aschoff body) characterised by
multinucleated giant cells (long arrow), lymphocytes, and some
cells with caterpillar nuclei (Anichkov cells, short arrow) in a dog.
H&E.
Fluoroacetate of plant origin is responsible for sometimes
devastatingly large episodes of poisoning of ruminants. Plants
known to accumulate fluoroacetate in lethal quantities for
ruminants are Gastrolobium spp. and Acacia georginae in
Australia, Dichapetalum spp. (gibflaar) in Africa, and Pali-
courea marcgravii in Brazil. Whether fluoroacetate has any role
in the physiologic economy of the plants is not known, but in
the case of A. georginae, there are differences in the develop-
ment of toxicity in the species. In D. cymosum, there are
seasonal differences, toxicity being greater in spring and
autumn, and especially in young leaves. Young leaves, includ-
ing sucker growth, and pods and seeds are more toxic than
the mature leaves of A. georginae.
The syndromes of intoxication vary with the species
affected but are either chiefly neurologic, as in dogs, which
become extremely excited and convulsive, or chiefly cardiac,
as in ruminants. Sheep may collapse suddenly and die within
a few minutes. Those less severely affected may develop car-
diorespiratory distress and weakness if driven, with death
supervening shortly thereafter. Some showing these signs, if
left undisturbed, may recover to appear normal until again
forced to exercise. The syndrome in cattle is the same as in
sheep, death occurring with cardiac failure, fibrillation, cyano-
sis, dyspnea, and terminal convulsions. Exercise, excitement,
or a large drink of water may precipitate clinical signs.
The postmortem findings in ruminants are referable to
myocardial injury. This may or may not be conspicuous,
depending on the size of the dose and the opportunity for
repeated episodes of poisoning. The concentration of fluoro-
acetate in D. cymosum is large, and histologic evidence of acute
myocardial injury is seen. In A. georginae poisoning, both acute
and chronic myocardial changes may be seen. There is some
flabbiness of the myocardium, with prominent hemorrhages
beneath the cardiac serosa. In acute cases, there are irregular
areas of myocardial pallor and mottling sometimes associated
with older scars. There is multifocal myocytolysis or hyaline
degeneration of the myocardial fibers, with intense infiltration
of mononuclear cells. Loss of sarcoplasm leaves an open mesh-
work of reticulum and vessels, which eventually condenses
and scars.
Myocardial Disease
Gousiekte
Gousiekte (“quick” disease) is a plant poisoning of ruminants in
southern Africa that is of great economic importance in that
region. The disease is characterized by acute heart failure 5-8
weeks after the ingestion of certain plants in the family Rubia-
ceae. Clinical signs are seldom seen in natural cases; animals
are usually found dead. A number of plants can cause the
disease, including Pachystigma pygmaeum, P. thamnus, P. latifo-
lium, Fadogia homblei, Pavetta harborii, and Pavetta schuman-
niana. Pavetamine is the water-soluble, heat-stable toxin
responsible for causing gousiekte.
Gross pathologic changes include generalized congestion,
ascites, hydropericardium, hydrothorax, and pulmonary edema.
Ventricular dilation is an inconsistent feature. However, the
ventricular walls are thinner and have a tough consistency. In
a small proportion of cases, the heart is macroscopically
normal. Microscopically, there is focal-to-extensive myofiber loss
with replacement fibrosis. The surviving myofibers may be atro-
phied, and groups of lymphocytes and macrophages may be
present in areas of fibrosis.
Avocado poisoning
Sheep and goats may die following the ingestion of fresh leaves
from some varieties of the avocado tree (Persea americana);
the active principle “persin” is a monoglyceride that has struc-
tural affinities with polyether ionophore antibiotics. Animals
may die suddenly after ingesting comparatively few leaves,
whereas others may show few ill effects. In those that die,
lesions consist of endocardial hemorrhage, especially of the
papillary muscles; hydropericardium; pale, flabby heart;
ascites; hepatic degeneration; and pale kidneys. Cardiac lesions
are those of cardiac myocyte necrosis and congestion and hem-
orrhage of variable severity. Although horses can be poisoned
following the ingestion of avocado leaves, it is not usually fatal.
Consumption of avocado leaves also results in depression
of milk production in lactating goats. The affected mammary
glands are edematous and reddened with clots in the large
ducts. The Guatemalan, but not the Mexican, variety of
avocado induces these changes in the mammary gland.
Taurine deficiency in cats
Taurine-deficiency myocardial failure (TDMF) in cats is a
primary systolic myocardial disorder associated with taurine defi-
ciency; many cases of feline dilated cardiomyopathy are actu-
ally examples of TDMF. Decreased systolic function results in
signs associated with decreased cardiac output giving rise to
bilateral congestive heart failure. End-diastolic ventricular
volume and pressure are increased, as are atrial volume and
pressure.
Taurine (2-aminoethane sulfonic acid), an essential amino
acid for cats, is abundant in fresh meat, but must be supple-
mented in commercial feline diets to prevent the develop-
ment of TDMF, central retinal degeneration, and developmental
abnormalities in kittens. Taurine is required in myocardium
for the modulation of tissue calcium influx through cardiac
calcium channels. Taurine supplementation will restore myo-
cardial function to normal in most cats with low plasma
taurine levels and echocardiographic evidence of cardiac
chamber dilation and myocardial failure. Cats, and other
mammals, have an obligatory need to conjugate bile acids with
taurine or glycine; cats not only have a limited capacity to
synthesize taurine, but are unable to use glycine for bile acid
conjugation.
Diseases of the Heart
As the syndrome is now well recognized, cats are  myocardial muscle. The development of PSS is intimately
unlikely to die of TDMF. In cats that do die, gross and histo-
logic cardiac lesions are as described later for feline dilated
cardiomyopathy.
Myocardial necrosis secondary to neural injury
The effect of the central nervous system on the myocardium
is mediated by the autonomic nervous system and, in particu-
lar, the sympathetic nervous system. The heart is richly inner-
vated with autonomic fibers, and myocytes, particularly
ventricular myocytes, have high concentrations of β receptors.
Both the rate and inotropic state of the heart are stimulated
by catecholamines. In a number of species, the continuous
administration of norepinephrine for 1-2 weeks results in focal
myocardial necrosis. Multifocal myocardial necrosis may
develop in dogs with paroxysmal tachycardia resulting from
functional pheochromocytomas. Also, experimentally induced
intracranial hemorrhage produces focal myocardial necrosis,
which can be prevented by prior administration of either
reserpine, a catecholamine-depleting drug, or propanolol,
which blocks β receptors.
Multifocal myocardial necrosis occurs in dogs, horses, cows,
sheep, pigs, goats, and wildlife in association with neurologic
disease of diverse origin (“brain-heart syndrome”), from exter-
nal trauma to infectious disease. The primary lesion may
involve the head, central nervous system, or major nerve plex-
uses. The microscopic appearance of the myocardial lesions is
dependent on the time elapsed between insult and death. It
varies from acute myocardial degeneration and necrosis to
almost complete resolution by fibrosis. There are, no doubt, a
number of cases with no gross or microscopic lesions where
insufficient time elapsed between the onset of clinical signs
and death. The findings of multifocal myocardial necrosis on
autopsy in any species should alert the pathologist to examine the
central nervous system for abnormality. Secondary multifocal
myocardial necrosis also occurs in dogs with gastric torsion,
and in dogs and cats with acute necrotizing pancreatitis and
septic peritonitis.
Doxorubicin (Adriamycin) cardiotoxicosis
Doxorubicin, an antineoplastic agent of the anthracycline
antibiotic group, is used in the treatment of lymphoma and
other neoplasia in dogs; cardiotoxicosis is the major factor limit-
ing its use. Acute cardiotoxicosis appears to be mediated by
peroxidative injury or expression of cytokines. As well, binding
of doxorubicin to nuclear and mitochondrial DNA causes
blockage of DNA, RNA, and protein synthesis. Chronic doxo-
rubicin cardiotoxicosis, which may be due to decreased protein
synthesis as well as altered divalent cation concentration,
occurs in dogs given cumulative doses. Congestive heart
failure occurs in such dogs; microscopic myocardial changes
consist of myocytic vacuolar degeneration (“adria cells”), myo-
cytolysis, myofibril atrophy, and fibrosis. The cardiotoxicity of
doxorubicin is reduced when administered as a pegylated
liposomal form.
Porcine stress syndrome (pale, soft, and exudative
[PSE] pork)
Porcine stress syndrome (PSS) is primarily a disease of skeletal
muscle (see Vol. 1, Muscle and tendon). A single nucleotide
mutation, HAL-1843, in the ryanodine receptor 1 increases the
susceptibility 4-fold to PSS, but pigs without the mutation can
also develop the disease. The mutation is not expressed in
Myocardial Disease 39
associated with stocking density, transportation time, and
other antemortem stressors. Death from PSS may occur as a
result of peracute heart failure secondary to the metabolic and
hormonal sequelae of PSS, namely, acidosis, hyperkalemia,
hyperthermia, and hypercatecholemia. The latter may produce
myocardial necrosis. Sudden death caused by cardiac failure
also occurs in sows, both with and without association with
the PSS gene mutation.
Clinically, affected pigs exhibit muscular tremor, dyspnea,
hyperthermia, and cutaneous blanching and erythema. Death
quickly ensues. Typical autopsy findings include the rapid
development of rigor, pulmonary edema, hydropericardium,
and splanchnic congestion. In some, there is epicardial and
endocardial hemorrhage with irregular areas of pallor in the
left ventricular myocardium. The presence or absence of myo-
cardial necrosis in PSS is a major difference between the
European and North American descriptions of the disease.
Myocardial necrosis is a common finding in European cases.
When present, the necrotic areas are prominent in the inner
third of the wall and papillary muscles. The microscopic
appearance of the necrotic fibers is characterized by loss of
the normal striation pattern, the presence of contraction
bands, and fine granulation of the sarcoplasm.
A variant of PSS associated with a mutation in the dystro-
phin gene, and markedly decreased expression of dystrophin in
both cardiac and skeletal myocytes has been recently described.
Mulberry heart disease of swine
The name “mulberry heart” is vaguely suggested by the exten-
sive hemorrhages on the surface of the heart, and its major fea-
tures are depicted in eFigure 1-7. The disease occurs in pigs
only, chiefly those 2-4 months of age and in excellent condi-
tion, but it has been observed in animals from 3 weeks to 4
years of age. Among old pigs, the incidence is sporadic, but in
young pigs, it occurs in short, snappy outbreaks. In most cases,
typically affected animals are found dead. The circumstances
of sudden death combined with the gross and microscopic
lesions strongly suggest that the affected animals die of acute
heart failure following the development of ventricular dys-
rhythmias (Figs. 1-43, 1-44). Despite the associated gross and
microscopic findings, mulberry heart disease is generally a
diagnosis of exclusion; this is particularly the case today when
Figure 1-43  Severe epicardial hemorrhage with excess pericar-
dial fluid containing fibrin strands in mulberry heart disease in a
pig. (Courtesy R.W. Cook.)
 39.e1

MULBERRY HEART DISEASE

Most probable cause-increased
metabolic demand for vitamin E

Gross Pathology Clinical Presentation

Hydrothorax, hydropericardium Most commonly occurs as short
Epicardial hemorrhage[mulberry heart] outbreaks in pigs 2-4 months of age
Myocardial necrosis[sometimes] Can occur sporadically in pigs of any age
Leukoencephalomalacia in some survivors

Histopathology
Myocardial necrosis
Widespread fibrinoid necrosis of arteriolar walls
Hyaline thrombi, disruption of endothelium
Leukoencephalomalacia

eFigure 1-7  Major features of mulberry heart disease.

40 CHAPTER 1  •  Cardiovascular System
Figure 1-44  Extensive necrosis of myocardium (pale areas) with
hemorrhage in mulberry heart disease. (Courtesy M. Culhane.)
extensive arrays of molecular diagnostic tests are often
available.
Raising weanling piglets on a diet deficient in selenium and
vitamin E can regularly reproduce the disease. Such animals may
develop disease within 2 weeks. As discussed with diseases of
muscle (in Vol. 1, Muscle and tendon), selenium is an integral
part of the membrane enzyme glutathione peroxidase, which
reduces toxic lipid peroxides to hydroxy acids. Vitamin E is
an antioxidant and acts synergistically with selenium to protect
membranes from high concentrations of lipoperoxides. Field
studies, particularly from the Scandinavian countries, have
shown that although dietary selenium supplementation mark-
edly reduces the incidence of hepatosis dietetica and nutri-
tional myopathy, the prevalence of mulberry heart disease
remains the same. It is also evident that tissue levels of sele-
nium, particularly those in the heart and liver, are within the
normal range. It is now considered that vitamin E deficiency
plays a central role in the development of mulberry heart disease.
However, there is not universal agreement on this. Although
some studies show lower tissue levels of vitamin E in affected
pigs, others show no difference. Additionally, it has been sug-
gested that the disease is the result of altered vitamin E
metabolism and not a consequence of inadequate dietary
vitamin E levels. It may be that mulberry heart disease is
precipitated following a lack of bioavailability of vitamin E in
tissues, or possibly a greater requirement for vitamin E under
certain dietary circumstances, such as diets containing large
amounts of unsaturated fat.
Animals dying of mulberry heart disease are always in
excellent body condition. There may be slight cyanosis of the
ears and ventral abdomen, and exophthalmos, the latter result-
ing from orbital and palpebral edema. The intermuscular con-
nective tissues are usually wet, and there may be obvious
edema, especially in the axillary and inguinal regions and near
the xiphoid process. The skeletal muscles are normal.
The principal gross lesions occur in the thorax. Some 50 mL
or more of heavy, straw-colored fluid that clots on exposure
to air is invariably present in the pleural cavity. The lungs are
edematous and slightly or severely congested, but not severely
enough to account for the degree of edema. The pericardium
is edematous and opaque and is always acutely distended with
fluid transudate. Either heavy strands or a lace of fibrin float
Myocardial Disease
Figure 1-45  Focal cerebrocortical leukomalacia (arrows) in mul-
berry heart disease. (Courtesy R.W. Cook.)
in the fluid. The fibrin is not fixed to the serous surface and,
from where it is in contact with the epicardium, it can easily
be lifted off to reveal a clean, glistening, serous membrane.
Hemorrhages, linear and ecchymotic, are present beneath the
epicardium. They may be few, or they may be extensive and
involve the epicardium of all chambers, the myocardium, and
beneath the endocardium of the papillary muscles and septum.
In some, multiple pale streaks and patches of necrosis extend
from the epicardial surface into the myocardium. There may
be similar lesions visible from the endocardial surface.
The abdominal cavity contains a small volume of clear
transudate and some fine unattached strands of fibrin on the
intestine. The stomach usually contains a mass of dry feed, 
and its fundic mucosa is diffusely congested. The small intes-
tine is empty and dry, with serosal vessels congested. The liver
is congested, sometimes markedly so, with edema of the 
wall of the gallbladder. In some animals that survive 24 
hours or more, there is bilaterally symmetrical softening of the
white matter forming the cores of the cerebral gyri. The soften-
ings are visible grossly as gray, translucent, depressed areas
studded with tiny hemorrhages that are sometimes confluent
(Fig. 1-45).
Microscopically in acute deaths, degeneration of myofibers
may be minimal or absent. In these cases, there is merely
subserosal edema, with some plugging of lymphatics by fibrin,
and interstitial hemorrhage. In others, which are probably less
acute cases, there are substantial areas of myocardial necrosis
(Fig. 1-46). The extent of mineralization of the necrotic fibers
varies, but never appears to be as severe as that seen in lambs
or calves with nutritional myopathy.
The second prominent lesion, which is most probably unrelated
to the myocardial necrosis, is observed in arterioles of many
organs. The change is seen in the heart, kidneys, liver, stomach,
intestine, mesentery, skeletal muscle, and skin. There appears
to be gradation in the severity of change, from endothelial
swelling with increased permeability, to necrosis of smooth
muscle cells of the media. The basic appearance includes the
accumulation of fibrinoid in arteriolar walls, formation of hyaline
thrombi, disruption of endothelium, and necrosis of smooth muscle
cells. Periodic acid–Schiff (PAS) staining of affected arterioles
emphasizes the accumulation of fibrinoid. The lungs show
congestion and edema only. There is congestion and edema of
Diseases of the Heart
Figure 1-46  Myocardial hemorrhage with necrosis and mineral-
ization of myocardiocytes in mulberry heart disease. H&E.
the liver, associated in some cases with central necrosis in the
lobules. Proteinaceous fluid produces focal detachments of the
retina and intercapillary edema of the glomerular tufts.
The development of the cerebral lesions can be correlated
roughly with the duration of the clinical illness. In the majority
of cases, where death occurs suddenly, there is no microscopic
change in the brain, or merely some slight venous congestion
and edema of the cortical white matter. In pigs that live for
some hours, there is edematous separation of the fiber tracts
of the white matter of the frontal cortex, with acute swelling
and fragmentation of oligodendroglia. The overlying gray
matter is edematous. In animals that survive for 24 hours or
more, it is usual to find severe lysis of the white matter in the
cerebrum, which is more or less extensive but usually avoids
the internal capsule, corpus medullare, and association fibers.
The cores of the gyri of the frontal lobes are most consistently
and severely involved, but in some cases, all portions of the
cerebrum are involved, and in these, there may be similar
lesions in the thalamus and brainstem. The vessels, venules
especially, in the degenerate areas are severely injured and may
be totally necrotic, although more frequently, there is only
endothelial and adventitial swelling and proliferation. Hyaline
thrombi are formed in many vessels, and droplets of similar
character form in the perivascular spaces. The overlying gray
matter is edematous. The vessels are hypertrophic and cuffed
by adventitial cells and a few eosinophils. In a few cases,
degenerate foci are also present in the cerebellum; these
involve the molecular layer with foci of softening or narrow
sheets of hemorrhage.
The lesions in mulberry heart disease depend on the length
of time pigs survive after the initial damage occurs. Most pigs
die from ventricular dysrhythmia, and those that die immedi-
ately no doubt have substantial areas of myofiber death, but
there has been insufficient time for the morphologic manifes-
tations of the necrosis to appear. A period of 6-12 hours must
elapse before myofiber necrosis can be reliably recognized.
After that, the lesions become increasingly evident and prog-
ress through stages to replacement fibrosis of the necrotic
areas if the pig survives.
In the experimentally induced disease, serum enzyme
levels indicative of myocardial damage may be raised for up
to 21 days before death. The extent of cardiac damage is
related to the length of time the serum enzymes are raised or,
Myocardial Disease 41
alternatively, to a large increase over a shorter period. The
microangiopathy prominent in this disease probably occurs inde-
pendently of the myofiber necrosis. It is also nonspecific, as the
same change is seen in many porcine viral infections and
bacterial toxemias. It is, however, a useful indicator of the
presence of mulberry heart disease.
Further reading
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Ganote CE. Contraction band necrosis and irreversible myocardial
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Kellerman TS, et al. Plant Poisonings and Mycotoxicoses of Livestock
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Panciera RJ, et al. Hairy vetch (Vicia villosa Roth) poisoning in cattle:
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Reiner AC, et al. Oleander toxicosis in equids: 30 cases (1995-2010).
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in pigs diagnosed with mulberry heart disease and evidence for viral
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Myocarditis, or inflammation of the myocardium, is a common
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42 CHAPTER 1  •  Cardiovascular System Myocardial Disease

Table • 1-6 
Causes of myocarditis in domestic animals
Viruses Canine herpesvirus, canine parvovirus 2,
encephalomyocarditis virus, equid herpesvirus 1,
foot-and-mouth disease virus, murid herpesvirus
(murine cytomegalovirus), porcine circovirus 2
and/or porcine parvovirus (in postweaning
multisystemic wasting syndrome [PMWS]),
pseudorabies virus, West Nile virus
Bacteria Actinobacillus equuli, Actinobacillus suis,
Bartonella vinsonii, Borrelia burgdorferi (Lyme
disease), Clostridium chauvoei, Histophilus
somni, Leptospira spp., Streptococcus suis,
Neorickettsia (Ehrlichia) risticii
Protozoa Neospora caninum, Sarcocystis, Toxoplasma
gondii, Trypanosoma spp.
Helminths Trichinella spiralis A

number of specific parasitic infestations also produce myocar-

ditis. Effectors of the immune and inflammatory responses in
myocarditis can have numerous deleterious effects on the
myocardium: cytolytic T lymphocytes can produce focal
cardiac myocyte necrosis; activated lymphocytes and macro-
phages can release a host of inflammatory cytokines that can
lead to altered cardiac myocyte metabolism, decreased con-
tractility, and dysrhythmias, and to increased matrix and myo-
cardial fibrosis. Death resulting from myocarditis may occur
acutely because of dysrhythmia where inflammation is often
focal and can be missed grossly. Nonfatal cases of myocarditis
may progress to congestive heart failure, subsequent to exten-
sive cardiac myocyte loss and fibrosis.
Pyogenic bacteria, which may originate from any other sup- B
purative focus in the body or, as in the case of Listeria mono-
Figure 1-47  Myocarditis. A. Myocardial blackleg (Clostridium
cytogenes and Actinobacillus equuli, produce foci of acute
chauvoei) with myocardial necrosis and hemorrhage in right ven-
suppurative myocarditis that may develop into abscesses with
tricular free wall, in an ox. (Courtesy S. Diab.) B. Multifocal to
inevitable destruction of the involved tissue (eFig. 1-8). In
coalescing myocarditis in ventricle wall, caused by Blastomyces
these, it is often possible to demonstrate bacterial emboli.
dermatitidis in a dog. (Courtesy M. Bouljihad.)
Clostridium chauvoei may produce necrotizing myocarditis
similar to the typical lesion in skeletal muscle (Fig. 1-47A).
Tuberculous myocarditis is rare, and when present, the granu-
lomatous reaction is typical of the species. Occasionally, fungal fibers vary widely in extent and in the severity of degeneration.
organisms can cause multifocal pyogranulomatous lesions (Fig. The cause may sometimes be apparent in the histologic nature
1-47B). Bartonella henselae is being increasingly recognized as of the lesion, as, for example, in malignant catarrhal fever of
a cause of both pyogranulomatous myocarditis and endocar- cattle, in which inflammation is centered on the blood vessels.
ditis in cats. An additional feature of this disease is myositis In toxoplasmosis, the degeneration of myocytes predominates
involving muscles of the diaphragm. over the inflammatory reaction and the organism is identifi-
Necrobacillary myocarditis occurs in cattle secondary to able. In most cases of interstitial myocarditis, however, diagnosis
extensive necrobacillosis in other tissues; the necrosuppura- of the cause can only be made by reference to the total pathologic
tive reaction is typical for the organism. Other bacterial causes picture. Only infrequently can death be attributed to the myo-
of suppurative myocarditis include Clostridium piliforme cardial lesions, and then only when considerable degeneration/
(Bacillus piliformis) and Citrobacter koseri. There is also exten- necrosis of the myocardial fibers has occurred, as in foot and
sive myocarditis in some systemic mycoses, such as Aspergillus mouth disease of young animals. Some other viral infections,
terreus in dogs, particularly the German Shepherd dog. such as canine parvovirus infection and encephalomyocarditis
Less specific interstitial myocarditis occurs in many infectious virus infection, are exceptions to this general principle.
diseases and is not detectable grossly. The basic pattern is usually Myocarditis is seen in systemic viral infections, such as
the same, the reaction being centered on the interstitial and canine distemper, canine herpesviral infection, and pseudora-
perivascular connective tissues, with edema and infiltration of bies in piglets and dogs. The myocarditis caused by canine
lymphocytes, plasma cells, macrophages, and some eosino- parvovirus 2 infection (Fig. 1-48) is discussed in Vol. 2, Ali-
phils. Neutrophils are few. The changes in the myocardial mentary system and peritoneum.
 42.e1

eFigure 1-8  Embolic suppurative myocarditis, caused by Trueper-

ella pyogenes, in a lamb. Multiple abscesses, one of which has
encroached upon and caused thrombosis in a coronary artery
(arrow).
Diseases of the Heart
Figure 1-48  Unusually severe parvoviral myocarditis (pale areas)
in a dog. (Courtesy D. Hayden.)
Myocarditis is part of a number of important and wide-
ranging clinical and pathologic syndromes in porcine fetuses,
stillborn piglets, and young piglets. These include postweaning
multisystemic wasting syndrome (PMWS), porcine dermatitis
and nephropathy syndrome (PDNS), and reproductive failure
caused by porcine circovirus 2; porcine reproductive and
respiratory syndrome (PRRS) caused by the PRRS arterivirus;
and porcine myocarditis syndrome (PMC) caused by the
novel Bungowannah pestivirus (see Vol. 3, Female genital
system).
“Eosinophilic myocarditis” is so called because the reaction
to sarcocysts is predominantly by eosinophils, which produce
the typical, small, green to gray-green foci observed occasion-
ally in cattle at routine meat inspection. This syndrome is not
to be confused with the eosinophilic myocarditis present in
cases of poisoning by ingestion of hairy vetch (Vicia villosa).
Atrial myocarditis is an infrequently reported entity of
undetermined cause in dogs that manifests clinically as an
arrhythmia (sinoatrial arrest, supraventricular tachyarrhyth-
mias). Lesions are confined to the atria and can vary from  organs, with the myocardium exhibiting the highest titer of
a lymphocyte predominant infiltration to extensive fibrosis
(Fig. 1-49).
Encephalomyocarditis virus infection
There are 3 members of the genus Cardiovirus in the family
Picornaviridae, and the type species is Encephalomyocarditis
virus (EMCV). All species are antigenically related and by
most tests are indistinguishable from each other. EMCV can
infect humans and other mammals, principally swine and sub-
human primates. Rodents, in which it appears to be clinically
inapparent and behaves as an enterovirus, may act as reservoir
hosts, but infection in laboratory rodents commonly produces
fatal encephalitis or myocarditis. The source of infection in
outbreaks of myocarditis in swine is thought to be through
consumption of feed or water contaminated with virus from
rats or other rodents. Ingestion of diseased rodent carcasses is
also a likely source of infection. Experimental transmission of
disease to swine has been accomplished by feeding the virus,
Myocardial Disease 43
Figure 1-49  Focally extensive myocarditis of the right atrium in
a dog.
but susceptible pigs kept in close contact with infected pigs
did not develop disease.
Sudden death or death following a brief period of excita-
tion and collapse characterizes the clinical disease in the per-
acute form in swine. In less severe cases, there may be fever,
anorexia, and progressive paralysis. The mortality rate is vari-
able. At autopsy, there is hydrothorax, hydropericardium,
ascites, and pulmonary congestion and edema. In severe cases,
there is extreme pallor of the ventricles, with yellow-to-white
foci 2-10 mm in diameter throughout the myocardium. In less
severe cases, gross lesions are minimal to absent. Microscopi-
cally, the dominant lesions are focal-to-diffuse myocardial
necrosis. Patchy mineralization of necrotic areas is evident,
accompanied by a mononuclear inflammatory reaction that
varies greatly in intensity. Survival allows fibrous scarring to
develop. There is little evidence of encephalomyelitis. EMCV
infection has also been associated with reproductive failure
characterized by mummified fetuses and stillbirth, as well as
failure of conception and early embryonic deaths. Fetuses that
die toward the end of gestation have multifocal myocardial
necrosis.
Experimentally infected swine may die between 2 and 11
days postinoculation. Virus is present in the feces for 7-9 days
following oral administration and may be isolated from all
virus. The virus titer falls rapidly and may not be found in
cases that have been infected for 11 days or more. Experimen-
tal inoculation of mice regularly produces both encephalitis
and myocarditis. Strains of EMCV may be adapted to produce
either encephalitis or myocarditis.
Parasitic myocarditis
The parasites that tend to localize in the myocardium are the
same as those that have an affinity for skeletal muscle. Parasites
without such affinity may also be found in the myocardium
in the course of their wanderings, especially if they are migrat-
ing in an abnormal host or in unusually large numbers in the
normal host.
Of those parasites with an affinity for cardiac and skeletal
muscle, the ubiquitous sarcocysts are the most common (see
Vol. 1, Muscle and tendon). The finding of myocardial sarcocysts
is very common in ruminants. This increases with the age of
the animal and implies a previous acute sarcocystosis in which
44 CHAPTER 1  •  Cardiovascular System
schizonts are formed in endothelial cells, usually with little
effect. The sarcocysts may be found in the cardiac conducting
fibers as well as myocardial fibers and normally appear to be
harmless. The multifocal eosinophilic granulomatous reaction to
degenerating Sarcocystis cruzi cysts may occur alone or in
association with similar lesions of eosinophilic myositis in
skeletal muscles. Degenerate cysts are occasionally visible
within foci of myocarditis. The cyst content is highly toxic,
but whether degeneration or rupture of the cyst is primary or
is secondary to some other cause of focal myocardial degen-
eration is unknown.
A rather severe myocarditis in dogs caused by the protozoal
parasite Neospora caninum is seen in association with myositis
and encephalomyelitis. Affected dogs vary in age from 2 days
to 7 years and may be presented with hindlimb paresis or
ataxia, skeletal muscle atrophy, and in some cases, sudden
collapse attributable to dysrhythmias induced by the myocar-
ditis. The differentiation of Neospora caninum from Toxo-
plasma gondii in paraffin-embedded tissue is best accomplished
by the use of immunohistochemistry. Additionally, Neospora
caninum is commonly associated with bovine abortion.
The various cysticerci of Taenia ovis, T. saginata, T. solium,
and hydatid cysts are frequently found in the myocardium,
which is one of their sites of predilection (eFig. 1-9). These
parasites are described with parasitic diseases of the intestine
(see Vol. 2, Alimentary system and peritoneum), which is the
habitat of their definitive stage.
Trichinella spiralis is described with diseases of muscle in
Vol. 1, Muscle and tendon. However, it is worth noting here
that the larvae of this parasite invade the myocardium,  Pathol 2003;129:161-168.
but are seldom found there, either because they continue  Rosa FA, et al. Cardiac lesions in 30 dogs naturally infected with Leish-
their migration or are destroyed. The myocardial reaction is a
severe interstitial myocarditis, with basophilic degeneration
and necrosis of fibers in the areas of inflammation.
The pyogranulomatous myocarditis caused by Trypano-
soma cruzi (Fig. 1-50) is described in Vol. 3, Hematopoietic
system. Leishmania infantum chagasi also causes a lympho-
plasmacytic and less commonly a granulomatous myocarditis
in dogs. In Africa, myocarditis can occur in dogs infected with
Trypanosoma brucei, and in cattle infected with T. congolense
or T. vivax.
Figure 1-50  Lymphoplasmacytic myocarditis (Chagas disease)
caused by Trypanosoma cruzi in a dog. Note the amastigote-
containing pseudocyst in a cardiac myocyte. H&E. (Courtesy B. F.
Porter.)
Myocardial Disease
Further reading
Allan GM, Ellis JA. Porcine circoviruses: a review. J Vet Diagn Invest
2000;12:3-14.
Chand RJ, et al. Pathogenesis of porcine reproductive and respiratory
syndrome virus. Curr Opin Virol 2012;2:256-263.
Cruz-Chan JV, et al. Immunopathology of natural infection with Try-
panosoma cruzi in dogs. Vet Parastiol 2009;162:151-155.
Finlaison DS, et al. Field and laboratory evidence that Bungowannah
virus, a recently recognized pestivirus, is the causative agent of the
porcine myocarditis syndrome (PMC). Vet Microbiol 2009;136:259-
265.
Finlaison DS, et al. Experimental infection of the porcine foetus with
Bungowannah virus, a novel pestivirus. Vet Microbiol 2010;144:
32-40.
Guedes PM, et al. Development of chronic cardiomyopathy in canine
Chagas disease correlates with high IFN-gamma, TNF-alpha, and
low IL-10 production during acute phase infection. Vet Immunol
Immunopathol 2009;130:43-52.
Haines DM, et al. Immunohistochemical study of Hemophilus somnus,
Mycoplasma bovis, Mannheimia haemolytica, and bovine viral diar-
rhea virus in death losses due to myocarditis in feedlot cattle. Can
Vet J 2004;45:231-234.
MacInnes JI, Desrosiers R. Agents of the “suis-ide diseases” of swine:
Actinobacillus suis, Haemophilus parasuis, and Streptococcus suis.
Can J Vet Res 1999;63:83-89.
Papaioannou N, et al. Pathogenesis of encephalomyocarditis virus
(EMCV) infection in piglets during the viraemia phase: a histo-
pathological, immunohistochemical and virological study. J Comp
mania infantum chagasi. Vet Pathol 2014;51:603-606.
Segales J. Porcine circovirus type 2 (PCV2) infections: clinical signs,
pathology and laboratory diagnosis. Virus Res 2012;164:10-19.
Snijder EJ, et al. Arterivirus molecular biology and pathogenesis. J Gen
Virol 2013;94:2141-2163.
Varanat M, et al. Identification of Bartonella henselae in 2 cats with
pyogranulomatous myocarditis and diaphragmatic myositis. Vet
Pathol 2012;49:608-611.
Warman S, et al. Dilatation of the right atrium in a dog with polymyo-
sitis and myocarditis. J Sm Anim Pract 2008;49:302-305.
Woolley R, et al. Atrial myocarditis as a cause of sinus arrest in a dog.
J Small Anim Pract 2007;48:455-457.
Cardiomyopathies
The term cardiomyopathy was originally coined for a group
of human myocardial diseases in that were of unknown or
obscure cause. Cardiomyopathies are now well-defined clini-
copathologic entities that have been increasingly shown to be
either genetically determined abnormalities of myocardial
contractile, cytoskeletal or mitochondrial proteins, or respon-
sive to substances such as taurine and carnitine. Initially, a
diagnosis of cardiomyopathy was arrived at by the absence of
common causes of heart failure and the presence of abnor-
malities not readily explained. In humans, where cardiomy-
opathies were first recognized, there must be absence of
significant coronary arterial disease; vascular disease or anomaly;
systemic hypertension, past or present; and vascular shunts inside
or outside the heart. Features usually present include cardio-
megaly, either as dilation or hypertrophy; mural thrombosis,
usually in the left ventricle; and, fibrosis or other lesions indicative
of generalized myocardial involvement.
 44.e1

eFigure 1-9  Parasitic myocarditis. Mineralized foci of degenerate

Cysticercus ovis in a lamb.
44.e2

Further reading
Agungpriyono DR, et al. Subacute massive necrotizing myocarditis by
canine parvovirus type 2 infection with diffuse leukoencephaloma-
lacia in a puppy. Vet Pathol 1999;36:77-80.
Appel MJG. Lyme disease in dogs and cats. Compend Contin Educ
Pract Vet 1990;12:617-626.
Barber JS, Trees AJ. Clinical aspects of 27 cases of neosporosis in dogs.
Vet Rec 1996;139:439-443.
Bolt DM, et al. Non-suppurative myocarditis in piglets associated with
porcine parvovirus infection. J Comp Pathol 1997;117:107-118.
Breitschwerdt EB, et al. Bartonella vinsonii subsp. berkhoffii and related
members of the alpha subdivision of the Proteobacteria in dogs
with cardiac arrhythmias, endocarditis, or myocarditis. J Clin Micro-
biol 1999;37:3618-3626.
Cassidy JP, et al. Myocarditis in sibling boxer puppies associated with
Citrobacter koseri infection. Vet Pathol 2002;39:393-395.
Deem DA, Fregin GF. Atrial fibrillation in horses: a review of 106 clini-
cal cases, and consideration of prevalence, clinical signs, and prog-
nosis. J Am Vet Med Assoc 1982;180:261-265.
Dubey JP, Lindsay DS. A review of Neospora caninum and neosporosis.
Vet Parasitol 1996;67:1-59.
Ellis J, et al. Reproduction of lesions of postweaning multisystemic
wasting syndrome in gnotobiotic piglets. J Vet Diagn Invest
1999;11:3-14.
Gajadhar AA, Marquardt WC. Ultrastructural and transmission evi-
dence of Sarcocystis cruzi associated with eosinophilic myositis in
cattle. Can J Vet Res 1992;56:41-46.
Hattel AL, et al. Neosporosis-associated bovine abortion in Pennsylva-
nia. Vet Parasitol 1998;74:307-313.
Hervas J, et al. Myocarditis associated with Theileria spp. in calves.
Zentralbl Veterinarmed B 1998;45:401-405.
Kimeto BA, et al. Haemorrhagic pancarditis in cattle infected with
Trypanosoma vivax. Vet Parasitol 1990;34:295-301.
Lange LG, Schreiner GF. Immune mechanisms of cardiac disease. N Engl
J Med 1994;330:1129-1135.
Lees W, et al. Outbreak of Cysticercus bovis (Taenia saginata) in feedlot
cattle in Alberta. Can Vet J 2002;43:227-228.
Machado EM, et al. A study of experimental reinfection by Trypano-
soma cruzi in dogs. Am J Trop Med Hyg 2001;65:958-965.
Machida N, et al. Cardio-histopathological observations on aborted
equine fetuses infected with equid herpesvirus 1 (EHV-1). J Comp
Pathol 1997;116:379-385.
Ndung’u JM, et al. Cardiac damage in dogs infected with T. brucei;
clinical and electrocardiographic features. J Small Anim Pract
1991;32:579-584.
Nho WG, et al. Detection of canine parvovirus in naturally infected
dogs with enteritis and myocarditis by in situ hybridization. J Vet
Diagn Invest 1997;9:255-260.
Reams RY, et al. Streptococcus suis infection in swine: a retrospective
study of 256 cases: II. Clinical signs, gross and microscopic lesions,
and coexisting microorganisms. J Vet Diagn Invest 1994;6:326-334.
Segales J, et al. Porcine circovirus diseases. Anim Health Res Rev
2005;6:119-142.
Thurmond MC, et al. Predictive values of fetal histopathology and
immunoperoxidase staining in diagnosing bovine abortion caused
by Neospora caninum in a dairy herd. J Vet Diagn Invest 1999;11:90-
94.
Uzal FA, et al. Outbreak of clostridial myocarditis in calves. Vet Rec
2003;152:134-136.
Van Rensburg IBJ. The differential diagnoses of myocarditis and myo-
cardial necrosis in puppies. J S Afr Vet Assoc 1988;59:107.
Young JK, et al. Naturally occurring Tyzzer’s disease in a puppy. Vet
Pathol 1995;32:63-65.
Diseases of the Heart
Of the features described for humans that must be  teins. There is massive loss of myocytes with fatty infiltration
absent, coronary arterial disease and systemic hypertension
may be disregarded in domestic animals because of their com-
parative rarity. In domestic animals, the diagnosis of a cardio-
myopathy rests on the absence of significant congenital or
acquired valvular or vascular abnormality, the presence of dila-
tion or hypertrophy of one or both ventricles and possibly all 4
chambers, and accompanied in some cases by diffuse fibrosis.
An additional exclusion, at least for cats, should be that of
hyperthyroidism.
Since the original definition, the term cardiomyopathy has
been used loosely to describe any abnormality of the myocar-
dium for which an etiology cannot be defined. There has also
been some attempt to classify cardiomyopathies into primary
(obscure etiology) and secondary (known systemic or etiologic
abnormalities) categories. A classification of similar style cat-
egorizes cardiomyopathies as either intrinsic or extrinsic in
cause. Under this classification, intrinsic causes are demonstra-
bly genetic or suspected to be so, whereas extrinsic cardiomy-
opathies include those of infectious, nutritional, or toxic
origin. At this stage, we prefer the categorization of cardiomyopa-
thies as either primary (of genetic or suspected genetic origin) or
secondary (of known cause other than genetic).
Great progress has been made in the understanding of
primary cardiomyopathies. Mutations in a number of genes
coding for proteins associated with cardiac contraction lead to
the development of hypertrophic cardiomyopathy in people
and gene abnormalities associated with cytoskeletal proteins or
mitochondrial enzymes lead to the development of dilated car-
diomyopathies. There is also evidence that one of the cardio-
myopathies in dogs, and a familial dilated cardiomyopathy in
people, results from a mutation in a carnitine transporter gene
causing an absolute or metabolic deficiency of carnitine and so
can be classified as primary. If the understanding of the etiology
and pathogenesis of the cardiomyopathies continues to prog-
ress, then the term cardiomyopathy may become obsolete.
Cardiomyopathies generally fall into 3 pathologic forms: (1)
dilated (congestive), (2) hypertrophic, and (3) restrictive
forms. As the clinical and pathologic patterns of the cardio-
myopathies were first described in people, a brief discussion
of the essential features in this species is warranted.
Dilated (congestive) cardiomyopathy (DCM) is a
common form in humans. The genetic basis of dilated cardio-
myopathies includes abnormalities in genes associated with
cytoskeletal proteins (such as desmin, lamin A and B) and mito-
chondrial genes, the latter leading to defects in oxidative
phosphorylation.
DCM is characterized by dysfunction of the systolic phase of
the cardiac cycle, where there is lowered force of contraction
and increased ventricular end-diastolic volume. There is
enlargement and dilation of both atria and ventricles. The
ventricles are hypertrophied, but, because of the dilation, the
hypertrophy is not as apparent as in the hypertrophic form of
the disease. Microscopically, there is variation in myocyte size,
myocyte degeneration and necrosis, and variably severe fibro-
sis. These changes are however, from a pathologist’s viewpoint,
disappointingly nonspecific.
A variant of DCM is that of arrhythmogenic right ventricular
cardiomyopathy (ARVC). ARVC is an inherited disease of
cardiac myocytes in humans that is characterized by right
ventricular failure and severe disturbances of cardiac rhythm,
including ventricular tachycardia or fibrillation. The molecular
basis of ARVC revolves around defects in desmosomal pro-
Myocardial Disease 45
and fibrosis. ARVC also occurs in dogs, especially Boxer dogs;
in cats; and in Hereford cattle.
Hypertrophic cardiomyopathy (HCM) is a diastolic rather
than a systolic ventricular disorder. The hypertrophic ventricle
is abnormally stiff (less compliant), resulting in impaired ven-
tricular filling. It is most commonly inherited as an autosomal
dominant characteristic within which there is a high preva-
lence of subclinical disease. Sudden unexpected death is often
the first manifestation of HCM. There is left, and sometimes
right, ventricular hypertrophy, reduced size of the ventricular
lumen, and dilation and often hypertrophy of the atria. The
pattern and extent of the ventricular hypertrophy varies from
localized hypertrophy of the ventricular septum (asymmetrical
septal hypertrophy), to the hypertrophy being symmetrical or
even apical in nature. Microscopically, the myocytes are hyper-
trophied, with many arranged in a whorled or disorganized
pattern. Although the disordered myocyte arrangement is not
unique to HCM, it is more severe. Fibrosis of variable severity
accompanies the hypertrophic process.
Mutations in genes that code for proteins associated with the
process of cardiac contraction have been identified in cases of
HCM. Understanding of the molecular nature of HCM in
people has progressed rapidly, providing insight into cardio-
myopathies in domestic species. Genes involved in HCM
include the cardiac troponin T gene (cTnT), the myosin heavy
chain gene (MyHC), and the cardiac myosin-binding protein C
gene (MyBPC3). The mutations in each gene appear not to be
singular in nature; for example, many mutations have been
identified in the MyBPC3 gene alone. The inherited form of
HCM is therefore a genetically diverse disease, which presents
as a common clinical and pathologic syndrome. Interestingly,
mutations of the cTnT gene can cause both DCM and HCM,
and mutation in the same codon in the cardiac troponin I
(cTnI) gene causes both HCM and RCM.
Restrictive cardiomyopathy (RCM) is characterized by
impaired ventricular filling because of reduced ventricular compli-
ance, with unimpaired systolic function. The ventricles are
usually of normal size, but both atria are usually dilated.
Reduced compliance of one or both ventricles may occur
because of interstitial or endomyocardial fibrosis with or
without eosinophilia of the ventricles. Restrictive cardiomy-
opathy may also result from the deposition of amyloid
or occur in association with the disease sarcoidosis. These
infiltrative cardiomyopathies are, strictly speaking, secondary
cardiomyopathies.
The endomyocardial form of human RCM is subdivided
into 2 major forms: Loeffler endomyocarditis occurs predomi-
nantly in temperate climates; endomyocardial fibrosis is most
common in equatorial Africa. Although the end-stage of both
forms is pathologically indistinguishable, the natural history
and clinical patterns are quite separable. The Loeffler (hypere-
osinophilic) variant principally affects males and is associated
with hypereosinophilia, thromboembolism, and arteritis. In
endomyocardial fibrosis, there is no male predominance, and
it occurs in younger patients with no accompanying eosino-
philia. At least for the Loeffler variant, endomyocardial fibrosis
results from release of granules from infiltrating eosinophils in
the earlier phase of the disease.
The major features of the primary cardiomyopathies are
depicted in eFigure 1-10. Cardiomyopathies occurring in
domestic animals have been similarly classified and have been
documented in cats, dogs, cattle, and pigs.
 45.e1

Classification of primary cardiomyopathies

Hypertrophic cardiomyopathy Dilated [congestive] Restrictive [infiltrative]

Hypertrophic ventricle
Diastolic disorder-reduced compliance
Restricted ventricular filling
Many have genetic basis associated with
mutations in contractile proteins-myosin/
cardiac troponin T/cardiac myosin binding protein
cardiomyopathy
Dilated ventricle
Systolic dysfunction-decreased contractility
Many have a genetic basis
Mutations in genes associated with
cytoskeletal proteins and mitochondria
Cardiomyopathy
Diastolic disorder
Restriction of ventricular filling
Severe endomyocardial fibrosis

eFigure 1-10  Major features of primary cardiomyopathies.

46 CHAPTER 1  •  Cardiovascular System
Further reading
Amat di San Filippo C, et al. Cardiomyopathy and carnitine deficiency.
Mol Genet Metab 2008;94:162-166.
Gomes AV, Potter JD. Molecular and cellular aspects of troponin car-
diomyopathies. Ann N Y Acad Sci 2004;1015:214-224.
Hare JM. The dilated, restrictive and infiltrative cardiomyopathies. In:
Bonow RO, et al., editors. Braunwald’s Heart Disease: A Textbook
of Cardiovascular Medicine. 9th ed. Philadelphia: Elsevier Saunders;
2012. p. 1561-1581.
Maron BJ. Hypertrophic cardiomyopathy. In: Bonow RO, et al., editors.
Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine.
9th ed. Philadelphia: Elsevier Saunders; 2012. p. 1582-1594.
Nout YS, et al. Cardiac amyloidosis in a horse. J Vet Intern Med
2003;17:588-592.
Schoen FJ, Mitchell RN. The heart. In: Kumar VK, et al., editors. Robbins
and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia:
Saunders Elsevier; 2010. p. 529-587.
Feline cardiomyopathies
Feline cardiomyopathies constitute a well-recognized, but diverse,
group of morphologic and functional disorders (eFig. 1-11).
Echocardiography is the definitive test used clinically to dif-
ferentiate and classify feline cardiomyopathies. Hypertrophic
cardiomyopathy is most commonly encountered (58%), fol-
lowed by restrictive (21%), dilated (10%), unclassified (10%),
and excessive left ventricular moderator band (<1%) cardio-
myopathies. Although feline cardiomyopathy was only recog-
nized as an entity in the relatively recent past, a common
consequence of cardiomyopathy, iliac thromboembolism, was
originally described >70 years ago. There is a wide range in
the age of onset of clinical signs, from 7 months to 24 years
of age. Presenting clinical signs include lethargy, anorexia,
dyspnea, tachypnea, and occasionally abdominal distension.
Murmurs, most often associated with mitral or tricuspid insuf-
ficiency, gallop rhythms, and dysrhythmias of various types are
frequently encountered. Approximately 13 of cats with car-
diomyopathy develop unilateral or bilateral thromboembolic
hindlimb ischemia. The causes of feline cardiomyopathy
include genetic and nutritional origins, and a possible role for
viral infection following the detection by PCR of feline pan-
leukopenia virus genome in cats with idiopathic hypertrophic,
dilated, and restrictive cardiomyopathies and myocarditis.
Hypertrophic cardiomyopathy, the most common form of
cardiomyopathy in cats, is a diastolic disorder, resulting from
ventricular myocardial hypertrophy in the absence of an
obvious cause. There is normal or near-normal systolic myo-
cardial function, but diminished capacity to accept diastolic
flow from the left atrium. Left ventricular volume is normal
or decreased, and the papillary muscles are usually greatly
enlarged in relation to the volume of the ventricle. The left
atrium is usually dilated.
It is inherited as an autosomal dominant trait in Maine
Coon and Ragdoll cats, the basis of which appear to be muta-
tions in the gene coding for myosin binding protein C3, a
defect also described in hypertrophic cardiomyopathy in
people. Similar and additional mutations in genes coding for
contractile genes are likely in other breeds, including the Sibe-
rian, Sphynx, Bengal, Chartreux, and Norwegian Forest cats.
The gross pathologic features of feline HCM include an
enlarged heart, with comparatively massive symmetrical con-
centric hypertrophy of both ventricles in the majority of cases,
Myocardial Disease
but especially notable for the left ventricle (Fig. 1-51A). The
left ventricular lumen is often slit-like. Some cases have asym-
metrical hypertrophy of the left ventricle, with the ventricular
septum thicker than the left ventricular free wall. Findings of
lesser frequency include atrial thrombi, focal areas of ventricu-
lar fibrosis, and fibrosis of the endocardium in the region of
the left ventricular outflow tract.
Microscopically, myofibers are hypertrophied and contain
vesicular nuclei. Myofiber disarray, characterized by inter-
weaving of myofibers in the left ventricular free wall and
ventricular septum, may be observed (Fig. 1-51B). This may
also be present in the right ventricle. Extensive interstitial fibro-
sis is also a consistent feature (Fig. 1-51C), especially in the
inner 2 3 of the left ventricular free wall. Scattered focal areas
of dense replacement fibrosis are seen in a minority of cats.
As indicated by increased plasma cTnI concentrations, cats
with moderate to severe HCM have ongoing myocardial
damage, which may be the stimulus for replacement fibrosis.
Focal endocardial thickening by fibrosis also occurs commonly.
Intramyocardial arteries may have medial hypertrophy, and
scattered perivascular accumulations of lymphocytes and
monocytes may be present.
Ultrastructurally, the hypertrophied myofibers have large
pleomorphic nuclei with undulating surfaces and prominent
nucleoli. Dense accumulations of Z-band material are also
evident in myocytes, as is the presence of lipofuscin granules.
Although these changes are seen in normal cat myocytes, the
intensity of the changes is greater in cardiomyopathic cases. 
A concentrically hypertrophied heart also occurs in cats 
with hyperthyroidism, and this should not be confused with
hypertrophic cardiomyopathy (see Cardiac hypertrophy,
previously).
Restrictive cardiomyopathy is a less common and less well-
defined form of feline cardiomyopathy and is characterized by
impaired diastolic ventricular filling, which may be due to
severe endomyocardial fibrosis. Systolic function is usually
normal. Feline RCM has also been termed “left ventricular
endocardial fibrosis” (LVEF). Endomyocarditis may be an ante-
cedent to LVEF. Feline RCM occurs predominantly in older
cats with clinical signs of left-sided or bilateral heart failure.
Cardiac murmurs and dysrhythmias are common. Pathologic
features include severe endocardial thickening with mural
thrombosis. Left atrial enlargement is marked, the result of the
restriction of ventricular filling. The left ventricle is thickened,
and the lumen volume may be significantly diminished.
Microscopically, the myocardium and endocardium may be
replaced by granulation tissue of various ages; adjacent myo-
cardium may be infiltrated by histiocytes, lymphocytes, and
plasma cells. Bartonella infection has been suggested as a pos-
sible cause of feline endomyocarditis. RCM has also been
reported in cats with hypereosinophilic syndrome.
Dilated cardiomyopathy has decreased markedly in pre­
valence since the discovery of taurine-deficiency myocardial
failure in cats. On postmortem, all chambers of the heart are
enlarged, and the ventricles are dilated and flabby with thinned
walls (Fig. 1-52). The endocardium may be pale and slightly
thickened by subendocardial fibrosis. The papillary muscles
and trabeculae may be atrophied and appear small in relation
to the ventricular volume. Often only minor lesions are found
on microscopy. Myocardial fibers are moderately hypertro-
phied, accompanied by mild diffuse interstitial fibrosis. There
may also be focal areas of myofiber loss with replacement
fibrosis. In some cases, there may be extensive areas of 
 46.e1

Further reading
Anan R, et al. Patients with familial hypertrophic cardiomyopathy
caused by a Phe110Ile missense mutation in the cardiac troponin T
gene have variable cardiac morphologies and a favorable prognosis.
Circulation 1998;98:391-397.
Dai KS, et al. Intramural coronary arterial disease in swine with natu-
rally occurring hypertrophic cardiomyopathy. J Submicrosc Cytol
Pathol 1997;29:511-519.
Hughes SE. The pathology of hypertrophic cardiomyopathy. Histopa-
thology 2004;44:412-427.
Kushwaha SS, et al. Restrictive cardiomyopathy. N Engl J Med
1997;336:267-276.
Liu SK, et al. Comparison of morphologic findings in spontaneously
occurring hypertrophic cardiomyopathy in humans, cats and dogs.
Am J Cardiol 1993;72:944-951.
Marian AJ, Roberts R. Molecular genetics of hypertrophic cardiomy-
opathy. Annu Rev Med 1995;46:213-222.
Moolman-Smook JC, et al. Identification of a new missense mutation
in MyBP-C associated with hypertrophic cardiomyopathy. J Med
Genet 1998;35:253-254.
Sauramura A, et al. Taurine modulates ion influx through cardiac
calcium channels. Cell Calcium 1990;11:251-259.
Sisson DD, Thomas WP. Myocardial diseases. In: Ettinger SJ, Feldman
EC, editors. Textbook of Veterinary Internal Medicine: Diseases of
the Dog and Cat. 7th ed. Philadelphia: WB Saunders; 1995.
p. 995-1031.
Yu B, et al. Molecular pathology of familial hypertrophic cardiomyopa-
thy caused by mutations in the cardiac myosin binding protein C
gene. J Med Genet 1998;35:205-210.
46.e2

Dilated
Taurine deficiency*
Systolic Dysfunction
Depressed contractility
Ventricles flabby/dilated.

Hypertrophic
Diastolic disorder-
decreased compliance
Concentric hypertrophy Restrictive
Autosomal dominant Feline Severe endomyocardial
in some breeds Cardiomyopathies fibrosis
Mutations in myosin Impaired diastolic filling
binding protein C
Myofiber disarray,
interstitial fibrosis

Excessive moderator
bands
Moderator bands enlarged
Probably a congential
defect rather than
a true primary
cardiomyopathy

eFigure 1-11  Major features of feline cardiomyopathies. Dilation resulting from taurine deficiency
is not technically a cardiomyopathy because of the known etiology.*
Diseases of the Heart
A bers. Ultrastructural examination contributes little to the
B a congenital defect that is only manifest later in life. Affected cats
C may be found. Microscopically, the abnormal moderator bands
Figure 1-51  Feline hypertrophic cardiomyopathy. A. Symmetri-
cal hypertrophic cardiomyopathy with increased thickness of the
left ventricular free wall and interventricular septum. (Courtesy
I. Matise.) B. Focal area of cardiac myofiber disarray. C. Extensive
replacement fibrosis (blue) of cardiac myocytes (red). Masson
trichrome.
Myocardial Disease 47
Figure 1-52  Feline dilated cardiomyopathy. Chamber of left
ventricle markedly increased in volume accompanied by thinned
ventricular walls. (Courtesy A. Wuenschmann.)
myocardial fibrosis. There is no significant disarray of myofi-
understanding of the pathologic picture.
An ARVC-like syndrome occurs in cats, where prominent
clinical features include supraventricular and ventricular
arrhythmias, marked enlargement of the right ventricle and
atrium, and right-sided congestive heart failure, Gross lesions
include right ventricular luminal dilation, wall thinning, and
apical aneurysm. Microscopically, the ventricles, especially the
right ventricle, have myocarditis, myocyte necrosis, myocyte
atrophy, fibrosis, and fatty replacement.
Excessive moderator bands (false tendons) in the left ven-
tricle bridging the ventricular septum and free wall and entan-
gling the papillary muscles are associated with heart failure
and death in cats. Although not strictly a cardiomyopathy, it
is considered under the heading of cardiomyopathies as the
clinical syndrome occurs in mature cats. In all probability, it is
exhibit a range of clinical signs that are mostly referable to
left-sided heart failure. They include lethargy, dyspnea,
anorexia, pale mucous membranes, and cardiac murmurs.
Radiographic findings include cardiomegaly, hydrothorax, 
and pulmonary edema. Various conduction disturbances also
occur.
Gross changes are dominated by the presence of numerous
pink-white bands spanning the left ventricular lumen and
papillary muscles. Most commonly, the bands connect the
cranial and caudal papillary muscles to the ventricular septum.
In others, the bands insert between the ventricular septum
and the left ventricular free wall. The left ventricle may be
dilated or show increased wall thickness. In neither case is the
heart weight significantly different from that of normal cats.
The left atrium is enlarged, and pulmonary edema, pleural
effusion, hepatic congestion, and aortic thromboembolism
consist of Purkinje cells and dense, mature collagen covered
by endothelium. Loose fibrous connective tissue is present
between the endothelium and the dense collagen, with the
variation in size of the moderator bands the result of more or
less mature collagen. Ventricular alterations include myocyte
atrophy or hypertrophy, focal fibrosis, and intramural coronary
arterial luminal narrowing, intimal thickening, medial hyper-
plasia, and perivascular fibrosis.
48 CHAPTER 1  •  Cardiovascular System Myocardial Disease

Canine DCM has the clinical features of a short history of

Further reading
Ferasin L, et al. Feline idiopathic cardiomyopathy: a retrospective study
of 106 cats (1994-2001). J Feline Med Surg 2003;5:151-159.
Fox PR, et al. Spontaneously occurring arrhythmogenic right ventricular
cardiomyopathy in the domestic cat: a new animal model similar
to the human disease. Circulation 2000;102:1863-1870.
Godiksen MT, et al. Hypertrophic cardiomyopathy in young Maine
Coon cats caused by the p.A31P cMyBP-C mutation—the clinical
significance of having the mutation. Acta Vet Scand 2011;9:
53-57.
Kershaw O, et al. Diagnostic value of morphometry in feline hypertro-
phic cardiomyopathy. J Comp Pathol 2012;147:73-83.
Longeri M, et al. Myosin-binding protein C DNA variants in domestic
cats (A31P, A74T, R820W) and their association with hypertrophic
cardiomyopathy. J Vet Intern Med 2013;27:275-285.
Payne JR, et al. Prognostic indicators in cats with hypertrophic cardio-
myopathy. J Vet Intern Med 2013;27:1427-1436.
Ripoll VT, et al. The R820W mutation in the MYBPC3 gene, associated
with hypertrophic cardiomyopathy in cats, causes hypertrophic car-
diomyopathy and left ventricular non-compaction in humans. Int J
Cardiol 2010;145:405-407.
Trehiou-Sechi E, et al. Comparative echocardiographic and clinical fea-
tures of hypertrophic cardiomyopathy in 5 breeds of cats: a retro-
spective analysis of 344 cases (2001-2011). J Vet Intern Med
2012;26:532-541.
cough, depression, dyspnea, weight loss, syncope, and polydip-
sia, or may occur without premonitory signs as sudden death.
Clinical signs are often referable to left-sided congestive heart
failure and hence pulmonary edema, or may be due to biven-
tricular failure and include ascites. Soft systolic murmurs,
indicative of left atrioventricular (LAV) or right atrioventricu-
lar (RAV) valvular insufficiency, may be heard on auscultation.
Atrial fibrillation is the most common electrocardiographic
abnormality; ventricular tachycardia and ventricular prema-
ture contractions are common in most Doberman Pinschers
with DCM. Echocardiographically, there is cardiomegaly, with
increased end-diastolic volume and poor contractile function.
The prognosis is poor, with mean survival times of 6-12 months
after the onset of treatment.
Autopsy findings in typically affected cases are those of
congestive heart failure. All chambers, particularly the left ven-
tricle, are markedly dilated and may be hypertrophied. The
AV rings are dilated (Fig. 1-53A), the endocardium may be
opaque due to subendocardial fibrosis, and there may be atrial
thrombosis. There may also be some evidence of infarction in

Canine cardiomyopathies
The most commonly recognized is dilated cardiomyopathy
(DCM), especially in young to middle-aged giant and large-
breed dogs, such as the St. Bernard, Irish Wolfhound, Estrela
Mountain dogs, and Great Dane, but also afflicting an ever-
growing list of other breeds, including Airedale Terriers,
Boxers, Doberman Pinschers, English Cocker Spaniels, 
Newfoundlands, Portuguese Water dogs, Presa Canario dogs,
Standard Poodles, and Toy Manchester Terriers. The major
features of the disease are depicted in eFigure 1-12.
Although the causes of canine DCM are still mostly unknown,
it is increasingly apparent that most have a genetic basis, but as
yet, no abnormalities in myocardial cytoskeletal genes have been
identified as they have been in human dilated cardiomyopathy. A
There is a familial tendency in the Doberman Pinscher, English
Cocker Spaniel, Boxer, Great Dane, Irish Wolfhound, and
Newfoundland; DCM may be an X-linked recessive trait in
Great Danes. Infantile dilated cardiomyopathy is inherited in
Portuguese Water dogs as an autosomal recessive trait. There
is a strong association between the presence of cardiomyopa-
thy and a particular complement C4 phenotype (C4:4) in the
English Cocker Spaniel. This is not suggested to be causal, but
to indicate a genotype that is predisposed to the development
of the disease. A singular finding is that of a deficiency in the
mitochondrial respiratory chain in affected Doberman Pin-
schers, which has its origin in a 16-bp deletion in the pyruvate
dehydrogenase kinase 4 (PDK4) gene on chromosome 14.
Carnitine deficiency may play a role in some subtypes of
cardiomyopathy, although the evidence is not strong. Low
blood taurine concentrations have also been found in dogs B
with DCM that had been fed certain lamb-rice commercial
diets. The DCM in Portuguese Water dogs can be reversed in Figure 1-53  Canine dilated cardiomyopathy. A. Dilated left ven-
some pups by oral taurine supplementation. Hypothyroidism tricular lumen accompanied by thinning of the left ventricular
has been noted as a reversible cause of myocardial failure in free wall and interventricular septum. B. Thin, wavy cardiac myo-
2 Great Danes. cytes often seen in dilated cardiomyopathies. (Courtesy E. Olson.)
 48.e1

Further reading
Baty CJ, et al. Natural history of hypertrophic cardiomyopathy and
aortic thromboembolism in a family of domestic shorthair cats.
J Vet Intern Med 2001;15:595-599.
Bond BR, et al. Echocardiographic findings in 103 cats with hyperthy-
roidism. J Am Vet Med Assoc 1988;192:1546-1549.
Fox PR, et al. Echocardiographic assessment of spontaneously occur-
ring feline hypertrophic cardiomyopathy. An animal model of
human disease. Circulation 1995;92:2645-2651.
Herndon WE, et al. Cardiac troponin I in feline hypertrophic cardiomy-
opathy. J Vet Intern Med 2002;16:558-564.
Liu SK, et al. Excessive moderator bands in the left ventricle of 21 cats.
J Am Vet Med Assoc 1982;180:1215-1219.
Liu SK, et al. Hypertrophic cardiomyopathy and hyperthyroidism in the
cat. J Am Vet Med Assoc 1984;185:52-57.
Meurs KM, et al. Molecular screening by polymerase chain reaction
detects panleukopenia virus DNA in formalin-fixed hearts from cats
with idiopathic cardiomyopathy and myocarditis. Cardiovasc Pathol
2000;9:119-126.
Nakagawa K, et al. Hypertrophic cardiomyopathy in a mixed breed cat
family. J Vet Med Sci 2002;64:619-621.
Pion PD, et al. Myocardial failure in cats associated with low plasma
taurine: a reversible cardiomyopathy. Science 1987;237:764-768.
Saxon B, et al. Restrictive cardiomyopathy in a cat with hypereosino-
philic syndrome. Can Vet J 1991;32:367-369.
Stalis IH, et al. Feline endomyocarditis and left ventricular endocardial
fibrosis. Vet Pathol 1995;32:122-126.
Taugner FM. Stimulation of the renin-angiotensin system in cats with
hypertrophic cardiomyopathy. J Comp Pathol 2001;125:122-129.
Van Vleet JF, et al. Pathologic alterations in hypertrophic and conges-
tive cardiomyopathy of cats. Am J Vet Res 1980;41:2037-2048.
48.e2

Breed association/inheritance Histopathology

Giant breeds and Airdale, Boxer, Two major types
Doberman, Standard Poodle 1. Fatty infiltration/degenerative type
Autosomal recessive in 2. Attenuated wavy fiber type
Portugese water dogs May see both forms in the one breed

Boxer cardiomyopathy
Arrhythmogenic Right Ventricular
Cardiomyopathy (AVRC)
Autosomal dominant [incomplete
penetrance]: 8bp deletion in striatin
gene on chromosome 17
Striatin colocates with 3
desmosomal proteins
Doberman cardiomyopathy
16bp deletion in pyruvate
Canine dilated dehydrogenase kinase
cardiomyopathies 4[PDK4]gene on chromosome
14 leading to mitochondral abnormalities
and lipofuscin accumulation

eFigure 1-12  Types of cardiomyopathies in dogs.

Diseases of the Heart
distant organs. The finding, in some cases, of multifocal myo-
cardial degeneration, necrosis, or fibrosis is expected, but  dogs is encouraging. Striatin co-localizes in the region of the
unrewarding, with regard to possible causes. Ultrastructural
examination of myocardium from cases of dilated cardiomy-
opathy shows increases in intermyofibrillar spaces, lipofuscin
granules, fat droplets and myelin figures, mitochondrial hyper-
plasia, disruption of myofibrils, and Z-band thickening. These
ultrastructural changes are not specific for cardiomyopathy,
but are more severe than seen with other causes of congestive
heart failure.
There appear to be 2 histologically distinct forms of DCM:
(1) the “fatty infiltration–degenerative” type seen, for example,
in Boxers and Doberman Pinschers, and (2) the “attenuated
wavy fiber” type seen in many giant-, large-, and medium-sized
breeds, including some Boxers and Doberman Pinschers (Fig.
1-53B). This histologic classification of canine DCM may be
superior to classification by breed-specific syndromes, because
both forms may affect some breeds, such as Boxers and  humans, affected and carrier dogs develop Duchenne cardio-
Doberman Pinschers. This postmortem classification does not
however assist antemortem etiologic diagnosis of DCM.
A variant of DCM is arrhythmogenic right ventricular
cardiomyopathy (ARVC), a primary familial myocardial
disease in humans and in Boxer dogs that is associated with
cardiovascular morbidity and risk of sudden death. It is trans-
mitted as an autosomal dominant trait in humans and Boxers.
ARVC in Boxers is characterized by various events, alone or
in combination, including ventricular arrhythmias of sus-
pected right ventricular (RV) origin, syncope, heart failure,
and/or sudden death. Right ventricular dilation or aneurysms
are common. Histopathologic findings include severe myocyte
loss in the RV, with replacement by adipose or fibroadipose
tissue (Fig. 1-54). Focal fibroadipose lesions may also be
present in both atria and in the left ventricle (LV). Myocarditis
may be present in the RV and LV in dogs that have died sud-
denly and may be the source of arrhythmias.
ARVC is an ion channel defect in humans, with mutations
in genes coding for protein constituents of the special junc-
tions and some nondesmosomal proteins. Mutations identified
include those coding for desmocollin-2, desmoplakin and pla-
kophilin, ryanodine receptor 2, desmin, lamins A and C, titin,
and striatin. The recent discovery of an 8-bp deletion in the
Figure 1-54  Arrhythmogenic right ventricular cardiomyopathy
in a Boxer dog. Note the extensive, cardiac myocyte replacement
by adipose tissue. (Courtesy E. Olson.)
Myocardial Disease 49
striatin gene located on chromosome 17 in affected Boxer
intercalated disc with 3 desmosomal proteins. Recent evi-
dence also shows that dysfunction in the Wnt/β-catenin
pathway is involved where there is mislocalization of 
β-catenin and striatin and an increase in the total amount of
β-catenin in Boxer dogs with ARVC.
Hypertrophic cardiomyopathy is much less common than
the dilated form. Associated clinical syndromes include sudden
death, death during anesthesia, and congestive heart failure.
Disproportionate thickening of the ventricular septum may
cause the ratio of the interventricular wall thickness to left
ventricular free wall thickness to exceed 1.2:1, and there may
be histologic evidence of myofiber disarray in the ventricular
septum.
In canine X-linked muscular dystrophy in Golden Retriev-
ers, an animal model for Duchenne muscular dystrophy in
myopathy characterized by myocardial interstitial, especially
subepicardial, fibrosis, leading to cardiac insufficiency.
Further reading
Bélanger MC, et al. Taurine-deficient dilated cardiomyopathy in a
family of golden retrievers. J Am Anim Hosp Assoc 2005;41:284-
291.
Delmar M, et al. The cardiac desmosome and arrhythmogenic
cardiomyopathies: from gene to disease. Circ Res 2010;107:
700-714.
Everett RM, et al. Dilated cardiomyopathy of Doberman pinschers:
retrospective histomorphologic evaluation of heart from 32 cases.
Vet Pathol 1999;36:221-227.
Legge CH, et al. Histological characterization of dilated cardiomyopa-
thy in the juvenile toy Manchester terrier. Vet Pathol 2013;50:1043-
1052.
Lobo L, et al. Histologic characterization of dilated cardiomyopathy in
Estrela Mountain Dogs. Vet Pathol 2010;47:637-642.
Meurs KM, et al. A splice site mutation in a gene encoding for PDK4,
a mitochondrial protein, is associated with the development of
dilated cardiomyopathy in the Doberman pinscher. Hum Genet
2012;131:1319-1325.
Muers KM, et al. Association of dilated cardiomyopathy with striatin
mutation genotype in Boxer dogs. J Vet Intern Med 2013;27:1437-
1440.
O’Sullivan ML, et al. Evaluation of 10 genes encoding cardiac proteins
in Doberman Pinschers with dilated cardiomyopathy. Am J Vet Res
2011;72:932-939.
Oxford EM, et al. Change in β-catenin localization suggests involve-
ment of the canonical Wnt pathway in Boxer dogs with arrhyth-
mogenic right ventricular cardiomyopathy. J Vet Intern Med
2014;28:92-101.
Ricklet S, Pieperhoff S. Mutations with pathogenic potential in proteins
located in or at the composite junctions of the intercalated disk
connecting mammalian cardiomyocytes: a reference thesaurus for
arrhythmogenic cardiomyopathies and for Naxos and Carvajal dis-
eases. Cell Tissue Res 2012;348:325-333.
Vollmar A, et al. Dilated cardiomyopathy in juvenile doberman pin-
schers. J Vet Cardiol. 2003;5:23-27.
Werner P, et al. A novel locus for dilated cardiomyopathy maps to
canine chromosome 8. Genomics 2008;91:517-521.
Wiersma AC, et al. Evaluation of 15 candidate genes for dilated car-
diomyopathy in the Newfoundland dog. J Hered 2008;99:73-80.
 49.e1

Tidholm A, et al. Canine idiopathic dilated cardiomyopathy: I. Aetiol-

Further reading ogy, clinical characteristics, epidemiology and pathology. Vet J
Alroy J, et al. Inherited infantile dilated cardiomyopathy in dogs: 2001;162:92-107.
genetic, clinical, biochemical, and morphologic findings. Am J Med Tidholm A, Jonsson L. Histologic characteristics of canine dilated car-
Genet 2000;95:57-66. diomyopathy. Vet Path 2005;42:1-8.
Basso C, et al. Arrhythmogenic right ventricular cardiomyopathy Thomas RE. Congestive cardiac failure in young Cocker Spaniels (a form
causing sudden cardiac death in boxer dogs: a new animal model of cardiomyopathy?): details of eight cases. J Small Anim Pract
of human disease. Circulation 2004;109:1180-1185. 1987;28:265-279.
Biesiadecki BJ, et al. Cardiac troponin T variants produced by aberrant Vollmar AC. The prevalence of cardiomyopathy in the Irish wolfhound:
splicing of multiple exons in animals with high instances of dilated a clinical study of 500 dogs. J Am Anim Hosp Assoc 2000;36:
cardiomyopathy. J Biol Chem 2002;277:50275-50285. 125-132.
Bishop L. Ultrastructural investigations of cardiomyopathy in the dog.
J Comp Pathol 1986;96:685-698.
Borgarelli M, et al. Canine idiopathic dilated cardiomyopathy: II. Patho-
physiology and therapy. Vet J 2001;162:182-195.
Calvert CA. Dilated congestive cardiomyopathy in Doberman pinschers.
Compend Contin Educ Pract Vet 1986;8:417-430.
Day MJ. Inheritance of serum autoantibody, reduced serum IgA and
autoimmune disease in a canine breeding colony. Vet Immunol
Immunopathol 1996;53:207-219.
Fascetti AJ, et al. Taurine deficiency in dogs with dilated cardiomyopa-
thy: 12 cases (1997-2001). J Am Vet Med Assoc 2003;223:1137-
1141.
Fernandez del Palacio MJ, et al. Arrhythmogenic right ventricular
dysplasia/cardiomyopathy in a Siberian husky. J Small Anim Pract
2001;42:137-142.
Gilbert SJ, et al. Increased expression of promatrix metalloproteinase-9
and neutrophil elastase in canine dilated cardiomyopathy. Cardio-
vasc Res 1997;34:377-383.
Gooding JP, et al. Echocardiographic characterization of dilated cardio-
myopathy in the English cocker spaniel. Am J Vet Res 1986;47:1978-
1983.
Keene BL, et al. Myocardial L-carnitine deficiency in a family of dogs
with dilated cardiomyopathy. J Am Vet Med Assoc 1991;98:647-
650.
Liu SK, et al. Hypertrophic cardiomyopathy in the dog. Am J Pathol
1979;94:497-508.
McCutcheon LJ, et al. Respiratory chain defect of myocardial mito-
chondria in idiopathic dilated cardiomyopathy of Doberman pin-
scher dogs. Can J Physiol Pharmacol 1992;70:1529-1533.
Meurs KM, et al. Clinical features of dilated cardiomyopathy in Great
Danes and results of a pedigree analysis: 17 cases (1990-2000).
J Am Vet Med Assoc 2001;218:729-732.
Meurs KM, et al. Genome-wide association identifies a deletion in the
3′ untranslated region of striatin in a canine model of arrhythmo-
genic right ventricular cardiomyopathy. Hum Genet 2010;128:315-
324.
Moise NS, et al. Duchenne’s cardiomyopathy in a canine model: elec-
trocardiographic and echocardiographic studies. J Am Coll Cardiol
1991;17:812-820.
Morales M, et al. Dilated cardiomyopathy in Presa canario dogs: ECG
findings. J Vet Med A Physiol Pathol Clin Med 2001;48:577-580.
Oxford EM, et al. Ultrastructural changes in cardiac myocytes from
Boxer dogs with arrhythmogenic right ventricular cardiomyopathy.
J Vet Cardiol 2011;13:101-113.
Phillips DE, Harkin KR. Hypothyroidism and myocardial failure in two
Great Danes. J Am Anim Hosp Assoc 2003;39:133-137.
Sandusky GE Jr, et al. Histological and ultrastructural evaluation of
cardiac lesions in idiopathic cardiomyopathy in dogs. Can J Comp
Med 1984;48:81-86.
Sleeper MM, et al. Dilated cardiomyopathy in juvenile Portuguese
water dogs. J Vet Intern Med 2002;16:52-62.
50 CHAPTER 1  •  Cardiovascular System Myocardial Disease

Bovine cardiomyopathies†
Several syndromes of cardiomyopathy are recorded in cattle.
Dilated cardiomyopathy occurs in Holsteins in many countries,
including Canada, Australia, and Japan, and in Simmental-Red
Holstein crossbreds in Switzerland. Many of the cases emanate
from common sires, and an autosomal recessive mode of
inheritance has been suggested. A nonsense mutation in the
optic atrophy 3 (OPA3) gene on chromosome 18 is present
in affected Red Holstein cattle. OPA3 is located on the mito-
chondrial membrane, and mutations lead to disruption of
mitochondrial morphology, and presumably, mitochondrial
dysfunction. OPA3 mutations are also involved in the devel-
opment of optic atrophy, cataracts, and neurologic disorders.
The cardiomyopathy occurs in young adult to mature animals, A
with the clinical signs particularly referable to right-sided
heart failure, including dependent subcutaneous edema,
hydrothorax, ascites, and severe hepatic congestion. There is
no indication of the presence of electrocardiographic abnor-
malities. The heart is enlarged with dilation of both ventricles.
Microscopically, there is a mixture of atrophied and hypertro-
phied myofibers with vacuolation, and there are islands of
interstitial and replacement fibrosis, fatty replacement, and
ongoing myofiber necrosis.
Dilated cardiomyopathy in Japanese black calves is con-
sidered to be inherited as an autosomal recessive trait. Sudden
death or death after a short period of severe dyspnea occurs
in calves younger than 30 days. Lesions found at autopsy
include marked cardiac enlargement with left ventricular 
dilation, hydropericardium, hydrothorax, ascites, pulmonary
edema, and hepatic and splenic congestion. Extensive myo- B
cardial degeneration and necrosis with fibrosis are present in
the left ventricle, particularly affecting the papillary muscles.
The right ventricle is similarly but less often involved. The
clinical and pathologic pattern is reminiscent of that seen in
Hereford calves with cardiomyopathy.
A cardiomyopathy associated with a tightly curled
(“woolly”) haircoat in polled and horned Herefords has also
been described. This cardiocutaneous syndrome is inherited
as an autosomal recessive trait and is now known to be caused
by a 7-bp duplication in the NF kappaB interacting protein 1
gene on chromosome 18. In contrast, similar human cardio-
cutaneous diseases, such as Naxos disease and Carvajal syn-
drome, are caused by mutations in genes encoding proteins
associated with composite intercellular junctions.
Affected animals are identifiable at birth by their distinc- C
tive haircoat and signs of cardiac dysfunction, including Figure 1-55  Cardiomyopathy and woolly haircoat syndrome in
arrhythmias. Some calves develop bilateral ocular keratitis Hereford calves. A. Extensive subepicardial fibrosis of the right
immediately after birth. Most calves are found dead at <12 ventricle in a 7-day-old calf. B. Severe myocardial necrosis, min-
weeks of age. Occasionally, calves are seen to collapse and die eralization, and fibrosis of both ventricles in a 5-day-old calf. 
following exertion. Even in some calves that die at 1 week of C. Extensive subepicardial myocyte loss with replacement fibrosis
age, there are severe lesions in the ventricles consisting of in a 17-day-old calf. Masson trichrome. (Courtesy R.W. Cook.)
necrosis, mineralization, and fibrosis of the myocardium, and
are detectable at birth, an indication of their in utero onset
(Fig. 1-55A-C). heart failure, and in these, the heart is eccentrically
Hypertrophic cardiomyopathy has been reported in hypertrophied.
Holsteins.
Bovine generalized glycogenosis type II (Pompe’s disease),
although not a primary cardiomyopathy, deserves mention. Further reading
Most affected animals have generalized muscle weakness. Furuoka H, et al. Hereditary dilated cardiomyopathy in Holstein-Friesian
Occasional cases, however, exhibit clinical signs of left-sided cattle in Japan: association with hereditary myopathy of the dia-
phragmatic muscles. J Comp Pathol 2001;125:159-165.
†
Contribution to this section by Dr. R. Cook is gratefully Nart P, et al. Morphometry of bovine dilated cardiomyopathy. J Comp
acknowledged. Pathol 2004;130:235-245.
 50.e1

Further reading
Bradley R, et al. Cardiomyopathy in adult Holstein Friesian cattle in
Britain. J Comp Pathol 1991;104:101-112.
Dolf G, et al. Evidence for autosomal recessive inheritance of a major
gene for bovine dilated cardiomyopathy. J Anim Sci 1998;76:1824-
1829.
Machida N, et al. Two necropsy cases of hypertrophic cardiomyopathy
in Holstein cattle. J Vet Med Sci 1996;58:929-932.
Storie GJ, et al. Cardiomyopathy and wooly haircoat syndrome of
Hereford cattle. Aust Vet J 1991;68:119.
Watanabe S, et al. Evidence for a new lethal gene causing cardiomy-
opathy in Japanese black calves. J Heredity 1979;70:255-258.
Weekes J, et al. Bovine dilated cardiomyopathy: proteomic analysis of
an animal model of human dilated cardiomyopathy. Electrophoresis
1999;20:898-906.
Diseases of the Heart
Owczarek-Lipska M, et al. A nonsense mutation in the optic atrophy
3 gene (OPA3) causes dilated cardiomyopathy in Red Holstein
cattle. Genomics 2011;97:51-57.
Simpson MA, et al. A mutation in NFkappaB interacting protein 1
causes cardiomyopathy and woolly haircoat syndrome of Poll Her-
eford cattle. Anim Genet 2009;40:42-46.
DISEASES OF THE CONDUCTION SYSTEM
The clinical and electrocardiographic features of primary con-
duction system disturbances are well documented, but com-
paratively rare. The clinical signs are primarily intermittent
collapse, and sometimes sudden death. Electrocardiography
may show a variety of abnormalities, such as sinoatrial  persistent atrial standstill, which occurs in dogs (most com-
arrest, second- or third-degree atrioventricular (AV) block,  monly in English Springer Spaniels) and has been described in
AV dissociation, left or right bundle branch block, Wolff-
Parkinson-White syndrome (rarely), and ventricular tachycar-
dia. It should not be forgotten that many if not most
dysrhythmias are secondary to more or less extensive myocardial
degeneration, necrosis, inflammation, or neoplasia, particularly
when in close proximity to the conduction system.
In contrast, reports on the gross and microscopic examination
of cases of primary conduction system disturbances are remark-
ably sparse. This may be due in part to negative pathologic
findings in some cases, or to time and effort required to ade-
quately examine the conduction system. When an abnormal-
ity of the conduction system is suspected, tissue samples from
the appropriate regions should be collected as part of the
postmortem (see Examination of the heart, previously). The
use of special stains such as Masson trichrome and phospho-
tungstic acid hematoxylin (PTAH) assist in highlighting the
presence of excessive fibrosis and the relative paucity of con-
tractile elements in the cells of the conduction system, respec-
tively. For purposes of comparison, it is advisable to have a
reference set of blocks of the conduction system from normal
animals.
Sudden unexpected death, sudden episodes of viciousness
or seizures have been associated with AV nodal, or common
bundle degeneration, particularly in the Doberman Pinscher.
Note that the presence of mineralized cartilage or osseous
metaplasia in the central fibrous body in close proximity to
conduction tissue is a normal finding in large-breed dogs at all
ages. The common bundle is fibrotic, degenerate, and in some
cases replaced by fat. In most cases, there is myointimal 
proliferation in arterioles in this region, possibly leading to
ischemia of the common bundle. A similar phenomenon  Fonfara S, et al. English Springer Spaniels with significant
has been observed in other breeds, including the German
Shepherd dog.
There is also a syndrome of sudden death in outwardly
healthy, nonsyncopal young German Shepherd dogs that is sus-
pected to be hereditary in nature. Affected animals die unex-
pectedly during sleep or during rest following exercise.
Ventricular tachycardia is the most common arrhythmia, the
frequency of which increases during rest when the heart rate
is slowest, and ends in ventricular fibrillation. The underlying
defect is suggested to be regional paucity of sympathetic
nerves in ventricular myocardium.
Hereditary stenosis of the common bundle has been
observed in cases of syncope and sudden death in Pug dogs.
Electrocardiographically, such dogs have intermittent sinus
arrest and paroxysmal second-degree AV block. The sinus
node, the AV node, and the bundle branches are normal. The
Diseases of the Conduction System 51
paroxysmal AV block could be related to the lesion in the
common bundle, but the sinus pauses are probably the result
of excessive parasympathetic activity. Affected dogs are abnor-
mally sensitive to small amounts of acetylcholine.
Deafness in the Dalmatian dog is associated with an abnor-
mal blotchy coat color, and such animals may die suddenly. A
proportion of affected dogs exhibit episodes of sinus pauses.
In one case, the right atrium was fibrotic and atrophied. This
was accompanied by marked narrowing of the coronary arter-
ies, including those of the sinus node. These clinical and patho-
logic findings are similar to those seen in congenital deafness
in humans.
The presence of an atrophic and fibrotic atrium in the
previous case is the outstanding feature of the syndrome of
Siamese cats. The atrium is grossly dilated, and the walls are
thin, transparent, and pink. Microscopically, there is myocyte
atrophy and fibrosis, with a variable mononuclear cell pres-
ence. In some cases, atrophy of skeletal musculature is also
evident. Given the nature of the end-stage lesions, the ante-
cedent may be an active myocarditis (see Fig. 1-49). The
syndrome is similar in many respects to a form of muscular
dystrophy in people termed Emery-Dreifuss disease.
Sick sinus syndrome occurs in Miniature Schnauzers, West
Highland White Terriers, and Dachshunds, and it is familial in
Miniature Schnauzers. Prolonged sinus pauses cause syncope.
Defects of the conduction system of Alaskan sled dogs
that died suddenly during the Iditarod race included marked
fibrosis or fatty infiltration of the sinus node, AV node, AV
bundle, and bundle branches, and focal scarring of the left
ventricle. These pathologic changes may have led to fatal
dysrhythmias.
Equine grass sickness (equine dysautonomia) is suspected
to be a clinical form of botulism. The neurodegenerative
changes noted in terminal parasympathetic ganglionic neurons
in the heart, which include chromatolysis and vacuolation,
may account for the tachycardia noted in this disease.
Ventricular pre-excitation, a rare cause of weakness,
syncope, or congestive heart failure in dogs and cats, can result
when sinus node impulses bypass the normal conduction
system via accessory pathways (bundle of Kent, James fibers,
Mahaim fibers, or intranodal tract) to cause premature ven-
tricular activation.
Further reading
bradyarrhythmias-presentation, troponin I and follow up after pace-
maker implantation. J Small Anim Pract 2010;51:155-161.
Kaneshige T, et al. Complete atrioventricular block associated with
lymphocytic myocarditis of the atrioventricular node in two young
adult dogs. J Comp Pathol 2007;137:146-150.
Park DS, Fishman GI. The cardiac conduction system. Circulation
2011;123:904-915.
Perkins JD, et al. Functional and histopathological evidence of cardiac
parasympathetic dysautonomia in equine grass sickness. Vet Rec
2000;146:246-250.
Sosunov EA, et al. Mechanisms of alpha-adrenergic potentiation of
ventricular arrhythmias in dogs with inherited arrhythmic sudden
death. Cardiovasc Res 2004;61:715-723.
Woolley R, et al. Atrial myocarditis as a cause of sinus arrest in a dog.
J Small Anim Pract 2007;48:455-457.
 51.e1

Further reading
Beckett SD, et al. Syncopal attacks and sudden death in dogs: mecha-
nisms and etiologies. J Am Anim Hosp Assoc 1978;14:378-386.
Bharati S, et al. The conduction system in sudden death in Alaskan sled
dogs during the Iditarod race and/or during training. Pacing Clin
Electrophysiol 1997;20(3 Pt 1):654-663.
Brain CM, et al. Sudden and unexpected death in horses and ponies:
an analysis of 200 cases. Equine Vet J 1988;20:99-103.
Gavaghan BJ, et al. Persistent atrial standstill in a cat. Aust Vet J
1999;77:574-579.
Hill BL, Tilley LP. Ventricular preexcitation in seven dogs and nine cats.
J Am Vet Med Assoc 1985;187:1026-1031.
James TN. Congenital deafness and cardiac arrhythmias. Am J Cardiol
1967;19:627-643.
James TN, et al. Hereditary stenosis of the His bundle in pug dogs.
Circulation 1975;52:1152-1160.
James TN, Drake EH. Sudden death in Doberman pinschers. Ann Intern
Med 1968;68:821-829.
Kiryu K, et al. Pathologic and electrocardiographic findings in sudden
cardiac death in racehorses. J Vet Med Sci 1999;61:921-928.
Liu SK, et al. Lesions of the conduction system in the cat with cardio-
myopathy. Recent Adv Cardiac Struct Metab 1975;10:681-693.
Meierhenry EF, Liu SK. Atrioventricular bundle degeneration associated
with sudden death in the dog. J Am Vet Med Assoc 1978;172:1418-
1422.
Moise NS. Inherited arrhythmias in the dog: potential experimental
models of cardiac disease. Cardiovasc Res 1999;44:37-46.
Robinson WF, et al. Sinoatrial arrest associated with primary atrial
myocarditis in a dog. J Small Anim Pract 1981;22:99-107.
Sandusky GE Jr, et al. Morphologic variations and aging in the atrio-
ventricular conduction system of large breed dogs. Anat Rec
1979;193:883-902.
52 CHAPTER 1  •  Cardiovascular System
Figure 1-56  Aortic body tumor in a dog. (Courtesy R. Kovi,
C. Foutz.)
NEOPLASMS OF THE HEART
Primary neoplastic disease of the heart in all domestic species is
rare, with the possible exception of hemangiosarcoma in the
right atrium of dogs (see Vascular neoplasms). In contrast,
metastasis to the myocardium from primary tumors of other
organs is relatively common. Primary tumors of the aortic body
(chemodectomas) and of ectopic thyroid and parathyroid may
arise at the base of the heart in dogs (Fig. 1-56) (see Vol. 3,
Endocrine glands).
Hemangiosarcoma, a tumor of high-grade malignancy, may
either arise as a primary in the myocardium, or metastasize to
the myocardium, most commonly from the spleen or the skin.
Characteristics of the tumor are described under Vascular
neoplasms.
Other primary cardiac tumors are rare, and include  reported in the dog, cat, and cattle. They are believed to arise
rhabdomyoma; rhabdomyosarcoma; angioleiomyoma; myxoma;
myxosarcoma; chondrosarcoma; osteosarcoma; granular cell
tumor; peripheral nerve sheath tumors, including neurofibroma;
fibroma; fibrosarcoma; leiomyoma; lipomas; pericardial mesothe-
lioma; and undifferentiated sarcoma.
Rhabdomyomas are anomalous formations (hamartomas) of
myocardial fibers seen as one or more circumscribed but non-
encapsulated nodules within the myocardium. It has been sug-
gested that swine cardiac rhabdomyomas are not hamartomas
but may represent congenital dysplasia of the perinatal cardiac
myocytes with myofibrillar degeneration. However, recent
evidence suggests that, at least in pigs, some rhabdomyomas
are of Purkinje cell origin. This is based on the fact that the
cells in question stain specifically for protein gene product 9.5,
a marker for neuronal tissue and Purkinje fiber cell origin.
Rhabdomyomas are rare in animals, but are most common in
pigs, and have been observed in cattle, sheep, and dogs; a breed
predisposition has been noted in red wattle pigs. Grossly, the
nodules are gray and may be found anywhere in the heart.
Those projecting into a chamber are very susceptible to hem-
orrhage and necrosis, and may become cystic (Fig. 1-57).  tumors are rare in animals but have been reported to occur in
Neoplasms of the Heart
Figure 1-57  Rhabdomyoma in a sheep. (Courtesy Massey Uni-
versity, Department of Pathobiology.)
Histologically, the cell type is predominantly mature myocar-
diocyte in type in a variant of rhabdomyoma, but cells in
rhabdomyomas are more typically large, vacuolated, glycogen
rich, with scant myofibrils, and resemble Purkinje cells; cells
with fine cytoplasmic strands extending from the nucleus to
the peripheral cytoplasm are referred to as “spider cells.”
Fibrosis can be extensive, and the connective tissues may be
impregnated with iron and calcium salts.
Angioleiomyomas have been recently recognized in
cattle (10-129 months of age) in Japan. These tumors were
previously diagnosed as schwannomas (neurofibroma), hem-
angiomas, leiomyosarcomas, or rhabdomyosarcomas. Angi-
oleiomyomas are characteristically located subendocardially 
in the right or left ventricle, involve the valve complex 
(valves, chordae tendineae, papillary muscles), are well cir-
cumscribed and project into the ventricular lumen. Two his-
tologic patterns coexist in each tumor to varying extents. The
first pattern is of interlacing fascicles of spindle-shaped cells,
the second of uniformly sized vascular channels. Giant cells,
positive for factor VIII–related antigen, are also a feature in
all tumors.
Myxomas are the most common cardiac tumor in adult
humans, but are rare in domestic animals; they have been
from multipotent vasoformative cells. They may originate
from the endocardium of any of the 4 cardiac chambers 
or from the heart valves. Gross appearance is often multilobu-
lar, soft, and gelatinous. Histologically, myxomas are covered
by endothelium on their surface, and are hypocellular, consist-
ing of stellate or globular cells, blood vessels, and smooth
muscle cells within an abundant myxoid matrix. Blood flow
may be interrupted by these intracavitary space-occupying
masses, and although they do not metastasize, they may gener-
ate emboli.
Primary cardiac chondrosarcoma occurs rarely and most
probably arises from cartilaginous or similar tissue that is
present in the cardiac skeleton. Of the few that have been
described, one arose in the right atrium, with the others arising
in the atrioventricular valves. As the tumors produce little
cartilaginous matrix, a positive reaction to the presence of
S100 protein is required to confirm the chondrocytic origin
of the neoplastic cells.
A granular cell tumor or granular cell myoblastoma has
been described in the right atrium of a dog. Granular cell
Diseases of the Heart Neoplasms of the Heart 53

Figure 1-58  Neurofibroma in an ox. (Courtesy Noah’s Arkive.)

A
a variety of organs, including the lung, brain, meninges, and
tongue. The tumor has a distinctive light and electron micro-
scopic appearance consisting of spindle-shaped to large polyg-
onal cells containing prominent cytoplasmic granules within
lysosomes. The cells are considered to be of neural origin as
nerve-specific S100 protein is present within the cytoplasmic
granules.
Neurofibromas (schwannomas) are either isolated or mul-
tiple benign neoplasms of peripheral nerves (Fig. 1-58, eFig.
1-13). Cattle are most frequently affected, with the most
common sites being peripheral nerves, brachial plexus, auto-
nomic ganglia, intercostal nerves, and cardiac nerves. The
disease is usually detected only at slaughter. When the heart
is involved, the tumors are single or multiple, round or nodular
masses, either on the epicardial surface or within the myocar-
dium. The microscopic appearance is of interwoven bundles
or whorls of elongated cells. There may be palisading of nuclei B
and variable amounts of collagen present. The principal cell is
Figure 1-59  Metastatic lymphoma in a dog. A. Lymphoma in all
probably of Schwann or perineural origin.
chambers of the heart. B. Opened atria showing lymphoma pro-
Lymphoma (lymphosarcoma) is the most common meta-
truding into atrioventricular lumen. (Courtesy A. G. Armien.)
static neoplasm involving the heart (Fig. 1-59A, B), and occurs
most commonly in the cow and the dog. It may be nodular
or diffuse, although the distinction is arbitrary because there
is overlap of the 2 forms. In the nodular form, there are foci,
primarily in the atria (particularly the right atrium), which
may be up to 5 cm or more in diameter. The nodules are Further reading
covered by endothelium and are therefore smooth. When Akkoc A, et al. Cardiac metastasing rhabdomyosarcoma in a great
beneath the epicardium, they may be difficult to distinguish dane. Vet Rec 2006;158:803-804.
from epicardial fat. They are prone to central necrosis, and this Aupperle H, et al. Primary and secondary heart tumours in dogs and
resembles necrotic adipose tissue. On section, the wall of the cats. J Comp Pathol 2007;136:18-26.
atrium is more diffusely thickened, is moderately soft to cut, Castleman WL, et al. Rhabdomyosarcoma in 8 horses. Vet Pathol
and has a pale appearance. If squeezed, milky fluid exudes 2011;48:1144-1150.
from the cut surface. Globular masses like those beneath the Jacobsen B, et al. Proposing the term purkinjeoma: protein gene
epicardium are also found under the endocardium projecting product 9.5 expression in 2 porcine cardiac rhabdomyomas indi-
into the cardiac cavities. In the diffuse or infiltrating form, the cates possible purkinje fiber cell origin. Vet Pathol 2010;47:738-
myocardium appears irregularly thickened and gray-white, 740.
with the ventricular walls being especially involved. These foci Misdorp W. Congenital and hereditary tumours in domestic animals:
or areas of infiltration blend with normal myocardium and 2. Pigs. A review. Vet Q 2003;25:17-30.
hence are difficult to distinguish from foci of myocardial Pavarini SP, et al. Malignant peripheral nerve sheath tumor as a cause
degeneration or myocarditis. If they cause some thickening of of chronic cardiac insufficiency in cattle. Acta Vet Scand 2013;55:
the myocardium, such lesions are to be first regarded as lym- 7-13.
phoma and indicate the need for careful search for primary Soilleux EJ, Davies DR. Epithelial cyst of the cardiac papillary muscle:
lesions elsewhere in the body. Lymphoid neoplasms are con- case report and review of the literature. J Clin Pathol 2006;59:1203-
sidered in detail in Vol. 3, Hematopoietic system. 1205.
 53.e1

eFigure 1-13  Neurofibroma, bovine. Section through a nodular

enlargement of an epicardial nerve.
53.e2

Further reading
Albers TM, et al. Histochemical and ultrastructural characterization of
primary cardiac chondrosarcoma. Vet Pathol 1997;34:150-151.
Balli A, et al. Cardiac tamponade due to pericardial mesothelioma in
an 11-year-old dog: diagnosis, medical and interventional treat-
ments. Schweiz Arch Tierheilkd 2003;145:82-87.
Bradley R, et al. Ovine and porcine so-called cardiac rhabdomyoma
(hamartoma). J Comp Pathol 1980;90:551-558.
Campbell MD, Gelberg HB. Endocardial ossifying myxoma of the right
atrium in a cat. Vet Pathol 2000;37:460-462.
Colbourne CM, et al. Mesothelioma in horses. Aust Vet J 1992;69:275-
278.
Foale RD, et al. Left ventricular myxosarcoma in a dog. J Small Anim
Pract 2003;44:503-507.
Girard C, et al. Intrapericardial neoplasia in dogs. J Vet Diagn Invest
1999;11:73-78.
Machida N, et al. Cardiac myxoma of the tricuspid valve in a dog.
J Comp Pathol 2003;129:320-324.
Machida N, et al. Primary malignant mixed mesenchymal tumour of
the heart in a dog. J Comp Pathol 2003;128:71-74.
Machida N, et al. Myocardial hamartoma of the right atrium in a dog.
J Comp Pathol 2002;127:297-300.
Merlo M, et al. Primary right atrium haemangiosarcoma in a cat.
J Feline Med Surg 2002;4:61-64.
Omi K, et al. An immunohistochemical study of peripheral neuro­
blastoma, ganglioneuroblastoma, anaplastic ganglioglioma,
schwannoma and neurofibroma in cattle. J Comp Pathol 1994;111:
1-14.
Perez J, et al. Right-sided heart failure in a dog with primary cardiac
rhabdomyosarcoma. J Am Anim Hosp Assoc 1998;34:208-211.
Sanford SE, et al. Primary cardiac granular cell tumor in a dog. Vet
Pathol 1984;21:489-494.
Swartant MS, et al. Intracardiac tumors in two dogs. J Am Anim Hosp
Assoc 1987;23:533-538.
Tanimoto T, Ohtsuki Y. The pathogenesis of so-called cardiac rhabdo-
myoma in swine: a histological, immunohistochemical and ultra-
structural study. Virchows Arch 1995;427(2):213-221. Erratum in:
Virchows Arch 1996;428:69.
Taylor DP, et al. Primary cardiac rhabdomyosarcoma in a steer. Aust Vet
J 2002;80:571-572.
Uno K, et al. Extraskeletal mesenchymal chondrosarcoma in a cow.
J Comp Pathol 1989;101:31-38.
Venco L, et al. Primary cardiac rhabdomyosarcoma in a cat. J Am Anim
Hosp Assoc 2001;37:159-163.
Ware WA, Hopper DL. Cardiac tumors in dogs: 1982-1995. J Vet Intern
Med 1999;13:95-103.
54 CHAPTER 1  •  Cardiovascular System
Tursi M, et al. Myocardial adenomatoid tumor in eight cattle: evidence
for mesothelial origin of bovine myocardial epithelial inclusions. Vet
Pathol 2009;46:897-903.
Une Y, et al. Cardiac angioleiomyoma in 44 cattle in Japan (1982-
2009). Vet Pathol 2010;47:923-930.
DISEASES OF THE VASCULAR SYSTEM
GENERAL CONSIDERATIONS
The vascular system may be arbitrarily divided into a delivery
system (the arterial system), an exchange network (the microcir-
culation), and a removal system (the venous and lymphatic
systems). Impaired function of the vascular system can be
generalized, as occurs in shock, or may be localized when the
supply of oxygenated arterial blood to tissue is decreased,
causing ischemia. Impaired venous drainage causes congestion,
and decreased lymphatic drainage of tissue fluids causes
lymphedema.
The arterial system is subdivided into large elastic arteries,
medium and small muscular arteries, and arterioles, with gradual
transitions between these divisions. Arterial vessels are char-
acterized histologically by walls composed of 3 layers: the
internal, middle, and external tunics; or tunica interna (intima),
tunica media (media), and tunica externa (adventitia).
The intima consists of endothelium; subendothelial con-
nective tissue, which contains collagen, elastin, proteoglycan
(ground substance), fibroblasts and smooth muscle cells; and
the internal elastic membrane, which is the outer limit of the
intima. The thickness of the intima decreases as the vessel size
decreases, until the subendothelial layer eventually disappears.
The internal elastic membrane is not readily distinguishable
in elastic arteries because of its continuity with medial elastic
tissue, but is very prominent in muscular arteries, and disap-
pears at the level of the smaller arterioles.
The media consists of concentric layers of smooth muscle
cells and elastic fibers, and the external elastic membrane.  there are large openings between the endothelial cells and a
In elastic arteries, the media consists of fenestrated elastic
laminae, with smooth muscle cells lying between laminae.
Intercellular ground substance is especially prominent in the
tunica media of elastic arteries in the horse. The elastic laminae
diminish and smooth muscle predominates as vessels become
more distant from the heart. The media of muscular arteries is
up to 40 muscle cells thick, whereas the media of arterioles
is 1-3 cells thick. Definitions of the upper limit of arteriolar
diameter range from 300 µm if tissues are fixed by perfusion
to 100 µm if allowed to contract, but there are no sharp dis-
tinctions between small arteries and large arterioles. The thick-
ness of the media as seen in routine material is greatest in
relation to the luminal diameter in small arteries and arteri-
oles, and it is these vessels, particularly arterioles, which par-
ticipate actively in blood pressure regulation and also bear the
consequences of hypertension. Contraction of muscular arter-
ies and arterioles upon an animal’s death forces blood from
the lumina, and causes longitudinal folding that appears as
scalloping of the internal elastic membrane when seen in
cross-section. The external elastic membrane is best defined
in the large elastic arteries, and becomes indistinct in muscular
arteries.
The adventitia consists of a feltwork of elastic and collagen
fibers continuous with the surrounding connective tissue. The
interlacing network of collagen fibers in the adventitia limits
General Considerations
expansion of the elastic arteries. Elastic fibers decrease in the
adventitia with decreasing vessel size. Vasa vasorum and nervi
vasorum supply the adventitia and the outer half of the media.
The intima and inner half of the media are avascular and depen-
dent upon diffusion from the vascular lumen, and are thus
more subject to degenerative changes than the outer media.
The microcirculation is the exchange system in which gases,
nutrients, and waste products are transferred between the blood
and the extravascular tissues. The microcirculation consists of
vessels of <100 µm in diameter: namely, arterioles, terminal
arterioles (metarterioles, precapillary sphincter areas), capillaries,
postcapillary venules, and venules. This classification overlaps
microcirculation and macrocirculation (arteries and veins),
but is useful conceptually as will be seen in disorders such as
disseminated intravascular coagulation, which affect primarily
the microcirculation. Arterioles open through precapillary
sphincters or through metarterioles into capillaries in most
tissues, or into sinusoids in the liver. Capillaries are low-
pressure tubules, of ~8 µm in diameter, composed of endo-
thelial cells surrounded by a basal lamina; the endothelial cells
are connected by tight junctions that allow rapid passage of
small molecules such as glucose. The basal lamina is a molecu-
lar sieve that prevents passage of larger protein molecules.
Capillary endothelial cells possess few endoplasmic organelles,
but often contain pinocytotic vesicles. Capillaries may be con-
tinuous, the most common type; fenestrated (60-80 µm fenes-
trae closed by thin diaphragms), as in the gastrointestinal tract
and endocrine glands; or porous (without diaphragms closing
the pores), as in renal glomeruli. Fenestration of the endothe-
lial cells allows increased permeability. During tissue healing,
cords of endothelial cells grow into the tissues by mitosis,
develop lumina, and become functional capillaries. Undiffer-
entiated perivascular cells, or pericytes, are ensheathed by gly-
cocalyx that is continuous with the capillary basal lamina.
Mitosis of pericytes is easily stimulated, and they may be
transformed into fibroblasts or smooth muscle cells. Sinusoids
are less uniform than capillaries and more permeable because
discontinuous basal lamina.
Veins are termed small, medium, or large or, alternatively,
venules, collecting veins, and great veins; all have large lumina
in relation to their wall thickness. Classification of veins by
wall characteristics is difficult because the layers in their walls
may be absent or difficult to distinguish. Venules of >30 µm
in diameter have an incomplete muscular media and thin
adventitia. Venular endothelium is normally more permeable
than that of capillaries and is also more sensitive to vasoactive
amines, the action of which can cause leakage. In the lymph
node paracortex, postcapillary venules, which are nonmuscular
venules with prominent endothelium, are important sites of
lymphocytic traffic. The media is of increasing thickness in
medium and large veins, and the internal elastic lamina
becomes more prominent. However, the adventitia is the thick-
est layer in veins, whereas the media predominates in arteries.
Backflow of blood in veins is prevented by the presence of
semilunar valves, which are invaginations of the intima into
the venous lumen. Venous valves are not present in venae
cavae or hepatic portal vein. Paucity of valves in veins of the
head and face may contribute to incidental venous congestion
in these areas.
Lymphatic capillaries originate in loose connective tissue,
and consist of very permeable walls and endothelial cells that
may lack, or have a discontinuous, basal lamina. In larger
Diseases of the Vascular System
lymphatics, valves are present, the basal lamina is continuous,
and walls consist of 3 ill-defined layers; an internal elastic
lamina is usually absent. The thin-walled veins and lymphatics
are more susceptible to compression and occlusion, are more
often involved by inflammation in adjacent tissue, and are
more liable to neoplastic invasion than are the thicker-walled
arteries.
Endothelium and smooth muscle, the main components of
vessel walls, play important roles in all types of vascular disease.
A wealth of information is accumulating about the important
properties and reactive capabilities of these seemingly simple
cells. For example, in addition to maintaining a permeability
barrier between blood and tissues, the endothelium is recognized
as the largest paracrine organ in the body. It produces antico-
agulants, procoagulants, fibrinolytic agents, prostanoids, con-
nective tissue components, adenosine, and a host of other
substances. Vascular homeostasis is maintained by complex
interactions among endothelial cells, leukocytes, and platelets,
each of which produce vasodilators and vasoconstrictors and
can interact to inhibit or promote thrombosis.
Vascular endothelial cells, as well as forming the throm­
boresistant monolayer lining of the vascular system,  activates the intrinsic pathway of coagulation. Fibronectin, or
mechanically insulate the circulating blood from the highly
thrombogenic subendothelial materials. The thromboresis-
tance of the endothelium is normally maintained by a balance
between antithrombotic and thrombotic factors; stimulation
of excessive prothrombosis can lead to clotting and thrombo-
sis, whereas excessive antithrombosis can lead to ineffective
hemostasis and bleeding (eFig. 1-14).
Antithrombosis is normally accomplished through
• Binding and inhibition of thrombin via activation by
thrombomodulin of protein C and protein S, via accentua-
tion of antithrombin activity by heparin-like molecules,
and via the presence of α2-macroglobulin
• Inhibition of platelet aggregation through elaboration of
prostacyclin (PGI2), a potent inhibitor of platelet aggrega-
tion and a vasodilator, and by adenosine diphosphatase
(ADPase)-mediated conversion of pro-aggregating ADP to
adenine nucleotide platelet inhibitors
• Promotion of fibrinolysis by synthesis of tissue plasminogen
activators
Procoagulant activities include:
• The presence of minute amounts of tissue factor (tissue
thromboplastin) in endothelial cells, further production of
which can be stimulated by endotoxin and by cytokines
such as interleukin-1 (IL-1) and tumor necrosis factor
• Synthesis and secretion of von Willebrand factor, needed
for adherence of platelets to subendothelial components,
and secretion of platelet activating factor, an activator and
aggregator of platelets
• Inhibition of fibrinolysis through release of plasminogen
activator inhibitors
In addition to their role in hemostasis, endothelial cells
participate in modulation of blood flow and vascular reactivity
by production of endothelium-derived relaxing factor (nitric
oxide); endothelin, a vasoconstrictor; angiotensin converting
enzyme, which converts angiotensin I to angiotensin II; and
prostacyclin. Endothelial cells modulate the actions of various
vasoconstrictors (catecholamines, serotonin, arginine, vaso-
pressin) and vasodilators (histamine, leukotrienes, adenine
nucleotides), and in concert with the endothelium-derived
factors can thereby allow blood vessels to rapidly adapt to
changes in hemodynamic conditions.
General Considerations 55
Endothelial cells aid in the regulation of inflammation and
immunity through production of IL-1 and various adhesion
molecules, which moderate adhesion and hence emigration of
leukocytes. The most important adhesion molecule pairs are
the selectins, the immunoglobulins intercellular adhesion 
molecule 1 (ICAM-1) and vascular cell adhesion molecule 1
(VCAM-1), and the β2 and β1 integrins. Endothelial cells also
aid in regulation of cell growth by production of growth stimula-
tors (platelet-derived growth factor, colony-stimulating factor,
and fibroblast growth factor), and production of growth inhib-
itors (heparin, transforming growth factor-β). Endothelial cells
produce basement membrane, and are capable of contraction.
The endothelium is a semipermeable membrane that can 
also transport metabolites, including proteins through the
cytoplasm via pinocytotic vesicles. Weibel-Palade bodies,
rod-shaped cytoplasmic organelles that store von Willebrand
factor, serve as ultrastructural markers of endothelial cells.
Subendothelial connective tissues consist of various types of
collagen, elastin, proteoglycans, fibronectin, laminin, and
thrombospondin. Of these, fibrillar collagen is the most potent
stimulus for platelet adhesion and activation; collagen also
“molecular glue,” normally functions to stabilize cell-to-cell
and cell-to-substrate attachments, but also becomes cross-
linked to fibrin and helps to anchor hemostatic plugs.
Mild endothelial injury, as occurs in the course of inflam-
mation, may be apparent histologically as hypertrophy of
endothelial cells (“reactive” cells). As well, increased vascular
permeability may lead to insudation of plasma proteins,
including fibrinogen, into the subendothelial area, and hence
contribute to vascular hyalinosis. Because the intima and inner
media depend upon diffusion of metabolites from the vascular
lumen for their nutrition, such subendothelial deposits may
impair the viability of smooth muscle cells and contribute to
degeneration, or fibrinoid necrosis, of vessel walls. Thus the
endothelial barrier must be preserved to maintain a normal envi-
ronment for medial smooth muscle cells. Necrosis of endothe-
lium, which may be caused by a wide variety of agents, leads
to exposure of subendothelial collagen, a potent inducer of
coagulation and platelet aggregation, and hence thrombosis.
Endothelial cells at the edges of denuded areas will proliferate
and migrate to repair the endothelial defect or to form an
endothelial covering over (endothelialize) a mural thrombus.
Severe microvascular damage, as occurs because of lipoperoxi-
dation of endothelial membranes in vitamin E/selenium defi-
ciency in pigs, can result in hemorrhage and organ failure.
Vascular smooth muscle cells are important both as effec-
tors of vasoconstriction and dilation, and as cells capable of
synthesizing basement membrane, collagen, elastin, and pro-
teoglycans of the extracellular space. In response to growth
factors derived from platelets and monocyte/macrophages,
smooth muscle cells of the media migrate through fenestrae
of the internal elastic lamina to the subendothelial area where,
as “myointimal” cells, they proliferate and are responsible for
organization or collagenization of deposits, including thrombi.
Examples of endoarterial organization and arterio-occlusive
disease are discussed later in this chapter. In common with
other muscle cells, medial smooth muscle cells respond to an
increased workload by hypertrophy. Medial hypertrophy is a
prominent consequence, as well as a cause, of pulmonary
hypertension. Sustained vasoconstriction, as is induced by
ergot (Claviceps purpurea) or fescue grass (Festuca arundina-
cea, Festuca eliator) poisoning, can lead to gangrene of the
 55.e1

The balance between thrombosis

and antithrombosis

Thrombosis
Release of tissue factor
from subendothelium after
endothelial cell injury.
Antithrombosis
Binding and inhibition of thrombin
via thrombomodulin activation
of protein C & S
Heparin-like molecules
-2 macroglobulin

Synthesis and secretion Inhibition of

of von Willebrand factor fibrinolysis via
Inhibition of platelet
Platelet aggregating factor plasminogen
aggregation by prostacyclins
activator inhibitors
ADPase-mediated ADP breakdown
Promotion of fibrinolysis via tissue
plasminogen activators

eFigure 1-14  Balance between thrombotic and antithrombotic factors. ADP, adenosine
diphosphate.
56 CHAPTER 1  •  Cardiovascular System
extremities; fescue toxicosis in cattle (summer syndrome) is
caused by infestation of the grass by the endophyte Neotypho-
dium (Acremonium) coenophialum, which produces the ergo-
peptide alkaloids, ergovaline, ergosine, and ergonine. Along
with the other components of the vessel wall, smooth muscle
cells may be involved in degenerative and inflammatory
changes, as described later, and contribute to fibrinoid necrosis
of the wall.
Normal aging changes of vessels include intimal thickening
resulting from proliferation of myointimal cells and accumula-
tion of their products, deterioration of medial elastic fibers,
medial fibrosis and loss of medial smooth muscle, and accu-
mulation of ground substance in the media. These slowly
progressive changes are usually of little consequence given the
large functional reserve of the vascular system, but do lead to
loss of resilience of the vessel walls and may cause vessel wall
thinning, stretching, and hence increased tortuosity.
Further reading
Bajema IM, Bruijn JA. What stuff is this! A historical perspective on
fibrinoid necrosis. J Pathol 2000;191:235-238.
Botha CJ, et al. Gangrenous ergotism in cattle grazing fescue (Festuca
elatior L.) in South Africa. J S Afr Vet Assoc 2004;75:45-48.
Galley HF, Webster NR. Physiology of the endothelium. Br J Anaesth
2004;93:105-113.
Miller LM, et al. Cardiovascular system and lymphatic vessels. In:
Zachary JF, McGavin MD, editors. Pathologoc Basis of Veterinary
Disease. 5th ed. St Louis: Elsevier; 2012. p. 539-588.
Mitchell RN, Schoen FJ. Blood vessels. In: Kumar V, et al., editors.
Robbins and Cotran Pathologic Basis of Disease. 8th ed.
Philadelphia: Saunders-Elsevier; 2010. p. 487-528.
Plendl J. Cardiovascular system. In: Eurell JO, Frappier BL, editors. Dell-
man’s Textbook of Veterinary Histology. 6th ed. Ames, Iowa: Wiley
Blackwell; 2007. p. 117-133.
ARTERIES
Congenital anomalies
Minor variations occur in the course and distribution of arter-
ies among individuals of a species, but these are of little sig-
nificance except possibly in surgical procedures.
Arteriovenous fistula, the communication of an artery and
vein that bypasses the capillary system, is a defect that may
arise developmentally or be acquired subsequent to physical
trauma, inflammatory necrosis involving adjacent vessels, neo-
plastic infiltration, or rupture of an arterial aneurysm into a
vein. Fistulas occur in dogs, cats, horses, and cattle, but are
uncommon. Clinically, fistulas most commonly occur in the
extremities and appear as a pulsating, fluctuant swelling in
which there is a palpable thrill and a machinery-like bruit on
auscultation. In general, arteriovenous fistulas cause decreased
peripheral resistance and increased venous return to the right
heart. When 20-50% of the cardiac output is shunted through
the fistula, high-output cardiac failure can occur. The veins
involved are usually thick-walled (“arterialized”), may be
dilated and extremely tortuous, and may have intimal sclero-
sis. Hepatic arteriovenous fistula (congenital hamartoma)
occurs in dogs and cats, and can cause portal hypertension,
portocaval shunts, and ascites (see Vol. 3, Liver and biliary
system).
Thebesian veins connect the cardiac chambers, between
the trabeculae carneae, with the myocardial sinusoids and
Arteries
capillaries. They may also connect with coronary arterioles to
form direct connections between the coronary arterioles and
the cardiac chambers. Areas of myocardium in which the
Thebesian vein system is richly persistent are randomly dis-
tributed, and the true nature of the defect may be overlooked
because of the tortuous aneurysmal dilation of the affected
coronary artery. Injection studies are necessary to demonstrate
the extent of the anastomosis.
Further reading
Hosgood G. Arteriovenous fistulas: pathophysiology, diagnosis, and
treatment. Compend Contin Educ Pract Vet 1989;11:625-636.
Koide K, et al. Congenital hepatic arteriovenous fistula with intrahe-
patic portosystemic shunt and aortic stenosis in a dog. J Vet Med
Sci 2004;66:299-302.
Nakata TM, et al. Transarterial coil embolization of an abdominal aor-
tocaval fistula in a dog. J Vet Intern Med 2014;28:656-660.
Degeneration of arteries
Arteriosclerosis
Arteriosclerosis literally means “hardening of the arteries,” and
is more fully defined as chronic arterial change consisting of
hardening, loss of elasticity, and luminal narrowing resulting
usually from proliferative and degenerative, rather than inflam-
matory, changes of the media and intima. The term athero­
sclerosis is applied to lesions of arteriosclerosis in which
degenerative fatty changes also occur. Atherosclerosis is the most
common and important type of arteriosclerosis in humans, and
the terms can thus be used interchangeably with little loss of
meaning when discussing this species. In domestic animals,
arteriosclerosis is common, but of little clinical importance, and
atherosclerosis is rare.
Arteriosclerosis develops slowly in animals, its extent and
incidence being greater in older animals. The disease may
become so widespread in individual animals that microscopi-
cally normal vessels may be difficult to find. The sclerotic
vessels are usually not accompanied by significant distur-
bances of blood flow, although ischemic change, especially of
brain and heart, may be seen. Well-developed lesions may be
good sites for thrombus formation in animals when thrombo-
genic circumstances prevail.
Arteriosclerosis uncomplicated by focal degeneration in the
sclerotic plaques and with no or minimal lipid deposition is the
lesion usually found in older horses, ruminants, and carnivores.
There is a predilection for the abdominal aorta and points of
arterial branching, but it is also seen in peripheral and pulmo-
nary arteries and in the thoracic aorta. The extensiveness of
the lesions is very variable, so that there is no clear differentia-
tion between a permissible aging change and a pathologic
process. The nature of the insult (or insults) to the vessel walls
that result in sclerosis is not known, although there are numer-
ous possibilities. Hemodynamic factors probably contribute,
especially to development of plaques about the orifices of
arterial branches.
Arteriosclerotic plaques produce a slight thickening and
wrinkling of the intima and are white, well delineated, and
oval to linear in shape. They can be found microscopically in
many animals in which they are not visible to the naked eye.
Their presence in peripheral, including coronary and cerebral
vessels, can be correlated with arteriosclerosis of the abdomi-
nal aorta.
 56.e1

Further reading
Adams JC, Lawler J. The thrombospondins. Int J Biochem Cell Biol
2004;36:961-968.
Bassenge E. Endothelial function in different organs. Prog Cardiovasc
Dis 1996;39:209-228.
Blodgett DJ. Fescue toxicosis. Vet Clin North Am Equine Pract
2001;17:567-577.
Carvalho D, Savage C. Cytokines, adhesion molecules, antiendothelial
cell autoantibodies and vascular disease. Cardiovasc Pathol
1997;6:61-78.
Cotran RS, Mayadas-Norton T. Endothelial adhesion molecules in
health and disease. Pathol Biol (Paris) 1998;46:164-170.
Fagrell B, Intaglietta M. Microcirculation: its significance in clinical and
molecular medicine. J Intern Med 1997;241:349-362.
Gwathmey JK, Paige JA. Endothelin and vasoactive peptides: new
cardiovascular mediators. J Vet Pharmacol Ther 1994;17:420-425.
Hirschi KK, D’Amore PA. Pericytes in the microvasculature. Cardiovasc
Res 1996;32:687-698.
Ju H, Dixon IM. Extracellular matrix and cardiovascular diseases. Can J
Cardiol 1996;12:1259-1267.
Michel CC. Capillaries, caveolae, calcium and cyclic nucleotides: a new
look at microvascular permeability. J Mol Cell Cardiol 1998;30:2541-
2546.
Schiffrin EL, Touyz RM. Vascular biology of endothelin. J Cardiovasc
Pharmacol 1998;32(Suppl. 3):S2-S13.
Turk JR. Physiologic and pathophysiologic effects of endothelin: impli-
cations in cardiopulmonary disease. J Am Vet Med Assoc
1998;212:265-270.
56.e2

Further reading
Bouayad H, et al. Peripheral acquired arteriovenous fistula: a report of
four cases and literature review. J Am Anim Hosp Assoc
1987;23:205-211.
Lamb CR, Naylor JM. Arteriovenous fistula in the orbit of a calf. Can
Vet J 1985;26:105-107.
Parks AH, et al. Lameness in a mare with signs of arteriovenous fistula.
J Am Vet Med Assoc 1989;194:379-380.
Diseases of the Vascular System
The initiating lesion(s) and the evolution of plaque forma-
tion are not fully elucidated. Microthrombi composed chiefly
of platelets are deposited at natural sites of turbulence or of
endothelial denudation, and may initiate the lesion. Platelets
secrete platelet-derived growth factor (PDGF), epidermal
growth factor, transforming growth factor-β, and other mito-
gens; PDGF stimulates migration and proliferation of smooth
muscle cells. Alternatively, the initial change in the vessel wall
may occur as the result of a nondenuding insult to the endo-
thelium; endothelial cells themselves produce several mito-
gens, including PDGF.
Histologically, the internal elastic lamina shows an early
distinctive change, becoming irregular in outline, partially
duplicated, and fragmented or discontinuous. Smooth muscle
cells migrate into the intima from the media to function as do
fibroblasts outside of arteries; these intimal smooth muscle
cells produce most of the connective tissue matrix of the
intimal plaque, including collagen, elastic tissue, and proteo-
glycans. In young plaques, or the deeper portions of older ones,
the smooth muscle cells (“myointimal cells”) are numerous and
intimately mixed with collagen, elastic fibrils, basement mem-
brane, and proteoglycans as the so-called musculoelastic layer.
In large and older plaques, a more superficial elastic hyper-
plastic layer may be recognized by a more compact arrange-
ment of collagen and elastica with relatively few cells. This
lamination of plaques is not always clearly evident, and its
development may depend on the age of the lesion as well as
on the segment of vessel involved, whether chiefly muscular
or chiefly elastic.
Further reading
Falk T, et al. Arteriosclerotic changes in the myocardium, lung, and
kidney in dogs with chronic congestive heart failure and myxoma-
tous mitral valve disease. Cardiovasc Pathol 2006;15:185-193.
Fishbein GA, Fishbein MC. Arteriosclerosis: rethinking the current clas-
sification. Arch Pathol Lab Med 2009;133:1309-1316.
Williams KJ. Coronary arteriosclerosis with myocardial atrophy in a
13-year-old dog. Vet Pathol 2003;40:695-697.
Atherosclerosis
Atherosclerosis is of little practical importance in domestic
animals, but is primarily of interest for the development of
animal models of the human disease. The atherosclerotic  and iliac arteries, as in man, and the plaques may cause con-
susceptibility of animals varies; rabbits, chickens, and pigs are
atherosensitive, whereas dogs, cats, cattle, goats, and rats are
atheroresistant. Swine and nonhuman primates are usually
considered to be the best large-animal models of human ath-
erosclerosis, and genetically modified mice are proving to be
valuable in the elucidation of the contribution of single factors
to the pathogenesis of the disease.
In humans, atherosclerosis and its complications of myocar-
dial infarction, stroke, and peripheral vascular disease are major
causes of morbidity and mortality in the developed world. Ath-
erosclerosis affects the large elastic arteries (aorta, iliac) and
the large and medium caliber muscular arteries (carotid, coro-
nary, femoral). The essential lesion is the atheroma or fibrofatty
plaque, which is a focal, raised, intimal plaque with a core of
lipid (predominantly cholesterol and its esters) covered by a
fibrous cap. Complications of plaques include mineralization,
ulceration, superimposed thrombosis, intraplaque hemorrhage,
and aneurysmal dilation. Fatty streaks, another type of fatty
Arteries 57
intimal lesion, are common in the aorta and large arteries of
domestic animals, especially ruminants and swine, and humans.
The streaks, which are soft, smooth, nonelevated lesions
ranging from pinpoint size up to several square centimeters,
are rarely visible grossly unless the aorta is stained with a fat
stain such as Sudan IV, which stains the lesions bright orange.
Streaks and plaques may coexist in the same area, but fatty
streaks also occur in areas in which plaques do not occur; thus,
the role of fatty streaks in the genesis of atherosclerosis is
unresolved. The major features of atherosclerosis are shown
in eFig. 1-15.
Multiple pathogenetic influences can contribute to the develop-
ment of plaques. The various events and theories of develop-
ment of atherosclerosis have been unified in the “response to
injury” hypothesis. Endothelial injury or dysfunction can occur
as the result of hyperlipidemia, with the cholesterol present
in low-density (LDL) and very-low-density lipoproteins
(VLDL) seen as a primary culprit. Additional risk factors in
humans are genetics, hypertension, smoking, obesity, inactiv-
ity, and diabetes mellitus. Immunologic mechanisms, toxins,
and viruses may also damage endothelium. Infectious agents,
such as Chlamydia pneumoniae, have been proposed as con-
tributing to the pathogenesis of atherosclerosis in humans, but
there is no evidence to date of a similar link in dogs or cats.
Endothelial injury leads to platelet adhesion, monocyte
adhesion and infiltration, and smooth muscle migration and
proliferation, as discussed above under Arteriosclerosis. The
involvement of various proinflammatory cytokines and che-
mokines are also considered to influence the development of
the atheromatous plaque. The feature added in atherosclerosis
is insudation of lipid, which is seen as extracellular lipid, often
with acicular clefts or as intracellular lipid in “foam cells.” The
lipid-laden foam cells that are characteristic of both fatty
streaks and atheromatous plaques may be either activated
macrophages or smooth muscle cells; macrophages predomi-
nate in streaks, whereas smooth muscle cells predominate in
the fibrous cap of plaques. Endothelial cell dysfunction is
emerging as an endocrinopathy that may contribute to the
effects of atherosclerosis through impaired ability of endothe-
lial cells to produce endothelial-derived relaxing factor and
through increased production of endothelin.
Atherosclerosis develops commonly only in the pig among
domestic species. Fatty streaks and atheromatous plaques
develop in the aorta, extramural coronary arteries, cerebral
siderable stenosis of vessels in swine 8-12 years of age. The
extent of lipid deposition can be influenced by feeding
extraordinary diets containing much lipid, including choles-
terol, but the atheromas rarely reach the degree of develop-
ment seen in humans, and they do not lead to occlusive
thrombus formation, which usually requires softening and
ulceration of the atheromatous plaque. The initial deposition
of lipid occurs in the proliferated smooth muscle cells, which
show signs of degeneration and which may become foam cells.
Macrophages also appear, containing lipid. Fat may be demon-
strable extracellularly, presumably released by degenerate
cells. Deposits of cholesterol and mineral, not extensive, may
be associated with softening of larger atheromatous plaques.
However, except in pigs fed high-fat diets, lipid is usually a
minor component of the predominantly fibromuscular
plaques.
Of the domestic animals, the deposition of cholesterol and
other lipids in the arteries in more than trace amounts occurs
 57.e1

Further reading
Fankhauser R, et al. Cerebrovascular disease in various animal species.
Ann N Y Acad Sci 1965;127:817-859.
Luginbuhl H. Vascular diseases in animals: comparative aspects of
cerebrovascular anatomy and pathology in different species. In:
Millikan CH, Siekert RG, et al., editors. Cerebral Vascular Diseases.
New York: Grune and Stratton; 1966. p. 3-27.
Maher ER Jr, Rush JE. Cardiovascular changes in the geriatric dog.
Compend Contin Educ Pract Vet 1990;12:921-931.
Marcus LC, Ross JR. Microscopic lesions in the hearts of aged horses
and mules. Pathol Vet 1967;4:162-185.
Nanda BS, Getty R. Age related histomorphological changes in the
cerebral arteries of domestic pig. Exp Gerontol 1971;6:453-460.
Prasad MC, et al. Caprine arterial diseases: I. Spontaneous aortic
lesions. Exp Mol Pathol 1972;17:14-28.
Schaub RG, et al. Platelet adhesion and myointimal proliferation in
canine pulmonary arteries. Am J Pathol 1981;104:13-22.
Whitney JC. Some aspects of the pathogenesis of canine arteriosclero-
sis. J Small Anim Pract 1976;17:87-97.
57.e2

Location
Large elastic arteries
and large/medium
muscular arteries

Atherosclerosis Complications
Essential lesion
Common in Mineralization/
Sub-intimal humans ulceration/
atheroma-fibrofatty
Uncommon in thrombosis of
plaque
domestic animals the plaque

Plaque
composition
Lipids especially
cholesterol both
intra and
extracellular

eFigure 1-15  Diagram of essential features of atherosclerosis.

58 CHAPTER 1  •  Cardiovascular System
Figure 1-60  Atherosclerosis of coronary arteries with irregular
thickening of vessels in a dog. (Courtesy J. Schefers.)
Figure 1-61  Atherosclerosis of meningeal arteries in a dog.
(Courtesy J. Schefers.)
only in dogs (Figs. 1-60 to 1-62), and then almost always in
association with hypothyroidism or diabetes mellitus. In dogs,
hypercholesterolemia is chiefly related to hypothyroidism, but
even in thyroidectomized, cholesterol-fed, hypercholesterol-
emic experimental dogs, only occasional dogs classed as
“hyper-responders” developed atherosclerosis, perhaps as a
result of an increased proportion of cholesterol-rich VLDL. A
breed predisposition to atherosclerosis in Miniature Schnau-
zers may be the result of idiopathic hyperlipoproteinemia.
The deposition of lipids in dogs begins in the middle and outer
layers of the media and occurs more extensively perhaps in the
small muscular arteries than in the large elastic ones; if present,
aortic lesions occur as intimal plaques. The veins are normal.
The vascular changes can be severe enough to be seen on gross
inspection. The vessels are enlarged, less pliable than normal,
and their walls are thickened and ill-defined because a hyper-
plastic adventitia merges irregularly with surrounding tissues.
Projecting into the lumens of the vessels on cross-section are
tiny yellow-brown nodules. In vessels large enough to be
opened longitudinally, there are numerous small yellow flat
elevations that may be confluent.
The media may be greatly increased in thickness by the
accumulation of lipid, most of which is in foam cells, but some
Arteries
Figure 1-62  Subintimal streaks and plaques of atherosclerosis in
the abdominal aorta in a dog. (Courtesy N. Kirchhof.)
is present in identifiable smooth muscle cells of the media or
free in the interstitium as droplets or crystals. The deposition
of lipid in the internal layers of the media leads to disruption
of the internal elastic lamina and involvement of the intima.
Substantial deposits of lipid may lead to eccentric enlarge-
ment of the vessel. Associated with the lipidosis, and possibly
as a response to it, there is progressive proliferation of fibrous
connective tissue. Beginning with the formation of fine fibrils
in and about the areas of lipid deposition, the fibrosis is pro-
gressive and may eventually completely transform the struc-
ture of the wall. The connective tissues become hyalinized and
relatively acellular and may be heavily impregnated with salts
of calcium and iron, present as granules, large aggregates, or
crystalline plaques.
Atheromatosis of the degree described above in dogs is rare.
Clinical consequences of severe atherosclerosis appear to be
infrequent in dogs, even though the vessels most severely
involved are those of the heart, brain, and kidney. Occasion-
ally, however, as in humans, rupture of the atheromatous area
into the lumen with thrombosis or even widespread lipid
embolism has been observed.
The morphology of atherosclerosis differs in dogs and in
humans; in dogs lipid is present in the intima, but is primarily
located in the media and adventitia of atherosclerotic arteries,
however, in humans, lipid is present primarily in the intima (Fig.
1-63A, B). The term “xanthomatosis” has been applied to the
canine condition in the past, but its use is inadvisable as it
may cause confusion with the human condition of primary
xanthomatosis (type II hyperlipoproteinemia), in which there
is premature atherosclerotic coronary artery disease, but also
xanthomatous infiltration of the myocardium, dermis, and
other organs with an associated granulomatous reaction. A
similar condition in other animal species is referred to as
xanthomatosis, and is characterized by the presence of lipid-
laden foam cells in subcutaneous or intracutaneous accumula-
tions known as xanthomas. A familial hyperlipoproteinemia
occurs in lipoprotein lipase deficient cats, and results in the
formation of xanthomata in a variety of organs; atherosclerosis
is not a feature of this condition.
Further reading
Furie MB, et al. Plaque attack—one hundred years of atherosclerosis
in the American Journal of Pathology. Am J Pathol 2012;180:2184-
2187.
 58.e1

Further reading
Armstrong ML, Heistad DD. Animal models of atherosclerosis. Athero-
sclerosis 1990;85:15-23.
Chastain CB, Graham CL. Xanthomatosis secondary to diabetes mel-
litus in a dog. J Am Vet Med Assoc 1978;172:1209-1211.
DeBowes LJ. Lipid metabolism and hyperlipoproteinemia in dogs.
Compend Contin Educ Pract Vet 1987;9:727-734.
Johnstone AC, et al. The pathology of an inherited hyperlipoprotein-
aemia of cats. J Comp Pathol 1990;102:125-137.
Maher ER Jr, Rush JE. Cardiovascular changes in the geriatric dog.
Compend Contin Educ Pract Vet 1990;12:921-931.
Ross R. Atherosclerosis-an inflammatory disease. N Eng J Med
1999;340:115-126.
Vanhoutte PM. Endothelial dysfunction: the first step toward coronary
arteriosclerosis. Circ J 2009;73:595-601.
Diseases of the Vascular System
A blood pressure, is an important disease of humans, and occurs
B lesion is a primary or a secondary event is difficult. Primary
Figure 1-63  Atherosclerosis. A. Extensive subintimal and medial
infiltration with lipid macrophages (“foam cells”) accompanied by
perivascular lymphocytic infiltration in a dog. B. Large complex
fibrofatty plaque within the subintima of a coronary artery of a
human. Note the severe vascular luminal compromise. (Courtesy
S. Mackey-Bojack.)
Galkina E, Ley K. Immune and inflammatory mechanisms of athero-
sclerosis. Annu Rev Immunol 2009;27:165-197.
Getz GS, Reardon CA. Animal models of atherosclerosis. Arterioscler
Thromb Vas Biol 2012;32:1104-1115.
Ginzinger DG, et al. Diet-induced atheroscelrosis in the domestic cat.
Lab Invest 1997;77:409-419.
Hamamdzic D, Wilensky RL. Porcine models of accelerated coronary
atherosclerosis: role of diabetes mellitus and hypercholesterolemia.
J Diabetes Res 2013;2013:761415.
Li X, et al. Animal models for the atherosclerosis research: a review.
Protein Cell 2011;2:189-201.
Libby P, et al. Progress and challenges in translating the biology of
atherosclerosis. Nature 2011;473:317-325.
Mizuno Y, et al. Inflammation and the development of atherosclerosis—
effects of lipid lowering therapy. J Atheroscler Thromb 2011;18:351-
358.
Soltaric-Quckermann IC, et al. Chlamydia in canine or feline coronary
arteriosclerotic lesions. BMC Res Notes 2011;4:350.
Arteries 59
Arteriolosclerosis
Arteriolosclerosis describes a heterogeneous group of arteriolar
lesions that may be predominantly hyaline or predominantly
hyperplastic. The major cause of these changes in vessels in
humans is hypertension, but the pathogenesis of the lesions
in domestic animals is often not determined. Endothelial
damage is likely the primary event in these conditions. Hyaline
degeneration—the microscopic appearance of amorphous,
brightly eosinophilic material in vessel walls—can occur as the
result of increased vascular permeability that allows insuda-
tion of various plasma components; it includes the amyloid
deposits of renal glomeruli and elsewhere, and the fibrin and
necrotic smooth muscle of “fibrinoid necrosis.” Fibrinoid necro-
sis may predate and initiate inflammatory cellular infiltration,
after which the reaction would be termed arteritis. Thickening
of the arteriolar wall may cause luminal narrowing and hence
ischemia of the region supplied.
Systemic hypertension, or persistently elevated systemic
as either primary (essential) hypertension or secondary hyperten-
sion. Both forms of hypertension are typically prolonged in
their clinical course, but accelerated or malignant hypertension
develops in about 5% of affected individuals. Both primary
and secondary hypertensions have been reported in dogs and
cats; the primary form is rare, and the secondary form is more
common. Hypertension may often go unrecognized as the
routine measurement of blood pressure in domestic animals
is problematic and as such is not part of the routine physical
examination. The diagnosis of hypertension could well become
more frequent as noninvasive techniques for measurement of
blood pressure come into common use.
Renal disease, likely the most common cause of hypertension
in dogs and cats, may be either a cause or an effect of hyper-
tension, thus determining whether a hypertensive vascular
hypertensive lesions can lead to decreased renal perfusion,
activation of the renin-angiotensin-aldosterone system, and
hence more hypertension. On the other hand, primary chronic
renal disease can lead to inadequate excretion of sodium and
water, blood volume expansion, and hence secondary hyper-
tension. In either case, hypertension is self-perpetuating as
medial hypertrophy and hyalinization of renal arteries 
lead to more nephrosclerosis, further hypertension, and more
pressure-induced vascular damage.
Secondary hypertension is reported to occur in >60% of
dogs with chronic renal disease, and may also occur in associa-
tion with endocardiosis, pheochromocytoma, hyperadreno-
corticism, hypothyroidism and hyperthyroidism, and diabetes
mellitus. In cats, hypertension occurs in association with
chronic renal disease, hyperthyroidism, and chronic anemia.
Systemic and local hypertensions reportedly accompany acute
and chronic laminitis in horses; hypertension is suggested to
occur in acute and chronic laminitis in cattle. The hyperten-
sion of feline hyperthyroidism is reversible on resolution of
the primary condition. The presenting sign in canine and feline
hypertension may be blindness due to hypertensive retinopathy;
ocular lesions include retinal vascular tortuosity, intraocular
hemorrhage, and retinal detachment, the results of retinal
arterial degeneration. In the face of hypertension, retinal and
choroidal arterioles constrict; sustained vasoconstriction may
lead to ischemic necrosis of the arteriolar smooth muscle,
increased vascular permeability, hyalinization, edema, and
hemorrhage. Left ventricular hypertrophy commonly occurs
60 CHAPTER 1  •  Cardiovascular System Arteries

in hypertension in response to increased demand for cardiac

output plus increased peripheral vascular resistance (increased
afterload).
Pulmonary hypertension—persistent elevation of pulmonary
arterial blood pressure—can occur both as the cause and as the
result of pulmonary arterial disease (see Vol. 2, Respiratory
system); and, in this chapter, Arterial hypertrophy, and Diro-
filariasis (heartworm disease).
Widespread arterial degeneration commonly occurs in dogs
with uremia, and is most frequently noted in small muscular
arteries and arterioles of the gastric submucosa, tongue, colon,
gallbladder, urinary bladder, and kidneys. Less frequently
affected are arteries of the small intestine, myocardium, and
other organs. The arterial and arteriolar lesions, in concert with
degenerative capillary lesions, produce ischemic injury, and
contribute to grossly observed lesions of uremia, such as
uremic gastric infarction.
The arterial lesions of acute renal insufficiency consist of
subendothelial deposition of fibrin, disruption of the internal
elastic lamina, necrosis of medial smooth muscle, mineraliza- Figure 1-64  Arteriolar hyalinosis. The tunica media of the small
tion, and sometimes, neutrophilic infiltration. These lesions caliber coronary artery is partially replaced by eosinophilic amor-
may be segmental or circumferential in the vessel wall. This phous material (arrow) in a dog. H&E.
arterial reaction is primarily degenerative rather than inflam-
matory, and is similar to hyaline arteriolosclerosis of benign
nephrosclerosis (patchy ischemic atrophy) in humans. In Arteriolar hyaline degeneration is seen in swine as part of
chronic renal insufficiency, medial hypertrophy and adventitial the pathologic picture in meninges in organomercurial poison-
fibrosis produce thickening and whorling of renal interlobular ing, in various organs in edema disease, and chiefly in the heart
and intralobular arteries and afferent arterioles. These changes in hepatosis dietetica and mulberry heart disease. The progres-
are similar to hyperplastic arteriolosclerosis of humans, which sion of arterial lesions in edema disease is from mural edema,
is characterized by concentric fibrosis and smooth muscle to hyaline degeneration, to medial necrosis and intramural and
proliferation in the intima (onion-skinning); these hyperplastic perivascular hemorrhage, at which stage acute severe hyper-
changes, in combination with fibrinoid necrosis of the media tension develops, likely as a result of increased vascular resis-
of arterioles, are features of malignant hypertension. tance, and hypertension in turn exacerbates vascular damage;
Hyalinosis is commonly observed in the splenic arterioles adventitial proliferation follows in survivors. Certain strains 
of dogs and pigs, affecting most frequently those of the lym- of Escherichia coli produce edema disease toxin (Shiga-like
phatic nodules. This change is more severe in dogs with a toxin-II variant, SLT-IIv), which preferentially targets vessels
variety of diseases, including diabetes mellitus and chronic of the gastric and colonic submucosa and the cerebellar folia,
renal disease, and thus may be of hypertensive origin. A hyper- perhaps because of concentration of a toxin receptor, such as
trophic hyalinization is regularly observed in the uterine  globotetraosylceramide, at these sites.
and ovarian arteries in pregnant and postpartum animals;  Cerebrospinal angiopathy in swine is characterized by
the elastic tissue is increased in amount, the intima is mark- lesions in arterioles, primarily in the brainstem, which include
edly thickened and hyaline, and the muscularis may be subendothelial hyaline deposits, degeneration or fibrinoid
atrophic. necrosis of the media, and perivascular eosinophilic droplets.
Hypertrophic hyalinization, or hyalinosis, is observed in old The vascular lesions cause demyelination and malacia, and
dogs, affecting principally the intramural coronary arteries (Fig. hence nervous signs, and are probably manifestations of sub-
1-64) and small meningeal and cerebral vessels. The hyaliniza- clinical edema disease.
tion is not clearly of clinical significance in the brain but may
cause multifocal intramural myocardial infarction (MIMI) and,
in concert with valvular endocardiosis, lead to congestive heart Further reading
failure. The hyaline deposits consist predominantly of fibrin Kellihan HB, Stepien RL. Pulmonary hypertension in dogs: diagnosis
or glycosaminoglycans or, less commonly, amyloid. Other and therapy. Vet Clin North Am Small Anim Pract 2010;40:623-
lesions encountered in the intramyocardial arteries include 641.
musculoelastic intimal thickenings, intimal cushions, and Reusch CE, et al. Endocrine hypertension in small animals. Vet Clin
microthrombi; these lesions occur at sites of turbulent blood North Am Small Anim Pract 2010;40:335-352.
flow, namely, bifurcations and branchings. Stepien RL. Feline systemic hypertension: diagnosis and management.
Sclerosis of intramural coronary arteries, predominantly of J Fel Med Surg 2011;13:35-43.
the left ventricle, occurs in dogs with congenital subaortic Zabka TS, et al. Pulmonary arteriopathy and idiopathic pulmonary arte-
stenosis and occurs in the right ventricle of dogs with pul- rial hypertension in six dogs. Vet Pathol 2006;43:510-522.
monic stenosis. Intimal thickening resulting from fibroelastic
and smooth muscle proliferation can result in myocardial
infarction and scarring. The intimal proliferation may occur in Mineralization
response to decreased coronary perfusion pressure and Mineralization (calcification) occurs quite frequently in the
increased intramural tension during systole. arteries of animals, either as a dystrophic or metastatic process.
 60.e1

Further reading
Andersson L, Bergman A. Pathology of bovine laminitis especially as
regards vascular lesions. Acta Vet Scand 1980;21:559-566.
Cheville NF. Uremic gastropathy in the dog. Vet Pathol 1979;16:292-
309.
Davies TS, et al. The pathology of subacute methylmercurialism in
swine. Cornell Vet 1976;66:32-55.
Dimski DS, Hawkins EC. Canine systemic hypertension. Compend
Contin Educ Pract Vet 1988;10:1152-1158.
Kamiya S, Daigo M. Relationship between glycosaminoglycans and
pregnancy-induced sclerosis in bovine uterine arteries. Jpn J Vet Sci
1988;50:1055-1059.
Kobayashi DL, et al. Hypertension in cats with chronic renal failure or
hyperthyroidism. J Vet Internal Med 1990;4:58-62.
MacLeod DL, et al. Reproduction of edema disease of swine with puri-
fied Shiga-like toxin-II variant. Vet Pathol 1991;28:66-73.
Nakamura K, et al. Perivascular eosinophilic droplets in swine brain
induced by Escherichia coli toxin. Can J Vet Res 1986;50:438-440.
Nielsen NO. Edema disease. In: Leman AD, et al., editors. Diseases of
Swine. 6th ed. Ames, Iowa: Iowa State University Press; 1986.
p. 528-540.
Paulsen ME, et al. Arterial hypertension in two canine siblings: ocular
and systemic manifestations. J Am Anim Hosp Assoc 1989;25:287-
295.
Perry LA, et al. Pulmonary hypertension. Compend Contin Educ Pract
Vet 1991;13:226-233.
Rau L. Hypertension, endothelium, and cardiovascular risk factors. Am
J Med 1991;90(Suppl. 2A):13S-18S.
Van Vleet JF, et al. Ultrastructural alterations in nutritional cardiomy-
opathy of selenium-vitamin E deficient swine: II. Vascular lesions.
Lab Invest 1977;37:201-211.
Diseases of the Vascular System
Figure 1-65  Extensive mineralization of the aorta in Solanum
glaucophyllum (S. malacoxylon) poisoning (vitamin D analogue
toxicosis) in a horse. (Courtesy E. Odriozola, F. Gianitti.)
Dystrophic mineralization, or mineralization of dying or dead
tissue, occurs in areas of inflammation, degeneration, and
thrombosis, and not necessarily in association with pre-existing
arteriosclerosis. Metastatic mineralization occurs as the result
of hypercalcemia and/or hyperphosphatemia. The distinction
between dystrophic and metastatic mineralization may be
artificial. In vitamin D toxicosis, for example, some maintain
that degeneration occurs prior to mineralization as a result of
direct vitamin D toxicity, and that hypercalcemia and miner-
alization are secondary events. Although the cardiovascular
system is particularly susceptible to mineralization, mineral-
ization of other soft tissues, such as the renal tubular and
pulmonary alveolar basement membranes, endocardium and
myocardium, and gastric mucosa, usually occurs concomi-
tantly with vascular mineralization.
Vitamin D poisoning occurs in a variety of circumstances,
and leads to mineralization of vessels and other tissues in
association with hypercalcemia and/or hyperphosphatemia (Fig.
1-65). The disease can be endemic in herbivores, cattle  and sites of predilection include the globus pallidus and inter-
most often, that have consumed plants (such as Solanum
glaucophyllum [formerly Solanum malacoxylon], S. torvum,
Trisetum flavescens, Cestrum diurnum) that contain 1,25-
dihydroxycholecalciferol or a related compound. Horses and
pigs are occasionally poisoned by inadvertent overdoses of
vitamin D in feed. Accidental poisoning of dogs and cats with
a cholecalciferol (vitamin D3) rodenticide is common.
Mineralization occurs in dogs with hypercalcemia resulting
from pseudohyperparathyroidism, in some dogs in association
with chronic renal insufficiency, and in hypomagnesemic
cattle. Mineralization also occurs spontaneously in animals of
advanced age and, in cattle especially, in a variety of chronic
debilitating diseases, such as Johne’s disease. In sporadic cases,
the causes of mineralization are generally unknown and may
be nonspecific.
Calcium and phosphorus are deposited in association with
extracellular vesicles adjacent to elastic fibers and, in the
smaller vessels, may produce a complete, concentric ring of
medial mineralization; this is the domestic animal equivalent
of Monckeberg’s arteriosclerosis (medial calcific sclerosis) of
humans. Mineralized lesions in the aorta and pulmonary artery
are usually in the form of flat plaques and are often very strik-
ing grossly; complete encirclement is seldom seen. The
Arteries 61
Figure 1-66  Intimal bodies (arrow) in a horse.
button-like protuberances that are seen in the aorta about the
orifices of smaller branches are not primarily aortic but,
instead, concentric lesions in the small efferents that project
when the opened vessel undergoes elastic recoil. The plaques
in the large vessels are brittle, and the smaller arteries are
transformed into rigid tubes that can be fractured easily.
Osseous metaplasia may also occur.
Intimal bodies occur commonly in small arteries and arteri-
oles of horses, particularly in the submucosa of the intestine,
but in other organs as well. Intimal bodies appear in section
as multiple irregular mineralized masses covered by endothe-
lium and usually protruding into the arterial lumen (Fig.
1-66). They occur in horses of all ages, are not associated with
strongyle infection, and have no apparent functional signifi-
cance. These bodies apparently arise from degeneration and
mineralization of subendothelial smooth muscle cells and
intercellular material.
The deposition of iron salts with calcium (siderocalcinosis)
is observed commonly in horses, the incidence and severity of
the change increasing with age. Vessels of all types are involved
nal capsule in the brain. Mostly, the deposits are without
notable consequence, but secondary malacia may occur. It is
also possible that malacia of other cause may exacerbate the
cerebrovascular siderosis.
The mineralized nodules in the intima of the aorta in the horse
are probably all healed lesions of verminous arteritis (Strongy-
lus vulgaris migration).
Further reading
Eason C, et al. Toxicity of cholecalciferol to rats in a multi-species bait.
N Z J Ecol 2010;34:233-236.
Falk T, et al. Arteriosclerotic changes in the myocardium, lung, and
kidney in dogs with chronic congestive heart failure and myxoma-
tous mitral valve disease. Cardiovasc Pathol 2006;15:185-193.
Murphy MJ, Talcott PA. Anticoagulant rodenticides. In: Peterson ME,
Talcott PA, editors. Small Animal Toxicology. 3rd ed. St Louis:
Elsevier; 2013. p. 435-446.
Schenck PA, Chew DJ. Hypercalcemia: a quick reference. Vet Clin North
Am Small Anim Pract 2008;38:449-453.
Schwarz T, et al. Aortic and cardiac mineralization in the dog. Vet
Radiol Ultrasound 2002;43:419-427.
 61.e1

Further reading
Bjotvedt G. Spontaneous renal arteriosclerosis in greyhounds. Canine
Pract 1986;13:26-30.
Bundza A, Stevenson DA. Arteriosclerosis in seven cattle. Can Vet J
1987;28:49-51.
De Oliveira AC, et al. Intimal asteroid bodies in horses: light and elec-
tron microscopic observations. Vet Pathol 1985;22:226-231.
Drazner FH. Hypercalcemia in the dog and cat. J Am Vet Med Assoc
1981;178:1252-1256.
Haggard DL, et al. Tetany associated with magnesium deficiency in
suckling beef calves. J Am Vet Med Assoc 1978;172:495-497.
Imaizumi K, et al. Morphological changes of the aorta and pulmonary
artery in thoroughbred racehorses. J Comp Pathol 1989;101:1-9.
Morris KML. Plant induced calcinosis: a review. Vet Human Toxicol
1982;24:34-48.
Rosol TJ, Capen CC. Pathogenesis of humoral hypercalcemia of malig-
nancy. Domestic Anim Endocrinol 1988;5:1-21.
Thomas JB, et al. Cholecalciferol rodenticide toxicity in a domestic cat.
Aust Vet J 1990;67:274-275.
62 CHAPTER 1  •  Cardiovascular System Arteries

Arterial rupture, aneurysms

Rupture of arteries as a result of physical trauma is common;
spontaneous ruptures are not. The aortic lesions produced by
Spirocerca lupi in dogs occasionally lead to rupture. Rupture of
a uterine artery is a cause of fatal hemorrhage in aged mares
at parturition and is associated with low serum copper levels.
Mycotic infection in the guttural pouch in horses may lead to
focal destruction of the wall of the internal carotid or maxil-
lary artery and can lead to fatal hemorrhage.
Rupture of the aorta is well known, but certainly uncommon,
in the horse. The ruptures occur during periods of excitement
and activity, such as racing or in stallions while breeding, and
are probably related to increased intra-aortic pressure. A pre-
disposing aortic lesion has not been definitely identified, but
fragmentation, degeneration, and mineralization of elastic A
fibers may contribute to weakening of the wall. “Cystic medial
necrosis,” the presence of pools of ground substance within
the elastic media, has been suggested to be an underlying
cause, but this change is present in the aortas of many normal
horses. Intimal thickening and medial fibrosis of vasa vasora
may predispose to aortic medial necrosis and rupture. Tears
occur in the ascending aorta at any level from the aortic val-
vular annulus to the level of the brachiocephalic trunk (Fig.
1-67A), and range from 0.5-1 cm tears in the right coronary
sinus to large transverse or 3-cornered tears in the cranial wall
of the aorta. Hemorrhage may occur into a number of differ-
ent sites. Hemopericardium, the most common sequel to aortic
rupture, leads to sudden death; hemorrhage into, and disrup-
tion of, the atrioventricular node or bundle of His also leads
to sudden death; dissection through the ventricular septum
and into the right ventricle (aortocardiac fistula) causes pro-
gressive right heart failure; dissection of blood along the aortic B
wall may lead to formation of an aneurysm, which may in turn Figure 1-67  A. Aortic rupture (arrow) in a horse. (Courtesy E.
rupture. Olson.) B. Rupture and linear tears in the root of the pulmonary
Spontaneous rupture of the pulmonary artery also occurs artery (arrows) in a horse (Courtesy M. Chalkley.)
in horses, but is even less frequent than aortic rupture 
(Fig. 1-67B).
Rupture of the aorta, pulmonary artery, or coronary artery
occurs experimentally, although not as a natural event, in greyhounds, possibly as a result of arteriosclerosis and hemo-
copper-deficient swine, and has been extensively investigated dynamic stresses, and can rupture with fatal consequences.
because of similarities with Marfan syndrome, an inherited Dissecting aneurysms may be of consequence by causing ste-
disorder in the fibrillin 1 (FBN1) gene in man and cattle in nosis of the aortic lumen, as well as by rupturing. True aneu-
which dissecting aortic aneurysms occur. Degeneration of elas- rysms are composed of all, or most, of the layers of the vessel wall.
tica appears to be the basis of the vascular lesions of copper Dilation of the cranial mesenteric artery may occur in the
deficiency, and is due to a deficiency of a copper-containing course of verminous arteritis in horses; the arterial wall is often
enzyme, lysyl oxidase, which is responsible for cross-linking of greatly thickened, but the dilation could be termed an inflam-
collagen and elastin. Similarly, feeding β-aminoproprionitrile matory rather than a true aneurysm. False aneurysms result
to pigs, rats or turkeys causes dissecting aortic aneurysms and from rupture of an artery or aneurysm and are essentially
skeletal changes, an experimental model known as lathyrism, hematomas communicating with an arterial lumen; their walls
but is due to inhibition, rather than deficiency, of lysyl oxidase. are formed by the surrounding fibrous tissue.
An aneurysm is a localized abnormal dilation of any vessel.
Aneurysms are of most importance when they affect the aorta;
they occur most commonly in humans as a complication of Further reading
atherosclerosis, but are infrequent occurrences in domestic Gershenson RT, et al. Abdominal aortic aneurysm associated with sys-
animals other than turkeys. On the basis of their gross appear- temic fungal infection in a German Shepherd dog. J Am Anim Hosp
ance, aneurysms may be classified as berry, saccular, fusiform, Assoc 2011;47:45-49.
or dissecting. In a dissecting aneurysm, blood enters the wall Hirano T, et al. Identification of an FBN1 mutation in bovine Marfan
of an artery through an intimal tear, dissects between medial syndrome-like disease. Anim Genet 2012;43:11-17.
layers, and creates a cavity within the arterial wall. A dissecting Lepage OM, et al. The mystery of fungal infection in the guttural
aortic aneurysm (dissecting hematoma, or acute aortic dissec- pouches. Vet J 2004;168:60-64.
tion) is one manifestation of aortic rupture in horses, and  Ploeg M, et al. Aortic rupture and aorto-pulmonary fistulation in the
may precede fatal aortic rupture. Dissecting aneurysms occur Friesian horse: characterization of the clinical and gross post-
in the coronary and renal arteries of young, male, racing  mortem findings in 24 cases. Equine Vet J 2013;45:101-106.
 62.e1

Further reading
Chetboul V, et al. Familial aortic aneurysm in Leonberg dogs. J Am Vet
Med Assoc 2003;223:1159-1162.
Coulson WF, et al. Lathyrism in swine. Arch Pathol 1969;87:411-417.
Marr CM, et al. Aorto-cardiac fistulas in seven horses. Vet Radiol Ultra-
sound 1998;39:22-31.
Potter KA, Besser TE. Cardiovascular lesions in bovine Marfan syn-
drome. Vet Pathol 1994;31:501-509.
Rings DM, et al. False carotid aneurysm in a sheep. J Am Vet Med Assoc
1986;189:799-801.
Robinson PN, Booms P. The molecular pathogenesis of the Marfan
syndrome. Cell Mol Life Sci 2001;58:1698-1707.
Simpson CF, et al. Similarity of aortic pathology in Marfan’s syndrome,
copper deficiency in chicks, and B-aminopropionitrile toxicity in
turkeys. Exp Mol Pathol 1980;32:81-90.
Stowe HD. Effects of age and impending parturition upon serum
copper of thoroughbred mares. J Nutr 1968;95:179-183.
van der Linde-Sipman JS, et al. Necrosis and rupture of the aorta and
pulmonary trunk in four horses. Vet Pathol 1985;22:51-53.
Diseases of the Vascular System
Figure 1-68  Organizing thrombus in the pulmonary artery of a
dog. H&E. (Courtesy E. Olson.)
Sleeper MM, et al. Aortic root disease in four horses. J Am Vet Med
Assoc 2001;219:491-496.
Waldrop JE, et al. Aortic dissection associated with aortic aneurysms
and posterior paresis in a dog. J Vet Intern Med 2003;17:
223-229.
Arterial thrombosis and embolism
The 3 major predispositions to thrombosis are
1. Injury to endothelium, for instance, via infectious, toxic, or
immunologic mechanisms
2. Altered blood flow, as occurs with stasis or turbulence
3. Hypercoagulability of the blood, which may result from
increased concentrations of activated procoagulants,
increased numbers or stickiness of platelets, or decreased
concentrations of inhibitors such as antithrombin in the
nephrotic syndrome.
The relative contribution of each of the above 3 features
(Virchow’s triad) may vary. Endothelial injury, by itself, is the
major cause of thrombosis, especially in the heart and arteries.
Stasis must usually be combined with endothelial damage
and/or hypercoagulability to induce thrombosis.
Thrombi are of importance because they occlude the vessel
at the site involved (Fig. 1-68), and because pieces of the
thrombus break off giving rise to emboli that may occlude
vessels distal to the site of thrombosis. Arterial occlusion is of
significance in organs with an end-arterial blood supply, such
as the kidney, because of the absence of collateral circulation
and the development of infarction. Simultaneous occlusion of
a large number of pulmonary arterioles or arteries by thrombi
can lead to right heart failure (cor pulmonale) and death. Even
in areas with extensive collateral circulation, blood flow in
vessels that are not thrombosed may be compromised by the
release of vasoactive substances, such as serotonin and/or pros-
taglandins from the thrombus.
Specific causes and examples of thrombosis abound. As
discussed later, thrombosis is a common complication of arte-
ritis. Specific examples of thrombosis, namely, aortic-iliac
thrombosis in horses and disseminated intravascular coagula-
tion, are discussed later.
Thromboembolism occurs in a variety of conditions and
species (eFig. 1-16). In verminous arteritis in horses, emboli
Arteries 63
Figure 1-69  Iliac thromboembolism in a cat.
arise from thrombi in the cranial mesenteric artery and cause
intestinal ischemia, and possibly infarction. Saddle thromboem-
boli of the aortic trifurcation in cats (Fig. 1-69) arise from
thrombi in the dilated left atrium in cases of cardiomyopathy
and cause paraparesis of acute onset; the clinical signs of aortic
trifurcation obstruction, referred to as the 5 p’s, are pain, paresis,
pulselessness, poikilothermy, and pallor. Arterial thromboembo-
lism occasionally occurs as a result of congenital cardiac
defects and the formation of intracardiac thrombi. Emboli
commonly arise from the cardiac valves in cases of vegetative
bacterial endocarditis. Thrombi that develop in animals under-
going extended anesthesia can result in fatal pulmonary
microthromboembolism, a common occurrence in humans,
but a condition that is seldom recognized in domestic animals.
Pulmonary thromboembolism may well complicate a variety
of conditions, such as cardiac or renal disease, physical 
trauma, disseminated intravascular coagulation, hyperadreno-
corticism, and neoplasia, but be underdiagnosed as a cause of
morbidity.
Thrombosis is by far the most common antecedent to
embolism, but emboli other than thromboemboli occasionally
occur. Venous air embolism is a rare complication of pneumo-
cystography, laparoscopy, or cryosurgery; an air trap develops
in the right ventricle and may cause fatal blockage of circula-
tion. Foreign bodies, such as pellets or bullets, may be embolic
and occlude major vessels such as the aorta. Larval and adult
parasites, such as strongyles and heartworms, may be embolic
in the arterial system, especially if killed by therapy, and may
cause arterial occlusion plus a granulomatous response. Emboli
of neoplastic cells can result in distant metastases. Fibrocarti-
laginous embolism can result in necrotizing myelopathy in
dogs, pigs, and humans (Fig. 1-70). Fractures of bones, espe-
cially of those of the pelvis, and trauma of soft tissues can
result in fat embolism; death may occur because of emboliza-
tion of the central nervous system. Embolic fat may also
originate from rupture of fat-laden hepatocytes.
Further reading
Carr AP, et al. Prognostic factors for mortality and thromboembolism
in canine immune-mediated hemolytic anemia: a retrospective
study of 72 dogs. J Vet Intern Med 2002;16:504-509.
de Laforcade AM. Diseases associated with thrombosis. Top Comp
Anim Med 2012;27:59-64.
Gandini G, et al. Fibrocartilaginous embolism in 75 dogs: clinical find-
ings and factors influencing the recovery rate. J Small Anim Pract
2003;44:76-80.
 63.e1

eFigure 1-16  Laminations in an arterial thrombus, with organi-

zation from the intima and markedly reduced eccentric lumen, in
aortic-iliac thrombosis in a calf.
63.e2

Further reading
Anderson WI, et al. Infarction of the pons and medulla oblongata
caused by arteriolar thrombosis in a horse. Cornell Vet 1990;80:285-
289.
Boswood A, et al. Aortic and iliac thrombosis in six dogs. J Small Anim
Pract 2000;41:109-114.
Du Preez ER, et al. Aortic thromboembolism associated with traumatic
reticuloperitonitis in a downer cow. J S Afr Vet Assoc 1995;66:254-
255.
Forrest LJ, et al. Digital arterial thrombosis in a septicemic foal. J Vet
Intern Med 1999;13:382-385.
Gilroy BA, Anson LW. Fatal air embolism during anesthesia for laparos-
copy in a dog. J Am Vet Med Assoc 1987;190:552-554.
Green RA. Pathophysiology of antithrombin III deficiency. Vet Clin
North Am Small Anim Pract 1988;18:95-104.
Jones RS, et al. Pulmonary micro-embolism following orthopaedic
surgery in a thoroughbred gelding. Equine Vet J 1988;20:382-384.
LaRue MJ, Murtaugh RJ. Pulmonary thromboembolism in dogs: 47
cases (1986-1987). J Am Vet Med Assoc 1990;197:1368-1372.
Meschter CL. Disseminated sweat gland adenocarcinoma with acrone-
crosis in a cat. Cornell Vet 1991;81:195-203.
Rudmann DG, Stevenson GW. Aortic-iliac thromboembolism as an
uncommon sequel to Staphylococcus aureus valvular endocarditis
in a calf. J Vet Diagn Invest 1993;5:288-290.
Schermerhorn T, et al. Pulmonary thromboembolism in cats. J Vet
Intern Med 2004;18:533-535.
Stuart BP, et al. Ischemic myopathy associated with systemic dirofila-
riasis. J Am Anim Hosp Assoc 1978;14:36-39.
Swanwick RA, Williams OJ. Fatal myocardial infarct in a greyhound.
J Small Anim Pract 1982;23:451-455.
Whigham HM, et al. Aortic foreign body resulting in ischemic neuro-
myopathy and development of collateral circulation in a cat. J Am
Vet Med Assoc 1998;213:829-832.
64 CHAPTER 1  •  Cardiovascular System
Figure 1-70  Fibrocartilaginous emboli in the meningeal and
spinal cord veins of a dog. H&E. (Courtesy A. Allen, coordinator,
Western Conference of Veterinary Diagnostic Pathologists.)
Figure 1-71  Large organized thrombus in the terminal aorta and
the internal and external iliac arteries in a horse with aortic-iliac
thrombosis. (Courtesy University of Guelph.)
Kuzi S, et al. Plasma antithrombin activity as a diagnostic and prognos-
tic indicator in dogs: a retrospective study of 149 dogs. J Vet Int
Med 2012;24:587-596.
Smith SA, Tobias AH. Feline arterial thromboembolism: an update. Vet
Clin North Am Small Anim Pract 2004;34:1245-1271.
Terrell SP, et al. Fatal intraoperative pulmonary fat embolism during
cemented total hip arthroplasty in a dog. J Am Anim Hosp Assoc
2004;40:345-348.
Whiteman T, Hassouna HI. Hypercoagulable states. Hematol Oncol Clin
North Am 2000;14:355-377.
Aortic-iliac thrombosis in horses
Aortic-iliac thrombosis causes exercise intolerance and hindleg
lameness (intermittent claudication) in affected horses. The
condition is seen most frequently in racing Thoroughbreds and
Standardbreds, especially young males. The oldest lesions are
located at the aortic quadrifurcation and in the distal portions
of the femoral and internal iliac arteries (Fig. 1-71, eFigs. 1-17,
1-18), and consist of partially or completely occlusive masses
Arteries
of well-organized and well-vascularized fibrous tissue, occa-
sionally containing hemorrhagic or degenerate areas. Proximal
to these organized masses, large unorganized thrombi are
often present. The tunica intima is obliterated by the occlusive
masses, except for the internal elastic lamina, which usually
remains intact. The tunica media is largely unaffected, except
for ischemic necrosis of the media in greatly distended arteries
or under thick plaques. The pathogenesis of the lesions is
unknown. The lesions may result from organization of
strongyle-related thromboemboli, or from progressive enlarge-
ment and organization of spontaneously developing fibrous
intimal plaques.
Further reading
Oyamada T, et al. Pathology of aortic-iliac thrombosis in two horses.
J Equine Sci 2007;18:59-65.
Swanson TD. Aortic-iliac thrombosis in horses. Compend Contin Ed
Pract Vet 2011;33:E1-E3.
Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) is a common and
important intermediary mechanism of disease, but is not a disease
in itself. It may be defined as a pathologic activation of the
coagulation system that leads to generalized intravascular clot-
ting involving, in particular, arterioles and capillaries. The
process may be acute, subacute, or chronic, and may be localized
or generalized. Macrothrombosis does not usually develop in
this disorder. The terms “consumption coagulopathy,” “defibrina-
tion syndrome,” and “consumptive thrombohemorrhagic disorder”
are also used because of the massive consumption of coagula-
tion factors that occurs and that may be sufficiently severe for
hemorrhagic diathesis to result.
A wide array of agents and conditions will initiate coagulation
(Box 1-1), either by
• Causing widespread endothelial damage and thus exposing
thrombogenic subendothelial collagen, or
• Directly activating the coagulation cascade via the intrinsic
or extrinsic pathway.
Exposure of monocytes, macrophages, and endothelial cells
to disease agents or mediators will cause expression of tissue
factor (tissue thromboplastin) on the cell surfaces and activation
of the extrinsic pathway of coagulation, and is likely a pre-
dominant pathway of DIC. As well as leading to expression
of intravascular tissue factor, inflammation promotes coagula-
tion by eliciting the expression of leukocyte adhesion molecules
on intravascular cell surfaces, and by downregulating the fibri-
nolytic and protein C anticoagulant pathways. Thrombin can
in turn promote inflammatory responses, leading to further
vascular injury. Stasis of blood flow and plasma hyperviscosity
are other factors that may contribute to DIC.
Many of the agents listed in Box 1-1 may initiate DIC by
more than one route. For example, gram-negative bacterial
endotoxin can cause
• Endothelial damage (either directly or via mediators such
as interleukin-1 and tumor necrosis factor), which exposes
subendothelial collagen and leads to activation of platelets
and Hageman factor
• Activation of the complement cascade and hence platelet
activation
• Direct activation of Hageman factor and hence the intrin-
sic pathway
 64.e1

eFigure 1-17  Organized thrombi partially occluding external

iliac and popliteal arteries in a horse with aortic-iliac thrombosis.
(Courtesy University of Guelph.)

a b c d

e f g

eFigure 1-18  Aortic-iliac thrombosis in a horse. Sections of left

external iliac-femoral-popliteal artery. (a) Peripheral organization
of partially occlusive thrombotic mass. (a-c, e-g) various degrees
of arterial occlusion by mature fibrous tissue. (d) unaffected artery
distal to lesion. Masson trichrome. (From Maxie MG, Physick-
Sheard PW. Aortic-iliac thrombosis in horses. Vet Pathol
1985;22:238-49.)
64.e2

Further reading
Brama PA, et al. Thrombosis of the aorta and the caudal arteries in the
horse; additional diagnostics and a new surgical treatment. Vet Q
1996;18(Suppl. 2):S85-S89.
Maxie MG, Physick-Sheard PW. Aortic-iliac thrombosis in horses. Vet
Pathol 1985;22:238-249.
Moore LA, et al. Aorto-iliac thrombosis in a foal. Vet Rec 1998;142:
459-462.
Diseases of the Vascular System Arteries 65

kallikrein-kinin system; generation of kinins contributes to

BOX • 1-1  increased vascular permeability, hypotension, and shock.
When coagulation is initiated, activated Hageman factor
Agents or conditions known to induce
simultaneously converts plasminogen to plasmin. Plasmin
disseminated intravascular coagulation cleaves fibrinogen/fibrin to produce fibrinogen/fibrin degrada-
in animals tion products that inhibit thrombin activity, fibrin polymeriza-
tion, and platelet aggregation. A negative feedback system
Bacteria normally exists between thrombosis (coagulation) and fibri-
• Gram-negative (endotoxin)
nolysis (anticoagulation) in which thrombin helps convert
• Gram-positive
plasminogen to plasmin to cause fibrinolysis and hence limit
• Rickettsia rickettsii (Rocky Mountain spotted fever)
thrombosis. In addition, a dynamic equilibrium exists between
production of tissue plasminogen activator and production of
Helminths plasminogen activator inhibitors by endothelial cells.
• Angiostrongylus vasorum
The clinical manifestations of DIC are protean and vary with
• Dirofilaria immitis
the organ(s) in which thrombosis predominates and the severity
of a hemorrhagic diathesis. Clinical presentations include shock,
Protozoa organ failure, hemorrhage, or hemolysis depending upon the
• Babesia spp.
relative activation of thrombin and plasmin and hence the
• Sarcocystis spp.
dominance of thrombosis or hemorrhage. Hemorrhage is
• Theileria spp.
usually only seen in animals that survive acute episodes with
• Trypanosoma spp.
thrombosis and shock, or in those reacting to a moderate
procoagulatory stimulus. Perhaps the most common result of
Viruses acute DIC is shock, which is due to reduced venous return to
• African swine fever virus
the right heart, plus systemic and pulmonary arterial hyper-
• Aleutian mink disease virus
tension resulting from thrombosis. Specific examples of DIC
• Bluetongue virus
include
• Canine adenovirus 1 (infectious canine hepatitis)
• The generalized Shwartzman-like reaction (GSR) (bilat-
• Classical swine fever virus
eral hemorrhagic renal cortical necrosis, induced experi-
• Epizootic hemorrhagic disease virus of deer
mentally by timed injections of endotoxin), which is seen
• Feline infectious peritonitis virus
as a cause of oliguric renal failure in septicemic or endo-
toxemic postpartum cows
Neoplasia • Hemorrhagic adrenal necrosis (Waterhouse-Friderichsen
• Carcinoma
syndrome) seen in septicemic calves
• Hemangiosarcoma
• Microangiopathic hemolytic anemia (MHA) (an intravas-
• Leukemia
cular fragmentation anemia) seen in septicemic calves
• Acrocyanosis and gangrene seen in the extremities of
Other calves recovering from septicemia
• Aflatoxicosis
• The hemolytic-uremic syndrome (HUS), in which coagula-
• Antigen-antibody complexes—incompatible blood
tion is combined with microangiopathic hemolytic anemia
transfusion
and acute renal failure; a similar syndrome is seen in Grey-
• Gastric dilation-volvulus
hound dogs with idiopathic cutaneous and renal glomeru-
• Heat stroke
lar vasculopathy (“Alabama rot”).
• Hyperlipemia in ponies
Animals that die with DIC may have petechial to ecchy-
• Hyperosmolality
motic hemorrhages on mucosae and serosae and in the skin,
• Immunologic endothelial injury
and may have variable thrombotic or hemorrhagic involve-
• Ingestion of red maple leaves
ment of internal organs. Histologically, microthrombi may be
• Nephrotic syndrome
associated with congestion, edema, hemorrhage, and necrosis.
• Proteolytic enzymes—pancreatitis, snakebite
Microthrombi are most easily detected microscopically in capil-
• Shock, vascular stasis, prolonged anesthesia, acidosis
laries of brain, renal glomeruli, adrenals, lungs, and myocardium,
• Tissue necrosis—hepatic, pneumonia, postsurgery, burns
but may occur in any organ. They consist primarily of fibrin
(hyaline thrombi), platelets (granular thrombi), or of fibrin
degradation products (hyaline globules or “shock bodies”); pul-
monary alveolar hyaline membranes are also said to be a form
• Leukocyte damage, which results in tissue factor (tissue of hyaline microthrombi. Because fibrinolysis is an ongoing
thromboplastin) release process that continues after death, most microthrombi are lysed
Viral infections are postulated to induce DIC by viral- or within 3 hours of death and may not be found if postmortem
antiplatelet antibody–mediated platelet aggregation, by examination is delayed. With routine hematoxylin and eosin
causing endothelial damage, and by causing Hageman factor staining, microthrombi appear as homogeneous pink masses
activation by immune complexes. Also, in feline infectious in dilated small blood vessels. Identification of microthrombi
peritonitis for example, hepatic necrosis impairs macrophage is aided by the use of special stains such as Martius-scarlet-
clearance of activated clotting factors and may potentiate the blue, which stains fibrin red, or phosphotungstic acid 
coagulation defect. Another important pathophysiologic event hematoxylin (PTAH), which stains fibrin purple. Even with
that accompanies activation of coagulation is activation of the special stains, incompletely polymerized fibrin is difficult 
66 CHAPTER 1  •  Cardiovascular System
to demonstrate. Red cells that impinge on fibrin strands in the
microcirculation may fragment; these red cell fragments
(schistocytes) may be detected within blood vessels in histo-
logic sections as well as blood smears, thus serving as indica-
tors of DIC.
Further reading
Bensaude E, et al. Classical swine fever virus induces proinflammatory
cytokines and tissue factor expression and inhibits apoptosis and
interferon synthesis during the establishment of long-term infection
of porcine vascular endothelial cells. J Gen Virol 2004;85:1029-
1037.
Chantrey J, et al. Haemolytic-uraemic syndrome in a dog. J Vet Med A
Physiol Pathol Clin Med 2002;49:470-472.
Dallap BL. Coagulopathy in the equine critical care patient. Vet Clin
North Am Equine Pract 2004;20:231-251.
De Laforcade AM, et al. Serial evaluation of protein C and antithrom-
bin in dogs with sepsis. J Vet Int Med 2008;22:26-30.
Dolente BA, et al. Clinicopathologic evidence of disseminated intravas-
cular coagulation in horses with acute colitis. J Am Vet Med Assoc
2002;220:1034-1038.
Gao H, et al. Bench-to-bedside review: sepsis, severe sepsis and septic
shock—does the nature of the infecting organism matter. Critical
Care 2008;12:212-217.
Gasser AM, et al. Canine Rocky Mountain spotted fever: a retrospec-
tive study of 30 cases. J Am Anim Hosp Assoc 2001;37:41-48.
Hardaway RM. A review of septic shock. Am Surg 2000;66:22-29.
Monreal L, et al. Hypercoagulation and hypofibrinolysis in horses with
colic and DIC. Equine Vet J Suppl 2000;32:19-25.
Putsche JC, Kohn B. Primary immune-mediated thrombocytopenia in
30 dogs (1997-2003). J Am Anim Hosp Assoc 2008;44:250-257.
Vallee I, et al. African swine fever virus infection of porcine aortic
endothelial cells leads to inhibition of inflammatory responses,
activation of the thrombotic state, and apoptosis. J Virol
2001;75:10372-10382.
Arterial hypertrophy
Hypertrophy of arteries may affect one or all components of
the arterial wall. High-altitude disease of cattle, described later,
is a result of hypoxia-induced pulmonary arterial constriction
and subsequent hypertrophy that lead to pulmonary hyper-
tension and eventual right heart failure (cor pulmonale).
Various cardiac anomalies cause pulmonary arterial hyperten-
sion and hyperperfusion, which result in pulmonary arterial
hypertrophy and additional pulmonary hypertension. Arterial
hypertrophy occurs in collateral vessels in response to the extra
load they carry after occlusion of the artery that usually sup-
plies an area. A specific form of hypertrophy occurs in the
pulmonary arteries of cats and is described later. Systemic arte-
rial involvement in the hypertension associated with chronic
renal disease is described previously.
“High-altitude disease” of cattle
This disease is caused by pulmonary hypertension that results in
dilation and hypertrophy of the right ventricle with the ultimate
development of cardiac decompensation and right-sided congestive
cardiac failure. Edematous swelling of the venter, as is typical
of congestive heart failure in cattle, is responsible for the
synonym “brisket disease.” The syndrome in cattle resembles,
in many respects, the chronic mountain sickness of humans
residing at high altitude, and represents failure of the
Arteries
cardiorespiratory system to adjust to the hypoxia of higher
altitudes. There are species differences in the hypertensive
response to hypoxia; sheep and dogs are hyporesponders,
humans are intermediate, whereas cattle and pigs are hyper-
responders and are prone to develop hypertensive heart failure
at altitudes of ~2,500 meters and above. There are also varia-
tions within species, and some cattle react dramatically to
degrees of hypoxia that only mildly inconvenience others.
Young cattle are more susceptible than adults, and the mor-
bidity rate is highest in animals exposed to high altitudes for
the first time. In animals imported from low altitudes to about
3,500 meters, the incidence of severe pulmonary hypertension
approaches 50%, whereas in herds maintained at such alti-
tudes for many generations, high-altitude disease may not
affect >2%. The different morbidity rates are probably attrib-
utable to natural selection in the resident population.
Cattle exposed to critical altitudes, or experimentally to
comparable degrees of hypoxic stimulation, develop a several-
fold increase in pulmonary arterial pressure and pulmonary
vascular resistance that may gradually be reduced to near-
normotensive levels when the animals are returned to low
altitudes. A distinctive feature of the pulmonary vasculature
in cattle is the inherently well-developed muscular media of
the arteries and veins with diameters as small as 20 µm, which
implies an unusual potential for vasomotor activity. Hypoxia-
induced vasoconstriction leads to work-induced hypertrophy of
the muscular media of pulmonary arteries and arterioles, and
hence hypertension, and may be compounded by reaction
hypertrophy that occurs in response to increased arterial pres-
sure. In cattle affected with high-altitude disease, there is
uniformly prominent hypertrophy of the muscular media of
pulmonary arteries and arterioles, and usually adventitial pro-
liferation around pulmonary arteries of all sizes. The activation
of platelet-derived growth factor-β receptor-JNK1 signaling
may initiate this proliferation. The hypertension may also
cause endothelial damage, thrombosis, intimal proliferation,
and medial mineralization, especially in elastic pulmonary
arteries.
Further reading
Newman JH, et al. High altitude pulmonary hypertension in cattle
(brisket disease): candidate genes and gene expression profiling of
peripheral blood mononuclear cells. Pulm Circ 2011;1:462-469.
Panzhinskiy E, et al. Hypoxia induces a unique proliferative response in
adventitial fibroblasts by activating PDGF( receptor-JNK1 signalling.
Cardiovasc Res 2012;95:356-365.
Congenital and acquired cardiac disease and
pulmonary arterial hypertension
Congenital heart diseases that feature increased pulmonary
arterial pressure (hypertension) and increased blood flow
(hyperperfusion) often occur with left-to-right shunting of
blood, such as a large ventricular septal defect or patent
ductus arteriosus. Pulmonary arterial hypertension, which
may even lead to reversal of the shunt and cyanosis (Eisen-
menger’s syndrome), produces pulmonary arterial constriction
and hypertrophy, increased pulmonary vascular resistance, and
sustained pulmonary hypertension by means of a number of
arterial responses. These responses range from persistence of
the normal thick muscular wall configuration of fetal life, to
acquired lesions that are the response to hypertension. These
 66.e1

Further reading
Amano H, et al. Effects on endotoxin pathogenicity in pigs with acute
septicemia of Haemophilus parasuis infection. J Vet Med Sci
1997;59:451-455.
Asakura H, et al. Pathophysiology of disseminated intravascular coag-
ulation (DIC) progresses at a different rate in tissue factor-induced
and lipopolysaccharide-induced DIC models in rats. Blood Coagul
Fibrinolysis 2003;14:221-228.
Boudreaux MK, et al. Evaluation of antithrombin-III activity as a coin-
dicator of disseminated intravascular coagulation in cats with
induced feline infectious peritonitis virus infection. Am J Vet Res
1989;50:1910-1913.
Cowell AK, et al. Severe systemic reactions to Hymenoptera stings in
three dogs. J Am Vet Med Assoc 1991;198:1014-1016.
Esmon CT, et al. Inflammation, sepsis, and coagulation. Haematologica
1999;84:254-259.
Grindem CB, et al. Thrombocytopenia associated with neoplasia in
dogs. J Vet Intern Med 1994;8:400-405.
Hargis AM, Feldman BF. Evaluation of hemostatic defects secondary to
vascular tumors in dogs: 11 cases (1983-1988). J Am Vet Med
Assoc 1991;198:891-894.
Hertzke DM, et al. Glomerular ultrastructural lesions of idiopathic cuta-
neous and renal glomerular vasculopathy of greyhounds. Vet Pathol
1995;32:451-459.
Hoffmann R. Adrenal lesions in calves dying from endotoxin shock,
with special reference to the Waterhouse-Friderichsen syndrome.
J Comp Pathol 1977;87:231-239.
Kraje AC, et al. Unusual metastatic behavior and clinicopathologic
findings in eight cats with cutaneous or visceral hemangiosarcoma.
J Am Vet Med Assoc 1999;214:670-672.
Long PH, Payne JW. Red maple-associated pulmonary thrombosis in a
horse. J Am Vet Med Assoc 1984;184:977-978.
Machida N, et al. Myocardial infarction secondary to a disseminated
coagulopathy in a cow. Cornell Vet 1991;81:129-135.
Maxie MG, et al. A comparative study of the disease in cattle caused
by Theileria parva or T. lawrencei: II. Hematology, clinical chemistry,
coagulation studies and complement. Vet Parasitol 1982;10:1-19.
Millis DL, et al. Abnormal hemostatic profiles and gastric necrosis in
canine gastric dilatation-volvulus. Vet Surg 1993;22:93-97.
Momotani E, et al. Histopathological evaluation of disseminated intra-
vascular coagulation in Haemophilus somnus infection in cattle.
J Comp Pathol 1985;95:15-23.
Morris CF, et al. Hemolytic uremic-like syndrome in two horses. J Am
Vet Med Assoc 1987;191:1453-1454.
Norris CR, et al. Pulmonary thromboembolism in cats: 29 cases (1987-
1997). J Am Vet Med Assoc 1999;215:1650-1654.
Semeraro N, Colucci M. Changes in the coagulation-fibrinolysis balance
of endothelial cells and mononuclear phagocytes: role in dissemi-
nated intravascular coagulation associated with infectious diseases.
Int J Clin Lab Res 1992;21:214-220.
Strickland KN. Canine and feline caval syndrome. Clin Tech Small Anim
Pract 1998;13:88-95.
Teige J Jr, Gamlem H. The generalized Shwartzman reaction in asso-
ciation with E. coli enterotoxemia in a pig. Acta Vet Scand
1977;18:316-322.
Valladares JE, et al. Study of haemostatic disorders in experimentally
induced leishmaniasis in beagle dogs. Res Vet Sci 1998;64:195-198.
Wellde BT, et al. Trypanosoma vivax: disseminated intravascular coagu-
lation in cattle. Ann Trop Med Parasitol 1989;83(Suppl. 1):177-183.
Yeruham I, et al. Clinical, clinico-pathological and serological studies
of Babesia ovis in experimentally infected sheep. Zentralbl Veteri-
narmed B 1998;45:385-394.
66.e2

Further reading
Bisgard GE. Pulmonary hypertension in cattle. Adv Vet Sci Comp Med
1977;21:151-172.
Tucker A, Rhodes J. Role of vascular smooth muscle in the development
of high altitude pulmonary hypertension: an interspecies evalua-
tion. High Alt Med Biol 2001;2:173-189.
Diseases of the Vascular System Arteries 67

acquired lesions include prominent medial hypertrophy, intimal

proliferations that may be obliterative, disruption of elastic
laminae, adventitial fibrosis, and plexiform lesions (vascular
occlusion by myointimal proliferations containing irregular
vascular channels). These changes may be mediated by
increased expression of various mediators, such as matrix
metalloproteinases and endothelin-1. In the early, cellular,
phase of the lesion, migration of medial smooth muscle cells
through the internal elastic lamina and into the intima, pos-
sibly in response to a chemical attractant, such as endothelial
cell–derived growth factor, is followed by their conversion to
myofibroblasts and production of ground substance, collagen,
and elastin, which produce marked intimal thickening. Aged
mature lesions become less cellular, myofibroblasts revert to
smooth muscle cells, and thin elastotic septa separate wide
vascular channels; these channels may be thrombosed. As the
pulmonary vascular lesions progress, the arteries may dilate
and their walls undergo fibrinoid degeneration. Together, these Figure 1-72  Medial hyperplasia/hypertrophy of pulmonary arte-
lesions constitute “plexogenic pulmonary arteriopathy,” which riole in a cat (normal variation in cats). H&E.
in its more severe manifestations is an end-stage irreversible
arterial condition that is associated with a poor prognosis, 
even if the underlying cardiac anomaly can be corrected
surgically.
Of the acquired heart diseases, there is increasing evidence
that valvular lesions of the left heart, such as canine LAV
valvular endocardiosis, can lead to pulmonary hypertension
and right-sided congestive heart failure. With this in mind, it
should not be surprising to expect recognition of pulmonary
hypertension in other species accompanying acquired chronic
left heart valvular disease.

Further reading
Connolly DJ, et al. Right-to-left shunting patent ductus arteriosus with
pulmonary hypertension in a cat. J Small Anim Pract 2003;44:184-
188. erratum in J Small Anim Pract 2003;44:226.
Glaus TM, et al. Clinical and pathological characterisation of primary
pulmonary hypertension in a dog. Vet Rec 2004;154:786-789.
Kellihan HB, Stephien RL. Pulmonary hypertension in dogs: diagnosis
and therapy. Vet Clin North Am Small Anim Pract 2010;40:623-
641.
Matsui K, et al. Immunohistochemical study of endothelin-1 and matrix
metalloproteinases in plexogenic pulmonary arteriopathy. Pathol
Res Pract 2002;198:403-412.
Medial hypertrophy of the pulmonary
arteries of cats
Pulmonary medial hypertrophy and hyperplasia commonly occur
in cats, but are of no clinical significance even when very severe
and generalized. The change is seen with equal frequency in
specific-pathogen-free and conventional cats; displays no age,
sex, or breed predilection; and appears to be normal anatomic
variation in cats. Pulmonary hypertension does not result from
the vascular change, right ventricular pressure does not
increase, nor does the right ventricle hypertrophy. The most
severely affected vessels may be grossly visible on the cut
surface of the lung and through the pleura when the lungs are
collapsed, and are even palpable in some cases. The histologic
spectrum of arterial changes ranges from mild sporadic (Fig.
1-72) or generalized hypertrophy of the tunica media, to
marked medial hypertrophy and hyperplasia with concomi-
tant intimal proliferation and severe luminal encroachment.
Figure 1-73  Medial hyperplasia/hypertrophy with mild periar-
teritis in dirofilariasis in a cat. H&E. (Courtesy A. Allen, coordina-
tor, Western Conference of Veterinary Diagnostic Pathologists.)
Thrombosis has not been observed, but adhesion of endothe-
lial surfaces across the lumen occurs, providing sinuous 
channels and an appearance similar to that of an organized,
recanalized thrombus. Frequently, the arterial hypertrophy is
accompanied by fibromuscular hyperplasia in the pulmonary
parenchyma and around alveolar ducts.
Similar pulmonary arterial lesions have been described in
cats infected with the parasites Aelurostrongylus abstrusus and
Dirofilaria immitis (Fig. 1-73).
Further reading
Browne LE, et al. Pulmonary arterial disease in cats seropositive to
Dirofilaria immitis but lacking adult heartworms in the heart and
lungs. Am J Vet Res 2005;66:1544-1549.
Vasculitis
Vasculitis, or inflammation of a vessel, is characterized by the
presence of inflammatory cells within and around the blood vessel
wall with concomitant vessel wall damage as indicated by fibrin
deposition, collagen degeneration, and necrosis of endothelial and
 67.e1

Further reading
Dorfmuller P, et al. Pathology and aspects of pathogenesis in pulmo-
nary arterial hypertension. Sarcoidosis Vasc Diffuse Lung Dis
2003;20:9-19.
Fishman AP. Changing concepts of the pulmonary plexiform lesion.
Physiol Res 2000;49:485-492.
Kolm US, et al. Plexogenic pulmonary arteriopathy in a Pembroke
Welsh corgi. J Small Anim Pract 2004;45:461-466.
Turk JR, et al. Plexogenic pulmonary arteriopathy in a dog with ven-
tricular septal defect and pulmonary hypertension. J Am Anim Hosp
Assoc 1982;18:608-612.
67.e2

Further reading
Lister AL, Atwell RB. Feline heartworm disease: a clinical review. J Feline
Surg Med 2008;10:137-144.
Rawlings CA, et al. Response of the feline heart to Aelurostrongylus
abstrusus. J Am Anim Hosp Assoc 1980;16:573-578.
Rogers WA, et al. Pulmonary artery medial hypertrophy and hyperplasia
in conventional and specific-pathogen-free cats. Am J Vet Res
1971;32:767-774.
68 CHAPTER 1  •  Cardiovascular System Arteries

smooth muscle cells. The fibrillary, homogeneous, or granular
eosinophilic material observed by light microscopy and
referred to as “fibrinoid” consists of fibrin, immunoglobulins,
complement, and platelets. Degenerate collagen and smooth
muscle also contribute to increased eosinophilia of the vascu-
lar wall. Thrombosis may occur because of endothelial injury
and initiation of coagulation. The above changes in the blood
vessel wall distinguish vasculitis from perivascular infiltration
with inflammatory cells. Neutrophils, lymphocytes, or macro-
phages may predominate in vasculitis, and the predominant
cell type may be used to classify the vasculitis. Neutrophilic
vasculitis may be further subdivided into leukocytoclastic, in
which fragmented neutrophil nuclei or “nuclear dust” are
present, and nonleukocytoclastic, in which there is little
nuclear dust. The predominant cell type may vary over the
course of the vasculitis, as the condition becomes chronic or
resolves (eFig. 1-19).
Vasculitis is an important component of a wide variety of
inflammatory diseases, both infectious and noninfectious (Box
1-2), although its origin remains undetermined in many cases.
Vascular degeneration that lacks a significant inflammatory cell
component occurs in a number of toxic and metabolic conditions,
such as mercury poisoning and mulberry heart disease, and
has been excluded from this classification. The terms vasculitis
and angiitis are used interchangeably and may be used in
preference to the more specific term arteritis, because arteries,
capillaries, and veins may be involved simultaneously in some
conditions. Also, the wall of the vessel may be obscured or
obliterated by inflammatory changes, precluding definitive
classification. The consequences of vasculitis depend upon the
size, numbers, and types of vessels affected, and upon the
degree of obstruction caused, as noted under Arterial throm-
bosis and embolism. Vasculitis in general and specific forms of
arteritis will be discussed in this section; phlebitis and lymphan-
gitis are discussed in the sections Veins and Lymphatics,
respectively.
Vasculitides may be classified according to the size of the
blood vessels involved (large, medium, small), the histologic

BOX • 1-2 
Causes of vasculitis in domestic animals

Infectious • Histoplasma farciminosum (lymphangitis)

• Viral • Mucor spp.
• African horse sickness virus • Sporotrichum schenkii (lymphangitis)
• African swine fever virus • Protozoal
• Bluetongue virus • Besnoitia besnoiti
• Border disease virus • Hepatozoon americanum
• Bovine adenovirus • Helminths
• Bovine ephemeral fever virus • Medium to large vessels, usually endovasculitis
• Bovine viral diarrhea virus • Aelurostrongylus abstrusus
• Classical swine fever virus (hog cholera) • Angiostrongylus vasorum
• Equid herpesvirus 1 • Brugia spp. (lymphangitis)
• Equine arteritis virus • Dirofilaria immitis
• Equine infectious anemia virus • Elaeophora spp.
• Feline infectious peritonitis virus • Onchocerca spp.
• Ovine herpesvirus 2 (sheep-associated malignant • Schistosoma spp. (phlebitis)
catarrhal fever) • Spirocerca lupi
• Porcine reproductive and respiratory syndrome virus • Strongylus vulgaris
• Visna/maedi virus (ovine progressive pneumonia)
• Chlamydial Noninfectious
• Chlamydophila abortus (Chlamydia psittaci) • Immune mediated
• Chlamydophila pecorum (sporadic bovine • Anaphylactoid purpura
encephalomyelitis) • Food hypersensitivity
• Bacterial • Foreign proteins (serum sickness)
• Actinobacillus pleuropneumoniae, A. suis • Paraneoplastic, for instance, lymphoma
• Corynebacterium pseudotuberculosis (lymphangitis) • Polyarteritis nodosa
• Coxiella burnetii • Purpura hemorrhagica
• Ehrlichia (Cowdria) ruminantium (heartwater) • Rheumatoid arthritis
• Ehrlichia canis, E. equi • Rabies vaccine reaction
• Erysipelothrix rhusiopathiae • Staphylococcal hypersensitivity
• Haemophilus parasuis • Systemic lupus erythematosus
• Histophilus somni • Nonimmune mediated
• Rickettsia rickettsii (Rocky Mountain spotted fever) • Drug reaction, for example, itraconazole, ivermectin,
• Salmonella spp. trimethoprim-sulfadiazine/sulfamethoxazole
• Streptococcus suis • Uremia
• Mycotic
• Aspergillus fumigatus, A. niger
• Encephalitozoon cuniculi
 68.e1

Primary area
affected
(Endotheluim,
media, adventitia)

Morphology
Etiologies
Fibrinoid change
in wall of vessel Infectious [bacteria,
viruses], immune-
Cell type present
mediated [type III
[neutrophils,
and Type IV],
lymphocytes,
toxins, drugs
macrophages] Vasculitis
(Angiitis)

Type and size Sequelae

of vessel affected Thrombosis/
Artery, vein, ischemia/
lymphatic large, infarction
medium, small DIC

eFigure 1-19  Common types of vasculitis and their major features. DIC, disseminated intravas-
cular coagulation.
Diseases of the Vascular System
characteristics of the lesion, or clinical effects. However, many
cases overlap in their morphologic and clinical manifestations,
and are simply termed “systemic necrotizing vasculitis.”
Improvement in the classification of necrotizing vasculitides
will require further characterization of causes and of the spec-
trum of immune-mediated changes in vessels. Until such time,
the use of accurate morphologic descriptions of vascular
lesions is preferable to placing vasculitides, especially those of
known cause, in such ill-defined categories as “polyarteritis
nodosa.” The wide range of lesions observed probably reflects
the variety of antigens or other agents involved, the intensity
and chronicity of antigenic exposure, the relative contribu-
tions of immune-complex versus delayed-hypersensitivity
reactions, the genetic variation among individuals, and the
stage of development at which the lesion is observed.
Vasculitis may be of considerable significance in the pathogen-
esis of a condition, usually because of the occurrence of thrombo-
sis, ischemia, and infarction (Fig. 1-74). As well as having local
effects resulting from thrombosis and infarction, arteritis may
affect distant organs, as occurs when obliterative pulmonary
endoarteritis leads to congestive heart failure in dogs infected
with Dirofilaria immitis. (The term endoarteritis is used in
preference to endarteritis to avoid implying that end arteries
are primarily affected.)
Arteritis of hematogenous origin occurs in the course of
conditions such as septicemias and bacterial endocarditis. The
primary injury may be to the endothelium and intima or it
may, when the organisms localize in the vasa vasorum, affect
first the adventitia and outer lamellae. The arteritis in pigs
with septicemic salmonellosis, erysipelas, or classical swine
fever is conspicuously expressed cutaneously as erythematous
areas of purple discoloration on the ears, perineum, snout, and
venter, which, if the animal survives, may become necrotic and
slough. Lesions with this basis may also occur in other organs,
and indeed are often seen as infarcts in the spleen in erysipelas
and classical swine fever. In affected portions of vessels, the
endothelium swells and proliferates, and vessel walls undergo
acute fibrinoid necrosis. The formation of thrombi in these
areas in turn gives rise to infarcts and necrosis.
Vasculitis arising by extension of inflammation and infection
from adjacent tissues may occur, especially if the original
inflammatory process is suppurative or necrotizing. It is
Figure 1-74  Necrotizing vasculitis of arteriole in malignant
catarrhal fever in an ox. H&E. (Courtesy J. Schefers.)
Arteries 69
encountered most often in bacterial pneumonias, adjacent to
abscesses, in purulent meningitis, in local lesions of aspergil-
losis and mucormycosis, and in acute metritis, especially if
complicated by necrobacillosis. Fungi of the family Mucorales
have a distinct affinity for arteries and produce necrotizing,
thrombotic arteritis.
Vasculitis may also develop from within the vessel as a result
of endothelial injury by infectious agents and/or immune reac-
tions. Endothelial damage and exposure of subendothelial
collagen leads to activation of Hageman factor, and hence
activation of complement, kinin, and plasmin systems, and to
increased vascular permeability and inflammation. Infectious
agents may cause endothelial damage either directly or
through the actions of various toxic products, such as endo-
toxins of gram-negative bacteria, or exotoxins of bacteria such
as Corynebacterium pseudotuberculosis. Mannheimia haemolyt-
ica endotoxin (lipopolysaccharide [LPS]) can directly damage
endothelial cells; such damage may be reduced or increased
by the activity of neutrophils, depending on the concentration
of LPS present. The mechanism of LPS-mediated damage may
involve prostaglandins or production of oxygen radicals by
endothelial cells. In the absence of LPS, M. haemolytica leu-
kotoxin may contribute to endothelial damage. In the case of
Actinobacillus pleuropneumoniae, rather than endotoxin causing
endothelial damage, cytotoxicity is apparently caused by a
104 kDa hemolysin. Histophilus somni lipo-oligosaccharide
has been shown to cause cytotoxicity and apoptosis of bovine
endothelial cells through the generation of reactive oxygen
and nitrogen intermediates. Many viruses are endotheliotro-
pic, for example, the viruses of equine arteritis, infectious
canine hepatitis, canine distemper, Hendra virus, African swine
fever, and classical swine fever (see Box 1-2).
Immune reactions are primary causes of vasculitis
in domestic animals, but appear to be less important than 
in man.
Type III hypersensitivity reactions, or Arthus reactions, cause
necrotizing vasculitis by the deposition of immune complexes
in vessel walls, usually in association with the endothelial
basement membrane. The complexes fix complement, and
complement fragments attract neutrophils that release lyso-
somal enzymes and oxygen radicals (superoxide anion, hydro-
gen peroxide, hydroxyl radical, hypochlorous acid) in the
process of phagocytosing immune complexes, and hence cause
necrosis. As the Arthus reaction matures, neutrophils diminish
and mononuclear cells, including plasma cells, predominate.
The morphology of immune-complex–mediated vasculitis can
be modified by the relative concentrations of immune reac-
tants or secondary mediators; increases in antibody or comple-
ment concentrations can change an Arthus-like reaction to a
Shwartzman-like reaction. Immune complexes can be found
in vessel walls in a variety of immune-mediated conditions,
including systemic lupus erythematosus, Aleutian disease of
mink, feline infectious peritonitis, and systemic coronavirus-
associated disease in ferrets. However, even though immuno-
globulins or immune complexes are found in the walls of
affected vessels, this is not definitive proof that the immune
reaction caused the vasculitis. Conversely, the absence of
immune complexes from a vessel wall lesion does not rule out
immune-complex vasculitis, because immune reactants can
disappear rapidly. The underlying lesion in porcine dermatitis
and nephropathy syndrome (PDNS) is necrotizing systemic
vasculitis, which has a predilection for skin and kidney, and 
is thought to have an immune-complex origin; porcine
70 CHAPTER 1  •  Cardiovascular System
circovirus 2 antibody titers were excessively high in PDNS
pigs in a case-control study.
Cell-mediated type IV, or delayed hypersensitivity, reactions
may be involved in some types of vasculitis in which there is
lymphocytic predominance, such as the arteritis of malignant
catarrhal fever and of Border disease. In malignant catarrhal
fever, the vasculitis is characterized by accumulations of prin-
cipally lymphocytes and fewer macrophages in the adventitia
and intima of affected small and medium arteries and veins
of the alimentary tract, eye, kidney, liver, lung, and brain;
neutrophils and plasma cells are rare. Lymphocytes may later
invade the media, although adventitial infiltration continues
to predominate, and there may be medial myocyte necrosis
with variable amounts of fibrinoid degeneration and endothe-
lial hyperplasia; thrombosis may be seen in advanced cases.
There is a possibility of, but little direct evidence for, direct
viral cytolysis in malignant catarrhal fever.
Vasculitis in humans has been associated with a variety  inflammatory immune response in placental tissues. J Comp Pathol
of drugs (see Hypersensitivity vasculitis). Examples of
hypersensitivities in dogs include itraconazole, ivermectin,
allergy immunotherapy (hyposensitization) injections, and
ibuprofen.
Genetic predisposition to vasculitis occurs in a number of
dog breeds, for instance, Beagle (“Beagle pain syndrome”),
Greyhound, Chinese Shar-Pei (“Shar-Pei fever”), German
Shepherd dog, Bernese Mountain dog. Vasculitis may be pre-
cipitated by vaccination or infection, but is more often of
obscure cause. Arteritis may be found as an incidental “back-
ground” lesion in clinically normal animals. For example, mild
idiopathic arteritis and intimal thickening occurs in extramu-
ral coronary arteries in 5-10% of young Beagle and mixed-
breed dogs, which can complicate the interpretation of lesions
in dogs used in arterial toxicity studies.
A more severe, febrile syndrome, variously named Beagle
pain syndrome, canine juvenile polyarteritis syndrome, or idio-
pathic canine polyarteritis, occurs in Beagles and other breeds.
In this syndrome, necrotizing arteritis affects the coronary,
mediastinal and cervical spinal arteries, resulting in thrombo-
sis, infarction, and hemorrhage as well as progressive atrophy
of temporal and cervical muscles; amyloidosis occurs in  454.
some chronically affected dogs (Fig. 1-75). The syndrome
appears to be immune mediated; some affected dogs have
Figure 1-75  Lymphoplasmacytic vasculitis in the leptomeninges
in Beagle pain syndrome. H&E.
Arteries
antineutrophil cytoplasmic antibodies (ANCA) and other
immunologic irregularities similar to Kawasaki disease in
humans.
An idiopathic vasculopathy occurs in kenneled and racing
Greyhound dogs (Alabama rot), involving skin and occasionally
kidneys. Deep, slowly healing cutaneous ulcers occur as the
result of fibrinoid arteritis, thrombosis, and hemorrhagic
infarction. Renal lesions include acute necrosis of glomeruli
and of afferent arterioles, glomerular capillary thrombosis, and
acute tubular necrosis. The pathogenesis of the condition is
thought to be the result of the effects of Shiga toxin from E.
coli O157:H7 producing a variant of the hemolytic-uremic
syndrome.
Further reading
Buxton D, et al. Ovine chlamydial abortion: characterization of the
2002;127:133-141.
Caswell JL, Nykamp SG. Intradural vasculitis and hemorrhage in full
sibling Welsh springer spaniels. Can Vet J 2003;44:137-139.
Eaton BT, Broder CC. Hendra and Nipah viruses: different and danger-
ous. Nat Rev Microbiol 2006;4:23-35.
Font A, et al. Acute paraplegia associated with vasculitis in a dog with
leishmaniasis. J Small Anim Pract 2004;45:199-201.
Garner MM. Clinicopathologic features of a systemic coronavirus-
associated disease resembling feline infectious peritonitis in the
domestic ferret (Mustela putorius). Vet Pathol 2008;45:236-246.
Hansen S, et al. Coxiella burnetii associated placental lesions and infec-
tion level in parturient cows. Vet J 2011;190:e135-e139.
Hooper P, et al. Comparative pathology of the diseases caused by
Hendra and Nipah viruses. Microbes Infect 2001;3:315-322.
Innerå M. Cutaneous vasculitis in small animals. Vet Clin North Amer
Sm Anim Pract 2013;43:113-134.
Kipar A, et al. Morphologic features and development of granuloma-
tous vasculitis in feline infectious peritonitis. Vet Pathol 2005;42:321-
330.
Maratea KA, et al. Vascular lesions in nine Gottingen minipigs with
thrombocytopenic purpura syndrome. Vet Pathol 2006;43:447-
McClenahan D, et al. Effects of lipopolysaccharide and Mannheimia
haemolytica leukotoxin on bovine lung microvascular endothelial
cells and alveolar epithelial cells. Clin Vaccine Immunol 2008;15:338-
347.
Opriessnig T, Langolir I. Current state of knowledge of porcine circovi-
rus type 2-associated lesions. Vet Pathol 2013;50:23-38.
Paessler S, Walker DH. Pathogenesis of viral hemorrhagic fevers. Ann
Rev Pathol 2013;8:411-440.
Richards A, Kavanagh D. Pathogenesis of thrombotic microangiopathy:
insights from animal models. Nephron Exp Nephrol 2009;113:97-
103.
Russell GC, et al. Malignant catarrhal fever: a review. Vet J 2009;
179:324-335.
Snyder PW, et al. Pathologic features of naturally occurring juvenile
polyarteritis in Beagle dogs. Vet Pathol 1995;32:337-345.
Wellenberg GJ, et al. Excessive porcine circovirus type 2 antibody titres
may trigger the development of porcine dermatitis and nephropa-
thy syndrome: a case-control study. Vet Microbiol 2004;99:203-
214.
Wong KT, Tan CT. Clinical and pathological manifestations of human
henipavirus infection. Curr Top Microbiol Immunol 2012;359:
95-104.
 70.e1

Shilton CM, et al. Adenoviral infection in captive moose (Alces alces)

Further reading in Canada. J Zoo Wildl Med 2002;33:73-79.
Ackermann MR, et al. Ventral dermatitis and vasculitis in a calf with Simon S, et al. The vascular lesions of a cow and bison with sheep-
bovine leukocyte adhesion deficiency. J Am Vet Med Assoc associated malignant catarrhal fever contain ovine herpesvirus
1993;202:413-415. 2-infected CD8+ T lymphocytes. J Gen Virol 2003;84(Pt 8):2009-
Anderson TD, et al. Pathogenesis of placentitis in the goat inoculated 2013.
with Brucella abortus: II. Ultrastructural studies. Vet Pathol Son WC. Idiopathic canine polyarteritis in control beagle dogs from
1986;23:227-239. toxicity studies. J Vet Sci 2004;5:147-150.
Andrew SE. Feline infectious peritonitis. Vet Clin North Am Small Anim Svensson C, Bergsten C. Laminitis in young dairy calves fed a high
Pract 2000;30:987-1000. starch diet and with a history of bovine viral diarrhoea virus infec-
Arteritis and arterial drug toxicity in the safety assessment of drugs. tion. Vet Rec 1997;140:574-577.
Toxicol Pathol 1989;17:65-231 (17 papers). Sylte MJ, et al. Reactive oxygen and nitrogen intermediates contribute
Bratberg B. Acute vasculitis in pigs: a porcine counterpart to malignant to Haemophilus somnus lipooligosaccharide-mediated apoptosis of
catarrhal fever. Proc Int Pig Vet Soc Congress, Copenhagen, bovine endothelial cells. Vet Immunol Immunopathol 2004;97:207-
Denmark, Am Assoc Swine Pract 1980;353. 217.
Breider MA, et al. Interaction of bovine neutrophils in Pasteurella hae- Szeredi L, et al. Detection of equine herpesvirus-1 in the fetal mem-
molytica mediated damage to pulmonary endothelial cells. Vet branes of aborted equine fetuses by immunohistochemical and
Immunol Immunopathol 1991;27:337-350. in-situ hybridization techniques. J Comp Pathol 2003;129:147-153.
Cowan LA, et al. Clinical and clinicopathological abnormalities in grey- Thomson JR, et al. Porcine dermatitis and nephropathy syndrome.
hounds with cutaneous and renal vasculopathy: 18 cases (1992- Clinical and pathological features of cases in the United Kingdom
1994). J Am Vet Med Assoc 1997;210:789-793. (1993-1998). J Vet Med A Physiol Pathol Clin Med 2002;49:430-
Crawford MA, Foil CS. Vasculitis: clinical syndromes in small animals. 437.
Compend Contin Educ Pract Vet 1989;11:400-415. Tunev SS, et al. Necrotizing mycotic vasculitis with cerebral infarction
Cutlip RC, et al. Ovine progressive pneumonia (maedi-visna) in sheep. caused by Aspergillus niger in a horse with acute typhlocolitis. Vet
Vet Microbiol 1988;17:237-250. Pathol 1999;36:347-351.
Darbes J, et al. Histopathological findings in pigs of various ages suf- Van Dellen AF, et al. Light and electron microscopical studies on canine
fering from spontaneous infection with the porcine reproductive encephalitozoonosis: cerebral vasculitis. Onderstepoort J Vet Res
and respiratory syndrome virus (PRRSV). Zentralbl Veterinarmed A 1978;45:165-186.
1996;43:353-363. van Moll P, et al. Immunocytochemical demonstration of Coxiella bur-
Fondati A, et al. Familial cutaneous vasculopathy and demodicosis in netii antigen in the fetal placenta of naturally infected sheep and
a German shepherd dog. J Small Anim Pract 1998;39:137-139. cattle. J Comp Pathol 1993;109:295-301.
Gavaghan BJ, et al. Acute onset of pulmonary necrotising arteritis in a Vincent-Johnson NA. American canine hepatozoonosis. Vet Clin North
dog with a left-to-right patent ductus arteriosus. Aust Vet J Am Small Anim Pract 2003;33:905-920.
1998;76:786-791. Wilkins PA, et al. Listeria monocytogenes septicemia in a thoroughbred
Hedstrom OR, et al. Pathology of Campylobacter jejuni abortion in foal. J Vet Diagn Invest 2000;12:173-176.
sheep. Vet Pathol 1987;24:419-426.
Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med 1997;337:1512-
1523.
Kemi M, et al. Histopathology of spontaneous panarteritis in beagle
dogs. Jpn J Vet Sci 1990;52:55-61.
Liggitt HD, DeMartini JC. The pathomorphology of malignant catarrhal
fever: I. Generalized lymphoid vasculitis. Vet Pathol 1980;17:58-72.
Malik R, et al. Acute febrile neutrophilic vasculitis of the skin of young
Shar-Pei dogs. Aust Vet J 2002;80:200-206.
Mathieson PW, et al. Animal models of systemic vasculitis. J Autoim-
mun 1993;6:251-264.
Morris DD. Cutaneous vasculitis in horses: 19 cases (1978-1985). J Am
Vet Med Assoc 1987;191:460-464.
Morris DO, Beale KM. Cutaneous vasculitis and vasculopathy. Vet Clin
North Am Small Anim Pract 1999;29:1325-1335.
Nichols PR, et al. A retrospective study of canine and feline cutaneous
vasculitis. Vet Dermatol 2001;12:255-264.
O’Toole D, et al. Chronic generalized obliterative arteriopathy in cattle:
a sequel to sheep-associated malignant catarrhal fever. J Vet Diagn
Invest 1995;7:108-121.
Reams RY, et al. Streptococcus suis infection in swine: a retrospective
study of 256 cases: II. Clinical signs, gross and microscopic lesions,
and coexisting microorganisms. J Vet Diagn Invest 1994;6:326-334.
Rotermund A, et al. Cutaneous and renal glomerular vasculopathy in
a Great Dane resembling “Alabama rot” of greyhounds. Vet Rec
2002;151:510-512.
Serebrin S, et al. Endothelial cytotoxicity of Actinobacillus pleuropneu-
moniae. Res Vet Sci 1991;50:18-22.
Diseases of the Vascular System
Polyarteritis nodosa (panarteritis,
or periarteritis nodosa)
The term “polyarteritis nodosa” has been applied to a hetero-
geneous group of arteritides, which occur sporadically in all
species of domestic animals, on the basis of similarities with
classic polyarteritis nodosa in humans, in which small and
medium-sized arteries undergo severe necrotizing inflammation,
often in a sharply segmental (nodose) pattern, and with a predi-
lection for branching points. As all layers of the arterial wall
are involved, the lesion is also referred to as “panarteritis.”
Arterioles, capillaries, and venules are not involved, and glo-
merulonephritis is not present.
The only agent thus far associated with the condition in
man is hepatitis B antigen, which is found in 25-40% of indi-
viduals with necrotizing vasculitis. High mortality occurred in
the human disease before the advent of corticosteroid and
cyclophosphamide therapy. Polyarteritis nodosa has been
reported in dogs having rheumatoid arthritis and systemic
lupus erythematosus; separation of the vasculitis component
from disease syndromes is of problematic value. Also, as noted
previously in the section Vasculitis, a more appropriate term
for idiopathic vasculitides is probably systemic necrotizing
vasculitis rather than polyarteritis nodosa, which has tended
to become a catchall term.
A wide variety of clinical and pathologic manifestations
occur in polyarteritis nodosa as described in man and domestic
animals. Although occasionally associated with the death of
an animal, lesions are also noted in otherwise normal animals
at slaughter. Renal, coronary, hepatic, and gastrointestinal
vessels are perhaps most commonly involved (Fig. 1-76). Arte-
rial lesions at all stages of development, namely, acute, healing,
and healed, may occur simultaneously in one individual and even
within the same vessel.
The acute lesions are often typical of immune-complex–
induced arteritis, and inflammation and necrosis of the arte-
rial wall may be segmental or circumferential. Thrombosis
may occur and lead to infarction and hemorrhage. As the
reaction progresses, neutrophils are replaced in the media by
mononuclear cells, and fibroplasia may result in grossly visible
fibrous thickening of the wall. The vascular lumen may be
obliterated by organization of a thrombus plus intimal prolif-
eration. The term “periarteritis” has been used in the past
Figure 1-76  Chronic fibrosing vasculitis in renal artery (polyar-
teritis nodosa) in a goat. H&E. (Courtesy E. Olson.)
Arteries 71
to describe a stage in the vascular reaction in which mono-
nuclear cells surround the vessel, but the term is now 
little used.
Microscopic polyangiitis (hypersensitivity vasculitis, micro-
scopic polyarteritis, leukocytoclastic vasculitis) affects smaller
vessels in humans, namely, arterioles, capillaries, and venules in
skin, mucous membranes, lungs, brain, heart, gastrointestinal
tract, kidneys, and muscle. Suspected causes include many
common drugs such as penicillin, microbes such as strepto-
cocci, heterologous proteins, and tumor antigens. The reaction
often occurs 7-10 days after exposure to the stimulus; remis-
sion usually follows removal of the agent. Lesions typical of
leukocytoclastic vasculitis are seen. Because larger arteries are
spared, macroscopic infarcts are uncommon. Hypersensitivity
vasculitis appears to be the basis of some cases of hemorrhagic
purpura in horses; other causes of subcutaneous edema and
mucosal hemorrhages, such as equine viral arteritis, equine
infectious anemia, and equine ehrlichiosis, must also be 
considered. Trimethoprim-sulfadiazine and trimethoprim-
sulfamethoxazole have caused hypersensitivity vasculitis
in dogs.
Further reading
Clemo FA, et al. Differentiating spontaneous from drug-induced vas-
cular injury in the dog. Toxicol Pathol 2003;31(Suppl.):25-31.
Eleftheriou D, et al. Systemic polyarteritis nodosa in the young: a single
centre experience over 32 years. Arthritis Rheum 2013;65:2476-
2485.
Ferreras MC, et al. Pathologic features of systemic necrotizing vasculi-
tis (polyarteritis nodosa) in sheep. J Comp Pathol 2013;149:74-81.
Hughes LB, Bridges SL Jr. Polyarteritis nodosa and microscopic polyan-
giitis: etiologic and diagnostic considerations. Curr Rheumatol Rep
2002;4:75-82.
Son WC. Idiopathic canine polyarteritis in control beagle dogs from
toxicity studies. J Vet Sci 2004;5:147-150.
Viral vasculitides
Equine viral arteritis.  This disease is caused by species
Equine arteritis virus (EAV), an RNA virus of the family
Arteriviridae, genus Arterivirus, which is pathogenic only for
horses and is cytopathic in equine kidney culture. Although
serologic surveys indicate that infection with EAV is common
in North America and Europe, clinical disease is uncommon.
Most strains of EAV are avirulent, and mortality is rare in
natural outbreaks. Long-lasting immunity follows recovery.
Transmission of virus occurs primarily by respiratory and vene-
real routes during the acute phase of infection; venereally
infected mares can infect nonimmune mares by aerosol trans-
mission. Long-term carrier stallions play an important role in
perpetuation and dissemination of the virus; a carrier state has
not been demonstrated in mares or foals. There is some evi-
dence for resistance/susceptibility to the severity of the disease
based on the host’s permissiveness of infection of CD3+ lym-
phocytes. The major features of the disease are shown in
eFigure 1-20.
The clinical disease is characterized by fever; variable
anorexia and depression; leukopenia; edema of the ventral
body wall and limbs, especially the hindlimbs; skin rash, most
commonly on the neck; serous, later mucopurulent, oculona-
sal discharge with rhinitis and conjunctivitis; and periorbital/
supraorbital edema. Dyspnea, coughing, ataxia, and diarrhea
 71.e1

Further reading
Carpenter JL, et al. Polyarteritis nodosa and rheumatic heart disease in
a dog. J Am Vet Med Assoc 1988;192:929-932.
Curtis R, et al. Polyarteritis in a cat. Vet Rec 1979;105:354.
Elling F. Nutritionally induced necrotizing glomerulonephritis and poly-
arteritis nodosa in pigs. Acta Path Microbiol Scand A 1979;87A:387-
392.
Gardiner AC, et al. Periarteritis in experimental border disease of
sheep: III. Immunopathological observations. J Comp Pathol
1980;90:469-474.
Jansen JH, Nordstoga K. Renal lesions in Norwegian slaughter pigs.
Macroscopic and light microscopic studies. Zentralbl Veterinarmed
A 1992;39:582-592.
Rae CA. Lymphocytic enteritis and systemic vasculitis in sheep. Can Vet
J 1994;35:622-625.
Werner LL, et al. Acute necrotizing vasculitis and thrombocytopenia in
a horse. J Am Vet Med Assoc 1984;185:87-90.
71.e2

Arterivirus
[RNA virus]
Virulence varies
Most strains avirulent
Transmission aerosol
and venereal

Clinical signs Pathogenesis

Fever; anorexia, Panvasculitis
depression; ventral
edema; leukopenia; Initial infection of
oculonasal discharge; macrophages followed
diarrhea; abortion by endothelial cells
Equine
viral arteritis

Gross lesions Histopathology

Widespread Hyaline to fibrinoid
hemorrhages necrosis of media
and edema; fluid of small muscular
in all serous cavities; arterioles
pulmonary edema; Thrombosis [sometimes]
enteritis [hemorrhagic
diphtheritic] Necrosis in
lymph nodes

eFigure 1-20  Major features of equine viral arteritis.

72 CHAPTER 1  •  Cardiovascular System
are less frequent. Pregnant mares often abort during or shortly
after the febrile period, probably resulting from myometritis
and decreased progesterone production by a hypoxic pla-
centa. Specific lesions are present occasionally in aborted
fetuses, and include necrotizing vasculitis, and inflammatory
foci in various organs. Newborn foals may succumb to inter-
stitial pneumonia. There is also a necrotizing vasculitis in the
placenta.
The virus is pathogenic to endothelial cells and causes pan-
vasculitis, that is, inflammation of veins, lymphatics, and arteries.
Following initial replication of the virus in macrophages, endo-
thelial cells are invaded beginning 3 days after experimental
aerosol infection. As inflammation progresses and neutrophils
damage the internal elastic lamina, medial cells are invaded.
The most severe edema occurs at days 6 and 7 when phlebitis,
lymphangitis, and capillary damage are most pronounced.
Arterial necrosis peaks at day 10, when edema has largely
disappeared. The vascular lesions will resolve if the horse
survives. Antibody appears to play little role in the pathogen-
esis of the disease, in contrast to the immune-complex com-
ponent of some other viral vasculitides.
The gross lesions of the disease, in addition to the changes
observed clinically, consist principally of hemorrhages and
edema. Petechial hemorrhages are found on all serous mem-
branes, in the substance of the lungs, and in the gastric mucosa.
Larger hemorrhages may be present in the adrenals. There is
excessive fluid that contains much protein and some strands
of fibrin in all serous cavities. As much as 10 L may be present
in the pleural and peritoneal cavities. The connective tissues
and mesenteries of the body cavities are saturated with edema
fluid, and the wall of the gut may be thickened by edema.
Enteritis, hemorrhagic, or diphtheritic in character, usually
more severe in the large than in the small intestine, is regularly
present. The lungs are more-or-less severely edematous.
Characteristic microscopic lesions occur focally or segmen-
tally in the media of small muscular arteries (Fig. 1-77). The
smooth muscle cells undergo necrosis and are replaced by
hyaline or fibrinoid material. There is edema of the wall and
adventitia and infiltration of leukocytes, chiefly lymphocytes,
the nuclei of which undergo fragmentation with necrosis. The
endothelium and intima may have been repaired so that
thrombosis is unusual; thrombosis may, however, occur in the
Figure 1-77  Multifocal vasculitis with fibrosing perivascular and
perineural inflammation in equine viral arteritis. (From an Armed
Force Institute of Pathology Wednesday Slide Conference, 2000.)
Arteries
intestine and lungs. The arterial lesions occur in many organs
but are perhaps most consistently present in the gut and adrenals.
Infarction is most common in the intestines, particularly in
the cecum and colon. Massive necrosis of lymph nodes also
occurs. Extensive necrosis of the adrenals may result from
direct viral injury and infarction.
Diagnosis is made through detection of seroconversion or
more commonly, identification of the virus in the presence of
compatible lesions. Differential diagnoses for EVA include dis-
eases caused by other viruses (equid herpesvirus 1, equine
adenovirus, influenza A virus, equine infectious anemia virus,
African horse sickness virus, Hendra virus, Getah virus), plus
purpura hemorrhagica, septic shock, and poisoning by the
toxic plant hoary alyssum (Berteroa incana).
Further reading
Del Piero F. Equine viral arteritis. Vet Pathol 2000;37:287-296.
Go YY, et al. Assessment of correlation between in vitro CD3+ T cell
susceptibility to EAV infection and clinical outcome following exper-
imental infection. Vet Microbiol 2012;157:220-225.
Miszczak F, et al. Emergence of novel equine arteritis virus (EAV)
variants during persistent infection in the stallion: origin of the
2007 French EAV outbreak was linked to an EAV strain present
in the semen of a persistently infected carrier stallion. Virol
2012;423:165-174.
African horse sickness.  African horse sickness (AHS) is a
vector-borne disease of solipeds, and occasionally of dogs 
and camels, caused by species African horse sickness virus
(AHSV), family Reoviridae, genus Orbivirus, that is closely
related to bluetongue virus. The disease is endemic in sub-
Saharan Africa, from where it spreads to southern Africa and
occasionally northern Africa. It has also extended on occasion
through the Middle East as far as India, and apparently with
climate change, the vector has become established in southern
Europe. Its importance lies in the extreme lethal potential of the
infection in susceptible horses and the very wide distribution of
the competent insect vectors.
The vectors of AHSV are primarily Culicoides biting
midges, particularly Culicoides imicola. Transmission by mos-
quitoes or ticks is of minor importance. AHSV requires an
ambient temperature of ≥15° C to replicate and be transmit-
ted by Culicoides. Historically, in enzootic areas south of the
Sahara, outbreaks of disease occurred in seasons when noctur-
nal biting insects were active, outbreaks subsiding shortly after
the first frosts. It is possible that, in climatically suitable areas,
transmission might occur throughout the year. Annual recru-
descence poses the question of reservoirs for over-winter per-
sistence; the natural reservoir remains unknown, although the
zebra is most likely. Even in districts where AHS occurs annu-
ally, the distribution tends to be limited to low-lying areas
such as valleys, swamps, and areas of summer rain.
African horse sickness is primarily a disease of the horse and
its close relatives, but a wide range of species is susceptible to
the virus experimentally, including goats, guinea pigs, mice,
ferrets, and rats. The major features of the disease are shown
in eFig. 1-21. The horse is the most susceptible to infection
and to illness; the mortality rate in susceptible populations of
horses may be as high as 95%. The mortality rate in mules
(~80%) is less than that in horses, but greater than that in the
 72.e1

Further reading
Cho HJ, et al. Detection of antibodies to equine arteritis virus by a
monoclonal antibody-based blocking ELISA. Can J Vet Res
2000;64:38-43.
Del Piero F. Diagnosis of equine arteritis virus infection in two horses
by using monoclonal antibody immunoperoxidase histochemistry
on skin biopsies. Vet Pathol 2000;37:486-487.
Hullinger PJ, et al. Seroprevalence of antibodies against equine arteritis
virus in horses residing in the United States and imported horses.
J Am Vet Med Assoc 2001;219:946-949.
Szeredi L, et al. Equine viral arteritis in a newborn foal: parallel detec-
tion of the virus by immunohistochemistry, polymerase chain reac-
tion and virus isolation. J Vet Med B Infect Dis Vet Public Health
2003;50:270-274.
72.e2

Orbivirus
Closely related to bluetongue
virus
Nine major antigenic types
Infects solipeds; sometimes
camels and dogs
insect tramsmitted

Clinical signs
Four clinical syndromes:
Peracute/pulmonary form [fever,
respiratory distress]; Pathogenesis not well
understood
Subacute/cardiac form [fever, severe
subcutaneous edema, petechial Virus in many tissues
hemorrhages] No obvious endothelial invasion
Mixture of pulmonary /cardiac form
Mild form - AHS fever
[remittent fever] African
horse sickness

Gross features
Depends on clinical form Histopathology
Hydrothrax; Pulmonary edema; Diffuse severe
petechial /ecchymotic hemorrhages;
Alveolar edema; Widespread
swollen and edematous lymph nodes'
hemorrhage;
subcutaneous edema;
hydropericardium

eFigure 1-21  Major features of African horse sickness (AHS).

Diseases of the Vascular System
Egyptian donkey. The South African donkey and the zebra are
resistant. The role of dogs, and other scavenging carnivores, in
the disease cycle is not known. The disease is not contagious
by contact, but dogs may acquire it from eating infected
horseflesh. Infection, detected by viral isolation/detection or
serologically, can be common in dogs in some circumstances,
but vector transmission from dogs is unlikely.
In many parts of Africa, the use of the horse, mule, and
donkey is dependent on the control of AHS, but this control
has been difficult to attain. The primary obstacle has been the
multiplicity of antigenic types of AHSV of which there are at
present 9 major antigenic types. These types have a basic anti-
genic relationship that may be demonstrated in the horse, but
the relationship is not sufficiently close to provide solid immu-
nity amongst types. Indeed, although all strains investigated
can be fitted into one of the major types, the antigenic diver-
sity of strains within a single type is such that very few strains
are identical. This is certainly the situation in enzootic areas
where a large number of different strains may be isolated
during an outbreak. On the other hand, there has been close
antigenic relationship between the viruses recovered during
the epizootic outbreaks that occurred outside the reservoir-
host range where the transmission was from horse to horse.
This suggests that, although the AHSV is extremely mutable,
mutations do not readily occur when the disease is transmitted
from horse to horse. Recovered horses are immune to homolo-
gous challenge, and possess some immunity to heterologous
challenge. Vaccines are currently available to either prevent or
to lower the severity of the disease.
Four clinical forms of AHS are described: pulmonary (per-
acute), mixed (acute), cardiac (subacute), and AHS fever (mild)
forms, from most to least severe. Most cases are of the mixed
form, perhaps reflecting variations in the susceptibility of the
host, the virulence of the virus, or the tropism of virus for
different parts of the vascular system.
The peracute or pulmonary form of the disease, the most
common form in epizootics, has an incubation period of 3-5
days. Fever occurs suddenly and is of short duration, followed
by the acute onset of respiratory distress. Death may occur in
a few hours from pulmonary edema, and frothy fluid fills the
respiratory tract and may flow from the nostrils.
The subacute or cardiac form is usually associated with
infections that are not fully virulent or are encountered in
animals in which infection by heterologous strains has stimu-
lated some immunity. The incubation period is 7-14 days with
clinical signs of fever lasting 3-6 days. As the fever subsides,
edematous swellings appear in the temporal or supraorbital
fossae and the eyelids. The swellings extend to the lips, cheeks,
tongue, intermandibular space, and throat. Swelling from sub-
cutaneous fluid may affect the upper neck and sometimes the
chest and shoulders. Terminally, petechial hemorrhages usually
occur on the conjunctiva and ventral surface of the tongue.
The mortality rate may be as high as 50%, and is attributed
to cardiac failure and pulmonary edema.
As observed above, many cases are mixtures of the pulmo-
nary and cardiac form. Initial pulmonary signs of relatively
mild degree may be followed by characteristic swelling of the
head and death from cardiac failure, or the cardiac form may
be followed by sudden onset of dyspnea and pulmonary edema.
The mild clinical form of the disease, AHS fever, may not
be noticed in outbreaks. It is characterized by remittent fever
lasting for a week or so. This is the form of the disease to be
expected in animals with immunity to heterologous strains
Arteries 73
and in resistant species such as donkey and zebra. The mortal-
ity rate is ~70%.
The pathogenesis of the signs and lesions is related to sites
of viral replication. Virus is found early and develops to
highest titer in spleen, lymph nodes, lung, and the large 
intestine; the titer in myocardium is low. Viral infection 
causes degeneration and loss of endothelium in myocardial
and pulmonary capillaries, with resulting increased vascular
permeability, edema, hemorrhage, and microthrombosis. 
Vascular permeability of pulmonary capillaries may be
increased through the action of inflammatory mediators
released by activated intravascular macrophages.
Gross lesions observed at autopsy depend largely on the
clinical form of disease. In the pulmonary form, the most char-
acteristic changes are edema of the lungs and hydrothorax
(Fig. 1-78A). In very acute cases, edema and mottled hyper-
emia of the lungs are seen, whereas in cases with a somewhat
more protracted course extensive interstitial and subpleural
edema are also present, but hyperemia is less evident. Other
lesions commonly observed are periaortic and peritracheal
edematous infiltration, diffuse or patchy hyperemia of the
glandular fundus of the stomach, hyperemia and petechial
hemorrhages in the mucosa and serosa of the small and large
intestines, subcapsular hemorrhages in the spleen, and conges-
tion of the renal cortex. All the lymph nodes are enlarged and
edematous, especially those in the thoracic and abdominal
cavities. The pericardial sac may contain variable amounts of
fluid, and numerous petechial hemorrhages occur in the peri-
cardium. Cardiac lesions are usually not conspicuous, but
epicardial and endocardial petechial hemorrhages may some-
times be evident.
In the cardiac form, the most characteristic lesions are the
edematous infiltration of the subcutaneous, subfascial, subse-
rous, and intermuscular tissues. Only the head and neck may
be involved, but in more severe cases, the edema also involves
lower parts of the neck, brisket, and shoulders (Fig. 1-78B).
Hydropericardium is a constant finding, the pericardial sac
often containing 2 L or more of fluid (Fig. 1-78C). The epi-
cardium and endocardium show numerous, almost confluent
ecchymotic hemorrhages. The lungs are usually normal or only
slightly engorged, and the thoracic cavity rarely contains an
excess of fluid. The lesions in the gastrointestinal tract are
generally similar to those found in the pulmonary form,
except that submucosal edema tends to be far more pro-
nounced. Ascites is unusual.
In the mixed form, the lesions are a combination of those
observed in the pulmonary and cardiac forms. In fact, most of
the fatal cases of AHS can be considered to be of the mixed form,
with lesions typical of either the pulmonary or the cardiac
form predominating.
The infective dose of AHS virus for dogs is large, and high
infective titers are not known to be gained except by ingestion
of infected horseflesh. The course of the disease in dogs is
similar to the pulmonary form in horses with fever and severe
respiratory distress. The mortality in dogs showing respiratory
signs is very high. At autopsy, the lungs are edematous and
may have some superimposed bronchopneumonia. There is
much froth in the airways, copious hydrothorax in which the
fluid gels on exposure, and saturation of mediastinal tissues.
Histologic changes are not helpful in diagnosis or understand-
ing of pathogenesis.
The clinical signs of AHS are usually characteristic, 
although AHS might be confused with equine encephalosis,
74 CHAPTER 1  •  Cardiovascular System
A
Figure 1-78  African horse sickness in a horse. A. Severe, acute pulmonary edema. B. Subcutane-
ous edema of a hindlimb. C. Excess blood-tinged fluid in the pericardial sac. (Courtesy Foreign
Animal Diseases Diagnostic Laboratory, National Veterinary Services Laboratories.)
anthrax, equine infectious anemia, equine babesiosis, purpura
hemorrhagica, equine viral arteritis, equine viral rhinopneu-
monitis, or trypanosomiasis.
Diagnosis requires virus isolation, virus identification, or
serology.
Further reading
Carrasco L, et al. The role of pulmonary intravascular macrophages in
the pathogenesis of African horse sickness. J Comp Pathol
1999;121:25-38.
Gomez-Villamandos JC, et al. Pathogenesis of African horse sickness:
ultrastructural study of the capillaries in experimental infection.
J Comp Pathol 1999;121:101-116.
Stern AW. African horse sickness. Compend Contin Educ Vet
2011;33:E1-E5.
African swine fever.  African swine fever (ASF) is an acute-
to-chronic, febrile, viral disease of swine, characterized by high
fever, cutaneous hyperemia, abortions, edema, and hemorrhage in
internal organs, particularly lymph nodes. Species African swine
fever virus (ASFV) infects only members of the Suidae family
and is a harmless companion of the warthog (Phacochoerus
aethiopicus) and the bush pig (Potamochoerus porcus). However,
Arteries
B
C
the virus is a constant and major threat to domestic pigs.
Originally limited to sub-Saharan Africa, the disease has
appeared in southern and western Europe, most recently in
Georgia in the Caucasus, the Caribbean, Brazil, Madagascar,
and Mauritius. International spread of ASF is primarily through
infected pork products in garbage fed to pigs. Once a focus of
infection is established, spread is most likely to occur by direct
or indirect contact. In Africa, the transmission of the virus
from wild Suidae to domestic pigs is primarily by the argasid
tick Ornithodoros moubata, a true biological vector and a
reservoir of the virus in nature. Additional arthropod vectors
exist.
The causative agent, ASFV, is an enveloped DNA virus,
family Asfarviridae, genus Asfivirus. It is a relatively resistant
virus that may survive in the environment or in uncooked
pork products for prolonged periods. There are several anti-
genically different strains of ASFV. Viral virulence is classified
as high, moderate, and mild. In an area free of the disease, ASF
is typically seen as a peracute or acute disease with high mor-
bidity and mortality, but as virulence diminishes with time,
subacute, chronic, and inapparent forms become increasingly
evident. Survivors remain persistently infected.
The immunologic response of swine to strains of ASFV is
unusual and is incompletely understood. Susceptible animals
infected with African field strains develop precipitating and
 74.e1

Further reading
Brown CC, et al. Presence of African horse sickness virus in equine
tissues, as determined by in situ hybridization. Vet Pathol
1994;31:689-694.
Mellor PS, Hamblin C. African horse sickness. Vet Res 2004;35:
445-466.
Diseases of the Vascular System Arteries 75

complement-fixing, but rarely neutralizing or protective, anti- contains ingesta, but the mucosa is apt to be inflamed and
bodies. The animals remain viremic and usually die within eroded. Changes in the small intestine may be absent or
7-10 days. Pigs that recover are resistant to infection with the consist of segmental areas of congestion and mucosal pete-
homologous virus. In the case of infection with highly virulent chiation. More severe intestinal changes may be found in the
ASFV, even though 10 days may have elapsed since infection, large intestine; these may include large areas of hemorrhage,
pigs typically die before development of anti-ASF immuno- severe congestion, and ulceration. Lesions suggesting “button
globulin, probably because of the demise of antigen-presenting ulcer” are very rare in this disease, presumably because few
cells in lymph nodes, spleen, and liver. animals survive long enough for their development.
There is no cross-protection conferred by infections by The postmortem appearance of subacute and chronic cases
classical swine fever virus (CSFV) and ASFV. of ASF varies considerably. In the subacute cases that die after
The ASFV replicates in and activates monocytes and mac- 3-4 weeks of illness, there may be lymph node and renal
rophages of various lymphoid tissues and organs, resulting in hemorrhage, an enlarged but not congested spleen, lobular
release of cytokines, such as interleukin-1 and tumor necrosis consolidation of cranial lung lobes, and intestinal mucosal
factor-α, and hence causes widespread cell death through hemorrhage (Fig. 1-79A, B). Prominent features of the chronic
apoptosis of T and B lymphocytes in lymphoid tissue and of form include fibrinous pericarditis and pleuritis; splenic and
endothelial cells in arterioles and capillaries, accounting for lymph node enlargement; lobular consolidation of the lungs,
the lesions of the acute disease. Activation of pulmonary intra- which may progress to necrosis and mineralization of an entire
vascular macrophages and release of cytokines incites pulmo- lobe; skin lesions ranging from raised hyperemic plaques to
nary edema, neutrophil sequestration, and formation of necrotic areas; swollen joints; and arthritis. The meningoen-
microthrombi in septal capillaries. It also appears that the cephalomyelitis and periportal hepatitis observed in the acute
virus modulates signaling pathways in macrophages, hence disease persist in the chronic disease. Lesions in aborted fetuses
interfering with the expression of host immunomodulatory are inconsistent but include petechiation of placentas, skin,
genes; this evasion of host defenses allows infections to be and myocardium, mottled lungs and liver, and anasarca.
persistent. The major features of the disease are shown in 
eFig. 1-22.
The peracute form of ASF is a severe acute viral hemorrhagic
fever characterized by a 1-3 day course of pyrexia, hyperpnea,
and cutaneous hyperemia, with morbidity and mortality
approaching 100%. However, the usual clinical course of ASF
is acute. Following an incubation period of 4-10 days, there is
a reduction in appetite, pyrexia, marked cutaneous reddening,
dyspnea, and severe leukopenia. Pregnant sows may abort. The
clinical signs in the less severe forms of the disease are variable.
The signs may be a mild expression of those seen in the acute
disease and may be confused easily with other diseases. There
are recurring periods of pyrexia, dyspnea, growth retardation,
and emaciation. Death may occur during one of the periods
of pyrexia. It is important to realize that the clinical signs of
chronic ASF may be indistinguishable from those seen in classical
swine fever (CSF).
The ASFV tends to affect the same organs and tissues as A
does the CSFV. The anatomic differences tend to be quantita-
tive and dependent on the more fulminating nature of ASF;
only splenomegaly and hematoma-like visceral lymph nodes are
particularly characteristic of ASF. The vascular lesions that can
develop rapidly, namely, hemorrhage and edema, are apt to be
more severe in ASF than in CSF, whereas the lesions that
develop more slowly, such as infarction, tend to be absent.
The pig dead from acute ASF shows few or no signs of
recent wasting. Gastrosplenic and renal lymph nodes are
usually intensely hemorrhagic, and ecchymotic hemorrhages
may be present on the serous membranes. The spleen is
usually enlarged and may be markedly enlarged and friable;
infarction cannot usually be recognized grossly. Pulmonary
edema, not common in CSF, is present frequently in pigs with
ASF. The pulmonary septa are thickened by a yellow gelati-
nous infiltrate. Pulmonary hemorrhage is also common. The B
gallbladder is often edematous, and the vessels of the wall are
engorged and conspicuous. Both petechiae and ecchymoses Figure 1-79  African swine fever. A. Enlarged hemorrhagic renal
are present on the serosal and mucosal surfaces. In some out- and sublumbar lymph nodes. B. Incised, enlarged and hemor-
breaks of the disease, there are extensive pancreatic hemor- rhagic, presternal lymph nodes. (Courtesy Foreign Animal Dis-
rhages and necrosis. The renal changes are similar to those of eases Diagnostic Laboratory, National Veterinary Services
CSF and consist of subcapsular petechiae. The stomach often Laboratories.)
 75.e1

African swine fever

Only Suidae infected
ASF virus an Asfivirus [enveloped DNA virus]
Several strains of virus of varying virulence

Gross lesions Clinical signs

Lymph nodes enlarged and A number of clinical forms which vary
intensely hemorrhagic mostly in the duration of the illness
Spleen enlarged, pulmonary High morbidiity and mortality
edema and hemorrahge in the peracute form. Clinical
Intestinal hemorrhage signs of a hemorrhagic fever
Petechiae and ecchymoses on Acute and subacute forms less
serosal and mucosal surafces severe and of longer duration
Subcapsular renal petechiae

Pathogenesis
ASFV replicates in cells of monocyte/
macrophage lineage and lymphoid tissues.
HISTOPATHOLOGY Subacute and chronic Leads to a massive release of cytokines
Extensive apoptosis/necrosis cases of ASF have from activated, dying and dead cells
of cells of the monocyte/ lymph node, renal
macrophage system hemorrhage, fibrinous
pericarditis and pleuritis
Extensive lymphoid
apoptosis/necrosis
Degeneration of
vascular endothelium,
fibrinoid change
and thrombosis

eFigure 1-22  Major features of African swine fever (ASF). ASFV, African swine fever virus.
76 CHAPTER 1  •  Cardiovascular System Arteries

A B

C D
Figure 1-80  African swine fever in a pig. A. Extensive hemorrhage and necrosis in lymph node.
B. Necrosis/apoptosis, especially of lymphocytes in tonsil. C. Extensive thrombosis in renal vessels.
D. Necrotizing vasculitis in renal arterioles. H&E. (Courtesy Armed Forces Institute of Pathology
[archive].)

Histologically, infection by a highly virulent strain of ASFV
causes extensive necrosis of cells of the mononuclear phago-
cyte system, whereas infection with a moderately virulent
strain causes little necrosis (Fig. 1-80A, B). The histologic find-
ings in acute ASF are very similar to those of CSF, but there are
important differences. A major difference is that ASFV does not
infect epithelium. Necrosis with karyorrhexis in lymphoid
tissue everywhere is often very obvious in ASF; frank necrosis
is quite rare in CSF, although mature lymphocytes are apt to
be absent in lymphoid tissue. Renal tubular degeneration with
amorphous casts in the medulla is frequent in ASF, but rare
in CSF. In ASF, necrosis of periportal hepatocytes and infiltrat-
ing lymphocytes is common, whereas microscopic hepatic
lesions are usually absent in CSF. The vascular cuffs in the
brain in ASF contain much more necrotic debris than do the
lesions in CSF. The degeneration of vascular endothelium and
the fibrinoid arterial changes are identical (Fig. 1-80C, D). Vas-
cular endothelial damage in the lung may cause thrombosis
of vessels and thickening of alveolar walls. Pigs dead of acute
ASF may have glomerular capillary thrombosis; surviving pigs
may develop focal segmental glomerulonephritis.
Because there is no treatment or effective vaccine against
ASF, rapid diagnosis is critical to disease control. A diagnosis
of ASF is confirmed by detection of ASFV antigen in tissues
by direct immunofluorescence, detection of ASF antibody by
indirect immunofluorescence or ELISA, detection of virus
genome by PCR, and virus isolation. Differential diagnoses
include classical swine fever (from which ASF cannot be dif-
ferentiated by clinical or postmortem examination), erysipe-
las, salmonellosis, pasteurellosis, and other septicemias.
Further reading
Blome S, et al. Pathogenesis of African swine fever in domestic pigs
and European wild boar. Virus Res 2013;173:122-130.
Costard S, et al. African swine fever: how can global spread be pre-
vented? Philos Trans R Soc Lond B Biol Sci 2009;364:2683-2696.
Gomez-Villamandos JC, et al. African swine fever and classical swine
fever: a review of the pathogenesis. Dtsch Tierarztl Wochenschr
2003;110:165-169.
Mozos E, et al. Cutaneous lesions in experimental acute and subacute
African swine fever: an immunohistopathological and ultrastruc-
tural study. Dtsch Tierarztl Wochenschr 2003;110:150-154.
Penrith ML. African swine fever. Onderstepoort J Vet Res 2009;76:
91-95.
Sanchez-Vizcaino JM, Mur L. African swine fever diagnosis update. Dev
Biol (Basel) 2013;135:159-165.
 76.e1

Further reading
Angulo A, et al. Virus-host interactions in African swine fever: the
attachment to cellular receptors. Arch Virol Suppl 1993;7:169-183.
Carrasco L, et al. African swine fever: expression of interleukin-1 alpha
and tumour necrosis factor-alpha by pulmonary intravascular mac-
rophages. J Comp Pathol 2002;126:194-201.
Dixon LK, et al. African swine fever virus proteins involved in evading
host defence systems. Vet Immunol Immunopathol 2004;100:117-
134.
Edwards JF, et al. Mechanism of thrombocytopenia in African swine
fever. Am J Vet Res 1985;46:2058-2063.
Gomez-Villamandos JC, et al. African swine fever virus infection of
bone marrow: lesions and pathogenesis. Vet Pathol 1997;34:97-
107.
Hervas J, et al. The lesional changes and pathogenesis in the kidney in
African swine fever. Vet Res Commun 1996;20:285-299.
Kleiboeker SB, Scoles GA. Pathogenesis of African swine fever virus in
Ornithodoros ticks. Anim Health Res Rev 2001;2:121-128.
Vallee I, et al. African swine fever virus infection of porcine aortic
endothelial cells leads to inhibition of inflammatory responses, acti-
vation of the thrombotic state, and apoptosis. J Virol 2001;75:
10372-10382.
Diseases of the Vascular System
Classical swine fever (hog cholera).  Classical swine fever
(CSF) is a highly contagious viral disease of swine; it may occur
as acute, subacute, chronic, or inapparent syndromes. Acute CSF
is a disease of high morbidity and mortality caused by a viru-
lent strain of the virus; low-virulence virus may cause inap-
parent disease. Classical swine fever is said to have developed
de novo in Ohio, United States, in the early 1800s. It subse-
quently spread to almost all countries and is also known as
swine fever, Schweinepest, peste du porc, and peste svina. Species
Classical swine fever virus (CSFV) produces disease only in
swine. The disease has been eradicated from Australia, Canada,
the United Kingdom, and the United States, but it remains a
problem in Central and South America and several European
countries.
CSF is caused by a Pestivirus, a member of the family Fla-
viviridae. Other members of the genus include bovine viral
diarrhea virus (BVDV), Bungowannah virus and border
disease virus (BDV). CSFV and BVDV are closely related
antigenically, and although pestiviruses other than CSFV are
thought to be harmless to pigs, natural BVDV infection can
cause clinical signs and postmortem lesions indistinguishable from
those of chronic CSF. Under appropriate circumstances, CSFV,
BVDV, Bungowannah virus, and BDV may produce transpla-
cental infection, and hence persistent infections and congeni-
tal anomalies. The CSFV is an enveloped, single-stranded
RNA virus that replicates intracytoplasmically. Most strains do
not produce a cytopathic effect in porcine cell cultures. The
enveloped nature of the virus makes it sensitive to lipid sol-
vents and to desiccation. However, the virus may persist for
prolonged periods in uncooked pork products.
Antigenic variation exists among strains of CSFV, and field
strains vary widely in virulence. The interaction of a particular
strain of virus and the host provides a range of disease syn-
dromes. Strains of CSFV are usually classified as being of high,
moderate, or low virulence, or as being avirulent. Highly virulent
strains produce the features of the classic acute disease in pigs
of all ages; the morbidity may reach 100%, with a mortality
rate of up to 90%. Strains of moderate virulence induce sub-
acute or chronic disease, and pigs may subsequently die or
recover. In pigs infected postnatally, strains of low virulence
produce few or no signs of disease and induce immunity, but
may cause fetal abnormalities. Artificially attenuated strains
used as vaccines are avirulent, even for fetuses. Virulence of
CSFV may be unstable; virulence can increase by one passage
through pigs.
Transmission of the disease is usually by direct contact of
infected pigs or wild boar with susceptible pigs; CSF is
endemic in wild boar in parts of Europe. The virus is present
in urine, feces, and lacrimal and oronasal secretions of infected
pigs, as well as semen of infected boars. Even with the less
virulent strains, the virus may be excreted in the urine for
periods up to 3 months. The major mechanism of spread of
virus of low virulence occurs from continuous virus shedding
by chronic or persistently infected asymptomatic pigs. Minor
modes of transmission include fomites and arthropods.
Clinically, classical swine fever is characteristically an acute
disease of high morbidity and mortality, most animals surviving
only to 14 days after showing the first signs of illness, namely,
anorexia, depression, fever, and leukopenia. Persistent infec-
tion (i.e., survival of >30 days) is caused by CSFV strains of
moderate or low virulence and may arbitrarily be divided into
chronic and late-onset types. In chronic CSF, typical acute
disease is followed by clinical improvement, the result of
Arteries 77
specific antibody formation, but later by immune exhaustion
and chronic disease in which the pig is viremic and more
susceptible to secondary bacterial infection. Late-onset CSF
occurs in pigs that are persistently viremic and immunotoler-
ant to CSFV as a result of fetal infection by CSFV of low viru-
lence. The latest date for the development of a persistent
infection of the fetus appears to be about day 70 of gestation;
by day 85 viral antigen may be detected in a few fetuses, but
virus cannot be isolated. Signs that develop in viremic, but
previously asymptomatic, pigs include anorexia, depression,
leukopenia, conjunctivitis, dermatitis, diarrhea, runting, and
paraparesis. The late-onset form of CSF is the porcine equivalent
of mucosal disease in cattle, in which BVDV infection of fetal
calves results in persistently viremic, immunotolerant animals.
The major clinical features of CSF are shown in eFig. 1-23.
The pathogenesis of CSF is not fully understood, but
involves the effects of the virus on the immune system (lym-
phoreticular cells and macrophages), the vascular endothelium,
and epithelial cells. The effect of the monocytotropic CSFV on
the immune system varies with the stage of differentiation;
mature cells degenerate, whereas undifferentiated cells
respond by proliferation. CSFV replicates in macrophages in
lymph nodes and lymphoid tissues and can cause depletion of
lymphocytes indirectly through expression of apoptotic cyto-
kines, such as tumor necrosis factor-α. Similarly, intestinal
epithelial cell necrosis appears be the product of release of
chemical mediators from activated macrophages, rather than
direct viral infection. Endothelial changes are primarily degen-
erative but some proliferative changes occur. Damage to endo-
thelial and other cells leads to thrombocytopenia, consumption
coagulopathy, and in turn disseminated intravascular coagula-
tion and hemorrhage.
The classic or acute form of the disease, which affects pigs
of all ages, commences by entry of the virus through the
mucous membranes with initial replication in the tonsillar
epithelium. This is followed by spread to the cervical lymph
nodes with viremia within 16 hours of infection. The virus has
a propensity to replicate in cells of the immune system, par-
ticularly in lymph nodes, bone marrow, and other lymphoid
aggregates, such as the spleen and Peyer’s patches. After 3-4
days, the virus invades endothelial cells and epithelial cells,
including those of the pharyngeal mucosa, gastrointestinal
tract, gallbladder, pancreas, salivary gland, uterus, adrenal, and
thyroid. The clinical signs are not specific and do not provide
good correlation with pathologic changes, although, in the
acute disease, they may be sufficient for presumptive diagnosis
where the disease is endemic.
Superficially, the eyelids are frequently adherent and sticky,
and the carcass is dehydrated and soiled by terminal diarrhea.
The irregular erythema that can be seen in the animal when
alive is less obvious, but hemorrhages, particularly in unpig-
mented areas of skin, may be seen. If present, they are most
numerous on the abdomen and the inner aspects of the thighs.
Diagnostic lesions may be sparse in CSF, especially if per-
acute, and it may be impossible to establish the diagnosis on
the basis of the gross lesions in a single animal. The lesions most
commonly present are hemorrhages in the periphery of the lymph
nodes and renal petechiae (Fig. 1-81A). The renal hemorrhages
may be very few, and in all cases the kidney capsule should
be removed and the surface examined in good light. Hemor-
rhages in the lymph nodes are more obvious; characteristically,
only the periphery of the node is involved. In acute cases, this
produces a distinctive bright red halo; if the case is more
 77.e1

Classical swine fever

Pestivirus
(Variation in strain virulence)

Transplacental infection Acute, chronic to

(70 days gestation) persistent infection
leads to immune in immunocompetent animals
tolerance of infection

Clinical syndromes vary

Fetal abnormalities
Abortion, stillbirth,
mummification, congenital
abnormalities-heart and CNS
from acute, subacute, chronic,
inapparent infection
Late onset runting
syndrome
Low virulence virus
Anorexia, depression,
conjunctivitis, runting,
paraparesis

eFigure 1-23  Major clinical syndromes of classical swine fever. CNS, central nervous system.
78 CHAPTER 1  •  Cardiovascular System
B outlined circular areas of hemorrhage and necrosis. The central
Figure 1-81  Classical swine fever (hog cholera). A. Cortical
surface of kidney with multiple petechial hemorrhages (turkey
egg kidney). B. Splenic infarct (arrow). (Courtesy Foreign Animal
Diseases Diagnostic Laboratory, National Veterinary Services
Laboratories.)
chronic, the halo may be the dirty brown of partially degraded
hemoglobin. Less frequently, the hemorrhage in the node is
diffuse. The nodal changes are generalized, but nodes most apt
to show severe changes are the mandibular, colonic, hepatic,
and iliac; changes in the renal lymph nodes are not useful in
this context.
Splenic infarction is almost pathognomonic of acute CSF.
Unfortunately, the tendency for infarcts to develop in the
disease varies with the strain of the virus, with reports of
incidence of 1-87%. When present, infarcts occur as single or
multiple, dark red, pyramidal blebs 0.5-2 cm in diameter,
usually along free edges but occasionally on the flat surface
(Fig. 1-81B). The spleen in CSF is not enlarged, as it is in
septicemias, and is red-brown so that the infarcts contrast
quite sharply with the meaty parenchyma. In addition to the
hemorrhages of the kidney, petechiae are common in the
urinary bladder (eFig. 1-24), the larynx (eFig. 1-25), the gastric
mucosa, the lung, and the epicardium, in about that decreas-
ing order of frequency. There is usually a small amount of
straw-colored fluid in the pericardial sac. There may be hem-
orrhagic lobular pneumonia.
Irregular, but sharply outlined areas of necrosis develop in
the tonsils and posterior fauces. The stomach of an animal
Arteries
Figure 1-82  Classical swine fever. Mild lymphoplasmacytic vas-
culitis with hypertrophied endothelial cells in the brain of a pig.
H&E. (From Joint Pathology Center Veterinary Systemic Pathol-
ogy Online database.)
dead of CSF is empty except for a small amount of watery
mucus and ingesta. The fundic mucosa is congested, and mild
or severe erosions may be present. Specific lesions do not
occur in the small intestine, but the mesentery is usually con-
gested. It is in the colon and cecum that the virus combines
with the intestinal flora to produce craterous mucosal defects,
“button ulcers,” which are characteristic of the subacute or
chronic stage of the disease. These lesions begin as sharply
area is yellow and dry. As the lesion ages, the rim, which is
composed of necrotic epithelium, bacteria, and detritus, is
raised above the surrounding mucous membrane, and concen-
tric rings form as if growth were cyclic. The center of lesions
sinks giving a slight diskoid shape. If this necrotic tissue and
debris is removed, a deep ulcer is revealed. Growth arrest lines
may be seen in the ribs of chronically sick pigs. Gross lesions
are not usually present in the brain, but the brain should be
removed because it is there that the histologic changes can be
best appreciated. The major features of the gross postmortem
findings are shown in eFigure 1-26.
Microscopically, all areas within the brain may be affected,
but the lesions are usually most conspicuous in the medulla,
pons, mid-brain, and thalamus. The response is largely con-
fined to the vessels and their supporting mesoderm. Many of
the venules have eccentric cuffs, which are formed in part by
transmural migration of monocytes. Mitotic figures and nuclear
chromatin of necrotic cells are frequently present together in
the cuff, as proliferation and necrosis are coexistent. Swelling
and degeneration of the endothelial cells occur in the walls of
the smaller vessels (Fig. 1-82). All changes from slight thicken-
ing to necrosis of the wall may be seen. The lumen is often
compromised by these reactions. The response of the neural
parenchyma appears to be entirely secondary to the vascular
lesions; often it is nonexistent or confined to minimal neuronal
degeneration, or it may consist of glial nodules formed about
obstructed or destroyed capillaries. If severe cerebral edema
develops, there may be widespread damage to the oligoden-
droglia. The vessels of the eyes, choroid plexuses, and the
leptomeninges are similarly involved.
 78.e1

eFigure 1-25  Laryngeal hemorrhages in acute classical swine

fever.

eFigure 1-24  Hemorrhages in mucosa of urinary bladder in acute

classical swine fever.

Classical swine fever

gross lesions

Hemorrhage, infarction, Petechiae

necrosis, (apoptosis)

Hemorrhage periphery Splenic infarction Necrosis, ulceration Renal cortical surface,

of lymph nodes [Not always present] Tonsils, button ulcers bladder, larynx, lung,
in colon and cecum epicardium, gastric mucosa

eFigure 1-26  Major gross postmortem findings in classical swine fever.

Diseases of the Vascular System
Vascular lesions usually are most severe in lymphoid tissue
but may occur anywhere. The lesions vary from slight thickening
of the capillary wall to fibrinoid necrosis of arterioles. As these
changes develop, there is a tendency for extravasations to
occur and for microthrombi to form.
Microscopic areas of infarction are common in the lymph
nodes and skin, but only in the spleen, tonsil, gallbladder, and
large intestine are these areas usually large enough to be
grossly visible. In some cases, swelling and paleness of the
capillary wall is obvious. The nuclei of endothelia in these
vessels are enlarged and the nuclear chromatin is dispersed as
fine dust. Less often, the endothelial proliferation is so marked
as to be the most conspicuous change. In general, in acute
cases the degenerative changes are most prominent, whereas
in chronic ones proliferative changes are more obvious.
In the periphery of lymph nodes (the equivalent of the
medulla in other species), lesions vary from slight edema and
proliferation of the reticuloendothelial elements to extensive
hemorrhage. It is the intermediate stages that are the most
common and in which the nature of the lesion is best visual-
ized; in these, there is necrosis of the small vessels and second-
ary hemorrhages and parenchymal necrosis.
In the spleen, the most pronounced lesions are in the fol-
licular arteries, particularly those at the apex of the pyramidal
infarcts. The swelling and hyalinization of these vessels may
be so severe as to occlude the lumen. Survival of tissue within
the infarcted area will depend on how long the infarction
preceded death. Even if the spleen is free of gross and microscopic
infarction, vascular changes of the type seen elsewhere can usually
be found. They are often associated with perivascular hemor-
rhage. In addition, there is reticuloendothelial hyperplasia and
absence of mature lymphocytes.
The kidney tubules often show nonspecific degenerative
changes. The subcapsular hemorrhages seen grossly are the
result of increased vascular permeability and erythrodiapede-
sis. Immune-complex–mediated mesangioproliferative glo-
merulonephritis occurs with deposition of IgM, IgG, and C1q
in mesangial, subepithelial, and subendothelial sites; infiltra-
tion of the mesangium by macrophages and later neutrophils;
and ultrastructurally, the fusion of foot processes and the  Middle East, Asia, and Australia. In temperate climates, BEF
presence of viral particles in glomerular endothelial cells  is a disease of summer and autumn, and ceases abruptly at the
and podocytes. The major histologic features are shown in  first frost; the host/reservoir for overwintering or between
eFigure 1-27.
In utero infections can result in a variety of effects, includ-
ing abortion, mummified fetuses, and stillborn piglets. Fetal
abnormalities, such as ascites, petechiation of skin and other
organs, hepatic nodularity, pulmonary hypoplasia, microceph-
alus, hydrocephalus, cerebellar hypoplasia, and hypomyelino-
genesis, may also be observed. Persistently infected pigs that
survive may be runts and die 2-11 months after birth. These
piglets have severe thymic atrophy and pale swollen lymph
nodes; some may have focal colonic mucosal necrosis.
Serologic diagnosis of CSF is difficult. Antibodies to CSFV
and BVDV cross-react in many assays; they may be differenti-
ated by specific virus neutralization tests. The prescribed tests
in the World Organization for Animal Health (OIE) Manual
are the neutralization peroxidase-linked assay, fluorescent
antibody virus neutralization, and ELISA. CSFV antigen can
be detected in live pigs by real-time (RT)-PCR, and in
formalin-fixed tissue by semi-nested RT-PCR or by in situ
hybridization.
Differential diagnoses for CSF include African swine fever
(clinicopathologically indistinguishable), BVDV infection,
Arteries 79
porcine reproductive and respiratory syndrome (PRRS), post-
weaning multisystemic wasting syndrome (PMWS), porcine
dermatitis and nephropathy syndrome (PDNS), salmonellosis,
erysipelas, acute pasteurellosis, other viral encephalomyeliti-
des, streptococcosis, leptospirosis, and coumarin poisoning.
Further reading
Calderon NL, et al. Ultrastructural glomerular changes in experimental
infection with the classical swine fever virus. Vet Res 2000;31:447-
453.
Elbers AR, et al. Assessment of the use of gross lesions at post-mortem
to detect outbreaks of classical swine fever. Vet Microbiol
2003;96:345-356.
Gogin A, et al. African swine fever in the North Caucasus region and
the Russian Federation in years 2007-2012. Virus Res 2013;173:198-
203.
Gomez-Villamandos JC, et al. African swine fever and classical swine
fever: a review of the pathogenesis. Dtsch Tierarztl Wochenschr
2003;110:165-169.
Paton DJ, Greiser-Wilke I. Classical swine fever: an update. Res Vet Sci
2003;75:169-178.
Sanchez-Cordon PJ, et al. A histopathologic, immunohistochemical,
and ultrastructural study of the intestine in pigs inoculated with
classical swine fever virus. Vet Pathol 2003;40:254-262.
Tao J, et al. Bovine viral diarrhea virus (BVDV) infections in pigs. Vet
Microbiol 2013;165:185-189.
Bovine ephemeral fever.  Bovine ephemeral fever (BEF), a
noncontagious vector-borne viral disease of cattle and water
buffalo, is characterized by sudden onset of fever, stiffness, and
lameness, usually with high morbidity and low mortality, and
with rapid recovery within 3-4 days of the onset of clinical signs.
The cause is species Bovine ephemeral fever virus (BEFV),
genus Ephemerovirus, family Rhabdoviridae. The disease is
endemic in tropical regions of Africa and Asia and occurs as
epidemics in subtropical and temperate regions of Africa, the
epizootics is probably in wild ruminants. Infection usually
confers lifelong immunity. The likely vectors are various
species of Culicoides and mosquitoes.
Clinical disease ranges from almost imperceptible clinical
signs to death, with considerable individual variation in an
outbreak. Mild disease may be exacerbated by environmental
stress, for instance, exposure causing dehydration. Disease is
milder in young than in mature animals, in lean than in fat
animals, in light steers and cows than in bulls, and in dry cows
than in those in heavy lactation. The incubation period is
usually 2-4 days. The fever may be biphasic, triphasic, or
multiphasic; clinical signs are milder in early than in later
phases of fever. Mildly affected animals may have fever, be
lame, or be stiff for 1-2 days, and then recover completely.
Neutrophilia with a left shift and concurrent lymphopenia,
hyperfibrinogenemia, and hypocalcemia occur early in the
course of disease. More severely affected animals are anorectic,
have oculonasal discharge, and may have muscle tremors, stiff-
ness, lameness, and patchy edema of the face or jaw. Rumen
motility ceases, and the animal may be constipated. Animals
in lateral recumbency are usually still able to rise. Lactation
 79.e1

Classical swine fever

Hemorrhage
Necrosis
Apoptosis
Proliferation

Immune system Vascular endothelium Epithelial cells

Degeneration/necrosis/ Combination of degeneration/ Necrosis/apoptosis-possibly
apoptosis of mature cells. necrosis/apoptosis and proliferation secondary to macrophage cytokines
Proliferation of immature cells Also thrombosis, infarction, DIC

Hemorrhage, necrosis/ Brain Sharply outlined areas of

apoptosis of lymphoid (medulla, pons, mid brain, thalamus) hemorrhage and necrosis
elements. Fibrinoid necrosis Monocytic perivascular cuffing
of arteriolar walls both proliferation and necrosis/apoptosis
kidney-glomerulonephritis

eFigure 1-27  Major histopathologic findings in classical swine fever. DIC, disseminated intravas-
cular coagulation.
79.e2

Further reading
Carrasco CP, et al. Interaction of classical swine fever virus with den-
dritic cells. J Gen Virol 2004;85:1633-1641.
Choi C, et al. Classical swine fever virus induces tumor necrosis factor-
alpha and lymphocyte apoptosis. Arch Virol 2004;149:875-889.
Floegel-Niesmann G, et al. Virulence of recent and former classical
swine fever virus isolates evaluated by their clinical and pathologi-
cal signs. J Vet Med B Infect Dis Vet Public Health 2003;50:214-220.
Ha SK, et al. Development of an optimized protocol for the detection
of classical swine fever virus in formalin-fixed, paraffin-embedded
tissues by semi-nested reverse transcription-polymerase chain reac-
tion and comparison with in situ hybridization. Res Vet Sci
2004;77:163-169.
Handel K, et al. Comparison of reverse transcriptase-polymerase chain
reaction, virus isolation, and immunoperoxidase assays for detect-
ing pigs infected with low, moderate, and high virulent strains of
classical swine fever virus. J Vet Diagn Invest 2004;16:132-138.
Kleiboeker SB. Swine fever: classical swine fever and African swine
fever. Vet Clin North Am Food Anim Pract 2002;18:431-451.
Moennig V, et al. Clinical signs and epidemiology of classical swine
fever: a review of new knowledge. Vet J 2003;165:11-20.
Ruiz-Villamor E, et al. Classical swine fever: pathogenesis of glomeru-
lar damage and immunocharacterization of immunocomplex
deposits. J Comp Pathol 2001;124:246-254.
Terpstra C, Wensvoort G. Natural infections of pigs with bovine viral
diarrhoea virus associated with signs resembling swine fever. Res
Vet Sci 1988;45:137-142.
80 CHAPTER 1  •  Cardiovascular System
falls by an average of 50%, and does not usually recover to
normal during that lactation. Cows in late pregnancy may
abort. In very severe cases, there may be temporary or perma-
nent paralysis of all limbs, inability to swallow, and drooling;
in 1-4 days, loss of reflexes, coma, and death follow.
Whether the disease is mild or severe, recovery commences
quite suddenly and is complete in 95-97% of uncomplicated cases,
giving rise to the name “ephemeral fever.” Although mortality is
usually <1%, the most productive mature animals are often
lost, plus there are losses of milk production, abortion losses,
and temporary infertility in bulls. Other sequelae include fatal
pulmonary emphysema, pneumonia, mastitis, and locomotor
disturbances. The total economic loss in an outbreak can be
severe.
The essential gross feature of BEF is serofibrinous polyserosi-
tis, which variously affects the synovial, pericardial, thoracic,
and peritoneal cavities, and is the result of increased vascular
permeability. The serosal membranes themselves are often
edematous and may be hemorrhagic; the edema fluid in cavi-
ties often contains fibrin clots. Severely affected joints may be
surrounded by brown or yellow gelatinous periarticular fluid
that also extends along tendon sheaths and fascial planes.
There may be patchy pulmonary edema, visceral and parietal
pleuritis, epicarditis at the base of the heart, edematous lymph
nodes in the febrile stages, and necrosis in some skeletal
muscles; myonecrosis is likely the result of recumbency.
Histologically, affected tissues are edematous and infil-
trated by neutrophils, and may also be hyperemic and hemor-
rhagic. Vascular changes include endothelial swelling and
hyperplasia, hyperplasia of pericytes, fibrinoid necrosis of arte-
rioles, perivascular fibroplasia, and thrombosis of occasional
vessels in muscles. Wallerian degeneration has been reported
in the upper cervical spinal cord in cases with chronic paraly-
sis, but may be secondary to trauma.
The pathogenesis of BEF is poorly understood, but is likely
mediated through cytokines. BEFV α1 protein is expressed in
infected cells and has the properties of a viroporin, which may
facilitate virus replication. Neutrophils appear to play a
central, but undefined, role in pathogenesis; cattle in which
neutrophils are experimentally depleted develop viremia but
not clinical disease. Interferon-α, interleukin 1, and tissue
necrosis factor circulate in high titer during the acute phase
of BEF.
The clinical signs observed in an epizootic are usually diag-
nostic. The diagnosis can be confirmed by virus detection/
isolation. Serologic diagnosis may be complicated by cross-
reaction with antibody to Kimberley virus, an arbovirus that
induces production of low levels of serum neutralizing anti-
body to BEFV but does not protect against BEFV.
Further reading
Aziz-Boaron O, et al. Circulation of bovine ephemeral fever in the
Middle East—strong evidence for transmission by winds and animal
transport. Vet Microbiol 2012;158:300-307.
Blasdell KR, et al. A reverse-transcription PCR method for detecting all
known ephemeroviruses in clinical samples. J Virol Methods
2013;191:128-135.
Joubert DA, et al. Bovine ephemeral fever rhabdovirus α1 protein has
viroporin-like properties and binds importin β1 and importin 7. J
Virol 2014;88:1591-1603.
Kirkland PD. Akabane and bovine ephemeral fever virus infections. Vet
Clin North Am Food Anim Pract 2002;18:501-514.
Arteries
Rickettsial vasculitides
Heartwater (cowdriosis).  Heartwater is a tick-borne rickett-
siosis of ruminants that is endemic in sub-Saharan Africa and
has been identified in several Caribbean islands. The common
name, heartwater, is derived from the pericardial effusion that
is typically present in small ruminants, but sometimes absent
in infected cattle. Heartwater is a major vector-borne disease
of ruminants in Africa, third in importance only to East Coast
fever and trypanosomiasis, but has a wider distribution than
either of these. Mortalities caused by heartwater are estimated
to be 3 times greater than those caused by babesiosis and
anaplasmosis. The causative agent is Ehrlichia (Cowdria)
ruminantium, order Rickettsiales. Isolates of E. ruminantium
cross-react strongly with Ehrlichia equi and to a lesser extent
with E. canis, in indirect fluorescent antibody tests. The vectors
are 3 host ticks of the Amblyomma genus, principally A. var-
iegatum, A. hebraeum, and A. pomposum. Amblyomma macu-
latum and A. cajennense are suitable vectors present on the
American mainland. Trans-stadial transmission occurs in
vector ticks; transovarian transmission is infrequent. When a
tick feeds on an infected host, organisms apparently first infect
and develop within gut cells. Subsequent stages of the organ-
ism continue their development in hemolymph and salivary
gland, and are transferred to the vertebrate host during tick
feeding.
The various strains of Ehrlichia ruminantium are antigeni-
cally similar, but differ considerably in their virulence. The
various domestic hosts also differ in their susceptibility.
Imported breeds of cattle, sheep, and goats are as a rule much
more susceptible than indigenous breeds. There is also an
important age difference in susceptibility. Calves and lambs
<3 weeks of age are highly resistant to heartwater. This is a
true age resistance, and it is independent of maternal immu-
nity. Ruminants are most susceptible at about the stage of
early maturity, and in the absence of treatment, mortality is
expected to be ~60% in cattle and close to 100% in European
breeds of sheep, although this will depend on the virulence of
the infecting strain.
There also appear to be differences in susceptibility among
the African antelopes. The blesbok and black wildebeest are
known to be susceptible to infection without showing signs
of illness. Wildlife may act as reservoirs of infection, although
this is not necessary as the tick itself is a reservoir; infection
survives in adult ticks for >15 months. Domestic ruminants
that have recovered from the disease seldom remain as carriers
of the circulating organism for >3 weeks after recovery, but it
is not clear whether the agent remains in a masked form in
tissues. Immunity of variable duration follows recovery, often as
premunity; sterile immunity may persist for a year or more
after disappearance of the organism. Immunity in natural
infections is expected to be reinforced by reinfections.
The early development of the parasite is not completely
understood, but probably takes place in reticulum cells and
macrophages of lymph nodes and spleen in which initial bodies
are demonstrable at about the fourth day of infection. Organ-
isms are then released into the blood and parasitize vascular
endothelial cells. The organism is demonstrable in capillary
endothelium of brain 1-3 days after it is demonstrable in
lymph nodes. Ehrlichia ruminantium parasitizes endothelial
cells but is also present in the blood; the infection is readily
transmissible by inoculation of blood collected during the
febrile stage or shortly thereafter. The colonies (groups,
clusters, morulae) of microorganisms in endothelial cells lie
 80.e1

Further reading
Losos GJ. Infectious Tropical Diseases of Domestic Animals. Harlow, UK:
Longman Scientific and Technical.; 1986. p. 452-477.
St George TD. Bovine ephemeral fever: a review. Trop Anim Health
Prod 1988;20:194-202.
Uren MF, et al. Studies on the pathogenesis of bovine ephemeral fever
in experimental cattle: III. Virological and biochemical data. Vet
Microbiol 1992;30:297-307.
Wang FI, et al. Bovine ephemeral fever in Taiwan. J Vet Diagn Invest
2001;13:462-467.
Young PL, Spradbrow PB. Demonstration of vascular permeability
changes in cattle infected with bovine ephemeral fever virus.
J Comp Pathol 1990;102:55-62.
Diseases of the Vascular System Arteries 81

characteristically in membrane-bound vacuoles in the cytoplasm

at the poles of the endothelial cell nuclei. Colonies and organisms
are pleomorphic; colonies are formed by binary fission of
organisms. Organisms range in size from 0.2 to >2.5 µm and
are termed small, medium, or large; each is surrounded by a
double membrane, and based on their internal morphology,
they may be termed elementary (electron-dense), intermediate,
or reticulate bodies; usually only organisms of the same form
are found within a vacuole. They can be found in sections and
are present in all organs and in vessels of all calibers, but are
best sought in the capillaries of the cerebral cortex in squash-
smear preparations or in imprints from the endothelium of a
large vessel, such as the jugular vein. Giemsa is the preferred
method of staining.
The natural incubation period of heartwater is 2-3 weeks
but varies considerably. In the peracute form of the disease,
death occurs rapidly in convulsions without warning. The
usual clinical syndrome in susceptible animals is acute, with a Figure 1-83  Hydrothorax in heartwater. (Courtesy Foreign
course of up to 6 days. There is high fever and its attendant Animal Diseases Diagnostic Laboratory, National Veterinary Ser-
signs, and dyspnea. As the course advances, nervous signs vices Laboratories.)
develop. These are especially prominent in cattle and consist
of chewing movements, protrusion of the tongue, twitching
of eyelids and blinking, unsteadiness of gait, circling, and a
terminal convulsive phase in which there is prominent cutane-
ous hyperesthesia. Diarrhea is common in cattle but less
common in sheep. Mild progressive anemia may develop, as
may leukopenia (neutropenia, eosinopenia, and lymphocyto-
sis) and hypoalbuminemia. In the subacute syndrome, the
course is prolonged and leads either to slow recovery or to
collapse and death. Animals with high natural resistance or
partial immunity may show transient fever only.
The pathogenesis of the increased capillary permeability
seen in heartwater is unclear; the severity of edema is often
thought to be out of proportion to the numbers of infecting
organisms. Production of a toxin has been suggested, but not
proven; Ehrlichia stains negatively with Gram’s stain, has a cell
wall similar to that of gram-negative bacteria, and has been
suggested to produce endotoxin. Complement and the prod-
ucts of arachidonic acid metabolism may play a role in the Figure 1-84  Hydropericardium in heartwater. (Courtesy Foreign
generation of vasoactive substances. Animal Diseases Diagnostic Laboratory, National Veterinary Ser-
The gross anatomic changes in heartwater are the same in vices Laboratories.)
each ruminant species but generally are less prominent in
cattle than in sheep or goats; lesions may be inconspicuous or
absent in treated animals. The disease does not alter the hyperemia with submucosal edema in the lower alimentary
general condition of the animal appreciably. Typical gross tract, but it is most pronounced in the abomasum. Petechial
lesions include effusion in body cavities, hydropericardium, hemorrhages are present in the endocardium, mucosa of
edema of lungs, brain, mediastinum, and associated lymph stomach and gut, tracheobronchial mucosa, and lymph nodes.
nodes, and splenomegaly, although all of the lesions rarely Lesions in the brain are common and account for the
occur simultaneously (Fig. 1-83). The name of the disease is nervous signs that characterize the disease, especially in cattle,
derived from the hydropericardium, but this is sometimes and for the failure of animals to recover with chemotherapy.
absent. The effusion, which is serous with some fibrinous Gross changes are inconstant on inspection of the surface of
strands, is more constant and copious in sheep than in cattle the brain. Petechial hemorrhages may be present over the
(Fig. 1-84). The other serous cavities also contain excess serous cerebellum, and the choroid plexus may be dull and thick-
fluid; there may be several liters in the pleural and peritoneal ened. On slicing, petechial, ecchymotic, and larger hemor-
cavities of cattle and up to half a liter in sheep and goats. rhages may be numerous in all parts of the brain.
When exudation is copious, the mediastinum and retroperi- The microscopic lesions in the brain are reflections of para-
toneal tissues are also edematous. The membranes remain sitism and injury to small vessels, especially capillaries and
clear and glistening. The lungs are severely edematous, espe- venules. Either histologic sections or impression smears will
cially in the peracute form. The lymph nodes of the head, show colonies of E. ruminantium visible in endothelial cyto-
neck, and cranial mediastinum especially are swollen and plasm of untreated cases (Fig. 1-85). There is acute inflamma-
edematous. The spleen is almost invariably much enlarged in tion of the choroid plexus with fibrinous exudate in the
sheep and goats, being sometimes up to 6 times its normal stroma, congestion, hemorrhage, and accumulation of inflam-
size, but splenomegaly in cattle is only moderate. There is matory cells about the vessels. Within the brain, vascular
82 CHAPTER 1  •  Cardiovascular System
Figure 1-85  Heartwater in an ox. Impression smear showing
intracellular Ehrlichia ruminantium organisms. (Courtesy M.
Domingo Alvarez.)
injury leads to perivascular or larger hemorrhages and accu-
mulation of protein droplets in the perivascular space. Focal
or larger areas of malacia surround the vessels and are in
various stages of development from edematous disruption of
white matter with glial activation to microcavitation.
The diagnosis of heartwater depends largely on the dem-
onstration of organisms in endothelial cells in brain either in
smears or section; brain biopsy can be used to establish the
diagnosis in the living animal. The pCS20 PCR assay is the
most reliable and specific assay for the detection of E. rumi-
nantium in ruminants and Amblyomma ticks. Various antibody
detection assays are available, including indirect fluorescent
antibody, polyclonal competitive ELISA, major antigenic
protein (MAP-1) ELISA, and Western blot, but often lack
specificity because of cross-reactivity with closely related
ehrlichiae.
Further reading
Allsopp BA. Natural history of Ehrlichia ruminantium. Vet Parastiol
2010;167:123-135.
Brown CC, Skowronek AJ. Histologic and immunochemical study of
the pathogenesis of heartwater (Cowdria ruminantium infection) in
goats and mice. Am J Vet Res 1990;51:1476-1480.
Mebus CA, Logan LL. Heartwater disease of domestic and wild rumi-
nants. J Am Vet Med Assoc 1988;192:950-952.
Vacheiry N, et al. Differential strain-specific diagnosis of the heart­
water agent: Ehrlichia ruminantium. Infect Genet Evolution
2008;8:459-466.
Rocky Mountain spotted fever.  Rocky Mountain spotted
fever (RMSF), a febrile exanthema caused by Rickettsia rick-
ettsii, is an important rickettsiosis of dogs and humans; R.
rickettsii or antigenically similar organisms infect a wide variety
of mammals and birds. RMSF occurs in dogs throughout the
Americas (and is known by various other names, for instance,
Brazilian spotted fever, BSF), with most cases in North
America occurring during the tick season (April to Septem-
ber). Canine monocytic ehrlichiosis (CME), a very similar
acute nonspecific febrile illness, is caused by Ehrlichia canis in
Brazil; BSF must be differentiated from CME.
Arteries
The ticks most commonly responsible for the transmission
of RMSF are Dermacentor variabilis and D. andersoni; these
ticks serve as vectors, reservoirs, and natural hosts for R. rick-
ettsii. The rickettsiae are maintained in nature in a primary
sylvan cycle, involving mostly small rodents. Dogs can develop
a high and persistent rickettsemia, and are a potential public
health danger; humans can be infected during tick removal by
contact with hemolymph of engorged ticks or with tick
excreta. Tetracycline therapy is effective, and dogs are immune
after recovery.
Dogs are usually infected via the bite of infected ticks. The
rickettsiae invade and replicate within endothelial cells of small
blood vessels; endothelial damage is probably mediated by
phospholipase A and a trypsin-like protease, of either rickett-
sial or host origin. There is little evidence for production of
endotoxin or exotoxin by R. rickettsii. Endothelial damage
leads to platelet activation and activation of coagulation and
fibrinolytic systems; thrombosis in RMSF is thought to arise in
reaction to endothelial damage.
Vasculitis in RMSF is a product of endothelial swelling and
necrosis with secondary contributions from the immune and
phagocytic host responses mounted by lymphocytes and 
macrophages, but is not primarily caused by immune- 
complex formation or by cell-mediated mechanisms. The
action of various mediators, such as those of the kallikrein-
kinin system, in addition to direct endothelial necrosis, leads
to increased vascular permeability and hence edema and mul-
tifocal hemorrhage.
Dogs <2 years of age are predominantly affected. Purebred
dogs, especially German Shepherd dogs, appear to be more
susceptible than are crossbreds. Following an incubation
period of a few days, clinical findings in affected dogs include,
in decreasing order of frequency, listlessness and depression,
high fever, history or actual presence of ticks, anorexia,
myalgia/arthralgia, lymphadenomegaly, vestibular deficits,
dyspnea, conjunctivitis, paralumbar hyperesthesia, edema of
face and extremities, petechiae or hemorrhagic diathesis, and
vomiting and diarrhea. Vasculitis may be visible by means of
ophthalmoscopic examination of retinal vessels.
Laboratory findings include anemia, leukopenia followed
by leukocytosis, thrombocytopenia, prolongation of acti-
vated partial thromboplastin time, hyperfibrinogenemia, and
increased concentrations of fibrin/fibrinogen degradation
products. The thrombocytopenia is at least partly due to the
development of antiplatelet antibodies. Serum biochemistry
usually reveals hypoalbuminemia, increased alkaline phospha-
tase activity, and hypercholesterolemia. Increased concentra-
tions of aldosterone and antidiuretic hormone may contribute
to expansion of plasma and extracellular fluid volumes and
hence edema. Edema of the medulla oblongata may contrib-
ute to cardiorespiratory depression. Death may occur in the
acute stages of disease as the result of peripheral vascular col-
lapse, hemorrhagic diathesis, and thrombosis, although fully
developed disseminated intravascular coagulation (DIC) is an
unusual event in RMSF in dogs. Necrosis of extremities 
may occur. Damage to the cardiovascular system, brain, or
kidneys may cause death or permanent organ dysfunction;
severely affected dogs may die with rapidly progressive
meningoencephalitis.
Gross lesions include edema of ears and muzzle; ulcerative
glossitis; scrotal dermatitis; petechiation of mucous mem-
branes, caudal abdominal skin, pleura, and gastric wall; hemor-
rhagic colitis; and hemorrhagic lymphadenopathy.
 82.e1

Further reading
Du Plessis JL. Electron microscopy of Cowdria-infected macrophages
suggests that in the absence of binary fission a mosaic of organisms
develops from an amorphous electron dense matrix. Onderstepoort
J Vet Res 1999;66:39-46.
Mwangi DM, et al. Cellular immune responses of cattle to Cowdria
ruminantium. Dev Biol Stand 1998;92:309-315.
Simbi BH, et al. Comparing the detection of exposure to Ehrlichia
ruminantium infection on a heartwater-endemic farm by the pCS20
polymerase chain reaction assay and an indirect MAP1-B enzyme
linked immunosorbent assay. Onderstepoort J Vet Res 2003;70:231-
235.
van Halderen A, et al. Abortion in a heifer associated with the intra-
uterine transmission of Cowdria ruminantium-like organisms fol-
lowing heartwater vaccination. J S Afr Vet Assoc 1996;67:158-160.
Van Heerden H, et al. Characterization of the pCS20 region of different
Ehrlichia ruminantium isolates. Vet Microbiol 2004;101:279-291.
Diseases of the Vascular System
The prominent histologic lesion of RMSF is necrotizing vas-
culitis of small veins, capillaries, and arterioles, with perivascular
accumulations predominantly of lymphocytes and macro-
phages. This lesion is seen most commonly in skin, testes,
alimentary tract, pancreas, kidneys, urinary bladder, myocar-
dium, meninges, retina, and skeletal muscle. Acute meningo-
encephalitis may be present. There may also be acute splenitis,
acute interstitial pneumonia, and multifocal necrosis of myo-
cardium, adrenals, and liver. A moderate degree of glomerulo-
nephritis may be present.
The most reliable serologic test for RMSF is the species-
specific microimmunofluorescent method. High antibody
titers develop to R. rickettsii, but usually decline after 3-5
months. Direct fluorescent antibody staining of a skin biopsy
is positive in up to 80% of infected dogs; coccobacillary organ-
isms are present in endothelial cells and vessel walls. Infection
may also be confirmed by PCR detection of the agent in
peripheral blood.
Further reading
Elchos BN, Goddard J. Implications of presumptive fatal Rocky Moun-
tain spotted fever in two dogs and their owner. J Am Vet Med Assoc
2003;223:1450-1452, 1433.
Gasser AM, et al. Canine Rocky Mountain spotted fever: a retrospec-
tive study of 30 cases. J Am Anim Hosp Assoc 2001;37:41-48.
Labruna MB, et al. Rocky Mountain spotted fever in dogs, Brazil. Emerg
Infect Dis 2009;15:458-460.
Piranda EM, et al. Experimental infection of dogs with a Brazilian strain
of Rickettsia rickettsii: clinical and laboratory findings. Mem Inst
Oswaldo Cruz 2008;103:696-701.
Verminous arteritis
Here we are concerned with those parasites whose natural
habitat is the lumen or the wall of arteries. Parasites that,
accidentally or as part of their life cycle, migrate in tissues
may, depending on the route they take, cause vasculitis in
various organs. The chief offenders in this regard are the larvae
of the genera Strongylus and Ascaris; the vascular lesions of
Ascaris infestations are described under diseases of the intes-
tine (see Vol. 2, Alimentary system and peritoneum). Angio-
strongylus vasorum, which inhabits the pulmonary arteries of
dogs, is described with the lungworms. Spirocerca lupi, which
passes part of its history in the adventitia of the thoracic aorta,
is described in its final habitat, the esophagus.
Dirofilariasis (heartworm disease).  The dog is the only
mammal commonly infected by Dirofilaria immitis (heart-
worm), and is the only significant reservoir of infection. In areas
where heartworm infection is enzootic in dogs, a number of
other mammals may become infected, including domestic cats
and wild felids, wild canids (coyotes, foxes, wolves), ferrets,
sea lions, muskrats, horses, and rarely humans. If D. immitis
develops to maturity in hosts other than the dog, microfilare-
mia is usually low or absent, and heart failure is rare. Pulmo-
nary dirofilariasis is of considerable importance in humans
because the spherical, subpleural granulomas produced may
be mistaken radiographically for primary or metastatic lung
tumors, leading to thoracotomy and excisional biopsy for diag-
nosis. Dirofilaria immitis is genetically heterogeneous and has a
tropical and subtropical distribution in southern Europe, Asia,
Australia, and North and South America, although its range
has extended into more northern temperate zones in North
Arteries 83
America and southern temperate zones in Australia. As with
most, if not all filarid worms, D. immitis contains the bacterial
endosymbiont, Wolbachia, which is essential for the normal
development of the parasite, and also contributes to the
pathogenesis of the disease.
There are 40 recognized species of Dirofilaria, 6 of which
have been shown to infect humans as accidental dead-end
hosts. Diagnostic tests based on genomics are being increas-
ingly used to differentiate among the Dirofilaria species infect-
ing the host. Adults of D. repens occur in subcutaneous
connective tissues of dogs and other carnivores (and rarely
humans). Similarly, D. tenuis is found in the subcutaneous
connective tissue of the raccoon in the southern United States.
None of these 3 filarids usually develops to maturity in
humans, but they may be found in cysts in various parts of
the body, especially in the lungs. D. striata, a parasite of
bobcats (Lynx rufus), has been reported in dogs in Florida. A
species of Dirofilaria found in both dogs and humans in Hong
Kong with a 94-95% homology with D. immitis and D. repens
has been tentatively named D. hongkongensis.
Adult D. immitis worms live in the pulmonary arteries and
right heart, but they can develop in various other arteries and
veins, and have been reported from a variety of unusual sites,
including the eye and brain. Adult males are 12-20 cm long
by 0.7-0.9 mm in diameter; females are 25-31 cm by
1.0-1.3 mm. The adult female worms are viviparous, and
release microfilariae into the bloodstream; mosquitoes obtain
microfilariae in blood meals. The first, second, and early third
larval stages of D. immitis are obligate parasites of mosquitoes,
predominantly of the genera Aedes, Culex, or Anopheles.
Larvae develop to the infective stage in about 13 days in the
malpighian tubules. They then migrate to the cephalic spaces
of the head or to the proboscis of the mosquito and escape
into a new host when the mosquito feeds. The infective larvae
are about 1.2 mm long when they enter the host, and are
about 5 cm long when they reach the right ventricle 3-4
months later. In the meantime, the parasites have wandered
and grown in the connective tissue, chiefly those of the sub-
cutis and muscles, finally leaving these to migrate to the heart
via the veins. They mature in a further 3 months. Thus the
prepatent period is 6-8 months. Adults may live for several
years and microfilariae can survive in a dog for as long as 2.5
years. Adult heartworms may be found in cutaneous nodules
occasionally in dogs, and rarely in cats.
The clinical diagnosis of dirofilariasis in dogs depends upon
the detection of microfilariae in the blood, preferably by the
microscopic examination of centrifuged sediment of lysed
blood (modified Knott’s test), or by a filter technique. Microfi-
lariae of D. immitis (290-315 µm long, straight body and tail,
tapered head) must be differentiated from those of Dipetalo-
nema reconditum (270-290 µm, curved body, blunt head,
most have a buttonhook tail), the adults of which are non-
pathogenic and are commonly found in the subcutaneous
connective tissue of dogs; these microfilariae can also be dif-
ferentiated by PCR or histochemical means. The average
number of circulating microfilariae per adult female D. immitis
decreases as the number of adult worms increases. Hence the
numbers of circulating microfilariae indicate neither the numbers
of adult worms present nor the severity of heartworm disease in
an individual dog. Although microfilariae are present in the
blood more or less continuously, there is a tendency to peri-
odicity, with maximum numbers occurring in the evening 
and in the summer, coincident with maximal activity of 
 83.e1

Further reading
Davidson MG, et al. Vascular permeability and coagulation during Rick-
ettsia rickettsii infection in dogs. Am J Vet Res 1990;51:165-170.
Grindem CB, et al. Platelet-associated immunoglobulin (antiplatelet
antibody) in canine Rocky Mountain spotted fever and ehrlichiosis.
J Am Anim Hosp Assoc 1999;35:56-61.
Paddock CD, et al. Short report: concurrent Rocky Mountain spotted
fever in a dog and its owner. Am J Trop Med Hyg 2002;66:197-199.
Procop GW, et al. Immunoperoxidase and immunofluorescent staining
of Rickettsia rickettsii in skin biopsies. A comparative study. Arch
Pathol Lab Med 1997;121:894-899.
84 CHAPTER 1  •  Cardiovascular System
mosquitoes. Microfilariae are pooled in internal organs, espe-
cially the lungs, in the daytime. Fetal pups may be infected by
microfilariae from the bitch and have microfilaremia, but the
pups do not harbor adult worms. Cats infected with D. immitis
are typically amicrofilaremic, given low numbers of adult
female worms or male-only infections, hence antigen- or
antibody-detection tests are required for diagnosis.
Occult dirofilariasis, that is, heartworm infection without
microfilaremia, occurs in 10-67% of infected dogs, primarily as
a result of destruction of microfilariae by immune mecha-
nisms (“immune-mediated occult disease”), but also as the
result of prepatent infections, single-sex infections, and drug-
induced sterility of adult heartworms. Clinical diagnosis of
occult dirofilariasis then rests on the findings of the indirect
fluorescent antibody test, antigen detection tests, and cardio-
pulmonary imaging. Circulating antibodies are usually detect-
able only in dogs without microfilaremia.
The clinical signs of canine dirofilariasis are usually those
of cardiovascular dysfunction, such as cough and tiring on
exercise, which may progress to congestive heart failure.
Heartworm disease is usually seen in dogs that are older than
5 years and have had continuous or multiple infections. There
is a rough correlation between the numbers of worms present
and the severity of the disturbance, but there are exceptional
cases, and severe signs may appear in dogs with only a few
worms. Clinically normal dogs may harbor up to about 30
worms, and clinically affected dogs 50 or more. Dirofilariasis
in cats usually causes cough and dyspnea, but may as well
cause vomiting, neurologic signs, and malaise; sudden death is
another possible outcome.
Adult heartworms are normally found in the pulmonary arter-
ies and right ventricle (Fig. 1-86), but may be found in the right
atrium and venae cavae in heavy infestations. Young adult
worms usually develop first in small pulmonary arteries, and
progressively involve more proximal arteries as they grow.
Adult worms may be found in the right ventricle if more than
about 25 are present, and in the right atrium and venae cavae
if there are 50 or more worms. The caudal lobar pulmonary
arteries are usually the most heavily infested vessels. Right
heart failure develops as a consequence of pulmonary hyperten-
sion, which in turn is the result of pulmonary vascular sclerosis.
Of secondary importance is mechanical interference of the
Figure 1-86  Dirofilaria immitis (heartworm) in pulmonary
artery and right ventricle of a dog.
Arteries
worms with cardiac blood flow and valve function. Pulmonary
sclerosis and hypertension slowly regress following removal of
the adult worms.
Heartworm disease is primarily a pulmonary vascular disease,
and is characterized by myointimal proliferations in small
peripheral arteries initially, and later in the large lobar arteries,
especially the right caudal lobar artery (Fig. 1-87A, B). The
fibromuscular intimal proliferations in the larger vessels produce
a grossly visible shaggy or roughened appearance, a change
pathognomonic of heartworm disease. The vascular reaction is
to both the immature and mature adult worms, and begins as
an endoarteritis with infiltration of leukocytes, primarily
eosinophils. Neutrophils are also present in the arterial wall,
partly in response to the intracellular bacteria Wolbachia har-
bored by D. immitis. The leukocytic response subsides and is
replaced by myointimal proliferation that produces irregular
rugose to villus projections enmeshing the worms; the myo-
intimal proliferation occurs at sites of direct contact with
worms, is likely due to mechanical irritation and endothelial
damage, and is possibly mediated by platelet-derived growth
factor.
Thrombosis may be associated with either live or dead
worms, and thromboembolism, especially following adulti-
cide therapy, may further exacerbate pulmonary hyperten-
sion; the presence of dead parasites initiates a granulomatous 
A
B
Figure 1-87  Heartworm infection in a dog. A. Pulmonary artery
with severe extensive vasculitis and heartworms in lumen. H&E.
B. Higher power of (A) showing subintimal myofibrosis and
villous projections into the pulmonary arterial lumen. H&E.
(Courtesy R. Kovi.)
Diseases of the Vascular System
reaction in the vessel wall, which may extend into the  cava and hepatic veins are similar to the reactions usually seen
pulmonary parenchyma. Thrombi may be organized and
recanalized. Pulmonary infarction is an uncommon sequel to
thromboembolism.
Pulmonary parenchymal changes that accompany the above
vascular changes include periarterial granulomatous inflam-
mation, hemosiderosis, diffuse interalveolar fibrosis, prolifera-
tion of alveolar epithelium, and fibrous pleural thickenings.
Dead worms commonly incite pulmonary granuloma forma-
tion. Adulticide therapy causes embolization of worms and
resulting thrombosis and granulomatous inflammation; resolu-
tion of these lesions is underway by 6 weeks post-treatment.
Proliferative intimal lesions will progressively resolve after
surgical removal of adult worms; resolution of advanced,
fibrotic, obstructive arterial lesions is unlikely. Severe pulmo-
nary arterial disease often results in chronic or low-grade DIC,
and hence thrombocytopenia and hemoglobinuria. Microfi-
lariae entrapped in the lung in a state of antibody excess are
surrounded by neutrophils and eosinophils, producing eosino-
philic pneumonitis. This allergic pneumonitis may be the
precursor of pulmonary eosinophilic granulomatosis, which is
characterized by 1-8 cm diameter nodules composed of eosin-
ophils, lymphocytes, plasma cells, and macrophages, and
devoid of microfilariae, plus peripheral blood eosinophilia.
Additional lesions of heartworm disease include those of
right heart failure, such as chronic passive congestion of the
liver, and occasionally ascites. Membranoproliferative glomeru-
lonephritis occurs primarily because of glomerular deposition
of immune complexes, either formed in circulating blood in
a state of antigen excess, or formed in situ in the glomeruli.
The intensity of the immune-complex deposition varies
directly with the intensity and duration of infection and the
antibody response; the immune response may be toward
immature heartworms, microfilariae, or adult heartworms.
Physical damage to glomerular endothelium has been attrib-
uted to microfilariae. The result of glomerular disease in diro-
filariasis is proteinuria, which is usually mild to moderate in
severity. Renal failure and uremia are uncommon. Microfi-
lariae are usually of little consequence to the dog, but when
they die, they may incite formation of microgranulomas in
various organs, such as the lung, liver, and kidney.
Aberrant migration of adult heartworms into the systemic
arterial circulation, a rare event, results in thromboembolism
and hence signs such as hindlimb lameness and interdigital
ischemic necrosis.
The vena caval syndrome (venae cavae syndrome, liver
failure syndrome) is a variant of heartworm disease seen
usually in young dogs in which large numbers of adult worms
(100+) fill the right atrium and venae cavae, likely as the result
of retrograde migration from the pulmonary arteries. The  in or on the intima of arterioles and arteries, being constrained
syndrome is characterized by sudden onset of weakness, anor­
exia, bilirubinuria, hemoglobinuria, and anemia. Shock occurs
because of obstruction and decreased venous return. The mass
of worms may also interfere with valve function, causing tri-
cuspid regurgitation, which, together with pulmonary hyper-
tension, results in decreased left ventricular preload and
congestive right ventricular failure. Hepatic congestion is very
severe, hepatic lymphatics may be distended, and ascites may
occur. Anemia develops because of right-atrial turbulence and
shear-induced mechanical hemolysis, with perhaps microan-
giopathic hemolysis resulting from platelet activation and
fibrin formation. Azotemia develops and death usually occurs
in 1-3 days. Phlebosclerosis and thrombosis in the caudal vena
Arteries 85
in the pulmonary arteries. Vena caval syndrome also occurs in
cats, and untreated has a poor prognosis and high mortality
rate in both dogs and cats; the treatment of choice is surgical
removal of the heartworms.
The major features of dirofilariasis are shown in eFig. 1-28.
Further reading
Atkins CE, et al. Heartworm infection in cats: 50 cases (1985-1997).
J Am Vet Med Assoc 2000;217:355-358.
Bourguinat C, et al. Genetic polymorphism in Dirofilaria immitis. Vet
Parasitol 2011;176:368-373.
González-Miguel J, et al. Surface associated antigens of Dirofilaria
immitis adult worms activate the host fibrinolytic system. Vet Para-
sitol 2013;235-240.
McCall JW, et al. Heartworm disease in animals and humans. Adv
Parasitol 2008;66:193-285.
McHaffie J. Dirofilaria immitis and Wolbachia pipientis: a thorough
investigation of the symbiosis responsible for canine heartworm
disease. Parasitol Res 2012;110:499-502.
Paes-de-Almeida EC, et al. Kidney ultrastructural lesions in dogs exper-
imentally infected with Dirofilaria immitis (Leidy, 1856). Vet Parasi-
tol 2003;113:157-168.
Reddy MV. Human dirofilariasis: an emerging zoonosis. Trop Parasitol
2013;3:2-3.
Simón F, et al. Immunopathology of Dirofilaria immitis infection. Vet
Res Commun 2007;31:161-171.
Simón F, et al. Human and animal dirofilariasis: the emergence of a
zoonotic mosaic. Clin Microbiol Rev 2012;25:507-544.
To KKW, et al. A novel dirofilaria species causing human and canine
infections in Hong Kong. Clin Microbiol 2012;50:3534-3541.
Strongylus vulgaris in horses.  Horses are commonly
infected with both large and small strongyles (see Vol. 2, Ali-
mentary system and peritoneum), but by far the most damaging
to the host is the large strongyle Strongylus vulgaris. Although
the adults of S. vulgaris share their large intestinal habitat with
many other strongylids, S. vulgaris is the only strongylid to
undergo development in the horse’s arterial system.
The usual route of migration of S. vulgaris is as follows.
Infective third-stage larvae are ingested; exsheath in the small
intestine; penetrate the mucosa and submucosa of the small
intestine, cecum, and colon within 3 days of infection; and
molt to fourth-stage larvae by day 7. The larval penetration of
the gut can cause the formation of large subserosal hemor-
rhages, called hemomelasma ilei. The fourth-stage larvae, which
are about 1 mm long, penetrate submucosal arterioles, migrate
by the internal elastic lamina from penetrating to the media,
and reach the cranial mesenteric artery, the predilection site
for further development, between day 11 and 21. After 3-4
months, the larvae molt to the fifth stage (immature adults,
10-18 mm long), return to the wall of the cecum and colon
via the intestinal arteries, and are encapsulated in subserosal
nodules before returning to the gut lumen as adults, when the
nodules rupture. The adults require another 6-8 weeks to
reach sexual maturity. The prepatent period of S. vulgaris is
thus about 6-7 months.
Virtually all horses are infected with S. vulgaris and have
arterial lesions resulting from larval migration, although the
prevalence of continuing S. vulgaris infection has been
 85.e1

Dirofilariasis
Dog is primary host
Many species accidental hosts
Dirofilaria immitis is genetically heterogeneous

Clinical signs Life cycle

Cough, exercise intolerance, dyspnea
Ascites
In severe cases, vena caval
syndrome and renal failure
Microfilaria from host ingested by
mosquitoes develop to infective stage
Introduced via mosquito to new
host; develops over 3-4 months
Adults reside in pulmonary artery

Pathology Disease pathogenesis

Obstructive, proliferative pulmonary
endoarteritis leading to right sided failure
Eosinophilic pneumonitis and granulomatosis
Membranoproliferative glomerulonephritis
With massive worm burden, vena cava
occluded by adult worms leading to
hemolytic anemia and hepatic failure
Predominantly the result of pulmonary
arterial proliferative endoarteritis and sclerosis
Leads to pulmonary hypertension
(cor pulmonale) and right sided heart failure
Accompanied by pulmonary granulomas

eFigure 1-28  Major features of canine dirofilariasis.

85.e2

Further reading
Atkins CE, et al. Investigation of caval syndrome in dogs experimentally
infected with Dirofilaria immitis. J Vet Intern Med 1988;2:36-40.
Bazzocchi C, et al. Immunological role of the endosymbionts of Diro-
filaria immitis: the Wolbachia surface protein activates canine neu-
trophils with production of IL-8. Vet Parasitol 2003;117:73-83.
Boreham PFL, Atwell RB, editors. Dirofilariasis. Boca Raton, Fla: CRC
Press; 1988.
Buoro IBJ, et al. Angles of branching and the diameters of pulmonary
arteries in relation to the distribution of pulmonary lesions in canine
dirofilariasis. Res Vet Sci 1983;35:353-356.
Calvert CA, et al. Pulmonary and disseminated eosinophilic granulo-
matosis in dogs. J Am Anim Hosp Assoc 1988;24:311-320.
Cornegliani L, et al. Two cases of cutaneous nodular dirofilariasis in the
cat. J Small Anim Pract 2003;44:316-318.
Frank JR, et al. Systemic arterial dirofilariasis in five dogs. J Vet Intern
Med 1997;11:189-194.
Goggin JM, et al. Ultrasonographic identification of Dirofilaria immitis
in the aorta and liver of a dog. J Am Vet Med Assoc 1997;210:1635-
1637.
Kaiser L, Williams JF. Dirofilaria immitis: worm burden and pulmonary
artery proliferation in dogs from Michigan (United States). Vet
Parasitol 2004;124:125-129.
Kitagawa H, et al. Comparison of laboratory test results before and
after surgical removal of heartworms in dogs with vena caval syn-
drome. J Am Vet Med Assoc 1998;213:1134-1136.
Mar PH, et al. Specific polymerase chain reaction for differential diag-
nosis of Dirofilaria immitis and Dipetalonema reconditum using
primers derived from internal transcribed spacer region 2 (ITS2). Vet
Parasitol 2002;106:243-252.
McCracken MD, Patton S. Pulmonary arterial changes in feline dirofi-
lariasis. Vet Pathol 1993;30:64-69.
Mupanomunda M, et al. Dirofilaria immitis: heartworm infection
alters pulmonary artery endothelial cell behavior. J Appl Physiol
1997;82:389-398.
Peribanez MA, et al. Histochemical differentiation of Dirofilaria immitis,
Dirofilaria repens and Acanthocheilonema dracunculoides microfi-
lariae by staining with a commercial kit, Leucognost-SP. Vet Parasi-
tol 2001;102:173-175.
Rawlings CA, et al. Pulmonary thromboembolism and hypertension
after thiacetarsamide vs melarsomine dihydrochloride treatment of
Dirofilaria immitis infection in dogs. Am J Vet Res 1993;54:920-
925.
Ro JY, et al. Pulmonary dirofilariasis: the great imitator of primary or
metastatic lung tumor. A clinicopathologic analysis of seven cases
and a review of the literature. Hum Pathol 1989;20:69-76.
Strickland KN. Canine and feline caval syndrome. Clin Tech Small Anim
Pract 1998;13:88-95.
86 CHAPTER 1  •  Cardiovascular System
markedly diminished by benzimidazole and macrocyclic
lactone anthelmintics. A degree of host resistance to vermin-
ous arteritis is slowly acquired under natural conditions, but
horses of all ages remain susceptible to infection. Lesions
range from the very common, but insignificant, tortuous
intimal tracks, to the less common, but more serious, occlusive
thrombotic lesions. Lesions of verminous arteritis are often
incorrectly called “verminous aneurysms,” but these dilations
are usually thick-walled resulting from inflammation and scar-
ring, rather than thinned. Saccular or fusiform aneurysms may
occasionally result from weakening of the arterial wall. Lesions
occur most frequently in the cranial mesenteric artery and its
extension, the ileo-cecocolic artery. This apparent larval predilec-
tion has been suggested to fit a “random-walk” model in which
the larvae sense blood vessel curvature, rather than direction
of blood flow, migrate longitudinally along arteries, and are
essentially trapped in the cranial mesenteric artery because of
its perpendicular connection with the aorta, a border which
most of the larvae do not cross. Larvae that spill over into the
aorta may be considered as aberrant and lost to their species,
in that they are unlikely to return to the cranial mesenteric
artery and hence to the gut.
Tortuous intimal tracks consist of fibrin, necrotic debris,
and a mixture of inflammatory cells, including eosinophils, in
the intima. The tracks become covered by endothelium, the
fibrin is removed, and the tracks are converted to fibromus-
culoelastic thickenings. More extensive larval migration causes
more extensive thromboarteritis (Figs. 1-88, 1-89). Small
mural thrombi are formed about the larvae attached to the
intima, and there is a reactive leukocytic infiltration, edema,
and resultant degeneration of the elastic and muscle fibers of
the underlying media. The initial acute inflammation persists
as long as the parasite remains but is soon accompanied by a
productive connective-tissue response, initiated by smooth
muscle cells from the media, with attempted organization of
the overlying thrombus and the accumulation of large numbers
of mononuclear leukocytes (Fig. 1-90). The proliferating con-
nective tissues of the intima and adventitia may ultimately
replace the normal structure of the arterial wall with the
affected walls becoming solid and very thick. The luminal
surfaces of active arterial lesions are always rough and covered
with layered thrombi in which the parasite is found partially
Figure 1-88  Hemorrhage, ulceration and inflammation of the
cranial mesenteric artery, with Strongylus vulgaris larva (arrow).
(Courtesy University of Minnesota Veterinary Diagnostic
Laboratory.)
Arteries
embedded. It is usual to find some worms, both fourth-stage
larvae and immature adults, in the thrombi, but the number
of worms in any location in any one case varies from a few to
several hundred. Following migration of the fifth-stage larvae
back to the intestine, or destruction of the larvae by anthel-
mintics, the intimal lesions resolve as fibrous intimal thicken-
ings, and the luminal diameter will hence increase. The arterial
wall thickness also decreases.
The lesions and accompanying worms are most common in
the cranial mesenteric artery, although they are also found
elsewhere, including the aorta, the renal arteries, the celiac
artery and its branches, and the spermatic vessels. They may
be in any branch of the cranial mesenteric artery but are
concentrated largely in the right division and the colic artery,
which is its continuation, and, to a slightly lesser extent, in
the cranial branch and its continuation, the right colic artery.
The worms are rarely found in the aorta caudal to the origin
of the renal vessels; they are relatively common about the
origin of the cranial mesenteric and celiac arteries, and less
common again in the thoracic aorta. Although this statement
on the prevalence of lesions in the thoracic aorta applies to
actively thrombotic lesions containing worms, it is probable
that older, warty, mineralized lesions of the type often seen in
the intima of the aortic arch have this origin; they occur
Figure 1-89  Focally dilated cranial mesenteric artery with hem-
orrhage, ulceration and inflammation of the vessel wall. (Courtesy
A. G. Armien.)
Figure 1-90  Chronic fibrosing arteritis of the cranial mesenteric
artery caused by Strongylus vulgaris infection in a horse, with
larvae present in one of the smaller vessels. Masson trichrome.
(Courtesy R. Kovi.)
Diseases of the Vascular System
frequently in sites where active lesions occur. The lesions in
the aortic bulb are located immediately proximal to the aortic
valves on the cranial wall of the bulb and in the adjacent
cranial aortic and caudal right aortic sinuses, but rarely in the
caudal wall and the left sinus. This localization has been
explained on the basis of the curve of the aortic arch and the
axis of systolic ejection, which should, theoretically, provide
a zone of turbulence and relatively low velocity of blood flow
in the cranial segment of the aortic bulb.
The sequelae of verminous arteritis caused by S. vulgaris are
varied and depend upon the location of the arteritis. Involve-
ment of the cranial mesenteric artery is almost constant in
horses, but untoward sequelae are much less common, no
doubt resulting from the extensive collateral arterial circulation
to the equine intestine, which may mitigate against the effects
of frequent thromboembolic episodes. Colic, which is com-
monly caused in horses by S. vulgaris if parasite control is poor,
may occur for a number of reasons: thromboembolism and
intestinal ischemia or infarction; interference with innervation
of the gut, resulting from pressure on abdominal autonomic
plexuses; or, release of toxic products from degenerating larvae.
Fatal acute intestinal infarction occasionally ensues, with isch-
emia of large areas of the cecum or colon. Thromboembolism
of the cecal and colic arteries may also lead to mucosal ulcer-
ation and diarrhea, and occasionally death. Hematochezia has
been reported in a horse as a consequence of fistulous con-
nections between a verminous cranial mesenteric arterial aneu-
rysm and the cecum and ileum. As a result of successful
suppression of S. vulgaris by anthelmintics, drug-resistant cya-
thostomes (small strongyles) have supplanted S. vulgaris as the
most important cause of verminous colic. Coronary arterial
thrombosis and occlusion, which occurs most commonly in the
right coronary artery, can lead to myocardial infarction and
death; similar consequences follow the development of ver-
minous aortic valvular endocarditis, a rare event in strongylosis.
Embolism of the brachiocephalic trunk can occur and is especially
significant when the emboli contain larvae that subsequently
migrate in the brain causing encephalomalacia and either
chronic incoordination or progressive fatal encephalitis. Renal
arterial verminous arteritis and thromboembolism have resulted
in renal infarction and, on rare occasions, passage of larvae in
the urine. Aortic-iliac thrombosis may be a consequence of
strongyle-related thromboembolism, but its pathogenesis
remains uncertain. Thrombosis of the celiac artery and embo-
lism of its branches is usually inconsequential.
The major features of Strongylus vulgaris infection are
shown in eFigure 1-29.
Further reading
Chapman MR, et al. Prevalence of strongyle nematodes in naturally
infected ponies of different ages and during different seasons of
the year in Louisiana. J Parasitol 2003;89:309-314.
DeLay J, et al. Verminous arteritis in a 3-month-old thoroughbred foal.
Can Vet J 2001;42:289-291.
Hubert JD, et al. Clinical signs and hematologic, cytokine, and plasma
nitric oxide alterations in response to Strongylus vulgaris infection
in helminth-naive ponies. Can J Vet Res 2004;68:193-200.
Ogbourne CP, Duncan JL. Strongylus vulgaris in the Horse: Its Biology
and Veterinary Importance. 2nd ed. Farnham Royal, UK: Common-
wealth Agricultural Bureaux; 1985.
Reinemeyer CR, Nielsen MK. Parasitism and colic. Vet Clin North Am
Eq Pract 2009;25:233-245.
Arteries 87
Onchocerciasis (parasitic aortitis).  Onchocerca armillata
is a parasite of the wall of the aorta of cattle, water buffaloes,
goats, and camels, in south Asia and equatorial Africa. As with
other filarids, O. armillata also contains the endosymbiotic
bacterium, Wolbachia, whose presence is not only essential for
the normal development of the parasite larvae and embryo,
but also contributes to the pathogenesis of the disease. Several
other Onchocerca spp. are described with tendons and aponeu-
roses under diseases of muscle in Vol. 1, Muscle and tendon.
The life cycle and vectors involved in the transmission of O.
armillata are unknown; however, black flies (Simulium) and
midges (Culicoides) are the intermediate hosts of other Oncho-
cerca spp.
Although virtually all older cattle may be infested in enzo-
otic areas, the lesions produced are apparently not of clinical
significance. The preferential site is the arch of the aorta. With
chronicity, lesions extend cranially to include the brachioce-
phalic trunk, costocervical arteries, and brachial arteries, and
caudally to include the abdominal aorta to the level of the
iliac bifurcation. The intima is corrugated, and numerous
sinuous tunnelings end in small nodules in the intima and media;
the nodules protrude into the vascular lumen or through the
adventitia. The males, which are about 7 cm long, inhabit the
nodules, along with the anterior end of the female, which bears
the vaginal opening, and the microfilariae, which escape into
the bloodstream. The body of the female lies in the sinuous
tracts, from which the complete specimen cannot be readily
dissected, but its length is estimated as >100 cm. Parasitic
tunnels in the inner media have a thin fibrous tissue lining
without cellular infiltration. There may be acute transmural
aortitis with a predominance of eosinophils, but subacute or
chronic focal granulomatous inflammation is more frequent and
occurs around tunnels containing dead, degenerate, or mineralized
worms. The granulomas in the media and adventitia become
encapsulated by fibrous tissue to form nodules of 0.5-2.5 cm
diameter containing caseous material and intact and/or dead
worms, and eventually dry mineralized debris. The granulo-
matous reaction will resolve with time, and, in very old cattle,
the aortic wall becomes thinner, has a corrugated lining with
irregular mineralized ridges, and may develop aneurysms up
to 3.5 cm in diameter. The suggested causes of the granulo-
matous aortitis include hypersensitivity to the parasite, foreign
body reaction to degenerate and dead onchocercal worms, and
the release of toxic factors from the parasites.
Microfilariae can be found in the blood of infected animals
at all times, but there is a tendency to nocturnal periodicity;
infection can be detected by examination of skin snips for
microfilariae. In some bulls with large numbers of circulating
microfilariae, repetitive episodes of collapse and tetanic con-
vulsion have been observed and attributed to the microfilariae.
Some of the bulls showing convulsions eventually developed
acute or recurrent ophthalmitis with ophthalmoscopic evi-
dence of retinal pigmentary degeneration and other changes
similar to those seen in ocular onchocerciasis in humans.
Further reading
Mtei BJ, Sanga HJ. Aortic onchocercosis and elaeophorosis in tradi-
tional TSZ-cattle in Tabora (Tanzania): prevalence and pathology. Vet
Parasitol 1990;36:165-170.
Neary JM, et al. Onchocerca armillata contains the endosymbiotic bac-
terium Wolbachia and elicits alimited inflammatory response. Vet
Parasitol 2010;174:267-276.
 87.e1

Strongylus vulgaris
Vasculitis

Vascular lesions Life cycle

Larvae mostly in cranial mesenteric 3rd stage larvae ingested and
and iliocecocolic artery penetrate gut
Lesions sometimes found in 4th stage larvae penetrate
other major arteries [aorta] submucosal arterioles
Essentially a thromboarteritis that varies from and migrate to cranial
intimal tracks to severe thickening of vessel wall mesenteric artery

Vascular lesions Sequelae Life cycle

Acute focal vasculitis that heals by
fibromusculoelastic thickening
Chronic infections result in connective
tissue response with prominent
vascular smooth muscle proliferation
Vascular wall greatly thickened
with narrowed lumen
Thromboembolism leading to
infarction/ischemia of areas of
cecum and colon
Coronary arterial thrombosis
from larvae in aorta [rare]
Neurologic disease from emboli
from brachiocephalic trunk [rare]
After 3-4 months 4th stage
larvae molt to 5th stage
5th stage larvae return to colon and
cecum via mesenteric arteries,
Larvae remain in subserosa
then return to gut lumen
Prepatent period 6-7 months

eFigure 1-29  Major features of Strongylus vulgaris infection.

87.e2

Further reading
Aref S. A random walk model for the migration of Strongylus vulgaris
in the intestinal arteries of the horse. Cornell Vet 1982;72:64-75.
Drudge JH, Lyons ET. Large strongyles: recent advances. Vet Clin North
Am Equine Pract 1986;2:263-280.
Herd RP. The changing world of worms: the rise of the cyathostomes
and the decline of Strongylus vulgaris. Compend Contin Educ Pract
Vet 1990;12:732-736.
Kiper ML, et al. Hematochezia attributable to cranial mesenteric arterial
aneurysm with connecting tracts to cecum and ileum in a horse.
J Am Vet Med Assoc 1988;193:1278-1280.
Klei TR, et al. Effects of repeated Strongylus vulgaris inoculations and
concurrent ivermectin treatments on mesenteric arterial lesions in
pony foals. Am J Vet Res 1990;51:654-660.
Morgan SJ, et al. Histology and morphometry of Strongylus vulgaris-
mediated equine mesenteric arteritis. J Comp Pathol 1991;104:89-
99.
Morgan SJ, Van Houten DS. The ultrastructure of Strongylus vulgaris-
mediated equine chronic mesenteric arteritis. Vet Res Commun
1990;14:41-46.
Pauli B, et al. Arterial repair after mechanical injury by migrating fourth-
stage larvae of Strongylus vulgaris in the horse. (A light and electron
microscopic study.). Beitr Pathol 1975;155:357-378.
Slocombe JOD, et al. Strongylus vulgaris in the tunica media of arteries
of ponies and treatment with ivermectin. Can J Vet Res 1987;51:232-
235.
Thamsborg SM, et al. Impact of mixed strongyle infections in foals after
one month on pasture. Equine Vet J 1998;30:240-245.
 87.e3

Further reading
Atta El, et al. Onchocerca armillata: prevalence and pathology in Suda-
nese cattle. Ann Trop Med Parasitol 1984;78:619-625.
Awad MA, et al. Note on Onchocerca armillata in the Sudanese camel
(C. dromedarius). A histological and anatomo-pathological
approach. Rev Elev Med Vet Pays Trop 1990;43:345-348.
Cheema AH, Ivoghli B. Bovine onchocerciasis caused by Onchocerca
armillata and O. gutturosa. Vet Pathol 1978;15:495-505.
Wahl G, et al. Bovine onchocercosis in north Cameroon. Vet Parasitol
1994;52:297-311.
88 CHAPTER 1  •  Cardiovascular System
Ogundipe GA, et al. The prevalence, gross lesions and histopathology
of aortic onchocerciasis in Nigerian cattle. Vet Q 1984;6:85-89.
Tamarozzi F, et al. Onchocerciasis: the role of Wolbachia bacterial endo-
symbionts in parasite biology, disease pathogenesis and treatment.
Clin Microbiol Rev 2011;24:459-468.
Elaeophoriasis.  The genus Elaeophora is another filarial
parasite. Three species of interest are E. poeli and E. schneideri,
which infect ruminants, and E. bohmi, a parasite of horses.
Elaeophora poeli occurs frequently in the aorta of cattle
and related species in tropical areas of the Far East, but is of
little clinical significance. Its life cycle is unknown. These are
thread-like worms, the female of which may be up to 30 cm
long. The lesions are found in the aorta and can be distin-
guished from those of Onchocerca armillata because the
females of E. poeli are attached to the vessel by the head, with
the body free in the lumen of the vessel (eFig. 1-30). The
males become encysted in intimal fibrous nodules that also
contain the head of the female. In light infestations, the lesions
are found chiefly on the dorsal wall of the aorta about the
openings of the intercostal arteries. Heavy infestations are
more diffuse and may provoke a prominent fibrous thickening
of the vessel wall.
Elaeophora schneideri is commonly found in the arteries
of mule deer and black-tailed deer, as well as in white-tailed
deer, domestic sheep and goats, elk (wapiti), moose, and
bighorn sheep in mountainous areas of the western and south-
western United States and southwestern Canada, and in
white-tailed deer in the southeastern United States. Mule deer
and black-tailed deer are little affected by the parasite, and
are considered the normal definitive hosts. Horseflies of the
genera Hybomitra and Tabanus are the intermediate hosts.
When the horsefly feeds, infective larvae invade the host and
migrate to the leptomeningeal arteries, where they develop to
immature adults that migrate against the blood flow to reside
in the common carotid arteries. The parasites reach sexual
maturity ~6 months later and begin producing microfilariae.
Although adult worms normally inhabit the carotid arteries
and their branches, they may be found in many other arteries
through the body. Adult females are 6-12 cm long by
0.6-0.9 mm thick, and adult males are 5.5-8.5 cm long by
0.4-0.7 mm thick; adults live 3-4 years. Microfilariae are about
280 µm long by 18 µm thick, and are found in the capillaries
of the forehead and face.
When larvae develop in the leptomeningeal arteries of elk,
moose, domestic sheep and goats, sika deer, and possibly
white-tailed deer, they can cause ischemic necrosis of brain
tissue, resulting in “clear-eyed” blindness or sudden death. In
elk, adult worms in the intracranial arteries cause mechanical
irritation and hence endothelial damage, intimal proliferation
and fibrosis, thrombosis, and embolism, which result in focal
ischemia and infarction in the brain, eyes, optic nerves, ears,
muzzle, nostrils, and other tissues of the head. Adult worms
usually cause only mild intimal sclerosis in deer and sheep,
and only rarely do they cause granulomatous verminous
thrombosis. Microfilariae can cause multifocal myocardial
infarction, myocarditis, and fibrosis in deer. Oral food impac-
tions have been associated with E. schneideri in white-tailed
deer, but a causal relationship has not been established.
Young domestic sheep and goats may develop nervous
signs and die suddenly 3-5 weeks after infection as a result  course through the liver to join the caudal vena cava. Other
of thrombosis of cerebral and leptomeningeal arteries. In
Veins
survivors, the most important consequence of elaeophorosis
in sheep is filarial dermatosis (sorehead), an often severe exu-
dative dermatitis affecting the poll, face, abdomen, and lower
parts of the legs, in up to 1% of sheep in enzootic areas. Sto-
matitis and rhinitis also occur. The lesions are due to microfi-
lariae released by adult females located in arteries supplying
the affected areas. Microfilariae can be demonstrated micro-
scopically in the lesions, and they are responsible for intense
leukocytic infiltration, chiefly of eosinophils and mononuclear
cells. There is hemorrhage, vesiculation, and ulceration of the
epidermis with exudation of serum and leukocytes to form
crusts. These lesions have the character of an allergic reaction
and are presumably related to the alien nature of the 
sheep as a host, because they rarely occur in deer. The skin
lesions are intensely pruritic and often lead to severe self-
trauma. Lesions often persist for 3-4 years and will regress
spontaneously following the death of adult parasites 
and microfilariae.
Elaeophora bohmi was found in ~6% of a sample of Aus-
trian horses, the vessels involved being arteries and veins of
the metacarpus, metatarsus, and more distal extremities. The
parasites rather selectively involve the media of the vessels
avoiding the intima and adventitia, although the fibrous reac-
tion that develops may cause stenosis of the lumen. The
worms are coiled and entwined amongst the tissue layers,
provoking parasitic granulomas with intense infiltration by
eosinophils and macrophages. In cases of longer standing,
diffuse or nodular fibrous thickenings are visible and palpable
in the vessel walls. Microfilariae were found in the blood of
14 of 161 horses (9%) sampled in Iran. The infection appears
to be of little clinical significance.
Further reading
Couvillion CE, et al. Elaeophoriasis in white-tailed deer: pathology of
the natural disease and its relation to oral food impactions. J Wildl
Dis 1986;22:214-223. (E. schneideri).
LeVan IK, et al. High elaeophorosis prevalence among harvested Colo-
rado moose. J Wildl Dis 2013;49:666-669. (E. schneideri).
Mirzayans A, Maghsoodloo H. Filarial infection of equidae in the Tehran
area of Iran. Trop Anim Health Prod 1977;9:19-20. (E. bohmi).
Mtei BJ, Sanga HJ. Aortic onchocercosis and elaeophorosis in tradi-
tional TSZ-cattle in Tabora (Tanzania): prevalence and pathology. Vet
Parasitol 1990;36:165-170. (E. poeli).
VEINS
Venous disorders may be of clinical significance by predisposing
to thrombosis and subsequent embolism, or by obstructing venous
return and hence causing passive congestion of the affected areas.
Obstruction of venous outflow may be followed by the devel-
opment of collateral venous drainage.
Anomalies of veins occur uncommonly. Arteriovenous fistulas
have been discussed previously with arterial anomalies. A
variety of congenital portosystemic anastomoses occur in dogs
and cats and allow portal blood, with its absorbed toxic sub-
stances, such as ammonia, to bypass the liver and cause hepatic
encephalopathy. The most common of these defects is persis-
tent ductus venosus a persistence of the normal fetal circulation
wherein the umbilical veins enter the ductus venosus, which
portosystemic anastomoses occur extrahepatically between
 88.e1

eFigure 1-30  Intimal fibrous nodules in bovine aorta contain

males and the heads of females of Elaeophora poeli; the body of
the female swings free in the aortic lumen. (Courtesy P.B. Little
and Canadian Veterinary Journal.)
88.e2

Further reading
Boyce W, et al. Elaeophorosis in bighorn sheep in New Mexico. J Wildl
Dis 1999;35:786-789. (E. schneideri).
Hibler CP, Adcock JL. Elaeophorosis. In: Davis JW, Anderson RC, editors.
Parasitic Diseases of Wild Mammals. Ames, Iowa: Iowa State Uni-
versity Press; 1971. p. 263-278.
Kemper HE. Filarial dermatosis of sheep. J Am Vet Med Assoc
1957;130:220-224. (E. schneideri).
Little PB. A Malaysian experience with animal disease. Can Vet J
1979;20:13-21. (E. poeli).
Pessier AP, et al. Probable elaeophorosis in a moose (Alces alces) from
eastern Washington state. J Vet Diagn Invest 1998;10:82-84. (E.
schneideri).
Santin-Duran M, et al. Elaeophorosis in red deer from Spain. J Wildl
Dis 2000;36:779-782. (E. elaphi).
Diseases of the Vascular System Veins 89

the portal vein and various branches of the caudal vena cava
or the azygous vein. As well, portosystemic anastomoses may
be acquired because of portal hypertension, which in turn is
caused by impedance of blood flow through a diseased liver,
an obstructed portal vein, or a kinked intrathoracic caudal
vena cava. Hepatic microvascular dysplasia can occur in dogs
and cats in the absence of macroscopic portosystemic 
shunts, and result in similar clinical signs. Portosystemic anas-
tomoses and hepatic encephalopathy are discussed in more
detail in Vol. 3, Liver and biliary system.
Dilation of a vein, variously termed phlebectasia, varicosity,
or aneurysm, occurs but is of little or no importance. A
common type of dilation is the so-called “varicocele” of the
pampiniform plexus. Dilation may also occur because of con-
genital defects, such as venous diaphragms, agenesis, hypopla-
sia, or ectopia, or secondary to trauma, neoplasia, or surgical A
intervention. The initial dilation causes insufficiency of the
venous valves, and the veins may become dilated, elongated,
and tortuous. Thrombosis or sclerosis may be sequelae. The
acquired portosystemic anastomoses noted above usually
result from dilation of pre-existing microscopic venous anas-
tomoses to produce collateral venous drainage.
Hepatic telangiectasis, peliosis hepatis, and hepatic “veno-
occlusive disease” are described with diseases of the liver in
Vol. 3, Liver and biliary system.
Rupture of a large vein, usually the result of physical
trauma, may result in fatal hemorrhage. Spontaneous idio-
pathic rupture of the venae cavae or portal vein of horses
occurs occasionally; rupture of the great coronary vein of the
heart is a rare cause of unexpected death in horses.
Veins may be invaded by neoplasms (Fig. 1-91A, B), which
may then metastasize, and may cause thrombosis or B
obstruction.
Figure 1-91  A. Invasion from adrenal gland tumor (pheochromo-
cytoma) into the caudal vena cava of a dog. B. Vena cava opened
to show invasion of a pheochromocytoma in a dog.
Further reading
Christiansen JS, et al. Hepatic microvascular dysplasia in dogs: a retro-
spective study of 24 cases (1987-1995). J Am Anim Hosp Assoc
cattle recumbent for >4-6 hours results in thrombosis of the
2000;36:385-389.
femoral tributaries (“downer cows”). Venous infarction com-
Koide K, et al. Congenital hepatic arteriovenous fistula with intrahe-
monly ensues, and necrosis of the medial muscle masses and
patic portosystemic shunt and aortic stenosis in a dog. J Vet Med
sciatic nerves causes permanent paraplegia.
Sci 2004;66:299-302.
The thickened, congested, red-black mucosa of the gastric
Leeman JJ, et al. Multiple congenital portosystemic shunts in a dog:
fundus in swine with acute septicemia is a venous infarct result-
case report and literature review. J Am Aim Hosp Assoc 2013;49:281-
ing from thrombosis of veins of the mucosa and submucosa,
285.
probably as a sequel to endothelial damage. Gastrointestinal
Zwingenberger AL, et al. Imaging diagnosis—portal vein aplasia and
infarction and ulceration can occur in phenylbutazone-
interruption of the caudal vena cava in three dogs. Vet Radiol
intoxicated horses as a result of degeneration of veins and
Ultrasound 2011;52:444-447.
phlebothrombosis. Thrombosis of the jugular veins follows
unsuccessful or repeated venipuncture, injection of irritant
solutions, and the use of indwelling catheters, especially if
Phlebothrombosis and thrombophlebitis contaminated with bacteria. Important sequelae to jugular
Venous thrombosis (phlebothrombosis) results from the usual thrombosis are pulmonary embolism, and, if the emboli are
pathogenetic factors and often leads to inflammation of the septic, valvular endocarditis and pulmonary abscessation.
vein wall, and hence becomes thrombophlebitis. Conversely, Endophlebitis may result from the implantation of bacteria
phlebitis inevitably leads to thrombosis. Spontaneous thrombo- carried in the blood stream, as in salmonellosis, and from 
sis affects the venae cavae and portal veins occasionally, and the injection of irritant solutions. An important form of 
the inciting factors are usually unknown. Neoplastic invasion, acute suppurative endophlebitis is the omphalophlebitis of the
for instance, by pheochromocytoma, is one cause of thrombo- newborn resulting from infection of the uncicatrized umbilical
sis of the caudal vena cava. Thrombosis of the renal vein and cord. The resultant bacteremia may result in acute death 
vena cava occasionally occurs in dogs with the nephrotic syn- or give rise to widespread suppurative lesions, often polyar-
drome as a result of urinary loss of antithrombin and resulting thritis. Hepatic thrombophlebitis is especially common in
hypercoagulability of the blood. Stasis of venous blood of “navel-ill.”
 89.e1

Further reading
Allen JR, et al. Spontaneous rupture of the great coronary vein in a
pony. Equine Vet J 1987;19:145-147.
Cornelius L, Mahaffey M. Kinking of the intrathoracic caudal vena cava
in five dogs. J Small Anim Pract 1985;26:67-80.
Fernandez del Palacio MJ, et al. Persistent left cranial vena cava associ-
ated with multiple congenital anomalies in a six-week-old puppy.
J Small Anim Pract 1997;38:526-530.
Reimer JM, et al. Diagnosis and surgical correction of patent ductus
venosus in a calf. J Am Vet Med Assoc 1988;193:1539-1541.
Valentine RW, Carpenter JL. Spleno-mesenteric-renal venous shunt in
two dogs. Vet Pathol 1990;27:58-60.
White RN, Burton CA. Anatomy of the patent ductus venosus in the
cat. J Feline Med Surg 2001;3:229-233.
90 CHAPTER 1  •  Cardiovascular System Veins

A B

C D

Figure 1-92  The vasculitis of feline infectious peritonitis. A. Renal vasculitis. (Courtesy E. Olson.)
B. Vasculitis within the choroid of the eye. H&E. C. Vasculitis within a small caliber renal vein.
H&E. D. Serial section of (C) immunostained with anti–feline infectious peritonitis virus
antibody.

In feline infectious peritonitis, phlebitis occurs as a result of

antigen-antibody complex deposition in the walls of small
veins and venules, which is followed by complement fixation
and neutrophil chemotaxis. Neutrophils cause tissue necrosis,
and hence thrombophlebitis, which is followed by the focal
pyogranulomatous reaction typical of this disease (Fig. 1-92).
Phlebitis very commonly occurs by extension from areas of
inflammation, and importantly provides for the hematogenous
dissemination of infection. The entire thickness of the wall of
the vein is inflamed, and thrombosis occurs rapidly. If the
thrombus is infected, it is likely to soften, disintegrate, and
produce emboli. An important example of this pathogenetic
sequence is thrombosis of the caudal vena cava in cattle, which
occurs as a sequel to rumenitis and hepatic abscessation (Fig.
1-93, eFig. 1-31). Perivascular hepatic abscesses often involve Figure 1-93  Thrombi in pulmonary vessels associated with val-
the vena cava causing thrombophlebitis and a variety of conse- vular endocarditis caused by Trueperella sp. in an ox. (Courtesy
quences: pulmonary thromboembolism and arteritis, pulmo- R.W. Cook.)
nary abscessation, or pulmonary arterial aneurysms that may
rupture and cause massive pulmonary hemorrhage. Valvular
endocarditis is an occasional sequel. As well, the abscess may
erode the wall of the vena cava wall and rupture into the vena
cava, causing massive septic embolization and sudden death.
 90.e1

eFigure 1-31  Thrombophlebitis of caudal vena cava originating

from hepatic abscess: bovine.
Diseases of the Vascular System
Further reading
Braun U. Clinical findings and diagnosis of thrombosis of the caudal
vena cava in cattle. Vet J 2008;175:118-125.
Dias DPM, de Lacerda Neto JC. Jugular thrombophlebitis in horses: a
review of fibrinolysis, thrombus formation and clinical manage-
ment. Can Vet J 2013;54:65-71.
Edwards JF, et al. Staphylococcus-associated abortions in ewes with
long-term central venous catheterization. Vet Pathol 2008;45:881-
888.
LeGrange SN, et al. Thrombosis of the caudal vena cava presenting as
an unusual cause of an abdominal mass and thrombocytopenia in
a dog. J Am Anim Hosp Assoc 2000;36:143-151.
Respess M, et al. Portal vein thrombosis in 33 dogs: 1998-2011. J Vet
Intern Med 2012;26:230-237.
Saridomichelakis MN, et al. Extensive caudal vena cava thrombosis
secondary to unilateral renal tubular cell carcinoma in a dog. J Small
Anim Pract 2004;45:108-112.
Schoster A, Anderson MEC. Caudal vena cava thrombosis-like syn-
drome in a horse. Can Vet J 2010;51:891-894.
Simpson KM, et al. Caudal vena caval thrombosis following treatment
of deep digital sepsis. Can Vet J 2012;53:182-186.
Parasitic thrombophlebitis
Schistosomes are important venous parasites in tropical Africa
and Asia, and are discussed at length later. Gurltia paralysans,
a metastrongyle, causes paralytic disease in domestic cats in
South America. The adults lodge in the veins of the thigh and
lumbar spinal cord and cause thrombosis and ectasia.
Schistosomiasis (bilharziasis)
Schistosomiasis, a snail-borne fluke infection, is prevalent in
domestic animals in Asia, Africa, and other tropical and subtropi-
cal areas, but does not usually occur as clinical disease; the
importance of the disease may increase as irrigation projects
enhance the habitat for the intermediate snail host. Damage
and clinical effects are the result of localization of adult flukes
and their eggs in blood vessels of the liver, lungs, alimentary and
urogenital tracts, and the nasal cavity. Schistosomiasis is often
a disease of long duration.
Members of the family Schistosomatidae are the blood
flukes of mammals and birds; species that parasitize mammals
include those of the genera Schistosoma, Heterobilharzia, and
Orientobilharzia.
It is characteristic of the trematodes, including the blood flukes,
that the intermediate stages of the parasite are selective in their
choice of hosts, mollusks, and that the infective and final phases
do quite well in a variety of definitive hosts, although there is
some host preference. The distribution of particular species of
schistosomes is closely linked to the geography of the obligate
intermediate hosts. The human schistosome, especially Schis-
tosoma japonicum, may be found in domestic animals, and the
other mammalian schistosomes may be discovered in man as
patent or nonpatent infestations.
Based on distribution, host specificity, egg morphology, and
intermediate snail hosts, the species that occur in domestic
animals may be grouped as follows:
1. S. haematobium group—S. bovis in the portal and mesen-
teric veins of ruminants and occasionally horses, camels,
and pigs, in southern Europe and tropical areas of Africa
and Asia; S. mattheei in the portal and mesenteric veins,
plus veins of the urogenital tract and stomach, of ruminants
Veins 91
in central and southern Africa; S. curassoni in ruminants in
West Africa; S. margrebowiei and S. leiperi in wild artiodac-
tyls in Central Africa
2. S. mansoni group—S. rodhaini in dogs and other carnivores
in Central Africa
3. S. indicum group, present in India and Southeast Asia—S.
spindale in mesenteric veins of ruminants and, occasionally,
of horses and dogs; S. nasale in nasal mucosal veins of
cattle and, occasionally, of goats and horses; S. indicum in
portal and mesenteric veins of herbivores; S. incognitum in
swine and dogs
4. S. japonicum group—S. japonicum, human by preference,
in all domestic animals in the Far East; S. mekongi in dogs
and humans in Southeast Asia
Based on genomic analysis, schistosomes have been placed
in 6 defined clades that correlate with the geographic distribu-
tions of the parasites (Fig. 1-94). It also appears that all schis-
tosomes are of Asian origin, with the S. japonicum group as
the original ancestor. S. bovis and S. japonicum are the most
pathogenic of the schistosomes of cattle and sheep. Mixed
infections with more than one species of schistosome occur;
hybridization may occur in this circumstance.
Other members of the family Schistosomatidae of veteri-
nary significance include Orientobilharzia turkestanicum in
mesenteric veins of herbivores and cats in the Near East,
Russia, China, and Mongolia; O. dattai and O. bomfordi in
artiodactyls in India; and Heterobilharzia americana in the
southern United States, especially Texas and Louisiana in its
definitive host the raccoon.
The life cycles of the schistosomes are comparable to those
of other flukes and follow the general pattern described else-
where for the liver fluke, Fasciola hepatica. As a point of dif-
ference, the redia phase of F. hepatica in the intermediate host
is replaced in the schistosome by a generation of daughter
sporocysts.
The eggs of the schistosome are laid in the vessels that the
adult parasites inhabit. When laid, the eggs are immature, but
contain a miracidium by the time they have worked their way
through the overlying mucous membrane to escape to the
exterior. The eggs hatch in water, and the miracidia actively
penetrate the soft tissues of aquatic snails to which they are
physiologically adapted. The fork-tailed cercariae that emerge
from the snail are the infective phase, and they enter the
definitive host by burrowing through the skin; patent infesta-
tions can also develop if the cercariae are ingested with water.
They will invade the skin of hosts that are quite alien to them,
provoking allergic reactions and dermatitis (swimmer’s itch,
swamp itch in humans).
Cutaneous lesions develop as a result of penetration of the
skin by cercariae. They occur only on those portions of the
skin that come in contact with infested water and are seldom
observed in animals except under experimental conditions.
The cutaneous lesions are tiny petechiated nodules in which
there is a sharp leukocytic reaction to the parasite. Passage of
a large number of parasites through the lungs will produce
pneumonia. Ectopic localization in various organs, such as the
kidney, produces small hemorrhages and inflammatory foci.
In the definitive host, the cercariae lose their tails and
become schistosomula, which enter venules in the dermis and,
thereafter, are conveyed passively in the blood, through the
lungs, and into the systemic circulation. Once in the blood,
there is probably no selective migration; those that are distrib-
uted to the vessels of their final habitat develop further, and
 91.e1

Further reading
Bressler C, et al. Portal vein and aortic thromboses in a Siberian
husky with ehrlichiosis and hypothyroidism. J Small Anim Pract
2003;44:408-410.
Clements CA, et al. Splenic vein thrombosis resulting in acute anemia:
an unusual manifestation of nephrotic syndrome in a Chinese shar
pei with reactive amyloidosis. J Am Anim Hosp Assoc 1995;31:411-
415.
Grosslinger K, et al. Iliopsoas abscess with iliac and femoral vein throm-
bosis in an adult Siberian husky. J Small Anim Pract 2004;45:113-
116.
Howard J, et al. Blastomycosis granuloma involving the cranial vena
cava associated with chylothorax and cranial vena caval syndrome
in a dog. J Am Anim Hosp Assoc 2000;36:159-161.
Lankveld DP, et al. Factors influencing the occurrence of thrombophle-
bitis after post-surgical long-term intravenous catheterization of
colic horses: a study of 38 cases. J Vet Med A Physiol Pathol Clin
Med 2001;48:545-552.
Meschter CL, et al. Vascular pathology in phenylbutazone intoxicated
horses. Cornell Vet 1984;74:282-297.
Sottiaux J, Franck M. Cranial vena caval thrombosis secondary to inva-
sive mediastinal lymphosarcoma in a cat. J Small Anim Pract
1998;39:352-355.
Van Winkle TJ, Bruce E. Thrombosis of the portal vein in eleven dogs.
Vet Pathol 1993;30:28-35.
Weiss RC, Scott FW. Pathogenesis of feline infectious peritonitis: patho-
logic changes and immunofluorescence. Am J Vet Res 1981;42:
2036-2048.
92 CHAPTER 1  •  Cardiovascular System Veins

99 Schistosoma ovuncatum

Schistosoma sinensium
Central and
100 Schistosoma japonicum S. japonicum clade
S. E. Asia
100 Schistosoma malayensis
Schistosoma mekongi

98 Schistosoma edwardiense
Africa S. hippopotami clade
Schistosoma hippopotami
Orientobilharzia turkestanicum Central Asia,
100 Near East Proto - S. mansoni clade
Schistosoma incognitum and E. Europe
100
Schistosoma mansoni
Africa S. mansoni clade
100 Schistosoma rodhaini
Schistosoma nasale

100 Schistosoma spindale India and

S. indicum clade
S. Asia
100
Schistosoma indicum
100
Schistosoma margrebowiei

Schistosoma leperi
100
Schistosoma mattheei
100 Schistosoma kisumuensis
97
80 Schistosoma intercalatum Africa S. haematobium clade

84 Schistosoma haematobium

Schistosoma guineensis
100
100 Schistosoma curassoni
99 Schistosoma bovis

Figure 1-94  Schistosoma clades. Summary schematic phylogeny of the interrelationships of members of the species within the Schisto-
soma genus estimated with a Bayesian analysis of combined partial lsrDNA, complete ssrDNA, and partial cox1. cox1, cyclooxygenase 1;
lsr, large subunit ribosomal; ssr, small subunit ribosomal. (From Lawton SP, et al. Genomes and geography: genomic insights into the
evolution and phylogeography of the genus Schistosoma. Parasit Vectors 2011;4:131-141.)

those that are distributed to other organs die. Schistosoma
nasale develops in the veins of the nasal mucosa; all other
species develop in veins of the abdominal cavity, principally
in the portal vessels, until sexual maturity is attained, when
they migrate out to the smaller veins of the mesentery. In
long-standing infections, S. mattheei may reside in veins of the
urinary bladder as well as in portomesenteric veins. The pre-
patent period in the mammalian host ranges from 30-77 days.
As would be expected, not all the eggs move in the proper
direction. Some break into lymphatics and are conveyed to
the regional nodes to produce granulomas but, more impor-
tantly, a great many of them pass to the liver, producing portal
phlebitis and granulomatous hepatitis, in concert with the
adult flukes. In heavy infestations and possibly by means of
venous shunts developed in the liver, many eggs may pass in
venous blood to and beyond the lungs, producing granuloma-
tous endoarteritis and adjacent granulomas wherever they
lodge. The development of hepatic lesions follows the same
course as for those that develop in the intestinal wall. In the
liver, the eggs break out of the portal venules to become
enclosed by granulomas. Sooner or later, they die and are
mineralized, and by that time have provoked extensive  may bear polypoid and papillary proliferations. The mesentery
surrounding fibrosis. The above course of events occurs simi-
larly in urinary schistosomiasis caused by S. mattheei, wherein
hematuria accompanies excretion of eggs in the urine, and
granulomatous cystitis and ureteritis result from the host’s
immunologic response to the schistosome eggs trapped in the
tissues.
Clinical signs of schistosomiasis of portomesenteric distri-
bution include lethargy, anemia, and weight loss. Diarrhea or
dysentery occur at the time of patency, persist for a few weeks,
and, in the absence of reinfection, may be followed by spon-
taneous recovery as the immune response of the host elimi-
nates the parasites and suppresses the egg laying of survivors.
The eggs can be found in the feces together with some mucus
and blood. Blood loss leads to anemia and hypoalbuminemia,
which may contribute to the presence of fluid in serous
cavities.
Gross and microscopic findings include thickening of the
wall of the intestine, chiefly the large bowel, by inflammatory
and scar tissue, and the wall may contain small granulomas
and lymphoid nodules. Scarring begins in the mucosa and
extends to involve all layers, including the serosa. The mucosa
Diseases of the Vascular System
is thickened and shortened by fibrous tissue, and the mesen-
teric nodes are enlarged and fibrotic. The adult parasites,
which are about 1-3 cm long, can be found in the mesenteric
and portal vessels (eFig. 1-32). There is fibrosis of the liver of
variable degree affecting particularly the portal vessels. The
liver may be enlarged or small depending on the course and
severity of the infestation. On cut surface, the periportal
nature of the fibrosis is quite apparent but, with time and
more severe infestations, the fibrosis becomes more diffuse
and the surface of the liver may have a hobnailed appearance
or be studded by numerous minute granulomas.
Proliferative granulomatous nasal lesions produced by S.
nasale result in clinical signs of dyspnea and mouth
breathing.
Granulomatous lesions are frequently present in the
urinary bladder and ureters of cattle with S. mattheei infection;
lesions in the ureters, and occasionally renal pelvis, are linear,
whereas those in the bladder become very extensive and
polypoid.
The stage of oviposition and extrusion of eggs through the
tissues and mucous membranes is the stage in which most damage
is done. In fact, a host inflammatory response is necessary for
the eggs to move across the mucosa of organs such as the
intestine and bladder. The mated schistosomes, in permanent
copula, move out into the smallest venous radicles, and the
eggs are deposited first in the lumen of the vessel. They adhere
to, and are eventually covered by, the endothelium. The eggs
of some species are spinous, and this probably facilitates
passive migration into the tissue. The migration does appear,
however, to be partly active by virtue of secretions elaborated
by the developing miracidium, which diffuse through the shell
of the egg into the tissues. These secretions may be also in
part responsible for inciting the inflammatory reaction to the
eggs. Initially, most of the eggs are deposited in the lamina
propria of the intestine, and break into the lumen with little
more than mechanical injury. Rupture of congested mucosal
venules accounts for the characteristic dysentery of schistoso-
miasis. Also contributing to diarrhea, loss of body condition,
and failure to thrive are ganglionitis and degeneration of the
enteric nervous system, which may result from a localized
type I hypersensitivity reaction involving mast cell–derived
chemical mediators.
As the disease progresses and the adults are excluded from
smaller venules resulting from endophlebitis, eggs are laid in
veins in deeper tissues, where antigens released by the mira-
cidium induce a delayed hypersensitivity response and forma-
tion of small granulomas (“pseudotubercles”). The granulomas
are characterized initially by the infiltration of leukocytes,
chiefly eosinophils, and later by the accumulation of mono-
nuclear leukocytes, epithelioid and giant cells, and reactive
fibrosis. Microabscesses occasionally form and rupture into the
gut lumen. Eggs in submucosal granulomas degenerate and are
removed, or may be mineralized and remain for a longer
period of time. Some of the mature or disintegrating eggs may
be coated with a bright eosinophilic deposit (the Splendore-
Hoeppli reaction), the result of antigen-antibody complex for-
mation. The granulomas gradually regress and are replaced by
fibrous tissue. Host cell responses to eggs are primarily the
result of host hypersensitivity to soluble egg antigens, and, to
a much lesser degree, resulting from physical and chemical
stimuli.
Adult schistosomes in mesenteric and portal veins elicit eosino-
philic endophlebitis, often with irregular intimal proliferation, and
Veins 93
may be found within thrombi. Adults may similarly cause reac-
tions in veins of the pancreas and the mesenteric and portal
lymph nodes, and in pulmonary arterioles. Dead parasites are
removed by a granulomatous reaction that is often followed
by the formation of a grossly visible lymphoid nodule. The
lumen of the vein may be occluded, and the venous wall
obliterated, by this lymphoid response. There may also be
diffuse intimal proliferation and endophlebitis of intrahepatic
portal veins, medial hypertrophy, and adventitial inflammation
and fibrosis leading to prominent portal fibrosis, which may
appear grossly as “clay pipe-stem” portal fibrosis. Irregular
dilated vascular bypasses develop in the portal areas. The
adults ingest erythrocytes and regurgitate hematin pigments,
which are picked up by the monocyte-macrophage system,
especially in the regional lymph nodes and liver; these black
iron-porphyrin pigments may be responsible for the gray color
of the liver and lungs in severe cases of schistosomiasis.
Heterobilharzia americana infection.  Heterobilharzia
americana, in the family Schistosomatidae, causes schistoso-
miasis in dogs as an accidental infection. The raccoon is the
definitive host. Dogs, among many other species, are acciden-
tal hosts, including the bobcat, armadillo, Brazilian tapir,
beaver, coyote, mountain lion, mink, nutria, opossum, red
wolf, swamp rabbit, and white-tailed deer. The trematode is
found in the southeastern United States, especially the Gulf
coast and southern Atlantic states, and the infection in the
vertebrate host is limited by the geographic distribution of the
intermediate host. Granulomas incited by H. americana have
been reported to occur in the liver, and uncommonly, in other
tissues of horses.
The life cycle of the trematode is well defined, with the
intermediate host a lymnaeid freshwater snail Bakerilymnaea
cubensis or Pseudosuccinea columnella. It follows the classic
schistosome pathway of cercariae—the cercariae penetrating
the skin of the vertebrate host, migrating via the blood to the
lungs and liver before finally coming to reside in the mesen-
teric and intrahepatic portal veins, where they mature into
adults. Eggs, assisted by the secretion of proteolytic enzymes,
move from the capillary lumen into the intestinal tract and
are expelled in feces. On contact with water, miracidia are
released from the eggs and actively seek the snail intermediate
host, which completes the life cycle. Clinical signs of the
infection in dogs include mucoid to bloody diarrhea, lethargy,
weight loss, vomiting, anorexia, and ascites. A distinctive
finding is the presence of hypercalcemia in >50% of cases,
which is thought to be the result of the synthesis and release
of calcitriol from macrophages as part of the granulomatous
reaction to egg migration. With or without hypercalcemia,
there may be areas of dystrophic tissue mineralization, espe-
cially of schistosome eggs, in the intestine and liver. At post-
mortem, the abdominal cavity may contain excess fluid, the
intestinal wall thickened, and the liver, small, pale, and nodular,
containing numerous 1-2 mm pale gray to white areas extend-
ing throughout the parenchyma. The lungs and kidneys may
contain similar lesions. Histologically, lesions in the liver,
intestinal submucosa, pancreas and lungs are multifocal lym-
phoplasmacytic, eosinophilic to granulomatous reactions in
response to deposited eggs that are sometimes arranged in
linear arrays (Fig. 1-95A, B). The eggs are often heavily min-
eralized. The liver, in particular, may exhibit additional lesions
of periportal to bridging fibrosis, lobular collapse, nodular
regeneration, bile duct hyperplasia, and cholestasis. Confirma-
tion of the suspected diagnosis of H. americana, even from
 93.e1

eFigure 1-32  Adult schistosome (arrow) in a mesenteric vein in

a lamb.
94 CHAPTER 1  •  Cardiovascular System
A
B or secondary:
Figure 1-95  Heterobilharzia americana infection in a dog.
A. Liver showing chronic inflammatory reaction, including
multinucleated giant cells, to H. americana eggs. H&E. B. Close
proximity of multinucleated giant cells to parasite eggs. H&E.
(From an Armed Forces Institute of Pathology Wednesday Slide
Conference, 2011.)
formalin-fixed tissue, can be achieved through the use of PCR
to demonstrate the presence of H. americana–specific small
subunit ribosomal RNA.
Further reading
Corapi WV, et al. Multi-organ involvement of Heterobilharzia ameri-
cana infection in a dog presented for systemic mineralization. J Vet
Diagn Invest 2011;23:826-831.
Corapi WV, et al. Natural Heterobilharzia americana infection in horses
in Texas. Vet Pathol 2012;49:552-556.
Fabrick C, et al. Clinical features and outcome of Heterobilharzia amer-
icana infection in dogs. J Vet Intern Med 2010;24:140-144.
Fradkin IM, et al. Elevated parathyroid hormone-related protein and
hypercalcemia in two dogs with schistosomiasis. J Am Anim Hosp
Assoc 2001;37:349-355.
Hams E, et al. The schistosoma granuloma: friend or foe? Front
Immunol 2013;4:89, 1-8.
Johnson FM. Canine schistosomiasis in North America: an underdiag-
nosed disease with an expanding distribution. Compend Contin
Educ Vet 2010;32:E1-E4.
Kusel JR, et al. The schistosome in the mammalian host: understanding
the mechanisms of adaptation. Parasitol 2007;134:1477-1526.
Lymphatics
Lawton SP, et al. Genomes and geography: genomic insights into the
evolution and phylogeography of the genus Schistosoma. Parasit
Vectors 2011;4:131-141.
Lu DB, et al. Contrasting reservoirs for Schistosoma japonicum between
marshland and hilly regions in Anhui, China—a two-year longitu-
dinal parasitological survey. Parasitol 2010;137:99-110.
Mourão MM, et al. Recent advances in Schistosoma genomics. Parasite
Immunol 2012;34:151-162.
LYMPHATICS
The richness of the lymphatic plexuses in almost all tissues
and their important role as drainage channels for interstitial
fluid makes for almost inevitable involvement of lymphatics
by any inflammation and by the many neoplasms that metas-
tasize via lymph channels. In most instances, the lymphatic
lesions are so small as to have no significance, but in some
cases, the consequence of lymphatic involvement may be the
major presenting clinical sign or lesion. Such, for example, is
the case when attention is drawn to papillary carcinoma of
the canine ovary by severe ascites; disrupted portions of the
neoplasm permeate and obstruct the ventral diaphragmatic
lymphatics, which are the main efferent channels of the peri-
toneal cavity.
Lymphedema is defined as swelling of a part of the body by
an increased quantity of lymph resulting from a lymphatic system
disorder. The term should not be used to describe edematous
swellings resulting from venostasis, hypoproteinemia, heart
failure, or cellulitis. Lymphedema may be classified as primary
• Primary lymphedema, which is usually congenital, and may
be hereditary, is due to anomalous development of the
lymphatic system.
• Secondary lymphedema occurs because of obstruction of
previously normal lymphatics, resulting from inflamma-
tion, neoplasia, surgery, or trauma.
Lymphedema is of significance because it may predispose
the affected area, usually a limb, to secondary bacterial infec-
tion and poor wound healing. Prolonged lymphedema leads to
fibrosis.
A lymphocele is a lymph-filled space that does not have a
distinct endothelial lining, and may be the result of disruption
of lymphatics by trauma or surgery.
Congenital anomalies
There are many degrees of variation of the standard disposi-
tion of the large lymphatic vessels, but these are of no clinical
importance. Epicardial lymphatics in horses and dogs are occa-
sionally dilated and tortuous, and may be anomalous; they are
of no apparent significance (Fig. 1-96).
Congenital hereditary lymphedema is a rare condition that
has been reported in calves, dogs, and pigs. The lymphatic
abnormality is inherited as an autosomal dominant trait in
most cases examined. One of the regulators of lymphatic
vasculature formation is T1α/podoplanin, a mucin-type trans-
membrane glycoprotein that is predominantly expressed by
lymphatic endothelium and is regulated by the lymphatic-
specific gene Prox1. T1α/podoplanin (−/−) mice die at birth
and have defects in lymphatic vessel formation, with conse-
quent congenital lymphedema.
The central lymphatic system normally forms as out-
growths from the endothelium of primitive veins, and
 94.e1

Further reading
Balemba OB, et al. Lesions of the enteric nervous system and the pos-
sible role of mast cells in the pathogenic mechanisms of migration
of schistosome eggs in the small intestine of cattle during Schisto-
soma bovis infection. Vet Parasitol 2000;90:57-71.
Bartsch RC, Van Wyk JA. Studies on schistosomiasis: 9. Pathology of
the bovine urinary tract. Onderstepoort J Vet Res 1977;44:73-94.
Buergelt CD, Greiner EC. Fibrosing granulomas in the equine liver and
peritoneum: a retrospective morphologic study. J Vet Diagn Invest
1995;7:102-107.
De Bont J, et al. The prevalence and pathology of Schistosoma nasale
Rao, 1933 in cattle in Sri Lanka. Parasitol 1989;98(Pt 2):197-202.
Ferreras MC, et al. Histopathological and immunohistochemical study
of lambs experimentally infected with Fasciola hepatica and Schis-
tosoma bovis. J Vet Med B Infect Dis Vet Public Health 2000;47:763-
773.
Ferreras-Estrada MC, et al. A pathological study of experimental long-
standing Schistosoma bovis infection in sheep. J Comp Pathol
1998;119:479-484.
Flowers JR, et al. Heterobilharzia americana infection in a dog. J Am
Vet Med Assoc 2002;220:193-196.
Fransen J, et al. Pathology of natural infections of Schistosoma spindale
Montgomery, 1906, in cattle. J Comp Pathol 1990;103:447-455.
Lawrence JA. The pathology of Schistosoma mattheei infection in the
ox: 1. Lesions attributable to the eggs. 2. Lesions attributable to
the adult parasites. J Comp Pathol 1978;88:1-14, 15-29.
Lindberg R, et al. Experimental Schistosoma bovis infection in goats:
the inflammatory response in the small intestine and liver in various
phases of infection and reinfection. J Parasitol 1997;83:454-459.
Losos GJ. Infectious Tropical Diseases of Domestic Animals. Harlow, UK:
Longman Scientific & Technical; 1986. p. 903-938.
Lu DB, et al. Evolution in a multi-host parasite: chronobiological circa-
dian rhythm and population genetics of Schistosoma japonicum
cercariae indicates contrasting definitive host reservoirs by habitat.
Int J Parasitol 2009;39:1581-1588.
Van Wyk JA, et al. Schistosoma mattheei infection in cattle: the course
of the intestinal syndrome, and an estimate of the lethal dose of
cercariae. Onderstepoort J Vet Res 1997;64:65-75.
Vercruysse J, et al. Pathology of Schistosoma curassoni infection in
sheep. Parasitol 1985;91(Pt 2):291-300.
Vercruysse J, Gabriel S. Immunity to schistosomiasis in animals: an
update. Parasite Immunol 2005;27:289-295.
Diseases of the Vascular System
Figure 1-96  Dilation of epicardial lymphatics in a foal.
Figure 1-97  Congenital lymphedema, especially of limbs of a
calf. (Courtesy F. Riet-Correa.)
subsequent outgrowths form the peripheral lymphatic system.
The primary lymph nodes develop from the primitive central
lymphatic anlagen, the jugular and iliac lymph sacs. Secondary
and tertiary lymph nodes later form along the peripheral
lymphatic system and are the most severely affected nodes in
congenital lymphedema. The earlier the stage at which lym-
phatic malformation occurs, that is, the more central the mal-
formation, the more severe the clinical manifestations and the
earlier their onset.
Grossly, the most severely affected individuals have gener-
alized subcutaneous edema and fluid in serous cavities and are
either stillborn or must be delivered by cesarean section. The
mortality rate of Ayrshire cows with lymphedematous fetuses
has been high. Moderate degrees of lymphedema are seen as
symmetrical swelling of the head, neck, limbs, and tail (Fig.
1-97). The ears of lymphedematous calves often have edema-
tous accessory lobes. Lesser degrees of lymphedema affect the
distal parts of the limbs, especially the hindlimbs, and may not
develop for several weeks postnatally. Mild regional lymph-
edema may be of little significance, although chronic subcu-
taneous edema will lead to fibrosis and may predispose to
Lymphatics 95
secondary bacterial infection. Mild lymphedema affecting
only the hindlimbs will in some cases disappear, presumably
resulting from postnatal development of the peripheral lym-
phatic system. The peripheral lymph nodes are usually smaller
than normal or absent in affected animals. Although obstruc-
tion may be demonstrated by lymphangiography, nodal hypo-
plasia or absence does not necessarily lead to obstruction.
Afferent and efferent nodal sinuses may be dilated and may
be evident on gross examination. The thoracic duct may be
dilated and tortuous in generalized lymphedema.
Histologically, a wide range of lymphatic abnormalities
may be seen in the edematous, and possibly fibrotic, subcutis
of affected areas. The lymphatics may be aplastic, that is, no
lymphatics are found; hypoplastic, in which case lymphatics
are too few or too small; or hyperplastic, or varicose, in which
case lymphatics are excessive in size and number, and dilation
has resulted in valvular incompetence and lymphostasis.
Ectatic lymph channels are commonly present around and
within hypoplastic peripheral lymph nodes. Central nodes are
similarly affected in animals with generalized lymphedema,
and will be absent in cases of lymphovascular agenesis.
Further reading
Fossum TW, Miller MW. Lymphedema. Etiopathogenesis. J Vet Intern
Med 1992;6:283-293.
Kang JH, et al. Secondary malignant lymphoedema after mastectomy
in two dogs. J Small Anim Pract 2007;48:579-583.
Schacht V, et al. T1α/podoplanin deficiency disrupts normal lymphatic
vasculature formation and causes lymphedema. EMBO J 2003;
22:3546-3556.
Yamaguchi R, et al. Congenital lymphedema in a calf with lymph node
dysplasia or aplasia. J Vet Med Sci 1995;57:797-799.
Dilation and rupture of lymphatics
Dilation of normally developed lymphatic vessels (lymphangiec-
tasis) almost invariably results from some form of obstruction and
leads to the accumulation of excess interstitial fluid in the drain-
age area. Causes of such lymphatic obstruction include infil-
trating neoplasms that may obstruct the lymphatic vessel or
the drainage node, inflammatory thrombosis and sclerosis of
the channels or nodal sinuses, and postsurgical scarring. The
vessels become irregularly dilated and tortuous distal to the
obstruction, and the accompanying increase in interstitial
fluid, if persistent, will cause an increase in interstitial and
subcutaneous fibrous tissue.
Intestinal lymphangiectasis is the most common cause of
protein-losing enteropathy in dogs, and contributes to intestinal
protein loss in cattle with Johne’s disease and other enteritides.
Dilated lacteals in intestinal villi rupture or leak their contents
into the intestinal lumen, and severe hypoproteinemia can
result. Leakage of protein from capillaries in the villi may also
be an important contributor to protein loss. Chyle may leak
from dilated subserosal lymphatics and contribute to the
hypoproteinemia-induced ascites.
Chylothorax, the result of leakage or rupture of the thoracic
duct, occurs infrequently in dogs and cats. The cause of chy-
lothorax in the absence of another complicating lesion is
usually not apparent; rupture resulting from thoracic trauma
is often postulated but rarely proven. An injured thoracic duct
has limited capacity for spontaneous healing. Reported com-
plicating causes of chylothorax include neoplasia, right-sided
 95.e1

Further reading
Carmichael NG, et al. Secondary lymphoedema in a dog. J Small Anim
Pract 1986;27:335-341.
Reynhout KM, et al. Lymphocele in a cat. J Am Vet Med Assoc
1994;204:400-403.
Schild AL, et al. Hereditary lymphedema in Hereford cattle. J Vet Diagn
Invest 1991;3:47-51.
van der Putte SCJ. The pathogenesis of congenital hereditary lymph-
edema in the pig. Lymphol 1978;11:10-21.
96 CHAPTER 1  •  Cardiovascular System Lymphatics

heart failure, dirofilariasis, thrombosis of the cranial vena cava,

congenital anomaly of the thoracic duct, fungal infections, and
lung lobe torsion. Obstruction of thoracic duct drainage may
lead to lymphangiectasis of intrathoracic lymphatics and
leakage of chyle. Chylopericardium is an unusual accompani-
ment of chylothorax. The diagnosis of chylothorax is confirmed
by analysis of the pleural fluid, which is opalescent to opaque,
milky-white to yellow, and on standing, forms a top layer of
cream (chylomicron fat) that is ether soluble. Microscopically,
the fluid contains large numbers of lymphocytes, a few neu-
trophils, red cells, plasma cells, and fat globules. The site of
the rupture is often difficult to locate surgically or at postmor-
tem. Ligation of the thoracic duct leads to the development
of alternative lymphaticovenous anastomoses, and cessation of
the chylothorax.
Chylous ascites results from rupture of the cisterna chyli,
and is a rare event.
Figure 1-98  Granulomatous lymphangitis in Johne’s disease in a
cow. (Courtesy J. Collins.)
Further reading
Myers NC, et al. Chylothorax and chylous ascites in a dog with medi-
Synonyms include Monday morning disease, bigleg, and weed.
astinal lymphangiosarcoma. J Am Anim Hosp Assoc 1996;32:263-
The disease is ushered in by acute lameness and severe cording
269.
of the lymphatics, although this is usually palpable only where
Schuller S, et al. Idiopathic chylothorax and lymphedema in 2 whippett
the lymphatics lie near the saphenous vein on the inner aspect
littermates. Can Vet J 2011;52:1243-1245.
of the thigh. The limb swells rapidly, the swelling beginning
Simmerson SM, et al. Clinical features, intestinal histopathology, and
about the pastern or metatarsus and reaching its zenith in 3
outcome in protein-losing enteropathy in Yorkshire Terrier dogs.
or 4 days, by which time it has usually extended beyond the
J Vet Intern Med 2014;28:331-337.
stifle. There are transient general disturbances associated with
Singh A, et al. Idiopathic chylothorax: pathophysiology, diagnosis,
fever. Recovery is usual, although repeated attacks may occur
and thoracic duct imaging. Compend Contin Educ Vet 2012;
and some cases are fatal, presumably as a result of septicemia.
34:E2.
There is edema of the connective tissues of the distal portion
of the limb, with very rapid fibroplasia. Above the stifle, the
edema is largely confined to the subcutis, this probably
Lymphangitis depending on the arrangement of fascia there. The lymphatics
Lymphangitis with anatomic specificity is a prominent feature are dilated, and the larger ones contain thick pus or a 
of a number of specific diseases. Most of the diseases are dis- thinner mixture of pus and lymph. There is regional acute
cussed elsewhere, but warrant brief mention here also. A lymphadenitis.
feature of the restricted form of anthrax is acute thrombotic The cause and pathogenesis of sporadic lymphangitis are
lymphangitis, the thrombi containing large numbers of bacilli, unknown. Various pyogenic organisms have been recovered
with a marked tendency towards necrosis, and is seen in pigs, from the lesions, but it appears that, in the usual case, the
dogs, and horses. Granulomatous lymphangitis occurs typi- initial acute infection is rapidly overcome. The occurrence of
cally in mycobacterial infections; the mesenteric lymphatics the disease after a period of inactivity, and the experimental
stand out like threads beneath the serosa in Johne’s disease, production of a similar lesion by inoculation of bacteria into
and are often beaded in intestinal tuberculosis; they bear the skin of the pasterns in undernourished horses, suggests that
specific microscopic lesions of these infections (Fig. 1-98). The “stocking” of the hindlimbs (stagnant edema that is common
spread of actinobacillosis can often be discerned as long rows in debilitated horses in periods of inactivity) predisposes to
of small granulomas from the site of primary infection on the the progress of infection. However, most horses with stocking
way to the regional nodes. The corded and nodular ulcerating of the hindlimbs do not develop lymphangitis. The entry of
lymphangitis of cutaneous glanders in horses must be distin- infection is probably traumatic.
guished from the specific forms of lymphangitis discussed
below. Lymphangitis is often a prominent development in
cutaneous streptothricosis in cattle, and can occur in various Further reading
species with cutaneous sporotrichosis. Lipogranulomatous lym- Hamid ME. Epidemiology, pathology, immunology and diagnosis of
phangitis has been found in association with intestinal lym- bovine farcy: a review. Prev Vet Med 2012;105:1-9.
phangiectasis in dogs. Kull PA, et al. Clinical, clinicopathologic, radiographic and ultrasono-
Bovine farcy is a chronic granulomatous disease of cattle graphic characteristics of intestinal lymphangiectasia in dogs: 17
in the tropics, and is characterized by nodular suppurative cases (1996-1998). J Am Vet Med Assoc 2001;219:197-202.
dermatitis, lymphangitis, and lymphadenitis. Most cases of Schubach TM, et al. Pathology of sporotrichosis in 10 cats in Rio de
bovine farcy are caused by Mycobacterium farcinogenes or M. Janeiro. Vet Rec 2003;152:172-175.
senegalense. Watson VE, et al. Focal intestinal lipogranulomatous lymphangitis in 6
Sporadic lymphangitis, a nonspecific, nonulcerative lym- dogs (2008-2011). J Vet Intern Med 2014;28:48-51.
phangitis affecting the hindlegs of horses, is relatively common.
 96.e1

Further reading
Birchard SJ, et al. Chylothorax in the dog and cat: a review. Lymphol
1995;28:64-72.
Campbell-Beggs CL, et al. Chyloabdomen in a neonatal foal. Vet Rec
1995;137:96-98.
Kull PA, et al. Clinical, clinicopathologic, radiographic, and ultrasono-
graphic characteristics of intestinal lymphangiectasia in dogs: 17
cases (1996-1998). J Am Vet Med Assoc 2001;219:197-202.
Peaston AE, et al. Combined chylothorax, chylopericardium, and
cranial vena cava syndrome in a dog with thymoma. J Am Vet Med
Assoc 1990;197:1354-1356.
White SD, et al. Acquired cutaneous lymphangiectasis in a dog. J Am
Vet Med Assoc 1988;193:1093-1094.
96.e2

Further reading
Hamid ME, et al. Differentiation between Mycobacterium farcinogenes
and Mycobacterium senegalense strains based on 16S-23S ribo-
somal DNA internal transcribed spacer sequences. J Clin Microbiol
2002;40:707-711.
Meschter CL, et al. Intestinal lymphangiectasia with granulomatous
lymphangitis in a dog. J Am Vet Med Assoc 1987;190:427-430.
Tufvesson G. Lymphangitis in horses. Nord Vet Med 1952;4:529-576,
729-744, 817-860, 1047-1058. (Nonspecific Monday-morning
type.).
Diseases of the Vascular System
Ulcerative lymphangitis
This is a chronic progressive inflammation of the subcutaneous
lymphatics of horses. Corynebacterium pseudotuberculosis
(ovis) is the cause of the classic condition, but similar lesions
may be caused by other pyogenic organisms, including strep-
tococci, staphylococci, Rhodococcus equi, and Pseudomonas
aeruginosa. Two biotypes of C. pseudotuberculosis are recog-
nized: a nitrate-negative type isolated from sheep and goats,
and a nitrate-positive type isolated from horses and cattle.
Corynebacterium pseudotuberculosis produces a potent phos-
pholipase exotoxin that attacks the sphingomyelin of vascular
endothelial cells, and may be important in aiding the spread
of the bacteria by acting as a permeability factor. Ulcerative
lymphangitis was an important cause of debility in the horse
era, but is now sporadic and rather rare.
Some features of the biology of C. pseudotuberculosis are
discussed with caseous lymphadenitis (see Vol. 3, Hematopoi-
etic system). In that disease, as in ulcerative lymphangitis, the
infection begins in cutaneous wounds. Ulcerative lymphangitis
typically begins about the fetlocks of the hindlimbs. As a result
of lymphangitis, there is diffuse swelling in the leg, soon fol-
lowed by development of dermal nodules. These are abscesses
that ulcerate and discharge thick white to light yellow viscous
pus that may be bloodstained. Only a small area of skin may
be sloughed so that, usually, the margins of the ulcer are
undermined. The ulcers heal and leave small areas of depil-
ated, depigmented skin. As the primary ulcers heal, new
nodules form in adjacent skin, suppurate, ulcerate, and cica-
trize, and in this way, the disease progresses slowly. As the new
nodules develop, the lymphatics between them become
corded and as much as 1-2 cm thick, and fresh abscesses
develop along the inflamed vessels. In uncontrolled infections,
over a course of many months much of the skin of the body
and neck as well as the limbs may be affected, and this leads
to death. Typically, the regional lymph nodes, although mod-
erately enlarged, do not become suppurative or fibrotic. In rare
instances, bacteremia results in internal dissemination, espe-
cially to the kidneys.
Ulcerative lymphangitis also occurs in cattle, but as well as
affecting the distal portions of the limbs, as in horses, the
initial lesions may also develop within the dermis or subcutis
of the neck, shoulder, or flank. The initial abscesses are large
and may be >5 cm in diameter. Extending away from them
are thickened lymphatics, along which new abscesses develop.
The abscesses ulcerate on the skin and the ulcers persist,
oozing a serum-like exudate. There is early lymphadenitis
with swelling of the node and its fixation to the surrounding
tissue. The inflammation spreads slowly, and there is progres-
sive suppurative lymphadenitis.
The equine biotype of Corynebacterium pseudotuberculosis
causes deep pectoral and ventral abdominal wall abscesses
(“pigeon fever”) in horses in the southwestern United States.
The transmission of C. pseudotuberculosis in these cases is
obscure, but may be by arthropod vectors. Ulcerative lym-
phangitis does not occur; dissemination is by bacteremia.
Untoward sequelae include prolonged resolution of the
abscesses, multiple and internal abscessation, and abortion.
Further reading
Abu-Samra MT, et al. Ulcerative lymphangitis in a horse. Equine Vet J
1980;12:149-150.
Lymphatics 97
Nogradi N, et al. Musculoskeletal Corynebacterium pseudotuberculosis
in horses: 35 cases (1999-2009). J Am Vet Med Assoc 2012;241:771-
777.
Szonyi B, et al. Re-emergence of Pigeon fever (Corynebacterium
pseudotuberculosis) infection in Texas horses: epidemiologic inves-
tigation of laboratory diagnosed cases. J Equine Vet Sci
2014;34:281-287.
Epizootic lymphangitis
Epizootic lymphangitis, or pseudofarcy, is caused by Histo-
plasma capsulatum var. farciminosum (HCF) and clinically
resembles ulcerative lymphangitis and cutaneous glanders
(“farcy”). Epizootic lymphangitis occurs almost exclusively in
horses and mules. “Equine histoplasmosis” is probably a more
appropriate name, because HCF infection may be manifest as
keratoconjunctivitis or pneumonia in the absence of past or
concurrent lymphangitis.
Epizootic lymphangitis is enzootic in some Mediterranean
countries, Africa, and the Near and Far East. The organism
apparently exists as a soil saprophyte, and enters the body
through skin wounds of the lower limbs to cause the classic
epizootic lymphangitis, but may also invade castration wounds,
ruptured abscessed lymph nodes after strangles, and gastric
ulcers. Histoplasma farciminosum may cause sinusitis, and/or
pneumonia via inhalation of contaminated dust; may cause
rhinitis by contact with skin lesions; and may be transmitted
by flies (Musca and Stomoxys) to cause keratoconjunctivitis.
The initial cutaneous lesion, or focus of infection in a
wound, has a tendency to ulcerate, or it may undergo alternat-
ing periods of discharge and closure for some weeks before
healing and scarifying. The infection may resolve, but often
spreads centripetally in the adjacent tissues and along the
lymphatics. In the adjacent tissues, which are swollen, small
nodules of ~1 cm diameter develop and, in the course of a
few days, these ulcerate to discharge, at first, a viscid gray
exudate and, later, pus. The initial lesions are intradermal and
are freely movable over the subcutaneous tissue. Spread of 
the infection is solely via the lymphatics, and these convey the
organisms into the subcutaneous and, occasionally, into the
deeper tissues. The inflamed lymphatics are thickened and
hard, and along their course new nodules form, ulcerate, dis-
charge, and eventually heal with scarification, although there
may be alternating periods of activity and quiescence with the
growth of excessive granulation tissue. Sometimes the ulcers
continue to enlarge and may coalesce. In this way, the cutane-
ous infection spreads gradually but irregularly, but is always
characterized by intradermal and subcutaneous nodules, ulcers,
and irregularly swollen lymphatics. In the early stages, the skin
between the lesions remains normal and mobile, but in areas
of extensive ulceration, it becomes very thick, indurated, and
firmly fused to the underlying tissues. When the thickened
skin is incised, it presents the lardaceous appearance of granu-
lation tissue in the horse and contains a number of small,
yellow, purulent foci, between which course the lymphatics,
dilated and filled with pus and serous fluid.
The regional lymph nodes are regularly involved and swollen.
In the early stages, the swollen nodes contain many small foci
of softening, but later the foci coalesce and are heavily encap-
sulated. The nodes may rupture. The condition is usually
chronic, persisting for 3-12 months, and causes considerable
debility, but low mortality.
 97.e1

Further reading
Aleman M, et al. Corynebacterium pseudotuberculosis infection in
horses: 538 cases (1982-1993). J Am Vet Med Assoc 1996;209:804-
809.
Costa LR, et al. Comparative molecular characterization of Corynebac-
terium pseudotuberculosis of different origin. Vet Microbiol
1998;62:135-143.
Steinman A, et al. Ulcerative lymphangitis and coronet lesions in an
Israeli dairy herd infected with Corynebacterium pseudotuberculo-
sis. Vet Rec 1999;145:604-606.
98 CHAPTER 1  •  Cardiovascular System
The disease may begin quite frequently on the conjunctiva
or nictitating membrane, producing at first a small papule and
a serous conjunctival discharge. The papules ulcerate to form
flat, button-like growths of granulation tissue, the eyelids
become severely swollen, and the inflammation extends to the
tissues of the forehead.
Nasal infection is usually accompanied by a mucopurulent
discharge containing large numbers of the fungus, and may be
bloodstained. The lesions begin as yellow papules or nodules
on the nasal mucosa, and these soon break down to form
craterous granulating ulcers that bleed easily. The nasal lesions
are usually found near the external nares, and they may extend
from there on to the muzzle, or they may be found deep in
the nasal cavity and in the pharynx. Similar lesions may occur
in the nasal sinuses, the larynx, and the bronchi.
The pulmonary lesions may be solid granulomatous areas,
or they may be liquefied with pus-like contents. When ulcer-
ative lesions are present on the nasal mucosa, there is suppura-
tive regional lymphadenitis. The typical nodules of epizootic
lymphangitis and the liquefied foci that form in deep tissues
may also be found in the pleura, spleen, liver, testes, tunica
vaginalis, and bone marrow.
The diagnosis of epizootic lymphangitis depends upon
demonstration of the fungus, which is usually present in very
large numbers in the contents of the nodules and fresh dis-
charges from ulcers. The parasitic phase of the fungus is yeast-
like, gram positive, globose or oval in shape, and 2-3 µm in
diameter. It occurs extracellularly and intracellularly in  from hemangiomas may be difficult. Hemangiopericytoma is
macrophages. The fluorescent antibody test is an effective
means of diagnosis. In histologic sections, the organism is
similar to H. capsulatum, consisting of a basophilic nuclear
mass and thin capsule that can be demonstrated by stains  coma, arising from vessel walls, especially in the aorta or
for polysaccharides.
Further reading
al-Ani FK. Epizootic lymphangitis in horses: a review of the literature.
Rev Sci Tech 1999;18:691-699.
Ameni G. Preliminary trial on the reproducibility of epizootic lymphan-
gitis through experimental infection of two horses. Vet J
2006;172:553-555.
Parasitic lymphangitis
Filarid worms of the genus Brugia (synonym Wuchereria),
family Filariidae, parasitize the lymphatic system of dogs and
cats in tropical areas. Brugia malayi occurs in cats and primates
in India and Malaysia; cats may be reservoir hosts for human
infection. B. patei occurs in dogs and cats in Africa, B. pahangi
in dogs and cats in Africa and the East, and B. ceylonensis in
dogs in Sri Lanka. Brugia spp. are transmitted by mosquitoes,
and their life cycles are similar to those of other filarial worms.
Infective larvae enter peripheral lymphatics, migrate to the
nearest lymph node and develop for 2 weeks before migrating
down afferent lymphatics, where they mature and produce
granulomatous lymphangitis, lymphangiectasis, and lymphadeni-
tis, but do not usually cause lymphedema and elephantiasis as
occurs in humans, resulting from infection with B. malayi or
the closely related Wuchereria bancrofti. The main importance
of Brugia spp. lies in the differentiation of their microfilariae
from those of Dirofilaria immitis, and in their role in human
infections.
Vascular Neoplasms
Further reading
Areekit S, et al. Molecualr genetics analysis for co-infection of Brugia
malayi and Brugia pahangi in cat reservoirs based on internal tran-
scribed spacer region 1. Southeast Asian J Trop Med Public Health
2009;40:30-34.
Chirgwin SR, et al. Tissue migration capability of larval and adult Brugia
pahangi. J Parasitol 2006;92:46-51.
Hise AG, et al. Innate immune responses to endosymbiotic Wolbachia
bacteria in Brugia malayi and Onchocerca volvulus are dependent
on TLR2, TLR6, MyD88, and Mal, but not TLR4, TRIF, or TRAM.
J Immunol 2007;178:1068-1076.
VASCULAR NEOPLASMS
Tumors of endothelial origin are classified as benign or malig-
nant, that is, angiomas or angiosarcomas. Benign tumors consist
of easily recognized vascular channels lined by a monolayer of
relatively normal endothelial cells. Malignant tumors may not
form well-organized vascular channels, are more cellular, and
display cytologic anaplasia. Intermediate forms exist, hence
immunohistochemistry, particularly CD31, CD34, and factor
VIII–related antigen, is commonly used to more definitively
diagnose vascular neoplasms.
Differentiation of vascular malformations or proliferations
discussed with skin neoplasms (see Vol. 1, Skin and append-
ages). There are rare reports of non-endothelial tumors, for
instance, leiomyosarcoma, malignant melanoma, chondrosar-
pulmonary artery.
The nomenclature of benign vascular tumors or malforma-
tions is confusing, and includes hemangioma, hemangioendo-
thelioma, hamartoma, vascular malformation, telangiectasis,
and angiokeratoma. Rare variants include angiolipoma, angio-
fibrolipoma, angioleiomyoma, arteriovenous hemangioma, and
papillary endothelial hyperplasia.
• Hemangioma, a benign tumor of endothelial cells, is sup-
posedly a true neoplasm capable of independent growth.
Some of the clinically observed “growth” of a hemangioma
may be due to congestion, hemorrhage, and thrombosis.
Hemangiomas may be present at birth or soon after in
children and foals, suggesting that they may in fact be non-
neoplastic vascular malformations.
• Hemangioendothelioma (HE) describes a benign vascular
tumor with hypertrophic endothelial cells forming small
hypercellular vascular channels, and is essentially a very
cellular capillary hemangioma. In medical pathology, HE is
used to describe a vascular tumor that is histologically and
clinically intermediate between hemangioma and angiosar-
coma. Reports of rare variants of HE include kaposiform
HE in a dog and a cow, epithelioid HE in a dog, epithelioid/
spindle cell HE in a calf, and retiform hemangioendothelioma
in 2 dogs.
• Hamartoma is a general term that refers to focally disor-
dered overgrowth of mature tissue that is indigenous to the
organ involved. Because vascular tissue is ubiquitous, vas-
cular hamartomas may occur in any site of the body; some
authors refer to angiomas as vascular hamartomas. Most
hamartomas are present at birth, and their growth is coor-
dinated with that of the surrounding tissue.
 98.e1

Further reading
Ameni G, Terefe W. A cross-sectional study of epizootic lymphangitis
in cart-mules in western Ethiopia. Prev Vet Med 2004;66:93-99.
98.e2

Further reading
Chansiri K, et al. PCR based method for identification of zoonotic
Brugia malayi microfilariae in domestic cats. Mol Cell Probes
2002;16:129-135.
Denham DA, Fletcher C. The cat infected with Brugia pahangi as a
model of human filariasis. Ciba Found Symp 1987;127:225-235.
Fader RC, Ewert A. Evolution of lymph thrombi in experimental Brugia
malayi infections: a scanning electron microscopic study. Lymphol
1986;19:146-152.
Sakamoto M, et al. Perturbation of lymphatic endothelial cells in exper-
imental Brugia malayi infections. Microcirc Endothelium Lymphatics
1985;2:487-498.
Snowden KF, Hammerberg B. The lymphatic pathology of chronic
Brugia pahangi infection in the dog. Trans R Soc Trop Med Hyg
1989;83:670-678.
Diseases of the Vascular System
• Vascular malformation is obviously a very broad term that
may be included under the term hamartoma, and may
include arteriovenous fistula in which thick-walled vessels
occur, in contrast to the thin-walled vessels of the other
benign vascular proliferations.
• Telangiectasis refers to congenital or acquired foci of abnor-
mally dilated capillaries, sinusoids, arterioles, or venules,
usually seen as small masses in the skin and mucous
membranes.
• Angiokeratoma is a rare benign tumor, usually of the nic-
titans and conjunctiva of dogs, in which dilated vascular
channels are associated with hyperplastic epithelium.
Fortunately, these distinctions, although of pathogenetic
interest, are of little practical importance because the lesions
described are uniformly benign, and excision, if possible, is
curative.
Angioma
Hemangioma is a benign tumor of endothelial cells and may
be classified as capillary or cavernous based on the size of the
vascular channels formed. The tumor may be difficult to dif-
ferentiate from vascular malformations and granulation tissue.
Hemangiomas occur most commonly in older dogs, and are
seen less frequently in other species. These tumors arise from
vascular endothelium and hence may be found in any site in
the body, but are most common in the dermis and subcutis, espe-
cially of the legs, flank, neck, face, and eyelid. The cutaneous
and ocular lesions may arise following exposure to ultraviolet
radiation. Hemangiomas are usually single, ovoid, red-black
masses of 0.5-3 cm in diameter, which ooze blood when cut.
Histologically, blood-filled vascular spaces are lined by a single
layer of well-differentiated endothelium, and may be throm-
bosed. The vascular spaces are separated by variable amounts
of connective tissue stroma. Hemangiomas are not encapsu-
lated, are not invasive, and do not recur after complete surgical
excision. A rare form of cavernous hemangioma, analogous to
the human hemangioblastoma, is reported in dogs, and is char-
acterized by thin-walled capillaries separated by pleomorphic
“stromal cells” of indeterminate origin. An epithelioid variant
of hemangioma and hemangiosarcoma has also been described.
Disseminated cavernous hemangioma is rare, but has been
reported in calves, and a similar multifocal hemangioma has
been reported in a pig. Multiple small tumors are present  in old dogs, but is less common than hemangioma. German
in skin, subcutis, gingiva, and internal organs. The condition
has been termed generalized congenital hemangiomatosis and
juvenile bovine angiomatosis, to include calves having either
solitary, for instance, gingival or spinal canal, or multiple angio-
matous lesions. Hemangiomas occur in the urinary bladder of
cattle affected with enzootic hematuria, which is discussed in
Vol. 2, Urinary system.
A number of hemangioma-like lesions occur in domestic
animals. Bovine cutaneous angiomatosis of adult dairy cows
is reported from Britain, France, and the United States.
Nodular dermal vascular proliferations occur anywhere in the
skin, but especially along the back, may have a considerable
inflammatory component, and resemble “pyogenic granuloma”
of humans. Varicose tumor of the scrotum of dogs is a benign
vascular proliferation that resembles cavernous hemangioma
when fully developed. Lesions resembling hemangioma occa-
sionally develop in the skin of the scrotum or perineum of
boars, or the vulva, mammary glands, or ovaries of sows.
Meningioangiomatosis, a rare condition reported in dog,
horse, and cow, is characterized by benign focal proliferation
Vascular Neoplasms 99
of blood vessels and meningothelial cells in the leptomeninges
and underlying brain parenchyma.
Although most vascular proliferations are idiopathic, there
is evidence that various Bartonella spp. (Bartonella vinsonii
subsp. berkhoffii, B. henselae, B. koehlerae) may contribute to
the pathogenesis of systemic reactive angioendotheliomatosis
(and hemangiopericytomas) in animals.
Formerly thought to be due to neoplastic proliferation of
endothelial cells and hence termed malignant angioendothelio-
matosis, intravascular lymphoma is a rare large cell lymphoma,
seen in humans, dogs, and a cat, in which neoplastic lympho-
cytes proliferate within the lumens of blood vessels. Lympho-
matoid granulomatosis (angioinvasive lymphoma) is a rare
pulmonary disorder of middle-aged dogs, characterized by
infiltration of lung and various other organs by neoplastic
mononuclear cells admixed with eosinophils, lymphocytes,
and plasma cells; originally thought to be angiocentric, this
pulmonary neoplasm is now thought to be an atypical T-cell
lymphoma that is angioinvasive.
Lymphangioma is a rare, benign tumor that consists of
lymph channels forming capillary, cavernous, or cystic tumors.
Lymphangiomas may occur as congenital malformations
(hamartomas) or may develop spontaneously in adults. Cav-
ernous and cystic lymphangiomas may progressively enlarge,
dissect along fascial planes, and be difficult or impossible to
remove surgically.
Glomangiomas (glomus tumors) of nonhuman primates,
dogs, cats, and horses are rare benign (even more rarely malig-
nant) neoplasms of the neuromyoarterial thermal receptors,
primarily in the digits, characterized by branching vascular
channels in a fibrous stroma that contains nests of specialized
glomus cells, a type of smooth muscle cell. Glomus jugulare
and glomus pulmonale tumors have been reported in dogs.
The glomus jugulare and pulmonale are chemoreceptors, and
tumors of these bodies resemble other chemodectomas,
namely, nests of monomorphic rounded cells with scant cyto-
plasm separated by thin septa. The tumor is encapsulated and
grows expansively.
Angiosarcoma
Hemangiosarcoma (malignant hemangioendothelioma), a
malignant tumor of endothelial cells, occurs most frequently
Shepherd dogs (Alsatians) are most commonly affected, and
some other breeds are over-represented. Hemangiosarcoma
occurs infrequently in cats, horses, cows, and sheep.
There is a current focus on a number of receptor tyrosine
protein kinases, such as platelet-derived growth factor
receptor-β and Src, as well as CD117(c-Kit) and vascular endo-
thelial growth factor-3, which are overexpressed in hemangio-
sarcomas. This suggests involvement of growth factor signaling
pathways, if not in the genesis, then in the development of the
tumor. The p16-cyclinD1-retinoblastoma pathway has also
been implicated. There is also increasing evidence that the
tumor cells arise from hematopoietic stem cell precursors. The
tumor may arise in any site of the body. The most common
primary sites in dogs are spleen, skin/subcutis, right atrium, and
liver; in cats, spleen, intestines, and subcutaneous tissue; in
horses, ocular, cutaneous, and multicentric. Hemangiosarcoma
is the most common primary cardiac tumor of dogs, and the tumor
usually occurs subepicardially in the wall of the right atrium at
the entrance to the auricle near the coronary groove (Fig. 1-99)
or in the auricular appendage. Hemangiosarcoma probably
100 CHAPTER 1  •  Cardiovascular System
arises de novo and not from pre-existing hemangiomas. The
tumors have a gray to red-black hemorrhagic appearance, and
may reach a diameter of 30 cm in the spleen as a result of
hemorrhage within the tumor. Large hemorrhagic masses can
often be found in the spleens of dogs; some are hematomas
Figure 1-99  Hemangiosarcoma in the right auricle of a dog.
(Courtesy D. Hayden.)
A B
C
Figure 1-100  Metastatic hemangiosarcoma in a dog. A. Lung. (Courtesy I. Matise.) B. Liver.
(Courtesy D. Hayden.) C. Brain. (Courtesy M. Bouljihad.)
Vascular Neoplasms
rather than either hemangiomas or hemangiosarcomas. The
distinction is important because splenic hemangiosarcomas
carry a very poor prognosis. However, the distinction can often
be difficult because splenic hemangiosarcomas often hemorrhage,
and if the resultant hematoma is not sampled carefully, its neoplas-
tic origin will be missed. Following rupture, implants of splenic
tissue or tumor may be found on the peritoneum. Hemangio-
sarcomas typically metastasize widely, especially to the lungs
(“cannonball” metastases) (Fig. 1-100A-C). Histologically,
these tumors consist of vascular spaces lined by elongated,
plump, anaplastic endothelial cells (Fig. 1-101A). Vascular
spaces must be identified in tumors with a highly cellular
stroma to differentiate hemangiosarcoma from fibrosarcoma.
Hemorrhage and necrosis commonly occur within these
tumors, and death may occur because of hemorrhage into the
peritoneal cavity, pericardial sac, or brain. When metastases are
widespread, the primary tumor site may be difficult to deter-
mine, and multicentric origin is a possibility. Poorly differenti-
ated hemangiosarcomas may usually be differentiated from
spindle cell sarcomas or other non-endothelial neoplasms by
immunohistochemical staining for factor VIII–related antigen
(Fig. 1-101B), a marker of endothelial cells, and claudin-5
protein, a tight-junction protein normally found on endothelial
cells. Ulex europaeus lectin, a marker of neoplastic human
endothelial cells, is unreliable as a marker of canine vascular
tumors. Ultrastructurally, Weibel-Palade bodies (granules
Diseases of the Vascular System
A tumour-like lesions. APMIS Suppl 2008;125:19-40.
B Pirie CG, et al. Canine conjunctival hemangioma and hemangiosar-
Figure 1-101  Hemangiosarcoma in a dog. A. Plump, pleomor-
phic, closely packed tumor cells, some forming vascular channels.
H&E. B. Tumor cells stain strongly for the presence of factor VIII
antigen.
containing factor VIII) are present in at least some of the typical
neoplastic endothelial cells.
Lymphangiosarcoma (malignant lymphangioendotheli-
oma) is an extremely rare tumor in domestic animals. The
tumor is histologically similar to hemangiosarcoma, but the
irregular vascular channels contain few red cells; it may be
diffusely invasive and metastasize widely. Ultrastructurally,
lymphangiosarcoma is distinguished from hemangiosarcoma,
at least in cats and humans, by the general lack of a basal
lamina, few micropinocytotic vesicles, few intercellular junc-
tions, lack of pericytes, and a discontinuous endothelial cell
layer in lymphangiosarcoma. Immunohistochemistry (factor
VIII, vimentin, laminin) and lectin histochemistry (RCA-I,
PHA-E) may be other useful adjuncts in differentiating the 2
tumors. As well, lymphatic vessels are characterized by the
expression of lymphatic vessel endothelial receptor-1 (LYVE-
1) and prospero-related homeobox gene-1 (PROX-1).
Further reading
Arenas-Gamboa AM, Mansell J. Epithelioid haemangiosarcoma in the
ocular tissue of horses. J Comp Pathol 2011;144:328-333.
Asa SA, et al. Expression of platelet-derived growth factor and its
receptors in spontaneous canine hemangiosarcoma and cutaneous
hemangioma. Histol Histopathol 2012;27:601-607.
Vascular Neoplasms 101
Beerlage C, et al. Bartonella vinsonii subsp. berkhoffii and Bartonella
henselae as potential causes of proliferative vascular diseases in
animals. Med Microbiol Immunol 2012;201:319-326.
Burns RE, et al. Glomus tumours in the skin and subcutis of three
horses. Vet Dermatol 2011;22:225-231.
Chandler HL, et al. Immunohistochemical analysis of ocular hemangio-
mas and hemangiosarcomas in dogs. Vet Ophthalmol 2009;12:83-
90.
Dickerson EB, et al. Imatinib and Dasatinib inhibit hemangiosarcoma
and implicate PDGFR-β and Src in tumor growth. Transl Oncol
2013;6:158-168.
Galofaro V, et al. Glomangioma in the prepuce of a dog. Reprod Dom
Anim 2006;41:568-570.
Gamlem H1, Nordstoga K. Canine vascular neoplasia—histologic clas-
sification and inmunohistochemical analysis of 221 tumours and
Jackson DE, et al. Locally invasive lymphangiosarcoma in a young
domestic shorthair. J Fel Med Surg 2011;13:796-799.
Jakab C, et al. Claudin-5 protein is a new differential marker for his-
topathological diagnosis of canine hemangiosarcoma. Histol Histo-
pathol 2009;24:801-813.
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For more information, please visit the companion site:
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