MODULE OF CARDIOVASCULAR

CASE OF VASCULAR
DISORDER
Acute Limb Ischemi
Module team of cardiovascular
1/6/2019

FAKULTAS KEDOKTERAN UNIVERSITAS ISLAM BANDUNG

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TUTORIAL GUIDE

BLOCK TITLE : Cardiovascular System

WEEK TITLE : Peripheral Arterial Disease
WEEK SCHEDULE : Sixth- Seven Week
WEEK THEME : Acute Limb Ischemi
INTRODUCTION :
Welcome to tutoring in the Cardiovascular block.
The case represents the sixth-seven week of the Cardiovascular block. It is designed for students to
learn issues around Acute Limb Ischemi. The primary focus of the case is anatomy, hystology and
physiology of vascular, introduction to peripheral arterial disease with its definition, classification,
pathogenesis, pathophysiology and sign symptom, clinical and laboratory assessment and the
treatment of peripheral arterial disease. The student also need to recognize about disease of aorta
and thromboangitis obliterans (Buerger's Disease)

CASE SYNOPSIS :
Patient has acute limb ischemi. He has several risk factor peripheral arterial disease.

CASE OBJECTIVES :
After completing this case, the students should be able to :
1. Explain about Anatomy blood vessel (arteries & veins)
2. Explain about Histology of the vascular : basic structure of vascular, differentiate structure of
large, middle, small arteries and veins
3. Explain about physiology (function of) blood vessel (arteries & veins)
4. Explain differential diagnosis based on chronic ulcer
5. Explain about Peripheral vascular disease :
 Definition
 Etiology
 Classification
6. Understand about disease of the aorta : etiology, classification,pathogenesis
7. Explain about peripheral artery disease (Claudicatio, Critical Limb Ischemia, Acute Limb Ischemia)
 Definition & etiology
 Epidemiology
 Risk factor
 Classification
 Pathogenesis & pathophysiology
 Clinical manifestation
 Clinical findings
 Management
8. Explain about thromboangiitis obliterans (Buerger’s disease)
 Definition & etiology
 Epidemiology
 Risk factor
 Pathogenesis & pathophysiology
 Clinical manifestation
 Clinical findings
 Management
 Complication and Prognosis

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CASE OF MR. PRISTO

TUTORIAL 1 PAGE 1

You are a medical doctor at an out-patient clinic when Mr. Pristo, a 41 year-old-man presents with chief
complaint of painful right calf.

Instruction:

1. Identify Mr Pristo’s problems from history and explain the problems mechanism !

2. Generate hypotheses which account for Mr Pristo’s problems!

3. Explain the mechanism of each hypotheses !

4. What further information is needed to prove or disprove the hypotheses?

TUTORIAL 1 PAGE 2

History:

He has noticed a pain arises after walking for 15 minutes; pain causes having to stop walking and resting
for 5-10 minutes after the pain can walk again. Complaints of calf pain after walking have suffered for six
months ago and getting worse 2 days before.
He felt numbness in his foot, and it became purplish and cold since yesterday. The foot still easily moved
although restricted due to pain. The symptoms felt at rest, continuously, and not worsened by standing or
sitting.
He has been treated by medical doctors in their private clinics, given with common pain killer, but so far he
feels no improvement. No history of calf cramps and numbness, or edema before. His past medical history
indicated a heart problem three years ago due to cardiomiopathy, and routinely prescribed furosemide,
bisoprolol, ramipril from his Cardiologist.
He stopped control since three months ago due to financial problem. He does not have diabetes mellitus,
hypertension and hypercholesterolemia. He denied any symptoms like tearing chest or back pain or a knee
problems, and history of having any cardiac or valve operation or trauma before. He is a cigarette smoker
till now

Family history: the disorder is not found in his family.

Instruction:

1. Identify Mr Pristo’s problems from history and explain the problems mechanism !
2. Reorder a list of hypothesis relating to the above problems
3. Elaborate the timeline of the problems and concluded each time condition !
4. Explain the mechanism of each hypotheses !
5. What further information is needed to prove or disprove the hypotheses?

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TUTORIAL 1 PAGE 3

Physical examination:
The patient seemed very uncomfortable due to the pain.
Temperature: 37oC; pulse: 110bpm, regular; respiration: 20x per min.; blood pressure: 120/80 mmHg.
HEENT : normal;
Neck : increased JVP
Heart : enlarge, regular beats and pansystolic murmurs grade III/VI at the apex.
Lungs : normal to percussion and auscultation.
Abdomen : normal to palpation/percussion/auscultation.
Rectal and neurologic examination: normal.
Extremity:
o Upper extremities: normal.
o Left lower extremity: normal, no visible wounds on the skin
o Right lower extremity:, pale ; edema and clubbing were not seen; right lower calf was mottled
and cooler if compared with the proximal part; there was no pulsation of the right popliteal,
dorsal pedis and posterior tibial arteries; common femoral artery was average and the same
compared to those of the left leg. There was no visible wounds on the skin, no ulcer or
gangrene. There is no varicose swelling.
The capillary filling was slower in the distal foot. The patient was able to actively and passively
move his left leg, but this was limited because he experienced pain with movement
o On neurologic examination, the patient was intact with regard to strength, sensation, and
cranial nerve examinations, except for a subjective complaint of numbness and tingling in his
entire right foot.

Instuction:
1. What is the patient’s problem ?
2. Do you change your hypothesis?
3. What further information do you need?

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CASE OF MR. PRISTO
TUTORIAL 1 PAGE 4

Blood and urine laboratory findings: within reasonable limits.

Electrocardiography: Q wave in V1-V6

Radiologic examinations:
Chest X-ray: cardiomegaly with CTR 70%

Portable doppler sonography : At popliteal level; inaudible arteries flow; audible venous flow

USG doppler : Triphasic Doppler curve morphology on abdominal aorta dan right common femoral rtery. It
showed that the colour code doesn’t fill blood vessel lumen of the right popliteal artery, right anterior tibial
artery. No collateral found. Normal vein flow in both leg. Deep vein thrombosis was not found in a deep vein of
both legs

Arteriography of the left limb: Complete occlusion of the right mid-femoral artery.

Instuction :
1. What is the patient’s problem ?
2. Do you change your hypothesis?
3. What further information do you need?
4. What is the management of this patient?

TUTORIAL 1 PAGE 5

The patient was diagnosed as Acute Limb Ischemia grade IIA

Management :
Due to the low risk of bleeding, i.v. heparin was initiated, and the patient was medicated for pain. Then referred
to catheterization lab and given reperfusion therapy.

EPILOGUE

SSS
Within the first 3 hours, the patient was much more comfortable, and it appeared as though perfusion to the
right lower leg was improving, based on diminished pain and decreased pallor. The patient was discharged on
the 5th post-revascularization day in good general condition. He returned to control to his Cardiologist monthly
to prevent the source of embolization. To date the patient has not presented any recurrence.

END OF CASE

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 Case 1 Page 1

You are a medical doctor at an out-patient clinic when Mr. Pristo, a 41 year-old-man presents with
chief complaint of painful right calf.

Guiding question:

1. What are Mr Pristo's problems?

The student might list as Mr. Pristo’s problems as follows :
41-year-old man
painful right calf.

2. What is the mechanism of pain  etiologi of the chief complain

3. Hyphotesis :
- dd/ nyeri di tungkai
- dd/ nyeri kronik/ akut
- dd/ bila ada luka (ulkus/ulcer)
- dd/ nyeri + luka

4. What further information is needed to prove or disprove the hypotheses?

History taking

Tutotial 1 page 2
History:
He has noticed a pain arises after walking for 15 minutes; pain causes having to stop walking and
resting for 5-10 minutes after the pain can walk again. Complaints of calf pain after walking have
suffered for six months ago and getting worse 2 days before.
He felt numbness in his foot, and it became purplish and cold since yesterday. The foot still easily
moved although restricted due to pain. The symptoms felt at rest, continuously, and not worsened by
standing or sitting.
He has been treated by medical doctors in their private clinics, given with common pain killer, but so
far he feels no improvement. No history of calf cramps and numbness, or edema before. His past
medical history indicated a heart problem three years ago due to cardiomiopathy, and routinely
prescribed furosemide, bisoprolol, ramipril from his Cardiologist.
He stopped control since three months ago due to financial problem. He does not have diabetes
mellitus, hypertension and hypercholesterolemia. He denied any symptoms like tearing chest or back
pain or a knee problems, and history of having any cardiac or valve operation or trauma before. He is
a cigarette smoker till now

 definisi nyeri akut / kronis; Dd/ nyeri kaki akut

 kepentingan menanyakan numbness/kebas-kebas, keunguan, onset terasa dingin,
pergerakan
 Kepentingan menanyakan terasa tidaknya saat istirahat, terus-menerus dan hal yang
meringankan / memperberat
 Kepentingan menanyakan riwayat kram, kebas atau bengkak kaki sebelumnya
 Kepentingan menanyakan riwayat penyakit pasien
 Kepentingan menanyakan faktor risiko kardiovaskular pada pasien
 Kepentingan menanyakan rasa nyeri dada dirobek, masalah lutut, riwayat operasi jantung
/ katup / trauma
 dd/ nyeri saat istirahat dan saat aktivitas

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  Dd/ bila ada keluhan klaudikasio sebelumnya
 Dd/ bila ada keluhan bengkak
 Exclude keluhan karena penyakit vena
 Perbedaan diagnosis klaudikasio dan CLI dan ALI, penyakit arteri lain (inflamasi) dan
penyakit vena berdasarkan keluhan

Case 1 Page 2

Physical examination:
The patient seemed very uncomfortable due to the pain.
Temperature: 37oC; pulse: 110bpm, regular; respiration: 20x per min.; blood pressure: 120/80 mmHg.
HEENT : normal;
Neck : increased JVP
Heart : enlarge, regular beats and pansystolic murmurs grade III/VI at the apex.
Lungs : normal to percussion and auscultation.
Abdomen : normal to palpation/percussion/auscultation.
Rectal and neurologic examination: normal.
Extremity:
o Upper extremities: normal.
o Left lower extremity: normal, no visible wounds on the skin
o Right lower extremity:, pale ; edema and clubbing were not seen; right lower calf was
mottled and cooler if compared with the proximal part; there was no pulsation of the right
popliteal, dorsal pedis and posterior tibial arteries; common femoral artery was average
and the same compared to those of the left leg. There was no visible wounds on the skin,
no ulcer or gangrene. There is no varicose swelling.
The capillary filling was slower in the distal foot. The patient was able to actively and
passively move his left leg, but this was limited because he experienced pain with
movement
o On neurologic examination, the patient was intact with regard to strength, sensation, and
cranial nerve examinations, except for a subjective complaint of numbness and tingling in
his entire right foot.

 pemeriksaan ekstremitas  kalau ada edema? clubbing? Apa kemungkinan penyebab,

mekanisme review
 palpasi : lebih dingin di bagian distal; disertai kelemahanmekanisme akibat
sumbatan
 kepentingan memeriksa ulcer  mekanisme luka yg tjd pd trauma dg yg tjd akibat
kelainan vaskular bedanya?
 Perbedaan diagnosis klaudikasio dan CLI dan ALI, penyakit arteri lain (inflamasi) dan
penyakit vena berdasarkan pemeriksaan fisik

Case 1 Page 4

Blood and urine laboratory findings: within reasonable limits.

Electrocardiography: Q wave in V1-V6

Radiologic examinations:
Chest X-ray: cardiomegaly with CTR 70%

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Portable doppler sonography : At popliteal level; inaudible arteries flow; audible venous flow

USG doppler : Triphasic Doppler curve morphology on abdominal aorta dan right common femoral
rtery. It showed that the colour code doesn’t fill blood vessel lumen of the right popliteal artery, right
anterior tibial artery. No collateral found. Normal vein flow in both leg. Deep vein thrombosis was not
found in a deep vein of both legs

Arteriography of the left limb: Complete occlusion of the right mid-femoral artery.

How does this information change your hypothesis?

Meyakinkan apa perbedaan akut dan kronis

Meyakinkan ada underlying penyakit sebagai source thrombus

 apa makna JVP meninggi, adanya kardiomegali, murmur? Menunjang apakah data ini?
 Perlu tidak memeriksa ABI ? Bagaimana caranya ?
 Perlu tidak memeriksa TBI ? Bagaimana caranya
 Kapan diperlukan Arteriography? MRA ? CT ?
 Perbedaan alur diagnosis klaudikasio dan CLI dan ALI, penyakit arteri lain (inflamasi)
dan penyakit vena berdasarkan imaging

Tutorial 1 Page 5

The patient was diagnosed as Acute Limb Ischemia grade IIA

Management :
Due to a low risk of bleeding, i.v. heparin was initiated, and the patient was medicated for pain. Then
referred to a catheterization lab and given reperfusion therapy.

LO :
1. Acute Limb Ischemia  penyebab, emboli
2. Faktor risiko (source emboli)
3. Klasifikasi ALI
4. Pemeriksaan imaging yang terpilih
5. Treatment dengan heparin . Mekanisme. Tujuan.
6. Treatment dengan revaskularisasi; trombolitik atau endovaskular atau trombektomi
(bedah)
7. Perbedaan manajemen klaudikasio dan CLI dan ALI, dan penyakit arteri lain (inflamasi)
8.

Epilogue

After his occlusion revascularized, the foot is going better. No sequelae at all. He returned to control
to his Cardiologist monthly to prevent the source of embolization.

Within the first 3 hours, the patient was much more comfortable, and it appeared as though
perfusion to the left lower leg was improving, based on diminished pain and decreased pallor. The
patient was discharged on the 5th post-revascularization day in good general condition. He returned
to control to his Cardiologist monthly to prevent the source of embolization. To date the patient has
not presented any recurrence.

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LO :
1. Pasca ALI dan revaskularisasi : seberapa sering pasien harus doppler USG ulang

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 TUTOR GUIDE

STRUCTURE AND FUNCTION OF BLOOD VESSELS

The five main types of blood vessels are arteries, arterioles, capillaries, venules, and veins. Arteries
(AR-ter-e¯z) carry blood away from the heart to other organs. Large, elastic arteries leave the heart
and divide into medium-sized, muscular arteries that branch out into the various regions of the body.
Medium-sized arteries then divide into small arteries, which in turn divide into still smaller arteries
called arterioles (ar-TE¯ R-e¯-o¯ls). As the arterioles enter a tissue, they branch into numerous tiny
vessels called capillaries (KAP-i-lar_-e¯z _ hairlike). The thin walls of capillaries allow the exchange of
substances between the blood and body tissues. Groups of capillaries within a tissue reunite to form
small veins called venules (VEN-u¯ ls). These in turn merge to form progressively larger blood vessels
called veins. Veins (VA¯ NZ) are the blood vessels that convey blood from the tissues back to the
heart.

BASIC STRUCTURE OF A BLOOD VESSEL

The wall of a blood vessel consists of three layers, or tunics, of different tissues: an epithelial inner
lining, a middle layer consisting of a smooth muscle and elastic connective tissue, and a connective
tissue outer covering. The three structural layers of a generalized blood vessel from innermost to
outermost are the tunica interna (intima), tunica media, and tunica externa (Figure 21.1).
Modifications of this basic design account for the five types of blood vessels and the structural and
functional differences among the various vessel types. Always remember that structural variations
correlate to the differences in function that occur throughout the cardiovascular system.

Tunica Interna (Intima)

The tunica interna (intima) (tunic _ garment; interna or intima _ innermost) forms the inner lining of
a blood vessel and is in direct contact with the blood as it flows through the lumen, or interior
opening, of the vessel (Figure 21.1a, b). Although this layer has multiple parts, these tissue
components contribute minimally to the thickness of the vessel wall. Its innermost layer is a simple
squamous epithelium, called endothelium, which is continuous with the endocardial lining of the
heart. The endothelium is a thin layer of flattened cells that lines the inner surface of the entire
cardiovascular system (heart and blood vessels). Until recently, endothelial cells were regarded as
little more than a passive barrier between the blood and the remainder of the vessel wall. It is now
known that endothelial cells are active participants in a variety of vessel-related activities, including
physically influencing blood flow, secreting locally acting chemical mediators that influence the
contractile state of the vessel’s overlying smooth muscle, and assisting with capillary permeability.
The second component of the tunica interna is a basement membrane deep to the endothelium. It
provides a physical support base for the epithelial layer. Its framework of collagen fibers affords the
basal lamina significant tensile strength, yet its properties also provide resilience for stretching and
recoil. The basal lamina anchors the endothelium to the underlying connective tissue while also
regulating molecular movement. It appears to play an important role in guiding cell movements
during tissue repair of blood vessel walls. The outermost part of the tunica interna, which forms the
boundary between the tunica interna and tunica media, is the internal elastic lamina (lamina _ thin
plate). The internal elastic lamina is a thin sheet of elastic fibers with a variable number of window-
like openings that give it the look of Swiss cheese. These openings facilitate diffusion of materials
through the tunica interna to the thicker tunica media.

Tunica Media
The tunica media (media _ middle) is a muscular and connective tissue layer that displays the greatest
variation among the different vessel types (Figure 21.1a, b). In most vessels, it is a relatively thick
layer comprised mainly of smooth muscle cells and substantial amounts of elastic fibers. The primary
role of the smooth muscle cells, which extend circularly around the lumen like a ring encircles your
finger, is to regulate the diameter of the lumen. As you will learn in more detail shortly, the rate of
blood flow through different parts of the body is regulated by the extent of smooth muscle
contraction in the walls of particular vessels. Furthermore, the extent of smooth muscle contraction
in particular vessel types is crucial in the regulation of blood pressure.

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In addition to regulating blood flow and blood pressure, smooth muscle contracts when vessels are
damaged to help limit loss of blood through the injured vessel, and smooth muscle cells help produce
the elastic fibers within the tunica media that allow the vessels to stretch and recoil under the applied
pressure of the blood. The tunica media is the most variable of the tunics. As you study the different
types of blood vessels in the remainder of this chapter, you will see that the structural differences in
this layer account for the many variations in function among the different vessel types.
Tunica Externa
The outer covering of a blood vessel, the tunica externa (externa _ outermost), consists of elastic and
collagen fibers (Figure 21.1a, b). Separating the tunica externa from the tunica media is a network of
elastic fibers, the external elastic lamina which is part of the tunica media. The tunica externa
contains numerous nerves and, especially in larger vessels, tiny blood vessels that supply the tissue of
the vessel wall. These small vessels that supply blood to the tissues of the vessel are called vasa
vasorum (vas _ vessel), or vessels to the vessels. They are easily seen on large vessels such as the
aorta. In addition to the important role of supplying the vessel wall with nerves and self-vessels, the
tunica externa helps anchor the vessels to surrounding tissues.

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Figure 11–6 Walls of arteries and veins.
Walls of both arteries and veins have three tunics called the intima, media, and the adventitia (or externa),
which correspond roughly to the heart’s endocardium, myocardium, and epicardium. An artery has a thicker
media and relatively narrow lumen. A vein has a larger lumen and its adventitia is the thickest layer. The intima
of veins is often folded to form valves. Capillaries have only an endothelium, with no subendothelial layer or
other tunics.

Arteries
Because arteries (ar- _ air; ter- _ to carry) were found empty at death, in ancient times they were
thought to contain only air. The wall of an artery has the three layers of a typical blood vessel, but has
a thick muscular-to-elastic tunica media (Figure 21.1a). Due to their plentiful elastic fibers, arteries
normally have high compliance, which means that their walls stretch easily or expand without tearing
in response to a small increase in pressure. Sympathetic fibers of the autonomic nervous system
innervate the smooth muscle of blood vessels. An increase in sympathetic stimulation typically
stimulates the smooth muscle to contract, squeezing the vessel wall and narrowing the lumen. Such a
decrease in the diameter of the lumen of a blood vessel is called vasoconstriction. In contrast, when
sympathetic stimulation decreases, or in the presence of certain chemicals (such as nitric oxide, H_,
and lactic acid), smooth muscle fibers relax. The resulting increase in lumen diameter is called
vasodilation.
Additionally, when an artery or arteriole is damaged, its smooth muscle contracts, producing vascular
spasm of the vessel. Such a vasospasm limits blood flow through the damaged vessel and helps
reduce blood loss if the vessel is small.

Elastic Arteries
Elastic arteries are the largest arteries in the body, ranging from the garden hose–sized aorta and
pulmonary trunk to the fingersized branches of the aorta. They have the largest diameter among
arteries, but their vessel walls (approximately one-tenth of the vessel’s total diameter) are relatively
thin compared to the overall size of the vessel. These vessels are characterized by well-defined
internal and external elastic laminae, along with a thick tunica media that is dominated by elastic
fibers, called the elastic lamellae (lamellae _ little plate). Elastic arteries include the two major trunks
that exit the heart (the aorta and the pulmonary trunk), along with the aorta’s major initial branches,

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such as the brachiocephalic, subclavian, common carotid, and common iliac arteries (see Figure
21.19a). Elastic arteries perform an important function: They help propel blood onward while the
ventricles are relaxing. As blood is ejected from the heart into elastic arteries, their walls stretch,
easily accommodating the surge of blood. As they stretch, the elastic fibers momentarily store
mechanical energy, functioning as a pressure reservoir (Figure 21.2a). Then, the elastic fibers recoil
and convert stored (potential) energy in the vessel into kinetic energy of the blood. Thus, blood
continues to move through the arteries even while the ventricles are relaxed (Figure 21.2b). Because
they conduct blood from the heart to medium-sized, more muscular arteries, elastic arteries also are
called conducting arteries.

Muscular Arteries
Medium-sized arteries are called muscular arteries because their tunica media contains more smooth
muscle and fewer elastic fibers than elastic arteries. The large amount of smooth muscle,
approximately three-quarters of the total mass, makes the walls of muscular arteries relatively thick.
Thus, muscular arteries are capable of greater vasoconstriction and vasodilation to adjust the rate of
blood flow. Muscular arteries have a welldefined internal elastic lamina but a thin external elastic
lamina. These two elastic laminae form the inner and outer boundaries of the muscular tunica media.
In large arteries, the thick tunica media can have as many as 40 layers of circumferentially arranged
smooth muscle cells; in smaller arteries there are as few as three layers.
Muscular arteries span a range of sizes from the pencil-sized femoral and axillary arteries to string-
sized arteries that enter organs, measuring as little as 0.5 mm in diameter. Compared to elastic
arteries, the vessel wall of muscular arteries comprises a larger percentage (25%) of the total vessel
diameter. Because the muscular arteries continue to branch and ultimately distribute blood to each of
the various organs, they are called distributing arteries. Examples include the brachial artery in the
arm and radial artery in the forearm (see Figure 21.19a).
The tunica externa is often thicker than the tunica media in muscular arteries. This outer layer
contains fibroblasts, collagen fibers, and elastic fibers all oriented longitudinally. The loose structure
of this layer permits changes in the diameter of the vessel to take place but also prevents shortening
or retraction of the vessel when it is cut.
Because of the reduced amount of elastic tissue in the walls of muscular arteries, these vessels do not
have the ability to recoil and help propel the blood like the elastic arteries. Instead, the thick,
muscular tunica media is primarily responsible for the functions of the muscular arteries. The ability
of the muscle to contract and maintain a state of partial contraction is referred to as vascular tone.

14
Vascular tone stiffens the vessel wall and is important in maintaining vessel pressure and efficient
blood flow.

Anastomoses
Most tissues of the body receive blood from more than one artery. The union of the branches of two
or more arteries supplying the same body region is called an anastomosis (a-nas-to¯-MO¯ -sis _
connecting; plural is anastomoses) (see Figure 21.21b). Anastomoses between arteries provide
alternative routes for blood to reach a tissue or organ. If blood flow stops for a short time when
normal movements compress a vessel, or if a vessel is blocked by disease, injury, or surgery, then
circulation to a part of the body is not necessarily stopped. The alternative route of blood flow to a
body part through an anastomosis is known as collateral circulation. Anastomoses may also occur
between veins and between arterioles and venules. Arteries that do not anastomose are known as
end arteries. Obstruction of an end artery interrupts the blood supply to a whole segment of an
organ, producing necrosis (death) of that segment. Alternative blood routes may also be provided by
nonanastomosing vessels that supply the same region of the body.

Arterioles
Literally meaning small arteries, arterioles are abundant microscopic vessels that regulate the flow of
blood into the capillary networks of the body’s tissues (see Figure 21.3). The approximately 400
million arterioles have diameters that range in size from 15 _m to 300 _m. The wall thickness of
arterioles is onehalf of the total vessel diameter.
Arterioles have a thin tunica interna with a thin, fenestrated (with small pores) internal elastic lamina
that disappears at the terminal end. The tunica media consists of one to two layers of smooth muscle
cells having a circular orientation in the vessel wall. The terminal end of the arteriole, the region
called the metarteriole (meta _ after), tapers toward the capillary junction. At the metarteriole–
capillary junction, the distal-most muscle cell forms the precapillary sphincter (_ to bind tight), which
monitors the blood flow into the capillary; the other muscle cells in the arteriole regulate the
resistance (opposition) to blood flow (see Figure 21.3).
The tunica externa of the arteriole consists of loose collagenous connective tissue containing
abundant unmyelinated sympathetic nerves. This sympathetic nerve supply, along with the actions of
local chemical mediators, can alter the diameter of arterioles and thus vary the rate of blood flow and
resistance through these vessels.
Arterioles play a key role in regulating blood flow from arteries into capillaries by regulating
resistance, the opposition to blood flow. Because of this they are known as resistance vessels. In a
blood vessel, resistance is due mainly to friction between blood and the inner walls of blood vessels.
When the blood vessel diameter is smaller, the friction is greater, so there is more resistance.
Contraction of the smooth muscle of an arteriole causes vasoconstriction, which increases resistance
even more and decreases blood flow into capillaries supplied by that arteriole. By contrast, relaxtion
of the smooth muscle of an arteriole causes vasodilation, which decreases resistance and increases
blood flow into capillaries. A change in arteriole diameter can also affect blood pressure:
Vasoconstriction of arterioles increases blood pressure, and vasodilation of arterioles decreases blood
pressure.

VEINS
While veins do show structural changes as they increase in size from small to medium to large, the
structural changes are not as distinct as they are in arteries. Veins, in general, have very thin walls
relative to their total diameter (average thickness is less than one-tenth of the vessel diameter). They
range in size from 0.5 mm in diameter for small veins to 3 cm in the large caval veins entering the
heart. Although veins are composed of essentially the same three layers as arteries, the relative
thicknesses of the layers are different. The tunica interna of veins is thinner than that of arteries; the
tunica media of veins is much thinner than in arteries, with relatively little smooth muscle and elastic
fibers. The tunica externa of veins is the thickest layer and consists of collagen and elastic fibers. Veins
lack the internal or external elastic laminae found in arteries (see Figure 22.1b). They are distensible
enough to adapt to variations in the volume and pressure of blood passing through them, but are not

15
designed to withstand high pressure. The lumen of a vein is larger than that of a comparable artery,
and veins often appear collapsed (flattened) when sectioned.
The pumping action of the heart is a major factor in moving venous blood back to the heart. The
contraction of skeletal muscles in the lower limbs also helps boost venous return to the heart (Figure
21.5). The average blood pressure in veins is considerably lower than in arteries. The difference in
pressure can be noticed when blood flows from a cut vessel. Blood leaves a cut vein in an even, slow
flow but spurts rapidly from a cut artery. Most of the structural differences between arteries and
veins reflect this pressure difference. For example, the walls of veins are not as strong as those of
arteries. Many veins, especially those in the limbs, also contain valves, thin folds of tunica interna that
form flaplike cusps. The valve cusps project into the lumen, pointing toward the heart (see Figure
21.9). The low blood pressure in veins allows blood returning to the heart to slow and even back up;
the valves aid in venous return by preventing the backflow of blood. A vascular (venous) sinus is a
vein with a thin endothelial wall that has no smooth muscle to alter its diameter. In a vascular sinus,
the surrounding dense connective tissue replaces the tunica media and tunica externa in providing
support. For example, dural venous sinuses, which are supported by the dura mater, convey
deoxygenated blood from the brain to the heart. Another example of a vascular sinus is the coronary
sinus of the heart (see Figure 20.3c on page 722).
While veins follow paths similar to those of their arterial counterparts, they differ from arteries in a
number of ways, aside from the structures of their walls. First, veins are more numerous than arteries
for several reasons. Some veins are paired and accompany medium- to small-sized muscular arteries.
These double sets of veins escort the arteries and connect with one another via venous channels
called anastomotic veins. The anastomotic veins cross the accompanying artery to form ladder-like
rungs between the paired veins (see Figure 21.25c). The greatest number of paired veins occurs
within the limbs. The subcutaneous layer deep to the skin is another source of veins. These veins,
called superficial veins, course through the subcutaneous layer unaccompanied by parallel arteries.
Along their course, the superficial veins form small connections (anastomoses) with the deep veins
that travel between the skeletal muscles. These connections allow communication between the deep
and superficial flow of blood. The amount of blood flow through superficial veins varies from location
to location within the body. In the upper limb, the superficial veins are much larger than the deep
veins and serve as the major pathways from the capillaries of the upper limb back to the heart. In the
lower limb, the opposite is true; the deep veins serve as the principal return pathways. In fact, one-
way valves in small anastomosing vessels allow blood to pass from the superficial to the deep veins,
but prevent the blood from passing in the reverse direction. This design has important implications in
the development of varicose veins.

16
ANATOMY AND PHYSIOLOGY OF AORTA
The aorta, the body’s largest artery, extends from the aortic valve in the chest to the midabdomen,
where it bifurcates into the common iliac arteries. Along its course the aorta is divided anatomically
into thoracic and abdominal components. The thoracic aorta is further subdivided into the ascending,
arch, and descending segments and the abdominal aorta into the suprarenal and infrarenal segments.
The ascending thoracic aorta has two distinct portions. The lower portion is the aortic root, which
begins at the level of the aortic valve and extends to the sinotubular junction. The aortic root
supports the bases of the three aortic valve leaflets, which bulge outward into the sinuses of Valsalva
to allow for full valve cusp excursion during systole. The right and left coronary artery origins arise
from within the sinuses of Valsalva. The upper portion of the ascending aorta begins at the
sinotubular junction and rises to join the aortic arch. The proximal portion of ascending aorta lies
within the pericardial cavity, anterior to the pulmonary artery bifurcation. The aortic arch gives rise to
the arch vessels, innominate artery, left common carotid artery, and left subclavian artery.
The descending thoracic aorta begins just past the origin of the left subclavian artery. The point at
which the aortic arch joins the descending aorta is called the aortic isthmus and is marked by the
location of the ligamentum arteriosum. The aortic isthmus is especially vulnerable to deceleration
trauma, because at this site, the relatively mobile portion of the aorta—the ascending aorta and
arch—becomes relatively fixed to the thoracic cage. The descending aorta gradually courses
downward, where it gives rise to paired intercostal arteries from the posterior aortic wall at each level
of the spine. At its distal extent, the thoracic aorta passes through the diaphragm, usually at the level
of the 12th thoracic vertebra, and becomes the abdominal aorta.
The abdominal aorta continues downward, giving rise to the celiac axis and the superior mesenteric
artery from its anterior wall, followed within several centimeters by the posterolateral origins of the
right and left renal arteries. This segment of the aorta is described as the suprarenal or visceral
segment. The infrarenal aorta continues along the anterior surface of the lumbar spine, where it gives

17
origin to the paired lumbar artery braches from its posterior wall. The aorta ends by bifurcation into
common iliac arteries, usually at the level of the fourth lumbar vertebra.

MICROSCOPIC STRUCTURE. The aortic wall is comprised of three layers—the innermost tunica intima,
which contacts the blood through its thin layer of endothelium, the musculoelastic tunica media,
which is the thickest layer of the aortic wall, and the fibrous tunica adventitia, which forms its
outermost layer (see Chap. 43). The intima consists of endothelial cells and the immediate
subendothelial space, and is demarcated from the media by the internal elastic lamina. The media
contains concentric layers of elastic fibers alternating with vascular smooth muscle cells (SMCs), with
each layer of elastin and SMC constituting a lamellar unit of medial structure. In addition to SMCs, the
aortic media normally contains a small number of fibroblasts, mast cells, and other cell types and,
although dominated by elastic fibers, the extracellular matrix of the media includes collagen fibers,
proteoglycans, and glycosaminoglycans. The microscopic architecture of the media gives the aorta its
circumferential resilience (elasticity), necessary to resist hemodynamic stress. The outer portion of
the aortic media is delineated from the adventitial layer by the external elastic lamina, which is
normally thinner than the internal elastic lamina. The aortic adventitia is composed of a loose
network of collagen fibers and fibroblasts, as well as small nerves and capillary-sized blood vessels.
The adventitial collagen fibers ultimately govern the tensile strength of the aortic wall.

The human ascending aorta normally contains approximately 55 to 60 elastic lamellae, with a gradual
decrease in the number of elastic lamellae down the length of the aorta to approximately 26 at the
aortic bifurcation. Despite this regional variation in medial thickness, there appears to be a relatively
consistent relationship between the number of elastic lamellae and the estimated amount of
hemodynamic stress placed on the vessel wall, except for in the infrarenal aorta, with fewer elastic
lamellae than predicted for its hemodynamic load.
Oxygen and nutrients reach the aortic wall by simple diffusion from the lumen, at least in segments of
the aorta that contain up to about 29 elastic lamellae. In the proximal aortic segments that contain a
greater number of elastic lamellae, additional nutrient supply is provided by an independent network
of microvessels, the vasa vasorum, which extends from the adventitia to the outer layers of the elastic
media. The outer third of the aortic media in the thoracic aorta contains many vasa vasorum, but the
infrarenal aorta normally lacks an independent microvascular supply.
The compliance of the aortic wall under normal conditions results from the reversible extension of
the elastic lamellar units in the media. This extensibility derives primarily from the properties of
elastic fibers, whereas SMCs make only a minor contribution. At mechanical strain levels that exceed
the extensile capacity of medial elastic fibers, the aortic tensile strength becomes dependent on the
collagen fiber meshwork of the media and adventitia. Although not functionally significant under
normal circumstances or in systemic hypertension, the dependence on adventitial collagen in
accommodating greater hemodynamic stress is an important feature of abdominal aortic aneurysms
(AAAs), where estimates of wall tension within the dilated segment may exceed that in the normal
aorta by several orders of magnitude. In AAAs, collagen fibers are reorganized to accommodate
higher degrees of tensile stress. In addition, there is evidence that aneurysmal dilation is
accompanied by an active process characterized by a marked increase in collagen production. Surgical
experience has shown that much of the inner arterial wall (endothelium and tunica media) can be
removed, as is performed during an endarterectomy, without resulting in aneurysmal dilation. This
observation illustrates that the structures conferring resistance aneurysmal dilation reside principally
within the outer aspect of the media and the adventitia.

PHYSIOLOGY. The aorta is responsible for transmitting pulsatile arterial blood pressure to all points in
the arterial tree, a function that depends on its properties as an elastic conduit. The aortic wall there-
fore requires properties of resilience to cyclic deformation, resistance to structural failure, and
durability. The biomechanical properties attributable to elastin and collagen in the media and
adventitia serve these demands. The aortic wall pressure-diameter relationship is nonlinear,
demonstrating a more distensible component at lower pressures and a stiffer component at higher
pressures, with the transition from distensible to stiff behavior occurring at pressures above 80 mm
Hg. Thus, the more distensible elastin is the principal load bearer at low pressures and small

18
distentions, whereas at higher pressures and large distentions, both elastin and the stiffer collagen
are load bearing.
It is important to point out that the pressure-diameter curve of the aorta becomes less steep with
increasing age (i.e., the aorta stiffens and aortic diameter increases). One explanation for this is an
increase in the collagen-to-elastin ratio because of an age-related decrease in elastin and a
simultaneous increase in collagen. Another factor is a gradual alteration of aortic wall architecture
with age, characterized by progressively disordered medial elastic fibers and lamellae displaying
thinning, splitting, and fragmentation in older individuals. A third factor is an increase in aortic wall
thickness with age because of increased deposition of collagen and proteoglycan, as well as age-
related calcification of elastic fibers. Finally, atherosclerotic changes are associated with aging, and
may contribute to aortic wall stiffening. In addition to the direct effects of aortic wall plaque,
stiffening may occur through compensatory increases in distensibility in areas free of disease (i.e.,
expansive arterial wall remodeling).

PERIPHERAL VASCULAR DISEASE

Peripheral vascular disease is an umbrella term that includes a number of diverse pathologic entities
that affect arteries, veins, and lymphatics. Although this terminology makes a distinction between
the “central” coronary and “peripheral” systemic vessels, the vasculature as a whole comprises a
dynamic, integrated, and multifunctional organ system that does not naturally comply with this
semantic division.
Blood vessels serve many critical functions. First, they regulate the differential distribution of blood
and delivery of nutrients and oxygen to tissues. Second, blood vessels actively synthesize and secrete
vasoactive substances that regulate vascular tone, and antithrombotic substances that maintain the
fluidity of blood and vessel patency (see Chapters 6 and 7). Third, the vessels play an integral role in
the transport and distribution of immune cells to traumatized or infected tissues.
Disease states of the peripheral vasculature interfere with these essential functions. Peripheral
vascular diseases result from processes that can be grouped into three categories:
(1) structural changes in the vessel wall secondary to degenerative conditions, infection, or infl
ammation that lead to dilatation, aneurysm, dissection, or rupture;
(2) narrowing of the vascular lumen caused by atherosclerosis, thrombosis, or infl ammation; and
(3) spasm of vascular smooth muscle.

These processes can occur in isolation or in combination.

DISEASES OF THE AORTA

The aorta is the largest conductance vessel of the vascular system. In adults, its diameter is
approximately 3 cm at its origin at the base of the heart. The ascending aorta, 5 to 6 cm in length,
leads to the aortic arch, from which arise three major branches: the brachiocephalic (which bifurcates
into the right common carotid and subclavian arteries), the left common carotid, and the left
subclavian arteries. As the descending aorta continues beyond the arch, its diameter narrows to
approximately 2 to 2.5 cm in healthy adults. As the aorta pierces the diaphragm, it becomes the
abdominal aorta, providing arteries to the abdominal viscera before bifurcating into the left and right
common iliac arteries, which supply the pelvic organs and lower extremities.
The aorta, like other arteries, is composed of three layers (Fig. 15.1). At the luminal surface, the
intima is composed of endothelial cells overlying the internal elastic lamina. The endothelial layer is a
functional interface between the vasculature and circulating blood cells and plasma. The media is
composed of smooth muscle cells and a matrix that includes collagen and elastic fibers. Collagen
provides tensile strength that enables the vessels to withstand high-pressure loads. Elastin is capable
of stretching to 250% of its original length and confers a distensible quality on vessels that allows
them to recoil under pressure. The adventitia is primarily composed of collagen fi bers, perivascular
nerves, and vasa vasorum, a rich vascular network that supplies oxygenated blood to the aorta.
The aorta is subject to injury from mechanical trauma because it is continuously exposed to high
pulsatile pressure and shear stress. The predominance of elastin in the media (2:1 over collagen)
allows the aorta to expand during systole and recoil during diastole. The recoil of the aorta against the

19
closed aortic valve contributes to the distal propagation of blood flow during the phase of left
ventricular relaxation. With advancing age, the elastic component of the aorta and its branches
degenerates, and as collagen becomes more prominent, the arteries stiffen. Systolic blood pressure,
therefore, tends to rise with age because less energy is dissipated into the aorta during left ventricular
contraction. Diseases of the aorta most commonly appear as one of three clinical conditions:
aneurysm, dissection, or obstruction.

AORTIC ANEURYSMS
An aneurysm is an abnormal localized dilatation of an artery. In the aorta, aneurysms are
distinguished from diffuse ectasia, which is a generalized yet lesser increase of the aortic diameter.
Ectasia develops in older patients as elastic fi ber fragments, smooth muscle cells decrease in number,
and acid mucopolysaccharide ground substance accumulates within the vessel wall. The term
aneurysm is applied when the diameter of a portion of the aorta has increased by at least 50%
compared with normal.
A true aneurysm represents a dilatation of all three layers of the aorta, creating a large bulge of the
vessel wall. True aneurysms are characterized as either fusiform or saccular, depending on the extent
of the vessel’s circumference within the aneurysm (see Fig. 15.1). A fusiform aneurysm, the more
common type, is characterized by symmetrical dilation of the entire circumference of a segment of
the aorta. A saccular aneurysm is a localized outpouching involving only a portion of the
circumference.

20
In contrast, a pseudoaneurysm, or false aneurysm, is a contained rupture of the vessel wall that
develops when blood leaks out of the vessel lumen through a hole in the intimal and medial layers
and is contained by a layer of adventitia or perivascular organized thrombus (see Fig. 15.1).
Pseudoaneurysms develop at sites of vessel injury caused by infection or trauma, such as puncture of
the vessel during surgery or percutaneous catheterization. They are very unstable and are prone to
rupture completely.
Aneurysms may be confi ned to the abdominal aorta (most common), the thoracic aorta, or involve
both locations. They may also appear in peripheral and cerebral arteries.

Etiology and Pathogenesis of True Aortic Aneurysms

The etiology of aortic aneurysm formation varies depending on the location of the lesion. Ascending
thoracic aortic aneurysms typically are characterized by cystic medial degeneration (also termed
cystic medial necrosis), a condition of degeneration and fragmentation of elastic fibers, with
subsequent accumulation of collagenous and mucoid material within the medial layer. Cystic medial
necrosis occurs normally with aging, but is also associated with hypertension. Additionally, it develops
in certain inherited disorders of connective tissue that affect the structural integrity of the aortic wall,
including Marfan syndrome, Loeys–Dietz syndrome, and the vascular form of Ehlers–Danlos syndrome
(type IV). Marfan syndrome is caused by missense mutations of the fi brillin-1 gene (FBN1), which
impair formation of functional microfi brils in elastin. Abnormal fi brillin-1 also limits the binding and
inactivation of transforming growth factor β (TGF-β), a signaling molecule that regulates cellular
proliferation and differentiation. Loeys–Dietz syndrome is an autosomal dominant disorder caused by

21
genetic mutations of TGF-β receptors. While thoracic aortic aneursyms have been associated with
both increased activity of TGF-β and mutations of its receptors, the mechanism by which aberrant
TGF-! signaling alters vascular integrity is not yet known. Ehlers–Danlos type IV syndrome results from
mutations encoding type III procollagen. Cystic medial necrosis also characterizes familial thoracic
aortic aneurysms and those associated with bicuspid aortic valves.
Aneurysms of the descending thoracic and abdominal aorta are usually associated with
atherosclerosis and its risk factors, including smoking, hypertension, dyslipidemia, male gender, and
advanced age. However, it is unlikely that atherosclerosis alone is responsible for such aneurysm
development. Rather, important contributions appear to derive from genetic predisposition (on a
polygenetic basis), local vessel infl ammation, and an imbalance between synthesis and degradation
of extracellular matrix proteins. For example, the breakdown of elastin and collagen is contributed to
by specifi c proteases (e.g., elastase, collagenase) and matrix metalloproteinases derived from
inflammatory cells and vascular endothelial and smooth muscle cells. Aneurysm formation is also
associated with markers of infl ammation, including C-reactive protein (CRP) and cytokines such as
interleukin 6 (IL-6). Levels of both CRP and IL-6 have been shown to correlate with the size of
aneurysms, and inflammatory cells such as B and T lymphocytes and macrophages are frequently
found on histologic examination. Angiotensin II, via its effect on infl ammation and oxidative stress,
has also been implicated in experimental models of abdominal aortic aneurysms.
Infrequent causes of aortic aneurysms (Table 15.1) include weakness of the media from infections of
the vessel wall by Salmonella species, staphylococci, streptococci, tuberculosis, syphilis, or fungi.
Inflammatory diseases such as Takayasu arteritis or giant cell arteritis (both described later in the
chapter) may similarly weaken the vessel and result in aneurysm formation.

Clinical Presentation and Diagnosis

Most aneurysms are asymptomatic, though some patients, especially those with abdominal aortic
aneurysms, may be aware of a pulsatile mass. Others present with symptoms related to compression
of neighboring structures by an expanding aneurysm. Thoracic aortic aneurysms may compress the
trachea or mainstem bronchus, resulting in cough, dyspnea, or pneumonia. Compression of the
esophagus can result in dysphagia, and involvement of the recurrent laryngeal nerve may lead to
hoarseness. Aneurysms of the ascending aorta may dilate the aortic ring, resulting in aortic
regurgitation and symptoms of congestive heart failure. Abdominal aortic aneurysms may cause
abdominal or back pain or nonspecific gastrointestinal symptoms. Aortic aneurysms are often first
suspected when dilatation of the vessel is observed on chest or abdominal radiographs, particularly if
the wall is calcified. Aneurysms of the abdominal aorta or of the large peripheral arteries may also be
discovered by careful palpation during physical examination. The diagnosis is confirmed by
ultrasonography, contrast-enhanced computed tomography (CT), or magnetic resonance angiography
(Fig. 15.2). The most devastating consequence of an aortic aneurysm is rupture, which can be fatal. An
aneurysm may leak slowly or burst suddenly, resulting in profound blood loss and hypotension.
Thoracic aortic aneurysms may rupture into the pleural space, mediastinum, or bronchi. Abdominal
aortic aneurysms may rupture into the retroperitoneal space or abdominal cavity or erode into the
intestines, resulting in massive gastrointestinal bleeding.
Natural history studies have shown that the risk of rupture is related to the size of the aneurysm, as
predicted by Laplace’s relationship (i.e., wall tension is proportional to the product of pressure and

22
radius). The mean rates of thoracic and abdominal aortic aneurysms expansion are 0.1 and 0.4
cm/year, respectively. Thoracic aneurysms rupture at an annual rate of 2% for aneurysms ˂5 cm in
diameter, 3% for aneurysms 5 to 5.9 cm, and 7% for aneurysms ˃6 cm. Abdominal aneurysms ˂4 cm,
4 to 4.9 cm, and 5 to 5.9 cm have annual rates of rupture of 0.3%, 1.5%, and 6.5%, respectively.
Abdominal aneurysms ˃6 cm have a markedly higher risk of rupture.

AORTIC DISSECTION
Aortic dissection is a life-threatening condition in which blood from the vessel lumen passes through a
tear in the intima into the medial layer and spreads along the artery. Other related acute syndromes
include aortic intramural hematoma, penetrating aortic ulcer, and aortic rupture. Acute intramural
hematoma is a variant of aortic dissection characterized by a hemorrhage in the wall of the aorta
without evidence of an intimal tear. A penetrating atherosclerotic ulcer results from erosion of a
plaque into the aortic wall. Aortic rupture may be a complication of aortic dissection, intramural
hematoma, penetrating atherosclerotic ulcer, or result from trauma.

Etiology, Pathogenesis, and Classification

Aortic dissection is thought to arise from a circumferential or transverse tear in the intimal layer of
the vessel wall that allows blood from the lumen, under the driving force of the systemic pressure, to
enter into the media and propagate along the plane of the muscle layer. Another postulated origin of
aortic dissection relates to rupture of vasa vasorum with hemorrhage into the media, forming a
hematoma in the arterial wall that subsequently tears through the intima and into the vessel’s lumen.
Any condition that interferes with the normal integrity of the elastic or muscular components of the
medial layer can predispose to aortic dissection. Such degeneration may arise from chronic
hypertension, aging, and/or cystic medial degeneration (which, as described earlier, is a feature of
certain hereditary connective tissue disorders, such as Marfan syndrome and Ehlers–Danlos
syndrome). In addition, traumatic insult to the aorta (e.g.,blunt chest trauma or accidental vessel
damage during intra-arterial catheterization or cardiac surgery) can also initiate dissection. Aortic
dissection is most common in the sixth and seventh decades and occurs more frequently in men.
More than two thirds of patients have a history of hypertension. Dissection most commonly involves
the ascending thoracic aorta (65%) and descending thoracic aorta (20%), while the aortic arch (10%)
and abdominal aortic (5%) segments are less commonly affected.
Dissections are commonly classifi ed into two categories (Stanford types A and B), depending on their
location and extent (Fig. 15.3). In a

23
In a type A dissection (proximal), the ascending aorta is involved, regardless of the site of the primary
tear. A type B dissection (distal) does not involve the ascending aorta or arch and is, therefore,
confined to the descending thoracic and abdominal aorta. This distinction is important because
treatment strategies and prognoses are determined by location. Proximal aortic involvement tends to
be more devastating because of the potential for extension into the coronary and arch vessels, the
support structures of the aortic valve, or the pericardial space. Approximately two thirds of
dissections are type A and one third are type B. Dissections may also be classified as acute or chronic,
with acute dissections presenting with symptoms of less than 2 weeks’ duration.

Clinical Presentation and Diagnosis

The most common symptom of aortic dissection is sudden, severe pain with a “tearing” or “ripping”
quality in the anterior chest (typical of type A dissections) or between the scapulae (type B
dissections). The pain travels as the dissection propagates along the aorta and can radiate anywhere
in the thorax or abdomen. Painless dissection is possible but uncommon (6.4% of cases). Other
symptoms relate to the catastrophic complications that can occur at the time of presentation or
thereafter (Table 15.2) and include (1) rupture through the adventitia anywhere along the aorta
(often into the left pleural space or pericardium); (2) occlusion of major branches of the aorta by the
propagating hematoma within the vessel wall, which compresses the lumen and can result in
myocardial infarction (coronary artery involvement), stroke (carotid artery involvement), visceral
ischemia, renal failure, or loss of pulse in an extremity; and (3) extension into the aortic root, with
disruption of the aortic valve support apparatus causing aortic regurgitation.
Several important physical fi ndings may be present. Hypertension is frequently detected, either as an
underlying cause of dissection, a result of the sympathetic nervous system response to the severe
pain, or because of diminished renal vascular fl ow, with activation of the renin–angiotensin system. If
the dissection has occluded one of the subclavian arteries, a difference in systolic blood pressure
between the arms is noted. Neurologic defi cits may accompany dissection into the carotid vessels. If
a type A dissection results in aortic regurgitation, an early diastolic murmur can be detected on
auscultation. Leakage from a type A dissection into the pericardial sac may produce signs of cardiac
tamponade (see Chapter 14). The diagnosis of aortic dissection must not be delayed, because
catastrophic complications or death may rapidly ensue. The confirmatory imaging techniques most
useful in detecting dissection include contrast-enhanced CT, transesophageal echocardiography (TEE),
magnetic resonance imaging, and contrast angiography.
Each of these techniques has specific advantages and disadvantages, and the decision of which to
employ is often guided by the hospital’s local expertise. In emergency situations, CT scanning or TEE
can generally be obtained rapidly and offer excellent sensitivity and specificity for the diagnosis.

PERIPHERAL ARTERY DISEASES

Peripheral artery disease (PAD) is defined by the presence of a flow-limiting lesion in an artery that
provides blood supply to the limbs. The major causes of such arterial stenosis or occlusion are

24
atherosclerosis, thromboembolism, and vasculitis. The clinical presentation of these disorders results
from decreased perfusion to the affected extremity.
Peripheral artery disease (PAD) generally refers to a disorder that obstructs the blood supply to the
lower or upper extremities.1 Most commonly caused by atherosclerosis, it may also result from
thrombosis, embolism, vasculitis, fibromuscular dysplasia, or entrapment. The term peripheral
vascular disease is less specific because it encompasses a group of diseases affecting blood vessels,
including other atherosclerotic conditions such as renal artery disease and carotid artery disease, as
well as vasculitides, vasospasm, venous thrombosis, venous insufficiency, and lymphatic disorders.
PAD correlates strongly with risk of major cardiovascular events, as it frequently associates with
coronary and cerebral atherosclerosis.2 Moreover, symptoms of PAD, including intermittent
claudication, jeopardize quality of life and independence for many patients. PAD is commonly
underdiagnosed and undertreated; thus, practitioners of cardiology have increasing interest in its
diagnosis and management. This chapter provides a framework for the diagnosis and management of
the patient with PAD.

EPIDEMIOLOGY
The prevalence of PAD varies according to the population studied, the diagnostic method used, and
whether symptoms are included to derive estimates. Most epidemiologic studies have used a
noninvasive measurement, the ankle-brachial index (ABI), to diagnose PAD. The ABI is the ratio of the
ankle to brachial systolic blood pressure (described in greater detail later). The prevalence of PAD
based on abnormal ABI ranges from approximately 4% among persons 40 years of age and older to
15% to 20% among those 65 years of age and older.3-6 PAD prevalence is greater in men than in
women in some studies, and greater in blacks than in non-Hispanic whites.7 In the Multi-Ethnic Study
of Atherosclerosis (MESA), the odds for development of PAD were 1.47 times higher in blacks than in
non-Hispanic whites, whereas it was less than 0.5 times higher in Hispanics and Chinese.8 These
aggregate data indicate that some 8 to 10 million individuals in the United States have PAD.
Questionnaires specifically designed to elicit symptoms of intermittent claudication can assess the
prevalence of symptomatic disease in these populations. Estimates vary by age and sex but generally
indicate that only 10% to 30% of patients with PAD have claudication. Overall, the estimated
prevalence of claudication ranges from 1.0% to 4.5% of a population older than 40 years.6,9 The
prevalence and incidence of claudication increase with age and are greater in men than in women in
most studies (Fig. 61-1).3,6,9,10 Less information exists about the incidence of critical limb ischemia,
but it is estimated at 400 to 450 per million population per year.6 The incidence of amputation ranges
from 112 to 250 per million population per year.

RISK FACTORS FOR PERIPHERAL ARTERY DISEASE

The well-known modifiable risk factors associated with coronary atherosclerosis also contribute to
atherosclerosis of the peripheral circulation. Cigarette smoking, diabetes mellitus, dyslipidemia, and
hypertension increase the risk of PAD11 (Table 61-1). Data from observational studies indicate a
twofold to threefold increase in the risk for development of PAD in smokers.6 Approximately 84% to
90% of patients with claudication are current or former smokers.12 Progression of disease to critical
limb ischemia and limb loss is more likely to occur in patients who continue to smoke than in those
who stop. Smoking can even increase the risk for development of PAD more than it does coronary
artery disease (CAD). Current smoking dose-dependently correlates with the presence of PAD in both
men and women, and smoking cessation lowers PAD risk.13 Patients with diabetes mellitus often
have extensive and severe PAD and a greater propensity for arterial calcification.14,15 Involvement of
the femoral and popliteal arteries resembles that of nondiabetic persons, but distal disease affecting
the tibial and peroneal arteries occurs more frequently. The risk for development of PAD increases
twofold to fourfold in patients with diabetes mellitus.6,16 Among patients with PAD, diabetic patients
are more likely to have an amputation than are nondiabetic patients.
Abnormalities in lipid metabolism also associate with an increased prevalence of PAD. Elevations in
total or low-density lipoprotein (LDL) cholesterol increase the risk for development of PAD and
claudication in most studies. Hypertriglyceridemia independently predicts risk for PAD.16 Some
epidemiologic studies have found a link between hypertension and PAD.17 Insulin resistance is
associated with a greater prevalence of PAD.18 Chronic kidney disease also increases the risk for

25
development of PAD.19 The risk for development of PAD and intermittent claudication increases
progressively with the burden of contributing factors. Contemporary views of atherogenesis
emphasize inflammation as a link between risk factors and the formation and complication of lesions.
Strong evidence supports the concept that the pathobiology of PAD also involves inflammation.
Classic studies associated high levels of fibrinogen with risk not only for coronary events but also for
the development of PAD. Current analyses suggest that adjustment for the trigger of the acute-phase
response, interleukin-6, or for inflammatory markers, such as C-reactive protein, eliminates the risk
for PAD associated with fibrinogen.20 Thus, the elevated fibrinogen levels in PAD may reflect
inflammation as much as or more than a procoagulant effect. Considerable evidence links leukocytes,
the crucial cellular mediators of the inflammatory response, with the development of PAD. Levels of
the soluble forms of leukocyte adhesion molecules correlate with the development and extent of PAD
and with the risk of complications.21-25 Levels of C-reactive protein and of monocytes in peripheral
blood independently associate with PAD, consistent with a role for innate immunity and chronic
inflammation in its pathogenesis.23,26 Conversely, serum bilirubin, an endogenous antioxidant with
anti-inflammatory properties, associates with reduced PAD prevalence.27 Inflammation provides the
mechanistic link between many of the common risk factors for atherosclerosis and the
pathophysiologic processes in the arterial wall that lead to PAD. Ongoing studies will determine
whether biomarkers of inflammation add to traditional risk factors in gauging susceptibility to PAD.

PATHOPHYSIOLOGY OF PERIPHERAL ARTERY DISEASE

Pathophysiologic considerations in patients with PAD must take into account the balance of
circulatory supply of nutrients to the skeletal muscle and the oxygen and nutrient demand of the
skeletal muscle (Table 61-2). Intermittent claudication occurs when skeletal muscle oxygen demand
during effort exceeds blood oxygen supply and results from activation of local sensory receptors by
accumulation of lactate or other metabolites. Patients with intermittent claudication may have single
or multiple occlusive lesions in the arteries supplying the limb. Blood flow and leg oxygen
consumption are normal at rest, but the obstructive lesions limit blood flow and oxygen delivery so
that the metabolic needs of the exercising muscle during exercise outstrip the available supply of
oxygen and nutrients. Patients with critical limb ischemia typically have multiple occlusive lesions that
often affect proximal and distal limb arteries. As a result, even the resting blood supply diminishes
and cannot meet the nutritional needs of the limb.
The most common cause of PAD is atherosclerosis. It is a prevalent vascular disorder, affecting
approximately 4% of persons over the age of 40 and 15% to 20% of those over the age of 70. The
pathology of atherosclerotic PAD is identical to that of coronary artery disease (CAD), and the major
coronary risk factors (e.g., cigarette smoking, diabetes mellitus, dyslipidemia, and hypertension) are
also associated with PAD. Approximately 40% of patients with PAD actually have clinically signifi cant
CAD. As a consequence of the systemic nature of atherosclerosis, patients with PAD have a twofold to

26
fi vefold increased risk of cardiovascular death compared with patients who do not have this
condition. Thus, detection of PAD is useful in identifying patients at increased risk of adverse
cardiovascular events.
The pathophysiology of atherosclerotic PAD is also similar to that of CAD. Ischemia of the affected
region occurs when the balance between oxygen supply and demand is upset; exercise raises the
demand for blood fl ow in the limbs’ skeletal muscle, and a stenosed or obstructed artery cannot
provide an adequate supply. Rest improves symptoms as the balance between oxygen supply and
demand is restored.

Factors Regulating Blood Supply

The primary determinant of inadequate blood supply to an extremity is a flow-limiting lesion of a
conduit artery (Fig. 61-2). Flow through an artery is directly proportional to perfusion pressure and
inversely proportional to vascular resistance. If atherosclerosis causes a stenosis, flow through the
artery is reduced, as described in Poiseuille’s equation:

where ΔP is the pressure gradient across the stenosis, r is the radius of the residual lumen, η is blood
viscosity, and l is the length of the vessel affected by the stenosis. As the severity of a stenotic lesion
increases, flow becomes progressively reduced. The pressure gradient across the stenosis increases in
a nonlinear manner, emphasizing the importance of a stenosis at high blood flow rates. Usually, a
blood pressure gradient exists at rest if the stenosis reduces the lumen diameter by more than 50%
because as distorted flow develops, kinetic energy is lost. A stenosis that does not cause a pressure
gradient at rest may cause one during exercise, when blood flow increases from higher cardiac output
and vascular resistance decreases. Thus, as flow through a stenosis increases, distal perfusion
pressure drops. As the metabolic demand of exercising muscle outstrips its blood supply, local
metabolites (including adenosine, nitric oxide, potassium, and hydrogen ion) accumulate, and periph-
eral resistance vessels dilate. Perfusion pressure then drops further because the stenosis limits flow.
In addition, intramuscular pressure rises during exercise and may exceed the arterial pressure distal
to an occlusion, causing blood flow to cease. Flow through collateral blood vessels can usually meet
the resting metabolic needs of the skeletal muscle tissue at rest but does not suffice during exercise.
Functional abnormalities in vasomotor reactivity also may interfere with blood flow. Vasodilator
capability of both conduit and resistance vessels is reduced in patients with peripheral
atherosclerosis. Normally, arteries dilate in response to pharmacologic and biochemical stimuli, such
as acetylcholine, serotonin, thrombin, and bradykinin, as well as to shear stress induced by increases
in blood flow. This vasodilator response results from the release of biologically active substances from
the endothelium, particularly nitric oxide (see Chap. 48). The vascular relaxation of a conduit vessel
that occurs after a flow stimulus, such as that induced by exercise, may facilitate the delivery of blood

27
to exercising muscles in healthy persons. Endothelium-dependent vasodilation subsequent to flow or
pharmacologic stimuli is impaired in the atherosclerotic femoral arteries and calf resistance vessels of
patients with PAD. This failure of vasodilation might prevent an increase in nutritive blood supply to
exercising muscle because endothelium-derived nitric oxide can contribute to hyperemic blood
volume after an ischemic stimulus. It is not known whether vasodilator function with respect to
prostacyclin, adenosine, or ion channels is abnormal in atherosclerotic peripheral arteries. Endoge-
nous vasoconstrictor substances, such as prostanoids and other lipid mediators, thrombin, serotonin,
angiotensin II, endothelin, and norepinephrine, may interfere with vasodilation.
Abnormalities in the microcirculation contribute to the pathophysiology of critical limb ischemia.
Patients with severe limb ischemia have a reduced number of perfused skin capillaries. Other
potential causes of decreased capillary perfusion in this condition include reduced red blood cell
deformability, increased leukocyte adhesivity, platelet aggregates, fibrinogen, microvascular
thrombosis, excessive vasoconstriction, and interstitial edema. Intravascular pressure may also
decrease because of precapillary arteriolar dilation due to locally released vasoactive metabolites.28

Skeletal Muscle Structure and Metabolic Function

Electrophysiologic and histopathologic examination has found evidence of partial axonal denervation
of the skeletal muscle in legs affected by PAD. There is preservation of type I, oxidative slow-twitch
fibers but a loss of type II, or glycolytic, fast-twitch fibers in the skeletal muscle of patients with
PAD.10 The loss of type II fibers correlates with decreased muscle strength and reduced exercise
capacity. In skeletal muscle distal to PAD, there is a shift to anaerobic metabolism earlier during
exercise, and it persists longer after cessation of exercise. Patients with claudication have increased
lactate release and accumulation of acylcarnitines during exercise and slowed oxygen desaturation
kinetics, indicative of ineffective oxidative metabolism.29,30 Moreover, mitochondrial respiratory
activity and phosphocreatine and adenosine triphosphate recovery time are delayed in the calf
muscles of PAD patients, as assessed after submaximal exercise by 31P magnetic resonance
spectroscopy.31

FIGURE 61-2 Pathophysiology of intermittent claudication. In healthy arteries (top), flow is laminar and endothelial function is
normal; therefore, blood flow and oxygen delivery match muscle metabolic demand at rest and during exercise. Muscle
metabolism is efficient, resulting in low oxidative stress. In contrast, in peripheral artery disease (bottom), the arterial stenosis
results in disturbed flow, and the loss of kinetic energy results in a pressure drop across the stenosis. Collateral vessels have
high resistance and only partially compensate for the arterial stenosis. In addition, endothelial function is impaired, resulting in
further loss of vascular function. These changes limit the blood flow response to exercise, resulting in a mismatch of oxygen
delivery to muscle metabolic demand. Changes in skeletal muscle metabolism further compromise the efficient generation of
high-energy phosphates. Oxidant stress, the result of inefficient oxidation, further impairs endothelial function and muscle
metabolism.

28
CLINICAL PRESENTATION
Symptoms
The cardinal symptoms of PAD include intermittent claudication and rest pain. The term claudication
is derived from the Latin word claudicare, “to limp.” Intermittent claudication refers to a pain, ache,
sense of fatigue, or other discomfort that occurs in the affected muscle group with exercise,
particularly walking, and resolves with rest. The location of the symptom often relates to the site of
the most proximal stenosis. Buttock, hip, or thigh claudication typically occurs in patients with
obstruction of the aorta and iliac arteries. Calf claudication characterizes femoral or popliteal artery
stenoses. The gastrocnemius muscle consumes more oxygen during walking than other muscle groups
in the leg and hence causes the most frequent symptom reported by patients. Ankle or foot
claudication occurs in patients with tibial and peroneal artery disease. Similarly, stenoses of the
subclavian, axillary, or brachial arteries may cause shoulder, biceps, or forearm claudication,
respectively. Symptoms should resolve several minutes after cessation of effort. Calf and thigh pain
that occurs at rest, such as nocturnal cramps, should not be confused with claudication and is not a
symptom of PAD. The history obtained from persons reporting claudication should note the walking
distance, speed, and incline that precipitate claudication. This baseline assessment evaluates disability
and provides an initial qualitative measure with which to determine stability, improvement, or
deterioration during subsequent encounters with the patient. Symptoms other than claudication can
limit functional capacity.32 Patients with PAD walk more slowly and have less walking endurance than
patients who do not have PAD.33
Several questionnaires have been developed to assess the presence and severity of claudication. The
Rose Questionnaire was developed initially to diagnose both angina and intermittent claudication in
epidemiologic surveys. It questions whether the patient develops pain in either calf with walking and
whether the pain occurs at rest, while walking at an ordinary or hurried pace, or on walking uphill.
There have been several modifications to this questionnaire, including the Edinburgh Claudication
Questionnaire and the San Diego Claudication Questionnaire,34 both of which are more sensitive and
specific than a physician’s diagnosis of intermittent claudication based on walking distance, walking
speed, and nature of symptoms. Another validated instrument, the Walking Impairment
Questionnaire, asks a series of questions and develops a point score based on walking distance,
walking speed, and nature of symptoms.35
Symptoms resembling limb claudication occasionally result from nonatherosclerotic causes of arterial
occlusive disease (Table 61-3). These other causes include arterial embolism; vasculitides such as
thromboangiitis obliterans, Takayasu arteritis, and giant cell arteritis; aortic coarctation;

29
fibromuscular dysplasia; irradiation; endofibrosis of the external iliac artery; and extravascular
compression due to arterial entrapment or adventitial cyst (see Chap. 89). Several nonvascular causes
of exertional leg pain should be considered in patients who present with symptoms suggestive of
intermittent claudication (see Table 61-3). Lumbosacral radiculopathy resulting from degenerative
joint disease, spinal stenosis, and herniated discs can cause pain in the buttock, hip, thigh, calf, or foot
with walking, often after very short distances, or even with standing. This symptom has been called
neurogenic pseudoclaudication. Lumbosacral spine disease and PAD both preferentially affect the
elderly and hence may coexist in the same individual. Arthritis of the hips and knees also provokes leg
pain with walking. Typically, the pain localizes to the affected joint and can be elicited on physical
examination through palpation and range-of-motion maneuvers. Exertional compartment syndrome
is most often seen in athletes with large calf muscles; increased tissue pressure during exercise limits
microvascular flow and results in calf pain or tightness. Symptoms improve after cessation of exercise.
Rarely, skeletal muscle disorders such as myositis can cause exertional leg pain. Muscle tenderness,
an abnormal neuromuscular examination finding, elevated skeletal muscle enzyme levels, and a
normal pulse examination finding should distinguish myositis from PAD. McArdle syndrome, in which
there is a deficiency of skeletal muscle phosphorylase, can cause symptoms mimicking the
claudication of PAD. Patients with chronic venous insufficiency sometimes report leg discomfort with
exertion, which is designated venous claudication. Venous hypertension during exercise increases
arterial resistance in the affected limb and limits blood flow. In the case of venous insufficiency,
elevated extravascular pressure caused by interstitial edema further diminishes capillary perfusion. A
physical examination demonstrating peripheral edema, venous stasis pigmentation, and occasionally
venous varicosities will identify this unusual cause of exertional leg pain.
Symptoms may occur at rest in patients with critical limb ischemia. Typically, patients complain of
pain or paresthesias in the foot or toes of the affected extremity. This discomfort worsens on leg
elevation and improves with leg dependency, as might be anticipated by the effect of gravity on
perfusion pressure. The pain can be particularly severe at sites of skin fissuring, ulceration, or
necrosis. Often the skin is very sensitive, and even the weight of bedclothes or sheets elicits pain.
Patients may sit on the edge of the bed and dangle their legs to alleviate the discomfort. Patients with
ischemic or diabetic neuropathy can experience little or no pain despite the presence of severe
ischemia.
Critical limb and digital ischemia can result from arterial occlusions other than those caused by
atherosclerosis. These include conditions such as thromboangiitis obliterans, vasculitides such as
systemic lupus erythematosus or scleroderma, vasospasm, atheromatous embolism, and acute
arterial occlusion caused by thrombosis or embolism (see later). Acute gouty arthritis, trauma, and
sensory neuropathy such as that caused by diabetes mellitus, lumbosacral radiculopathies, and
complex regional pain syndrome (previously known as reflex sympathetic dystrophy) can cause foot
pain. Leg ulcers also occur in patients with venous insufficiency and sensory neuropathy, particularly
that related to diabetes. These ulcers are easily distinguished from those caused by arterial disease.
The ulcer of venous insufficiency usually localizes near the medial malleolus and has an irregular
border and a pink base with granulation tissue. Ulcers due to venous disease produce milder pain
than those caused by arterial disease. Neurotrophic ulcers occur where there is pressure or trauma,
usually on the sole of the foot. These ulcers are deep, frequently infected, and usually not painful
because of the loss of sensation (Fig. 61-3).

PHYSICAL FINDINGS
The complete cardiovascular examination includes palpation of pulses and auscultation of accessible
arteries for bruits (see also Fig. 12-4). Pulse abnormalities and bruits increase the likelihood of PAD.36
Readily palpable pulses in healthy individuals include the brachial, radial, and ulnar arteries of the
upper extremities and the femoral, popliteal, dorsalis pedis, and posterior tibial arteries of the lower
extremities. The aorta also can be palpated in thin people. A decreased or absent pulse provides
insight into the location of arterial stenoses. For example, a normal right femoral pulse but absent left
femoral pulse suggests the presence of left iliofemoral arterial stenosis. A normal femoral artery pulse
but absent popliteal artery pulse would indicate a stenosis in the superficial femoral artery or
proximal popliteal artery. Similarly, disease of the anterior and posterior tibial arteries can be inferred
when the popliteal artery pulse is present but the dorsalis pedis and posterior tibial pulses,

30
respectively, are not palpable. Bruits often indicate accelerated blood flow velocity and flow
disturbance at sites of stenosis. A stethoscope should be used to auscultate the supraclavicular and
infraclavicular fossae for evidence of subclavian artery stenosis; the abdomen, flank, and pelvis for
evidence of stenoses in the aorta and its branch vessels; and each groin for evidence of femoral artery
stenoses. Pallor can be elicited on the soles of the feet of some patients with PAD by performing a
maneuver in which the feet are elevated above the level of the heart and the calf muscles are
exercised by repeated dorsiflexion and plantar flexion of the ankle. The legs are then placed in the
dependent position, and the time to the onset of hyperemia and venous distention is measured. Each
of these variables depends on the rate of blood flow, which in turn reflects the severity of stenosis
and adequacy of collateral vessels.
The legs of patients with chronic aortoiliac disease may show muscle atrophy. Additional signs of
chronic low-grade ischemia include hair loss, thickened and brittle toenails, smooth and shiny skin,
and subcutaneous fat atrophy of the digital pads. Patients with severe limb ischemia have cool skin
and may also have petechiae, persistent cyanosis or pallor, dependent rubor, pedal edema resulting
from prolonged dependency, skin fissures, ulceration, or gangrene. Ulcers due to PAD typically have a
pale base with irregular borders and usually involve the tips of the toes or the heel of the foot or
develop at sites of pressure (Fig. 61-3). These ulcers vary in size and may be as small as 3 to 5 mm.

31
CATEGORIZATION
Classification of patients with PAD depends on the severity of the symptoms and abnormalities
detected on physical examination. Categorization of the clinical manifestations of PAD improves
communication among professionals caring for these patients and provides a structure for defining
guidelines for therapeutic interventions. Fontaine described one widely used scheme that classified
patients in one of four stages progressing from asymptomatic to critical limb ischemia (Table 61-4).
Several professional vascular societies have adopted a contemporary, more descriptive classification
that includes asymptomatic patients, three grades of claudication, and three grades of critical limb
ischemia ranging from rest pain alone to minor and major tissue loss (Table 61-5).37

32
Clinical Presentation and Diagnosis (Patophysiology Heart Disease, Lily)
PAD may affect the aorta or the iliac, femoral, popliteal, and tibioperoneal arteries (Fig. 15.4). Patients
with PAD may therefore develop buttock, thigh, or calf discomfort precipitated by walking and
relieved by rest. This classic symptom of exertional limb fatigue and pain is known as claudication. In
severe PAD, patients may experience pain at rest, usually affecting the feet or toes. The chronically
reduced blood fl ow in this case predisposes the extremity to ulceration, infection, and skin necrosis
(Fig. 15.5). Patients who smoke or have diabetes mellitus are at high risk of these complications.
The location of claudication corresponds to the diseased artery, with the femoral and popliteal
arteries being the most common sites (Table 15.3). The arteries of the upper extremities are less
frequently affected, but brachiocephalic or subclavian artery disease can cause arm claudication.
Physical examination generally reveals loss of pulses distal to the stenotic segment. Bruits (swishing
sounds auscultated over a region of turbulent blood fl ow) may be audible in the abdomen (because
of stenoses within the mesenteric or renal arteries) or over iliac, femoral, or subclavian arterial
stenoses. In patients with chronic severe ischemia, the lack of blood perfusion results in muscle
atrophy, pallor, cyanotic discoloration, hair loss, and occasionally gangrene and necrosis of the foot
and digits.
Ischemic ulcers resulting from PAD often begin as small traumatic wounds in areas of increased
pressure or in regions prone to injury, such as the tips of toes and lateral malleolus (see Fig. 15.5A).
These often painful ulcers fail to heal owing to the inadequate blood supply. Diabetic patients with
peripheral sensory neuropathies are particularly susceptible to ulcers at sites of trauma or pressure
from ill-fi tting footwear. Ischemic ulcers can be distinguished from venous insuffi ciency ulcers, which
develop more proximally and on the medial portion of the leg. Venous ulcers are also associated with
reddish-brown pigmentation and varicose veins (see Fig. 15.5B).
In the evaluation of PAD, it is helpful to measure the ratio of blood pressure in the ankles to that in
the arms (termed the anklebrachial index [ABI]) using a blood pressure cuff and a Doppler instrument
to detect blood fl ow. A normal ABI is ≥1.0 (i.e., the ankle pressure is equal to, or slightly greater than,
that in the arms). An index ˂0.9 is diagnostic of PAD and may be associated with symptoms of
claudication, whereas an index ˂0.5 is often observed in patients with rest pain and severe arterial

33
compromise of the affected extremity. Other testing to assess peripheral perfusion includes limb
segmental systolic pressure measurements (using pneumatic cuffs placed along the extremity) and
pulse volume recordings (i.e., graphical measurement of volume changes in segments of the extremity
with each pulse). Duplex ultrasonography is a commonly used noninvasive method to visualize and
assess the extent of arterial stenoses and the corresponding reductions in blood fl ow.
Other more advanced imaging studies (e.g.,magnetic resonance angiography, computed tomographic
angiography, or intra-arterial contrast angiography) are obtained when revascularization procedures
are planned.

Ankle-Brachial Index
Determination of the ABI furnishes a simplified application of leg segmental blood pressure
measurements readily used at the bedside (see Fig. 61-4 and Fig. 12-4). This index is the ratio of the
systolic blood pressure measured at the ankle to the systolic blood pressure measured at the brachial
artery. A pneumatic cuff placed around the ankle is inflated to suprasystolic pressure and
subsequently deflated while the onset of flow is detected with a Doppler ultrasound probe placed
over the dorsalis pedis and posterior tibial arteries, thus denoting ankle systolic blood pressure.
Brachial artery systolic pressure can be assessed in a routine manner, with use of either a stethoscope
to listen for the first Korotkoff sound or a Doppler probe to listen for the onset of flow during cuff
deflation. The normal ABI should be 1.0 or greater; recognizing the variability intrinsic to sequential
blood pressure measurements, however, an ABI of less than 0.90 is considered abnormal and is 90%
to 95% sensitive and 98% to 100% specific for angiographically verified peripheral arterial stenosis.6
The ABI is often used to gauge the severity of PAD. Patients with symptoms of leg claudication often
have ABIs ranging from 0.5 to 0.8, and patients with critical limb ischemia usually have an ABI of less
than 0.5. The ABI correlates inversely with walking distance and speed. Fewer than 40% of patients
whose ABI is less than 0.40 can complete a 6-minute walk.38 In patients with skin ulcerations, an
ankle pressure of less than 55 mm Hg would predict poor ulcer healing. One limitation of leg blood
pressure recordings is that they cannot be used reliably in patients with calcified vessels, as might
occur in persons with diabetes mellitus or renal insufficiency. The calcified vessel cannot be
compressed during inflation of the pneumatic cuff, and therefore the Doppler probe indicates
continuous blood flow, even when the pressure exceeds 250 mm Hg.

34
Treatment
For all patients with PAD, antiplatelet therapy and risk factor modifi cation (including smoking
cessation, lipid lowering, and control of diabetes and hypertension) are important in reducing the
likelihood of coronary events. Platelet inhibitors such as aspirin have been shown to reduce
cardiovascular morbidity and mortality in patients with PAD. It has not been established if antiplatelet
agents reduce symptoms or prevent thrombotic complications of PAD itself.
Specific treatment of PAD includes supportive care of the feet to prevent trauma or restriction of
blood flow. Exercise, particularly walking, improves endurance in part by increasing metabolic
efficiency in the skeletal muscle of the legs. A formal exercise program is considered fi rst-line therapy
in the management of PAD.
Certain medical therapies are sometimes useful in the treatment of claudication. Cilostazol is a
selective phosphodiesterase inhibitor that increases cyclic adenosine monophosphate and has
vasodilator and platelet- inhibiting properties; it has been shown to improve exercise capacity in
patients with PAD. Pentoxifylline is a drug purported to improve the deformability of red and white

35
blood cells and may improve claudication symptoms in some patients. Conversely, most vasodilator
drugs (see Chapter 17) are not helpful in relieving claudication.
More effective medical therapies for PAD are on the horizon. Advances in angiogenesis research and
ongoing clinical trials provide hope that pharmacologic revascularization with angiogenic growth
factors, such as vascular endothelial growth factor and basic fibroblast growth factor, may be
possible. Mechanical revascularization is indicated when medical therapy has failed for patients with
disabling claudication and as fi rst-line therapy in cases of severe limb ischemia. In advanced cases,
therapy is directed at healing ischemic ulcerations and preventing limb loss.
Catheter-based interventions, such as percutaneous transluminal angioplasty and stent implantation,
can be performed on selected patients with low morbidity. Surgical procedures include bypass
operations to circumvent the occluded arteries using saphenous vein or prosthetic grafts. However,
amputation may be necessary if blood flow cannot be satisfactorily reestablished to maintain limb
viability.

TREATMENT (Braunwald’s Heart Disease)

The goal for treatment of PAD is reduction in cardiovascular morbidity and mortality, as well as
improvement in quality of life by decreasing symptoms of claudication, eliminating rest pain, and
preserving limb viability. Therapeutic considerations therefore include risk factor modification by
lifestyle measures and pharmacologic therapy to reduce the risk of adverse cardiovascular events,
such as MI, stroke, and death. Symptoms of claudication can improve with pharmacotherapy or
exercise rehabilitation. Optimal management of critical limb ischemia often includes endovascular
interventions or surgical reconstruction to improve blood supply and to maintain limb viability.
Revascularization is also indicated in some patients with disabling symptoms of claudication that
persist despite exercise therapy and pharmacotherapy.6,9

Risk Factor Modification (see Chaps. 47 and 49)

Lipid-lowering therapy can reduce the risk of adverse cardiovascular events (see Chap. 47). The Heart
Protection Study found that lipid-lowering therapy with simvastatin reduced the risk of adverse
cardiovascular outcomes by 25% in patients with atherosclerosis, including more than 6700 patients
with PAD (Fig. 61-11).55 Pooled results from 17 lipid-lowering trials found that lipid-lowering therapy
reduced the risk of cardiovascular events in patients with PAD by 26%.56 Thus, patients with PAD
should receive diet and drug therapy to achieve a target LDL-cholesterol level of 100 mg/dL or less.9
Also, several prospective trials have found that statins improve walking distance in patients with
PAD.57-59 In the Treatment of Peripheral Atherosclerotic Disease with Moderate or Intensive Lipid
Lowering (TREADMILL) trial, atorvastatin (80 mg) increased pain-free walking distance by more than
60%, compared with a 38% increase with placebo (Fig. 61-12).58 Additional trials support these
findings.60 Also, patients treated with statins have superior leg functioning, as assessed by walking
speed and distance, compared with those not treated.61 It is not known whether other lipid-lowering
therapies (such as niacin, ezetimibe, or fibrates) reduce the risk for cardiovascular events in patients
with PAD. In the Fenofibrate and Event Lowering Intervention in Diabetes (FIELD) study, fenofibrate
reduced the risk of minor amputation, primarily among patients who did not have known PAD.62

36
Smoking Cessation
Prospective trials examining the benefits of smoking cessation are lacking, but observational evidence
unequivocally shows that cigarette smoking increases the risk of atherosclerosis and its clinical
sequelae. Nonsmokers with PAD have lower rates of MI and mortality than those who have smoked
or continue to smoke, and PAD patients who discontinue smoking have approximately twice the 5-
year survival rate of those who continue to smoke.12 Smoking cessation also lowers the risk for the
development of critical limb ischemia. In addition to frequent physician advice, pharmacologic
interventions that effectively promote smoking cessation include nicotine replacement therapy,
bupropion, and varenicline.63,64

Treatment of Diabetes (see Chap. 64)

Aggressive treatment of diabetes decreases the risk for microangiopathic events such as nephropathy
and retinopathy, but current data fail to support the notion that aggressive treatment of diabetes
with glucose-lowering agents favorably affects the clinical manifestations and outcomes of
atherosclerosis in general and of PAD in particular (see Chap. 64). In the Diabetes Control and
Complications Trial (DCCT), which involved patients with type 1 diabetes mellitus, a 13-year follow-up
analysis found that intensive insulin therapy, compared with usual care, reduced the risk of
cardiovascular events by 42%.65 After 6 years, the rate of growth of carotid intima-media thickness
was lower in the intensive treatment group, indicating a favorable effect on atherosclerosis
progression.66 Long-term follow-up of the United Kingdom Prospective Diabetes Study (UKPDS) of
patients with type 2 diabetes mellitus found that intensive treatment with sulfonylureas or insulin
was associated with a 15% reduction in MI but no decrease in the incidence of PAD.67 Several recent
trials have examined the efficacy of intensive glucose control on cardiovascular events in patients
with type 2 diabetes. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study,
intensive glucose control compared with placebo did not reduce the primary composite endpoint of
nonfatal MI, nonfatal stroke, or cardiovascular death,68 but intensive glucose control increased the
risk of death and decreased the risk of nonfatal MI, which were secondary outcome measures. In the
ADVANCE study, intensive glucose control reduced microvascular events, primarily the incidence of
nephropathy, but did not affect macrovascular events, notably cardiovascular death.69 In the
Veterans Affairs Diabetes Trial (VADT), intensive glucose control did not affect the primary composite
endpoint of MI, stroke, cardiovascular death, congestive heart failure, revascularization, and

37
amputation for ischemic gangrene.70 The PROactive (Prospective Pioglitazone Clinical Trial in
Macrovascular Events) study assessed the effect of pioglitazone versus placebo on a broad range of
cardiovascular endpoints in patients with type 2 diabetes and established atherosclerosis, including
CAD, cerebrovascular disease, and PAD, and found no significant benefit of pioglitazone on the
primary outcome.71 Among patients with no PAD at baseline, composite primary and secondary
event rates were less with pioglitazone than with placebo treatment. In the PAD patients, however,
pioglitazone did not affect these cardiovascular events in patients with PAD.72 A meta-analysis of five
prospective randomized controlled trials found that intensive glycemic control resulted in a 17%
reduction in events of nonfatal MI and a 15% reduction in coronary heart disease events, but it had
no significant effect on stroke or all-cause mortality.73 Current guidelines recommend that patients
with PAD and diabetes be treated with glucose-lowering agents to achieve a hemoglobin A1c of
<7.0%.9 Blood Pressure Control
Antihypertensive therapy reduces the risk of stroke, CAD, and vascular death. In the Appropriate
Blood Pressure Control in Diabetes (ABCD) trial, intensive blood pressure control to levels
approximating 128/75 mm Hg substantially reduced cardiovascular events compared with moderate
blood pressure control in patients with PAD.75 In the ACCORD study of patients with diabetes at high
risk for cardiovascular events, there was no difference in cardiovascular outcomes between intensive
antihypertensive therapy to achieve a systolic blood pressure less than 120 mm Hg and standard
therapy to a target systolic blood pressure less than 140 mm Hg.76 It is not known whether
antihypertensive therapy limits the progression of PAD. Treatment of hypertension might decrease
perfusion pressure to extremities already compromised by peripheral artery stenoses. In addition,
concern has been raised about the potential adverse affects of beta-adrenergic receptor blockers
(beta blockers) on peripheral blood flow and symptoms of claudication or critical limb ischemia. A
recent systematic review including six studies of beta blocker therapy compared with placebo found
no significant impairment on walking capacity in a total of 119 patients with intermittent
claudication.77 Beta blockers reduce the risk of MI and death in patients with CAD, a problem
affecting many patients with PAD. Thus, if clinically indicated for other conditions, these drugs should
not be withheld in patients with PAD. The balance of evidence supports the treatment of
hypertension in patients with PAD according to established clinical guidelines (see Chap. 46).78
Angiotensin-converting enzyme inhibitors reduce cardiovascular events in patients with
atherosclerosis. In the Heart Outcomes Prevention Evaluation (HOPE) study, the angiotensin-
converting enzyme inhibitor ramipril decreased the risk for vascular death, MI, or stroke by 22%.79
Forty-four percent of the patients enrolled in the HOPE trial had evidence of PAD, as manifested by an
ABI less than 0.9. In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint
Trial (ONTARGET) of patients with vascular disease or diabetes, both ramipril and the angiotensin
receptor antagonist telmisartan reduced the rate of the composite endpoint of cardiovascular death,
MI, stroke, or hospitalization for heart failure by approximately 17%.80 More than 13% of the
patients in ONTARGET had PAD. Current guidelines recommend that patients with PAD and
hypertension be treated with blood pressure–lowering agents to achieve a target blood pressure of
<140/90 mm Hg, or <130/80 mm Hg in patients with diabetes.9

Antiplatelet Therapy (see Chap. 87)

Substantial evidence supports the use of antiplatelet agents to reduce adverse cardiovascular
outcomes in patients with atherosclerosis. A meta-analysis that included approximately 135,000 high-
risk patients with atherosclerosis, including those with acute and prior MI, stroke, or transient
cerebrovascular ischemia, and other high-risk groups including those with PAD, found that
antiplatelet therapy yielded a 22% reduction in subsequent vascular death, MI, or stroke.81 Among
the 9214 patients with PAD, included in this analysis, antiplatelet therapy reduced the risk of MI,
stroke, or death by 22%. The majority of the PAD trials in this report, however, included antiplatelet
therapy other than aspirin. A recent meta-analysis that included 18 prospective, randomized
controlled trials, comprising 5269 persons with PAD, found that aspirin therapy compared with
placebo was not associated with significant reductions in all-cause or cardiovascular mortality, MI, or
major bleeding.82 Included in this analysis was the Prevention of Progression of Arterial Disease and
Diabetes (POPADAD) trial of diabetic patients with asymptomatic PAD, which found that aspirin did
not decrease the risk of a composite primary endpoint including death from coronary heart disease or

38
stroke, nonfatal MI or stroke, or amputation above the ankle for critical limb ischemia.83 Within the
Aspirin for Asymptomatic Atherosclerosis trial, in the 3350 participants with ABI ≤0.95, aspirin (100
mg daily) did not significantly reduce vascular events (Fig. 61-13).84 The Clopidogrel versus Aspirin in
Patients at Risk of Ischemic Events (CAPRIE) trial compared clopidogrel with aspirin for efficacy in
preventing ischemic events in patients with recent MI, recent ischemic stroke, or PAD. Overall, there
was an 8.7% relative risk reduction for MI, ischemic stroke, or vascular death in the group treated
with clopidogrel.85 Notably, among the 6452 patients in the PAD subgroup, clopidogrel treatment
reduced adverse cardiovascular events by 23.8%. The Clopidogrel for High Atherothrombotic Risk and
Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial compared the efficacy of dual
antiplatelet therapy with clopidogrel plus aspirin to aspirin alone in patients with established CAD,
cerebrovascular disease, or PAD, as well as in patients with multiple atherosclerotic risk factors.86
Overall, dual antiplatelet therapy produced no significant benefit compared with aspirin alone on the
primary efficacy endpoint, a composite of MI, stroke, or cardiovascular death. Among the 3096
patients with PAD in the CHARISMA trial, dual antiplatelet therapy reduced the rates of MI and
hospitalization for ischemic events (Fig. 61-14).87 The Warfarin Antiplatelet Vascular Evaluation
(WAVE) trial compared combination antiplatelet and oral anticoagulant therapy with antiplatelet
therapy alone in patients with PAD.88 There was no significant difference between the two
treatments on the primary composite endpoint of MI, stroke, or cardiovascular death, but life-
threatening bleeding occurred more frequently in patients receiving combination antiplatelet and
anticoagulant therapy.
Current guidelines recommend that patients with PAD be treated with an antiplatelet drug, such as
aspirin or clopidogrel.9 Oral anticoagulation with warfarin is not recommended to reduce
cardiovascular events in patients with PAD because it is no more effective than antiplatelet therapy
and confers a higher risk of bleeding. Antiplatelet therapy also prevents occlusion in the peripheral
circulation after revascularization procedures. Of approximately 3000 patients with peripheral arterial
procedures previously analyzed by the Antiplatelet Trialists Collaboration, the odds reduction for
arterial or graft occlusion by antiplatelet therapy (primarily aspirin or aspirin plus dipyridamole) was
43%.

ACUTE ARTERIAL OCCLUSION

Acute arterial occlusion is caused either by embolization from a cardiac or proximal vascular site or by
thrombus formation in situ. The origin of arterial emboli is most often the heart, usually resulting
from disorders involving intracardiac stasis of flow (Table 15.4). Emboli may also originate from
thrombus or atheromatous material overlying a segment of the aorta. Rarely, arterial emboli originate
from the venous circulation. If a venous clot travels to the right-heart chambers and is able to pass
through an abnormal intracardiac communication (e.g., an atrial septal defect), it then enters the
systemic arterial circulation (a condition known as a paradoxical embolism).
Primary arterial thrombus formation may appear at sites of endothelial damage or atherosclerotic
stenoses, or within bypass grafts. The extent of tissue damage from thromboembolism depends on
the site of the occluded artery, the duration of occlusion, and the degree of collateral circulation
serving the tissue beyond the obstruction. Common symptoms and signs that may develop from
reduced blood supply include pain, pallor, paralysis, paresthesia, and pulselessness (termed the “fi ve
Ps”). A sixth P, poikilothermia (coolness), is also often manifest.
Patients with a proven acute arterial occlusion should be treated with anticoagulant agents such as
heparin (followed by warfarin) to prevent propagation of the clot and to reduce the likelihood of
additional embolic events. A revascularization procedure (catheter-based thrombolysis or
thrombectomy, surgical embolectomy, or bypass surgery) is indicated if limb viability is at risk.
Atheroembolism is the condition of peripheral arterial occlusion by atheromatous material (i.e.,
cholesterol, platelets, and fibrin) derived from more proximal vascular sites, such as atherosclerotic
lesions or aneurysms. The emboli lodge distally, resulting in occlusion of small arteries in the muscle
and skin. Patients typically present with acute pain and tenderness at the involved site. Occlusion of
digital vessels may result in the “blue toe” syndrome, culminating in gangrene and necrosis. Other fi
ndings may include livedo reticularis (purplish mottling of involved skin), kidney failure (caused by
renal atheroembolism), and intestinal ischemia. Although an estimated 50% to 60% of cases are
spontaneous, atheroembolism may occur after intra-arterial procedures (e.g., cardiac catheterization)

39
when atherosclerotic material is unintentionally dislodged from the proximal vasculature. Ischemia
resulting from atheroemboli is difficult to manage because the heterogeneous composition and
distribution of emboli often precludes surgical removal or thrombolytic therapy. Surgical intervention
to remove or bypass the source of emboli may be necessary to prevent recurrences.

Current percutaneous
methods for transluminal removal of
thrombus (TRT) include thrombolytic
therapy (ie, catheter-directed, pharmacomechanic),
percutaneous aspiration
thrombectomy (PAT), and percutaneous
mechanical thrombectomy (PMT).
These methods may be used in combination.
Surgical techniques entail an
“open” procedure that necessitates an
arteriotomy for the removal of thrombus.
Of the various TRT methods used
to treat acute limb ischemia, catheterdirected
thrombolytic therapy with
urokinase has been the most widely
studied.
VASCULITIC SYNDROMES
Vasculitis (vessel wall infl ammation) results from immune complex deposition or cell mediated
immune reactions directed against the vessel wall. Immune complexes activate the complement
cascade with subsequent release of chemoattractants and anaphylatoxins that direct neutrophil
migration to the vessel wall and increase vascular permeability. Neutrophils injure the vessel by
releasing lysosomal contents and producing toxic oxygen-derived free radicals. In cell-mediated
immune reactions, T lymphocytes bind to vascular antigens and release lymphokines that attract
additional lymphocytes and macrophages to the vessel wall. These infl ammatory processes can cause
end-organ ischemia through vascular necrosis or local thrombosis. The cause of most of the vasculitic
syndromes is unknown, but they often can be distinguished from one another by the pattern of
involved vessels and by histologic characteristics (Table 15.5).

Takayasu arteritis is a chronic vasculitis of unknown etiology that targets the aorta and its major
branches. The estimated annual incidence is 1.2 to 2.6 cases per million. Between 80% and 90% of
affected persons are women, with onset typically between the ages of 10 and 40.

40
Most reported cases have been from Asia and Africa, but it is a worldwide disease. Patients typically
present with systemic complaints such as malaise and fever; focal symptoms are related to
inflammation of the affected vessel and include cerebrovascular ischemia (brachiocephalic or carotid
artery involvement), myocardial ischemia (coronary artery), arm claudication (brachiocephalic or
subclavian artery), or hypertension (renal artery). The carotid and limb pulses are diminished or
absent in nearly 85% of patients at the time of diagnosis; hence, this condition is often termed
“pulseless” disease. Takayasu arteritis is also an uncommon cause of aortic aneurysm or aortic
dissection. Histologic examination of affected vessels reveals continuous or patchy granulomatous infl
ammation with lymphocytes, histiocytes, and multinucleated giant cells, resulting in intimal
proliferation, disruption of the elastic lamina, and fibrosis. Antiendothelial antibodies may also play a
role in the disease. Steroid and cytotoxic drugs may reduce vascular infl ammation and alleviate
symptoms of Takayasu arteritis. Surgical bypass of obstructed vessels may be helpful in severe cases.
The 5-year survival rate is 80% to 90%.

Giant cell arteritis (also termed temporal arteritis) is a chronic vasculitis of medium-sized to large
arteries that most commonly involves the cranial vessels or the aortic arch and its branches. It is an
uncommon disease, with an incidence of 24 per 100,000, and the typical onset is after age 50; 65% of
patients are female. Giant cell arteritis may be associated with the infl ammatory condition known as
polymyalgia rheumatica. Histologic fi ndings in affected vessels include lymphocyte and macrophage
infi ltration, intimal fi brosis, and focal necrosis, with granulomas containing multinucleated giant
cells. Symptoms and signs of giant cell arteritis depend on the distribution of affected arteries and
may include diminished temporal pulses, prominent headache (temporal artery involvement), or
facial pain and claudication of the jaw while chewing (facial artery involvement). Ophthalmic artery
arteritis leads to impaired vision, with permanent partial or complete loss in 15% to 20% of patients.
In giant cell arteritis, the erythrocyte sedimentation rate and CRP are invariably elevated as markers
of infl ammation. Ultrasound examination can support the diagnosis by demonstrating a hypoechoic
halo around the involved arterial lumen with vessel stenosis and/or occlusion. The diagnosis can be
confi rmed by biopsy of an involved vessel, usually a temporal artery, but treatment should not wait
for biopsy results. High-dose systemic steroids are effective in treating vasculitis and preventing visual
complications. Giant cell arteritis usually has a self-limited course of 1 to 5 years.

Thromboangiitis obliterans (Buerger disease) is a segmental infl ammatory disease of small and
medium-sized arteries, veins, and nerves involving the distal vessels of the upper and lower
extremities. It is most prevalent in the Far and Middle East and has a very strong association with
cigarette smoking. It is most common in men younger than age 45; only 10% to 25% of patients are
female. There is an increased incidence of human leukocyte antigen A9 (HLA-A9) and HLA-B5 in
affected persons. Thromboangiitis obliterans presents with a triad of symptoms and signs: distal
arterial occlusion, Raynaud phenomenon (described in the next section), and migrating superfi cial
vein thrombophlebitis. Arterial occlusion results in arm and foot claudication as well as ischemia of
the digits. Traditional laboratory markers of infl ammation and autoimmune disease are usually not
detected. Arteriographic features of involved arteries include areas of stenosis interspersed with
normalappearing vessels with more severe disease distally, collateral vessels with a “corkscrew”
appearance around the stenotic regions, and lack of atherosclerosis in proximal arteries. The
diagnosis can be established by tissue biopsy, although this is rarely needed. Biopsy specimens of
affected vessels reveal an occlusive, highly cellular, infl ammatory thrombus, with limited involvement
of the vessel wall and preservation of the internal elastic lamina (Fig. 15.6). The most important
treatment for thromboangiitis obliterans is smoking cessation, which usually prevents progression of
the disease and its complications. Debridement of necrotic tissue may be necessary in advanced
cases. Revascularization is not usually an option because of the distal location of the arterial lesions.

41
VASOSPASM: RAYNAUD PHENOMENON
Raynaud phenomenon is a vasospastic disease of the digital arteries that occurs in susceptible people
when exposed to cool temperatures or sometimes during emotional stress. Vasospasm is an extreme
vasoconstrictor response that temporarily obliterates the vascular lumen, inhibiting blood flow.
Typically, such episodes are characterized by a triphasic color response. First, the fingers and/or toes
blanch to a distinct white as blood flow is interrupted (Fig. 15.7). The second phase is characterized by
cyanosis, related to local accumulation of desaturated hemoglobin, followed by a third phase of ruddy
color as blood fl ow resumes. The color response may be accompanied by numbness, paresthesias, or
pain of the affected digits. This condition may occur as an isolated disorder, termed primary Raynaud
phenomenon or Raynaud disease. Patients are predominantly women between the ages of 20 and 40.
Primary Raynaud phenomenon most often manifests in the fi ngers, but 40% of patients also have
involvement of the toes. The prognosis of primary Raynaud phenomenon is relatively benign, with
only a minority reporting a worsening of symptoms over time.
Secondary Raynaud phenomenon may appear as a component of other conditions. Common causes
include connective tissue diseases (e.g., scleroderma and systemic lupus erythematosus) and arterial
occlusive disorders.
Other causes of secondary Raynaud phenomenon include carpal tunnel syndrome, thoracic outlet
syndrome, blood dyscrasias, certain drugs, and thermal or vibration injury. Even in healthy vessels,
cold exposure normally produces a vasoconstrictor response.
Cooling stimulates the sympathetic nervous system, resulting in local discharge of norepinephrine,
which binds to vascular adrenergic receptors. In the fingers and toes, only vasoconstricting α-
receptors are present; other regional circulations have both constrictor and dilator adrenergic
responses. Thus, a modest vasoconstriction of the digits results when healthy people are exposed to
cooling. In contrast, in Raynaud phenomenon, cold exposure induces severe vasoconstriction.
A variety of mechanisms have been proposed to explain the vasospastic response to cold and stress in
patients with primary Raynaud phenomenon, including an exaggerated sympathetic discharge in
response to cold, heightened vascular sensitivity to adrenergic stimuli, or excessive release of
vasoconstrictor stimuli, such as serotonin, thromboxane, and endothelin. In patients with secondary
Raynaud phenomenon caused by connective tissue diseases or arterial occlusive disease, the digital
vascular lumen is largely obliterated by sclerosis or infl ammation, resulting in lower intraluminal
pressure and greater susceptibility to sympathetically mediated vasoconstriction.

Treatment of Raynaud phenomenon involves avoiding cold environments, dressing in warm clothes,
and wearing insulated gloves or footwear. There has also been some success in preventing vasospasm
with pharmacologic agents that relax vascular tone, including calcium-channel blockers and α-
adrenergic blockers (see Chapter 17), but such therapies are reserved for severe cases.

VENOUS DISEASE
Veins are high-capacitance vessels that contain more than 70% of the total blood volume. In contrast
to the muscular structure of arteries, the subendothelial layer of veins is thin, and the tunica media
comprises fewer, smaller bundles of smooth muscle cells intermixed with reticular and elastic fibers.
While veins of the extremities possess intrinsic vasomotor activity, transport of blood back to the
heart relies greatly on external compression by the surrounding skeletal muscles and on a series of
one-way endothelial valves. Veins of the extremities are classified as either deep or superficial. In the

42
lower extremities, where most peripheral venous disorders occur, the deep veins generally course
along the arteries, whereas the superfi cial veins are located subcutaneously. The superfi cial vessels
drain into deeper veins through a series of perforating connectors, ultimately returning blood to the
heart.

Varicose Veins
Varicose veins (Fig. 15.8) are dilated, tortuous superfi cial vessels that often develop in the lower
extremities. Clinically apparent varicose veins occur in 10% to 20% of the general population. They
affect women two to three times more frequently than men, and roughly half of the patients have a
family history of this condition. Varicosities can occur in any vein in the body but are most common in
the saphenous veins of the leg and their tributaries.
They may also develop in the anorectal area (hemorrhoids), in the lower esophageal veins
(esophageal varices varicose veins), and in the spermatic cord (varicocele). Varicosity is thought to
result from intrinsic weakness of the vessel wall, from increased intraluminal pressure, or from
congenital defects in the structure and function of venous valves. Varicose veins in the lower
extremities are classified as either primary or secondary.

Primary varicose veins originate in the superficial system, and factors that lead to their development
include pregnancy, prolonged standing, and obesity. During pregnancy or prolonged standing, the
high venous pressure within the legs contributes to varicosities when there is an underlying weakness
of the vessel walls. In obese patients, the adipose tissue surrounding vessel walls offers less structural
support to veins than lean mass.

Secondary varicose veins occur when an abnormality in the deep venous system is the cause of
superfi cial varicosities. These may develop in the setting of deep venous insufficiency or occlusion, or
when the perforating veins are incompetent. In such cases deep venous blood is shunted
retrogradely through perforating channels into superfi cial veins, increasing intraluminal pressure and
volume and causing dilatation and varicosity formation.

Many people with varicose veins are asymptomatic but seek treatment for cosmetic reasons. When
symptoms do develop, they include a dull ache, “heaviness,” or a pressure sensation in the legs after
prolonged standing. Superfi cial venous insufficiency may result when venous valves are unable to
function normally in the dilated veins. This can cause swelling and skin ulceration that is particularly
severe near the ankle. Stasis of blood within varicose veins can promote superfi cial vein thrombosis,
and varicosities can also rupture, causing a localized hematoma.
Varicose veins are usually treated conservatively. Patients should elevate their legs while supine,
avoid prolonged standing, and wear external compression stockings that counterbalance the
increased venous hydrostatic pressure. Small symptomatic varicosities are sometimes treated by
injection of a sclerosing agent into the vein. Laser treatments can be used to improve the cosmetic
appearance of small affected vessels. Endovenous laser therapy, radiofrequency ablation procedures,
and surgical vein ligation and removal are used for patients who are very symptomatic, suffer
recurrent superfi cial vein thrombosis, or develop skin ulcerations.

SUPERFICIAL THROMBOPHLEBITIS
Superfi cial thrombophlebitis is a benign disorder associated with infl ammation and thrombosis
of a superfi cial vein, just below the skin.
It may occur, for example, as a complication of an in-dwelling intravenous catheter. It is characterized
by erythema, tenderness, and edema over the involved vein. Treatment consists of local heat and rest
of the involved extremity. Aspirin or other anti-infl ammatory medications may relieve the associated
discomfort. Unlike DVT, superfi cial thrombophlebitis does not lead to PE.

43
THROMBOANGIITIS OBLITERANS
Thromboangiitis obliterans (TAO) is a segmental vasculitis that affects the distal arteries, veins, and
nerves of the upper and lower extremities. It typically occurs in young persons who smoke.123

PATHOLOGY AND PATHOGENESIS

TAO primarily affects the medium and small vessels of the arms, including the radial, ulnar, palmar,
and digital arteries, and their counterparts in the legs, including the tibial, peroneal, plantar, and
digital arteries. Involvement can extend to the cerebral, coronary, renal, mesenteric, aortoiliac, and
pulmonary arteries.123 The pathologic findings include an occlusive, highly cellular thrombus
incorporating polymorphonuclear leukocytes, microabscesses, and occasionally multinucleated giant
cells. The inflammatory infiltrate can also affect the vascular wall, but the internal elastic membrane
remains intact. In the chronic phase of the disease, the thrombus becomes organized and the vascular
wall becomes fibrotic.
The precise cause of TAO is not known. Tobacco use or exposure is present in virtually every patient.
Potential immunologic mechanisms include increased cellular sensitivity to types I and III collagen and
the presence of antiendothelial cell antibodies. CD4 T cells have been identified in cellular infiltrates
of vessels of patients with TAO.123,124 Decreased endothelium-dependent vasodilation to
acetylcholine can occur in both affected and unaffected limbs of patients with TAO, raising the
possibility that reduced bioavailability of nitric oxide contributes to the disorder.124

CLINICAL PRESENTATION
The prevalence of TAO is greater in Asia than in North America or western Europe. In the United
States, TAO occurs in approximately 13 per 100,000 population.123,124 Most patients develop
symptoms before 45 years of age, and 75% to 90% are men. Patients can have claudication of the
hands, forearms, feet, or calves. The majority of patients with TAO present with rest pain and digital
ulcerations; often, more than one extremity is affected. Raynaud phenomenon occurs in
approximately 45% of patients, and superficial thrombophlebitis, which may be migratory, occurs in
approximately 40%. The risk of amputation within 5 years is approximately 25%.125
The radial, ulnar, dorsalis pedis, and posterior tibial pulses may be absent if the corresponding vessel
is involved. The clinical characteristics of critical limb ischemia and ischemic digital ulcerations are
described earlier in this chapter. The Allen test result is abnormal in two thirds of patients. To perform
the Allen test, both radial and ulnar arteries are compressed while the hand is clenched and then
opened. This maneuver causes palmar blanching. Release of compression from either pulse should
normally produce palmar erythema if the palmar arches are patent. If these are occluded, pallor
persists on the side where compression is maintained. The distal aspects of the extremities may have
discrete, tender, erythematous subcutaneous cords, indicating a superficial thrombophlebitis.

DIAGNOSIS
No specific laboratory tests, other than biopsy, can diagnose TAO. Most tests, therefore, aim to
exclude other diseases that might have similar clinical presentations, including autoimmune diseases
such as scleroderma or systemic lupus erythematosus, hypercoagulable states, diabetes, and acute
arterial occlusion due to embolism. Acute-phase indicators, such as the erythrocyte sedimentation
rate or C-reactive protein, are usually normal. Serum immunologic markers, including antinuclear
antibodies and rheumatoid factor, should not be present, and serum complement levels should be
normal. If it is clinically indicated, a proximal source of embolism should be excluded by cardiac and
vascular ultrasonography or by computed tomography, magnetic resonance angiography, or
conventional arteriography. Arteriography of an affected limb supports the diagnosis of TAO if there is
segmental occlusion of small and medium arteries, absence of atherosclerosis, and corkscrew
collateral vessels circumventing the occlusion (Fig. 61-18). These same findings, however, can occur in
patients with scleroderma, systemic lupus erythematosus, mixed connective tissue disease, and
antiphospholipid antibody syndrome. The conclusive test is a biopsy showing the classic pathologic
findings. This procedure is rarely indicated, and biopsy sites may fail to heal because of severe
ischemia. The diagnosis, therefore, usually depends on an age at onset of younger than 45 years, a
history of tobacco use, physical examination demonstrating distal limb ischemia, exclusion of other
diseases, and if necessary, angiographic demonstration of typical lesions.

44
TREATMENT
The cornerstone of treatment is a cessation of tobacco use. Patients without gangrene who stop
smoking rarely require amputation.123,125 In contrast, one or more amputations may ultimately be
required in 40% to 45% of patients with TAO who continue to smoke. There is no definitive drug
therapy for limb ischemia in patients with TAO. Vascular reconstructive surgery is usually not a viable
option because of the segmental nature of this disease and the involvement of distal vessels. An
autogenous saphenous vein bypass graft can be considered if a target vessel for the distal
anastomosis is available. Long-term patency rates are better in ex-smokers than in smokers.

References: ??

45