■■FURTHER READING TABLE 265-1  Classification of Pericarditis
Gilboa SM et al: Congenital Heart Defects in the United States: Clinical Classification
Estimating the magnitude of the affected population in 2010.
Circulation 134:101, 2016.
Gurvitz M et al: Emerging Research Directions in Adult Congenital
Heart Disease: A report from an NHLBI/ACHA Working Group.
J Am Coll Cardiol 67:1956, 2016.
Regitz-Zagrosek V et al: ESC guidelines on the management of cardio-
vascular diseases during pregnancy: The Task Force on the Manage-
ment of Cardiovascular Diseases during Pregnancy of the European
Society of Cardiology (ESC). Eur Heart J 32:3147, 2011.
Warnes CA et al: ACC/AHA 2008 guidelines for the management
of adults with congenital heart disease: A report of the American
College of Cardiology/American Heart Association Task Force on
Practice Guidelines (writing committee to develop guidelines on the
management of adults with congenital heart disease). Circulation
118:e714, 2008.
Webb G et al: Specialized adult congenital heart care saves lives.
Circulation 129:1795, 2014.
Webb G et al: The care of adults with congenital heart disease across
the globe: Current assessment and future perspective: A position
statement from the International Society for Adult Congenital Heart
Disease (ISACHD). Int J Cardiol 195:326, 2015.
265 Pericardial Disease
Eugene Braunwald
■■NORMAL FUNCTIONS OF THE PERICARDIUM
The normal pericardium is a double-layered sac; the visceral pericar-
dium is a serous membrane that is separated from the fibrous parietal
pericardium by a small quantity (15–50 mL) of fluid, an ultrafiltrate
of plasma. The normal pericardium, by exerting a restraining force,
prevents sudden dilation of the cardiac chambers, especially the right
atrium and ventricle, during exercise and with hypervolemia. It also
restricts the anatomic position of the heart, and probably retards the
spread of infections from the lungs and pleural cavities to the heart.
Nevertheless, total absence of the pericardium, either congenital or
after surgery, does not produce obvious clinical disease. In partial left
pericardial defects, the main pulmonary artery and left atrium may
bulge through the defect; very rarely, herniation and subsequent stran-
gulation of the left atrium may cause sudden death.
ACUTE PERICARDITIS
Acute pericarditis, by far the most common pathologic process
involving the pericardium (Table 265-1), has four principal diagnostic
features:
1. Chest pain is usually present in acute infectious pericarditis and in
many of the forms presumed to be related to hypersensitivity, autoim-
munity, or of unknown cause (idiopathic). The pain of acute pericar-
ditis is often severe, retrosternal and/or left precordial, and referred
to the neck, arms, or left shoulder. Frequently the pain is pleuritic,
consequent to accompanying pleural inflammation (i.e., sharp and
aggravated by inspiration and coughing), but sometimes it is steady,
radiates to the trapezius ridge, or into either arm, and resembles that
of myocardial ischemia; therefore, confusion with acute myocardial
infarction (AMI) is common. Characteristically, pericardial pain may
be intensified by lying supine, and relieved by sitting up and leaning
forward (Chap. 11). Pain is often absent in slowly developing tubercu-
lous, postirradiation, neoplastic, and uremic pericarditis.
  The differentiation of AMI from acute pericarditis may be chal-
lenging when, with the latter, serum biomarkers of myocardial
damage such as troponin and creatine kinase-MB rise, presumably
because of concomitant involvement of the epicardium in the
Harrisons_20e_Part6_p1649-p1942.indd 1841
1841
I.  Acute pericarditis (<6 weeks)
A. Fibrinous
CHAPTER 265 Pericardial Disease
B.  Effusive (serous or sanguineous)
II.  Subacute pericarditis (6 weeks to 6 months)
A. Effusive-constrictive
B. Constrictive
III.  Chronic pericarditis (>6 months)
A. Constrictive
B.  Adhesive (nonconstrictive)
Etiologic Classification
I.  Infectious pericarditis
A. Viral (coxsackievirus A and B, echovirus, herpesviruses, mumps,
adenovirus, hepatitis, HIV)
B. Pyogenic (pneumococcus, Streptococcus, Staphylococcus, Neisseria,
Legionella, Chlamydia)
C. Tuberculous
D.  Fungal (histoplasmosis, coccidioidomycosis, Candida, blastomycosis)
E.  Other infections (syphilitic, protozoal, parasitic)
II.  Noninfectious pericarditis
A. Acute idiopathic
B. Renal failure
C. Neoplasia
1.  Primary tumors (benign or malignant, mesothelioma)
2. Tumors metastatic to pericardium (lung and breast cancer,
lymphoma, leukemia)
D. Trauma (penetrating chest wall, nonpenetrating)
E. Aortic dissection (with leakage into pericardial sac)
F. Acute myocardial infarction
G. Postirradiation
H. Familial Mediterranean fever
I. Familial pericarditis
1.  Mulibrey nanisma
J. Metabolic (myxedema, cholesterol)
III.  Pericarditis presumably related to hypersensitivity or autoimmunity
A.  Rheumatic fever
B. Collagen vascular disease (systemic lupus erythematosus, rheumatoid
arthritis, ankylosing spondylitis, scleroderma, acute rheumatic fever,
granulomatosis with polyangiitis [Wegener’s])
C. Drug-induced (e.g., procainamide, hydralazine, phenytoin, isoniazid,
minoxidil, anticoagulants, methysergide)
D.  Postcardiac injury
1. Postpericardiotomy
2. Posttraumatic
3.  Postmyocardial infarction (Dressler’s syndrome)
a
An autosomal recessive syndrome characterized by growth failure, muscle
hypotonia, hepatomegaly, ocular changes, enlarged cerebral ventricles, mental
retardation, ventricular hypertrophy, and chronic constrictive pericarditis.
inflammatory process (an epi-myocarditis) with resulting myocyte
necrosis. However, these elevations, if they occur, are quite modest
compared to those in AMI, given the extensive electrocardiographic
ST-segment elevation in pericarditis. This dissociation is useful in
differentiating between these conditions.
2. A pericardial friction rub is audible at some point in the illness in
about 85% of patients with acute pericarditis, it may have up to
three components per cardiac cycle, is rasping, scratching, or grating
(Chap. 234). It is heard most frequently at end expiration with the
patient upright and leaning forward.
3. The electrocardiogram (ECG) in acute pericarditis without massive
effusion usually displays changes secondary to acute subepicardial
inflammation (Fig. 265-1A). It typically evolves through four stages.
In stage 1, there is widespread elevation of the ST segments, often
with upward concavity, involving two or three standard limb leads
6/1/18 12:54 PM
 1842
I aVR
PR
ST
PART 6
II aVL
Disorders of the Cardiovascular System
III aVF
I aVR
II aVL
III aVF
II
B
FIGURE 265-1  A. Acute pericarditis. There are diffuse ST-segment elevations in leads I, II, aVF, and V2–V6). There is PR-segment depression due to a concomitant atrial
injury current. B. Electrical alternans. This tracing was obtained from a patient with a large pericardial effusion with cardiac tamponade.
and V2–V6, with reciprocal depressions only in aVR and sometimes
V1. Also, there is depression of the PR segment below the TP seg-
ment, reflecting atrial involvement. Usually there are no significant
changes in QRS complexes, unless a large pericardial effusion
develops (see below). After several days, the ST segments return
to normal (stage 2), and only then, or even later, do the T waves
become inverted (stage 3). Weeks or months after the onset of acute
pericarditis, the ECG returns to normal (stage 4). In contrast, in
AMI, ST elevations are upwardly convex, and reciprocal depression
is usually more prominent; these changes may return to normal
within a day or two. Q waves may develop, with loss of R-wave
amplitude, and T-wave inversions; these changes are usually
seen within hours before the ST segments have become isoelectric
(Chaps. 268 and 269).
4. Pericardial effusion is usually associated with pain and/or the ECG
changes mentioned above, and if the effusion is large with electrical
alternans (Fig. 265-1B). Pericardial effusion is especially important
clinically when it develops within a relatively short time because
it may lead to cardiac tamponade (see below). Differentiation from
cardiac enlargement on physical examination may be difficult, but
heart sounds may be fainter with large pericardial effusion. The
friction rub and the apex impulse may disappear. The base of the
left lung may be compressed by pericardial fluid, producing Ewart’s
sign, a patch of dullness and increased fremitus beneath the angle of
the left scapula. The chest roentgenogram may show enlargement of
the cardiac silhouette, with a “water bottle” configuration, but may
be normal in patients with small effusions.
Harrisons_20e_Part6_p1649-p1942.indd 1842
V1 V4
ST
PR
V2 V5
V3 V6
V1 V4
V2 V5
V3 V6
Diagnosis  Echocardiography (Chap. 236) is the most widely used
imaging technique. It is sensitive, specific, simple, noninvasive, may
be performed at the bedside, and allows localization and estimation
of the quantity of pericardial fluid. The presence of pericardial fluid
is recorded by two-dimensional transthoracic echocardiography as a
relatively echo-free space between the posterior pericardium and left
ventricular epicardium and/or as a space between the anterior right
ventricle and the parietal pericardium just beneath the anterior chest
wall (Fig. 265-2).
The diagnosis of pericardial fluid or thickening may be confirmed
by computed tomography (CT) or magnetic resonance imaging (MRI).
These techniques may be superior to echocardiography in detecting
loculated pericardial effusions, pericardial thickening, and the identifi-
cation of pericardial masses. MRI is also helpful in detecting pericardial
inflammation (Fig. 265-3).
TREATMENT
Acute Pericarditis
There is no specific therapy for acute idiopathic pericarditis, but bed
rest and anti-inflammatory treatment with aspirin (2–4 g/d), with
nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibupro-
fen (600–800 mg tid) or indomethacin (25–50 mg tid), and should
be administered along with gastric protection (e.g., omeprazole
20 mg/d). In responsive patients, these doses should be continued
for 1–2 weeks and then tapered over several weeks. In addition,
6/1/18 12:54 PM

FIGURE 265-2  Two-dimensional echocardiogram in lateral view in a patient with a
large pericardial effusion. Ao, aorta; LV, left ventricle; pe, pericardial effusion; RV,
right ventricle. (From M Imazio: Curr Opin Cardiol 27:308, 2012.)
colchicine (0.5 mg qd [<70 kg] or 0.5 mg bid [>70 kg]), should be
administered for 3 months. Colchicine enhances the response to
NSAIDs and also aids in reducing the risk of recurrent pericarditis.
This drug is concentrated in and interferes with the migration of
neutrophils, may cause diarrhea and other gastrointestinal side
effects, and is contraindicated in patients with hepatic or renal dys-
function. Glucocorticoids (e.g., prednisone 1 mg/kg per day) usually
suppress the clinical manifestations of acute pericarditis in patients
who have failed therapy with or do not tolerate NSAIDs and colchic-
ine. However, since they increase the risk of subsequent recurrence,
full-dose corticosteroids should be given for only 2–4 days and then
tapered. Anticoagulants should be avoided because their use could
cause bleeding into the pericardial cavity and tamponade.
In patients with multiple, frequent, and disabling recurrences that
continue for more than 2 years, and are not prevented by continuing
colchicine and other NSAIDs and are not controlled by glucocor-
ticoids, azathioprine, or anakinra (an IL-1β receptor antagonist)
have been reported to be of benefit. Rarely, pericardial stripping
may be necessary but this procedure may not always terminate the
recurrences.
The majority of patients with acute pericarditis can be managed
as outpatients with careful follow-up. However, when specific
causes (tuberculosis, neoplastic disease, bacterial infection) are sus-
pected, or if any of the predictors of poor prognosis (fever >38°C,
subacute onset, or large pericardial effusion) are present, hospital-
ization is advisable.
RV
LV
A B
FIGURE 265-3  Pericardial inflammation by cardiac magnetic resonance imaging. A. Short axis view. The pericardium is thickened and enhanced on T2 magnetic
images. Note thickened white line denoted by arrow. B. Long axis view. Late gadolinium enhancement of thickened, inflamed pericardium. AO, aorta; LA, left atrium;
LV, left ventricle; RV, right ventricle. (From RY Kwong: Cardiovascular magnetic resonance imaging, in Braunwald’s Heart Disease, 10th ed, Mann DL et al [eds]. Philadelphia:
Elsevier, 2015, pp 320–40.)
Harrisons_20e_Part6_p1649-p1942.indd 1843
■■CARDIAC TAMPONADE 1843
The accumulation of fluid in the pericardial space in a quantity suf-
ficient to cause serious obstruction of the inflow of blood into the
ventricles results in cardiac tamponade. This complication may be fatal
if it is not recognized and treated promptly. The most common causes
CHAPTER 265 Pericardial Disease
of tamponade are idiopathic pericarditis and pericarditis secondary to
neoplastic disease, tuberculosis, or bleeding into the pericardial space
after leakage from an aortic dissection, cardiac operation, trauma, and
treatment with anticoagulants.
The three principal features of tamponade (Beck’s triad) are hypoten-
sion, soft or absent heart sounds, and jugular venous distention with
a prominent x (early systolic) descent but an absent y (early diastolic)
descent. The limitations to ventricular filling are responsible for reduc-
tions of cardiac output and arterial pressure. The quantity of fluid
necessary to produce cardiac tamponade may be as small as 200 mL
when the fluid develops rapidly to as much as >2000 mL in slowly
developing effusions when the pericardium has had the opportunity
to stretch and adapt to an increasing volume.
A high index of suspicion for cardiac tamponade is required because
in many instances no obvious cause for pericardial disease is apparent,
and this diagnosis should be considered in any patient with otherwise
unexplained sudden enlargement of the cardiac silhouette, hypotension,
and elevation of jugular venous pressure. There also may be reductions
in amplitude of the QRS complexes, and electrical alternans of the P, QRS,
or T waves should raise the suspicion of cardiac tamponade (Fig. 265-1).
Table 265-2 lists the features that distinguish acute cardiac tampon-
ade from constrictive pericarditis.
Paradoxical Pulse  This important clue to the presence of cardiac
tamponade consists of a greater than normal (10 mmHg) inspiratory
decline in systolic arterial pressure. When severe it may be detected by
palpating weakness or even disappearance of the arterial pulse during
inspiration, but usually sphygmomanometric measurement of systolic
pressure during slow respiration is required.
Because both ventricles share a tight incompressible covering, i.e.,
the pericardial sac, the inspiratory enlargement of the right ventricle
causes leftward bulging of the interventricular septum, compresses
and reduces left ventricular volume; stroke volume, and arterial sys-
tolic pressure. Paradoxical pulse also occurs in approximately one-third
of patients with constrictive pericarditis (see below), and in some cases
of hypovolemic shock, acute and chronic obstructive airway disease,
and pulmonary embolism. Right ventricular infarction (Chap. 269)
may resemble cardiac tamponade with hypotension, elevated jugular
venous pressure, an absent y descent in the jugular venous pulse, and,
occasionally, a paradoxical pulse (Table 265-2).
Diagnosis  Because immediate treatment of cardiac tamponade
may be lifesaving, prompt establishment of the diagnosis, usually by
echocardiography, should be undertaken. When pericardial effusion
causes tamponade, Doppler ultrasound shows that tricuspid and
pulmonic valve flow velocities increase markedly during inspiration,
AO
LA
LV
* *
*
6/1/18 12:54 PM
 1844 TABLE 265-2  Features That Distinguish Cardiac Tamponade from Constrictive Pericarditis and Similar Clinical Disorders
EFFUSIVE
CONSTRICTIVE RESTRICTIVE CONSTRICTIVE
CHARACTERISTIC TAMPONADE PERICARDITIS CARDIOMYOPATHY RVMI PERICARDITIS
Clinical
PART 6

Pulsus paradoxus +++ + + + +++

Jugular veins
 Prominent y descent – ++ + + –
 Prominent x descent +++ ++ +++ + +++
Disorders of the Cardiovascular System

  Kussmaul’s sign – +++ + +++ ++

Third heart sound – – + + +
Pericardial knock – ++ – – –
Electrocardiogram
Low ECG voltage ++ ++ + – +
Electrical alternans ++ – – – +
Echocardiogram
Thickened pericardium – +++ – – ++
Pericardial calcification – ++ – – _
Pericardial effusion +++ – – – ++
RV size Usually small Usually normal Usually normal Enlarged Usually normal
Exaggerated respiratory +++ +++ – +++ +
variation in flow velocity
CT/MRI
Thickened pericardium – +++ – ++
Equalization of diastolic +++ +++ – ++ ++
pressures
Abbreviations: +++, always present; ++, usually present; +, rare; –, absent; DC, diastolic collapse; ECG, electrocardiogram; RV, right ventricle; RVMI, right ventricular
myocardial infarction.
Source: Adapted from GM Brockington et al: Cardiol Clin 8:645, 1990, with permission.

whereas pulmonic vein, mitral, and aortic flow velocities diminish (as injury. In developing nations, tuberculosis, often associated with
in constrictive pericarditis, see below) (Fig. 265-4). In tamponade, there HIV infection, may also cause exudative and/or bloody effusion.
is late diastolic inward motion (collapse) of the right ventricular free The pericardial fluid should be analyzed for red and white blood
wall and the right atrium. Transesophageal echocardiography, CT, or cells and cytology for neoplastic cells. Cultures should be obtained.
cardiac MRI may be necessary to diagnose a loculated effusion respon- The presence of DNA of Mycobacterium tuberculosis determined by
sible for cardiac tamponade. the polymerase chain reaction strongly supports the diagnosis of
tuberculous pericarditis (Chap. 173).
TREATMENT
Cardiac Tamponade ■■VIRAL OR IDIOPATHIC ACUTE PERICARDITIS
In many instances, acute pericarditis occurs in association with or
Patients with acute pericarditis should be observed frequently for following illnesses of known or presumed viral origin and probably
the development of an effusion. If a large effusion is present, pericar- is caused by the same agent. There may be an antecedent infection
diocentesis should be carried out or the patient watched closely for
signs of tamponade with serial echocardiography and monitoring of
Inspiration Expiration
arterial and venous pressures.
E Septum Septum
PERICARDIOCENTESIS A E
A
If manifestations of tamponade appear, pericardiocentesis using an
apical, parasternal, or, most commonly, subxiphoid approach must TV MV TV MV
be carried out at once because if left untreated, tamponade may be RV LV
Doppler
rapidly fatal. Whenever possible, this procedure should be carried transvalvular
out under echocardiographic guidance. Intravenous saline may be inflow patterns
administered as the patient is being readied for the procedure, but Thickened
the pericardiocentesis must not be delayed. If possible, intrapericar- pericardium
dial pressure should be measured before fluid is withdrawn, and RA
Pulmonary
the pericardial cavity should be drained as completely as possible. LA vein
A small, multiholed catheter may be advanced over the needle
inserted into the pericardial cavity and left in place to allow drain- DIASTOLE DIASTOLE
ing of the pericardial space if fluid reaccumulates. Surgical drainage IVC and hepatic veins
through a limited (subxiphoid) thoracotomy may be required in Apical 4-chamber views
recurrent tamponade to remove loculated effusions, and/or when it
FIGURE 265-4  Constrictive pericarditis. Doppler schema of respirophasic
is necessary to obtain tissue for diagnosis.
changes in mitral and tricuspid inflow. Reciprocal patterns of ventricular filling
Pericardial fluid obtained from an effusion may have the physical are assessed on pulsed Doppler examination of mitral valve (MV) and tricuspid
characteristics of an exudate. In developed nations, bloody fluid valve (TV) inflow. IVC, inferior vena cava; LA, left atrium; LV, left ventricle; RA, right
is most commonly due to neoplasm, renal failure, or after cardiac atrium; RV, right ventricle. (Courtesy of Bernard E. Bulwer, MD; with permission.)

Harrisons_20e_Part6_p1649-p1942.indd 1844 6/1/18 12:54 PM

 of the respiratory tract, but viral isolation and serologic studies are
usually negative. In some cases coxsackievirus A or B or the virus of
influenza, echovirus, mumps, herpes simplex, chickenpox, adenovi-
rus, or cytomegalovirus has been isolated from pericardial fluid and/
or appropriate elevations in viral antibody titers have been observed.
Frequently, a viral cause cannot be established, and the term idiopathic
acute pericarditis is appropriate.
Viral or idiopathic acute pericarditis occurs at all ages but is most
common in young adult males, and is often associated with pleural
effusion and pneumonitis. The almost simultaneous development of
fever and precordial pain, often 10–12 days after a presumed viral
illness, constitutes an important feature in the differentiation of acute
pericarditis from AMI, in which chest pain precedes fever. The con-
stitutional symptoms are usually mild to moderate, and a pericardial
friction rub is often audible. The disease ordinarily runs its course in a
few days to 4 weeks. Elevations of C-reactive protein and of the white
blood cell count are common. The ST-segment alterations in the ECG
usually disappear after 1 or more weeks, but the abnormal T waves
may persist for several years and be a source of confusion in persons
without a clear history of pericarditis. Accumulation of some pericar-
dial fluid is common, and both tamponade and constrictive pericarditis
are possible, but infrequent, complications.
The most frequent complication is recurrent (relapsing) pericarditis,
which occurs in about one-fourth of patients with acute idiopathic peri-
carditis. In a smaller number, there are multiple recurrences.
Postcardiac Injury Syndrome  Acute pericarditis may appear
in a variety of circumstances that have one common feature—previous
injury to the myocardium with blood in the pericardial cavity. The
syndrome may develop after a cardiac operation (postpericardiotomy
syndrome), after blunt or penetrating cardiac trauma (Chap. S8), or
after perforation of the heart with a catheter; rarely, it follows AMI.
The clinical picture mimics acute viral or idiopathic pericarditis.
The principal symptom is the pain of acute pericarditis, which usually
develops 1–4 weeks after the cardiac injury. Recurrences are common
and may occur up to 2 years or more following the injury. Fever, pleuri-
tis, and pneumonitis are accompanying features, and the illness usually
subsides in 1 or 2 weeks. The pericarditis may be of the fibrinous vari-
ety, or it may be a pericardial effusion, which is often serosanguineous
and rarely causes tamponade. ECG changes typical of acute pericarditis
may also occur. This syndrome is probably the result of a hypersen-
sitivity reaction to antigen(s) that originate from injured myocardial
tissue and/or pericardium.
Often no treatment is necessary aside from aspirin and analgesics.
When the illness is severe or followed by a series of disabling recur-
rences, therapy with another NSAID, colchicine, or a glucocorticoid,
such as described for treatment of acute pericarditis, is usually effective.
■■DIFFERENTIAL DIAGNOSIS
Because there is no specific test for acute idiopathic pericarditis, the diag-
nosis is one of exclusion. Consequently, all other disorders that may be
associated with acute fibrinous pericarditis must be considered. A com-
mon diagnostic error is mistaking acute viral or idiopathic pericarditis
for AMI and vice versa.
Pericarditis secondary to postcardiac injury is differentiated from
acute idiopathic pericarditis chiefly by timing. If it occurs within a few
days or weeks of a chest blow, a cardiac perforation, a cardiac opera-
tion, or an AMI, the two are probably related.
It is important to distinguish pericarditis due to collagen vascular dis-
ease from acute idiopathic pericarditis. Most important in the differen-
tial diagnosis is the pericarditis due to systemic lupus erythematosus
(SLE; Chap. 349) or drug-induced (procainamide or hydralazine)
lupus. When pericarditis occurs in the absence of any obvious under-
lying disorder, the diagnosis of SLE may be suggested by a rise in the
titer of antinuclear antibodies. Acute pericarditis is an occasional com-
plication of rheumatoid arthritis, scleroderma, and polyarteritis nodosa, and
other evidence of these diseases is usually obvious.
Pyogenic (purulent) pericarditis is usually secondary to cardiothoracic
operations, by extension of infection from the lungs or pleural cavities,
from rupture of the esophagus into the pericardial sac, or from rupture
Harrisons_20e_Part6_p1649-p1942.indd 1845
of a valvular ring abscess in a patient with infective endocarditis. It 1845
may also complicate the viral, bacterial, mycobacterial, and fungal
infections that occur with HIV infection. It is generally accompanied
by fever, chills, septicemia, and evidence of infection elsewhere and
generally has a poor prognosis. The diagnosis is made by examination
CHAPTER 265 Pericardial Disease
of the pericardial fluid. It requires immediate drainage as well as vig-
orous antibiotic treatment.
Pericarditis of renal failure (uremic pericarditis) occurs in up to one-third of
patients with severe renal dysfunction, and is also seen in patients under-
going chronic dialysis who have normal levels of blood urea (dialysis-
associated pericarditis). These two forms of pericarditis may be fibrinous
and are generally associated with serosanguineous effusions. A pericar-
dial friction rub is common, but pain is usually absent or mild. Treatment
with an NSAID and intensification of dialysis are usually adequate.
Occasionally, tamponade occurs and pericardiocentesis is required. When
the pericarditis of renal failure is recurrent or persistent, a pericardial win-
dow should be created or pericardiectomy may be necessary.
Pericarditis due to neoplastic diseases results from extension or inva-
sion of metastatic tumors (most commonly carcinoma of the lung and
breast, malignant melanoma, lymphoma, and leukemia) to the pericar-
dium. The pain of pericarditis, tamponade, and atrial arrhythmias are
complications that occur occasionally. Diagnosis is made by pericardial
fluid cytology or pericardial biopsy. Mediastinal irradiation for neoplasm
may cause acute pericarditis and/or chronic constrictive pericarditis.
Unusual causes of acute pericarditis include syphilis, fungal infection
(histoplasmosis, blastomycosis, aspergillosis, and candidiasis), and
parasitic infestation (amebiasis, toxoplasmosis, echinococcosis, and
trichinosis) (Table 265-1).
■■CHRONIC PERICARDIAL EFFUSIONS
Chronic pericardial effusions are sometimes encountered in patients
without an antecedent history of acute pericarditis. They may cause
few symptoms per se, and their presence may be detected by finding
an enlarged cardiac silhouette on a chest roentgenogram. Tuberculosis
and myxedema may be causal. Neoplasms, SLE, rheumatoid arthritis,
mycotic infections, radiation therapy to the chest, and chylopericardium
may also cause chronic pericardial effusion and should be considered
and specifically sought in such patients. Aspiration and analysis of the
pericardial fluid are often helpful in diagnosis. Pericardial fluid should
be analyzed as described under pericardiocentesis. Grossly sanguineous
pericardial fluid results most commonly from a neoplasm, tuberculosis,
renal failure, or slow leakage from an aortic dissection. Pericardiocen-
tesis may resolve large effusions, but pericardiectomy may be required
in patients with recurrence. Intrapericardial instillation of sclerosing
agents may be used to prevent reaccumulation of fluid.
CHRONIC CONSTRICTIVE PERICARDITIS
This disorder results when the healing of an acute fibrinous or serofi-
brinous pericarditis or the resorption of a chronic pericardial effusion is
followed by obliteration of the pericardial cavity with the formation of
granulation tissue. The latter gradually contracts and forms a firm scar
encasing the heart, which may become calcified. In developing nations,
a high percentage of cases are of tuberculous origin, but this is now an
uncommon cause in North America or Western Europe. Chronic con-
strictive pericarditis may follow acute or relapsing viral or idiopathic
pericarditis, trauma with organized blood clot, or cardiac surgery of any
type, or results from mediastinal irradiation, purulent infection, histo-
plasmosis, neoplastic disease (especially breast cancer, lung cancer, and
lymphoma), rheumatoid arthritis, SLE, or chronic renal failure treated
by chronic dialysis. In many patients, the cause of the pericardial disease
is undetermined, and in these patients an asymptomatic or forgotten
bout of viral pericarditis, idiopathic or acute, may have been the inciting
event.
The basic physiologic abnormality in patients with chronic constric-
tive pericarditis is the inability of the ventricles to fill because of the
limitations imposed by the rigid, thickened pericardium. Ventricular
filling is unimpeded during early diastole but is reduced abruptly
when the elastic limit of the pericardium is reached, whereas in cardiac
tamponade, ventricular filling is impeded throughout diastole. In both
6/1/18 12:54 PM
 1846 conditions, ventricular end-diastolic and stroke volumes are reduced
and the end-diastolic pressures in both ventricles and the mean pres-
sures in the atria, pulmonary veins, and systemic veins are all elevated
to similar levels (i.e., within 5 mmHg of one another). Despite these
hemodynamic changes, systolic function may be normal or only
slightly impaired at rest. However, in advanced cases, the fibrotic pro-
PART 6
cess may extend into the myocardium and cause myocardial scarring
and atrophy, and venous congestion may then be due to the combined
effects of the pericardial and myocardial lesions.
In constrictive pericarditis, the right and left atrial pressure pulses
Disorders of the Cardiovascular System
display an M-shaped contour, with prominent x and y descents. The
y descent, which is absent or diminished in cardiac tamponade, is the
most prominent deflection in constrictive pericarditis; it reflects rapid
early filling of the ventricles. The y descent is interrupted by a rapid
rise in atrial pressure during early diastole, when ventricular filling is
impeded by the constricting pericardium. These characteristic changes
are transmitted to the jugular veins, where they may be recognized by
inspection. In constrictive pericarditis, the ventricular pressure pulses
in both ventricles exhibit characteristic “square root” signs during
diastole. These hemodynamic changes, although characteristic, are not
pathognomonic of constrictive pericarditis and may also be observed in
restrictive cardiomyopathies (Chap. 254, Table 254-2).
■■CLINICAL AND LABORATORY FINDINGS
Weakness, fatigue, weight gain, increased abdominal girth, abdominal
discomfort, and edema are common. The patient often appears chron-
ically ill, and in advanced cases, anasarca, skeletal muscle wasting,
and cachexia may be present. Exertional dyspnea is common, and
orthopnea may occur, although it is usually not severe. The cervical
veins are distended and may remain so even after intensive diuretic
treatment, and venous pressure may fail to decline during inspiration
(Kussmaul’s sign). The latter is common in chronic pericarditis but may
also occur in tricuspid stenosis, right ventricular infarction, and restric-
tive cardiomyopathy.
The pulse pressure is normal or reduced. A paradoxical pulse can be
detected in about one-third of cases. Congestive hepatomegaly is pro-
nounced and may impair hepatic function and cause jaundice; ascites is
common and is usually more prominent than dependent edema. Pleural
effusions and splenomegaly may also be present. The apical pulse is
reduced and may retract in systole (Broadbent’s sign). The heart sounds
may be distant; an early third heart sound (i.e., a pericardial knock)
occurring at the cardiac apex with the abrupt cessation of ventricular
filling is often conspicuous.
The ECG frequently displays low voltage of the QRS complexes
and diffuse flattening or inversion of the T waves. Atrial fibrillation is
present in about one-third of patients. The chest roentgenogram shows
a normal or slightly enlarged heart. Pericardial calcification is most
common in tuberculous pericarditis. Pericardial calcification may, how-
ever, occur in the absence of constriction, and constriction may occur
without calcification.
Inasmuch as the common physical signs of cardiac disease (mur-
murs, cardiac enlargement) may be inconspicuous or absent in chronic
constrictive pericarditis, hepatic enlargement, and dysfunction associ-
ated with jaundice and intractable ascites may lead to a mistaken diag-
nosis of hepatic cirrhosis. This error can be avoided if the neck veins are
inspected and found to be distended.
The transthoracic echocardiogram often shows pericardial thickening,
dilation of the inferior vena cava and hepatic veins, and a sharp halt to
rapid left ventricular filling in early diastole, with normal ventricular
systolic function and flattening of the left ventricular posterior wall.
There is a distinctive pattern of transvalvular flow velocity on Doppler
echocardiography (Fig. 265-4). During inspiration, there is an exag-
gerated reduction in blood flow velocity in the pulmonary veins and
across the mitral valve and a leftward shift of the ventricular septum;
the opposite occurs during expiration. Diastolic flow velocity in the
inferior vena cava into the right atrium and across the tricuspid valve
increases in an exaggerated manner during inspiration and declines
during expiration. However, echocardiography cannot definitively
establish or exclude the diagnosis of constrictive pericarditis; CT and
Harrisons_20e_Part6_p1649-p1942.indd 1846
MRI are more accurate, the latter is useful in evaluating myocardial
involvement.
■■DIFFERENTIAL DIAGNOSIS
Like chronic constrictive pericarditis, cor pulmonale (Chap. 252) may
be associated with marked systemic venous hypertension, little pul-
monary congestion, a heart that is not enlarged, and a paradoxical
pulse. However, in cor pulmonale, advanced parenchymal pulmonary
disease is usually apparent and venous pressure falls during inspira-
tion (i.e., Kussmaul’s sign is negative). Tricuspid stenosis (Chap. 261)
may also simulate chronic constrictive pericarditis with congestive
hepatomegaly, splenomegaly, ascites, and venous distention. However,
the characteristic murmur and that of accompanying mitral stenosis
are usually present.
Because it can be corrected surgically, it is important to distin-
guish chronic constrictive pericarditis from restrictive cardiomyopathy
(Chap. 254), which has a similar physiologic abnormality (i.e., restric-
tion of ventricular filling). The differentiating features are summa-
rized in Table 265-2. When a patient has progressive, disabling, and
unresponsive congestive heart failure and displays any of the features
of constrictive heart disease, Doppler echocardiography to record
respiratory effects on transvalvular flow (Fig. 265-4) and an MRI or CT
scan should be obtained to detect or exclude constrictive pericarditis,
because the latter is usually correctable.
TREATMENT
Constrictive Pericarditis
Pericardial resection is the only definitive treatment of constrictive
pericarditis and should be as complete as possible. Dietary sodium
restriction and diuretics are useful during preoperative prepara-
tion. Coronary arteriography should be carried out preoperatively
in patients aged >50 years to exclude unsuspected accompanying
coronary artery disease. The benefits derived from cardiac decorti-
cation are usually progressive over a period of months. The risk of
this operation depends on the extent of penetration of the myocar-
dium by the fibrotic and calcific process, the severity of myocardial
atrophy, the extent of secondary impairment of hepatic and/or renal
function, and the patient’s general condition. Operative mortality is
in the range of 5–10% even in experienced centers; the patients with
the most severe disease, especially secondary to radiation therapy,
are at highest risk. Therefore, surgical treatment should, if possible,
be carried out as early as possible.
Subacute Effusive-Constrictive Pericarditis  This form of
pericardial disease is characterized by the combination of a tense
effusion in the pericardial space and constriction of the heart by thick-
ened pericardium. As such, it shares a number of features with both
chronic pericardial effusion producing cardiac compression and with
pericardial constriction. It may be caused by tuberculosis (see below),
multiple attacks of acute idiopathic pericarditis, radiation, traumatic
pericarditis, renal failure, scleroderma, and neoplasms. The heart is
generally enlarged, and a paradoxical pulse is usually present. After
pericardiocentesis, the physiologic findings may change from those of
cardiac tamponade to those of pericardial constriction. Furthermore,
the intrapericardial pressure and the central venous pressure may
decline, but not to normal. The diagnosis can be established by pericar-
diocentesis followed by pericardial biopsy. Wide excision of both the
visceral and parietal pericardium is usually effective therapy.
Tuberculous Pericardial Disease  This chronic infection is
a common cause of chronic pericardial effusion, especially in the
developing world where active tuberculosis and HIV are endemic.
Tuberculous pericarditis may present as pericardial effusion, chronic
constrictive pericarditis, or subacute effusive constrictive pericarditis
(see above). The clinical picture is that of a chronic, systemic illness
in a patient with pericardial effusion. It is important to consider this
diagnosis in a patient with known tuberculosis, with HIV, and with
fever, chest pain, weight loss, and enlargement of the cardiac silhouette
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 of undetermined origin. If the etiology of chronic pericardial effusion
remains obscure despite detailed analysis including culture of the peri-
cardial fluid, a pericardial biopsy, preferably by a limited thoracotomy,
should be performed. If definitive evidence is still lacking but the spec-
imen shows granulomas with caseation, antituberculous chemotherapy
(Chap. 173) is indicated.
If the biopsy specimen shows a thickened pericardium after
2–4 weeks of antituberculous therapy, pericardiectomy should be car-
ried out to prevent the development of constriction. Tubercular cardiac
constriction should be treated surgically while the patient is receiving
antituberculous chemotherapy.
■■FURTHER READING
Adler Y et al: 2015 ESC guidelines for the diagnosis and management
of pericardial diseases. Eur Heart J 36:2921, 2015.
Alraies MC et al: Usefulness of cardiac magnetic resonance-guided
management in patients with recurrent pericarditis. Am J Cardiol
115:542, 2015.
Cremer PC et al: Complicated pericarditis: Understanding risk factors
and pathophysiology to inform imaging and treatment. J Am Coll
Cardiol 68:2311, 2016.
Garcia MJ: Constrictive pericarditis versus restrictive cardiomyopa-
thy? J Am Coll Cardiol 67:2061, 2016.
Imazio M et al: Efficacy and safety of colchicine for treatment of multi-
ple recurrences of pericarditis (CORP-2); a multicentre, double-blind,
placebo-controlled, randomised trial. Lancet 383:2232, 2014.
LeWinter MM: Acute pericarditis. N Engl J Med 371:2410, 2014.
Lotan D et al: Usefulness of novel immunotherapeutic strategies for
idiopathic recurrent pericarditis. Am J Cardiol 117:861, 2016.
Vistarini N et al: Pericardiectomy for constrictive pericarditis. Ann
Thorac Surg 100:107, 2015.
266 Atrial
Myxoma and Other
Cardiac Tumors
Eric H. Awtry
Cardiac tumors can be broadly classified into those that arise primarily
in the heart and those that reflect metastatic disease from a distant pri-
mary source. Primary cardiac tumors can be further divided into those
that are pathologically benign and those that are malignant. Overall,
primary cardiac tumors are relatively uncommon, whereas secondary
involvement of the heart or pericardium occurs in as many as 20% of
patients with end-stage metastatic cancer. While patients with cardiac
tumors may present with a variety of symptoms, many patients are
asymptomatic at the time of diagnosis as the tumor may be identified
incidentally on imaging studies performed for other reasons. Such
findings need to be differentiated from other cardiac masses such as
vegetation, thrombus, or myocardial hypertrophy. Echocardiography
is usually the initial method of evaluation of cardiac tumors; however,
a variety of imaging modalities are now available and a multimodality
approach is often necessary for accurate diagnosis and clarification of
treatment options (Table 266-1).
■■PRIMARY TUMORS
Primary tumors of the heart are rare. Approximately three-quarters are
histologically benign, and the majority of these tumors are myxomas.
Malignant tumors, almost all of which are sarcomas, account for 25%
of primary cardiac tumors. All cardiac tumors, regardless of pathologic
type, have the potential to cause life-threatening complications. Many
tumors are now surgically curable; thus, early diagnosis is imperative.
Clinical Presentation  Cardiac tumors may present with a wide
array of cardiac and noncardiac manifestations. These manifestations,
Harrisons_20e_Part6_p1649-p1942.indd 1847
TABLE 266-1  Imaging Modalities and Their Utility in the Evaluation 1847
of Cardiac Tumors
MODALITY UTILITY IN CARDIAC TUMOR EVALUATION
Transthoracic Assessment of tumor location and size, and
CHAPTER 266 Atrial Myxoma and Other Cardiac Tumors
echocardiography (TTE) its impact on adjacent structures (e.g., valves,
(including 2-D, 3-D, and pericardium).
contrast)
Transesophageal Improved tumor characterization and spatial
echocardiography (TEE) resolution compared with TTE. May aid in
determining surgical approach.
Cardiac MRI with Improved tissue characterization, definition
gadolinium contrast of tumor size and identification of local
invasion when compared with TTE or TEE. May
differentiate tumor from thrombus.
Gated cardiac CT Provides anatomic assessment and tissue
characterization of the tumor. Useful when
patients cannot tolerate MRI or when MRI is
not feasible (e.g., patients with implantable
cardiac devices). Allows for better assessment of
calcified lesions and evaluation of extra-cardiac
tumor involvement.
Nuclear Imaging (including Definition of extra-cardiac disease. May be
18
F-fluorodeoxyglucose useful in diagnosis of certain cardiac tumors
positron emission (e.g., neuroendocrine tumors) but assessment
tomography [FDG-PET]) of smaller tumors may be limited by surrounding
myocardial FDG uptake.
which depend in large part on the location and size of the tumor as
well as its impact on surrounding cardiac structures, are often non-
specific features of more common forms of heart disease, such as chest
pain, syncope, congestive heart failure (CHF), murmurs, arrhythmias,
conduction disturbances, and pericardial effusion with or without
tamponade. Additionally, embolic phenomena and constitutional
symptoms may occur.
Myxoma  Myxomas are the most common type of primary cardiac
tumor in adults, accounting for one-third to one-half of all cases at post-
mortem examination, and approximately three-quarters of the tumors
treated surgically. They occur at all ages, most commonly in the third
through sixth decades, with a female predilection. Approximately 90%
of myxomas are sporadic; the remainder are familial with autosomal
dominant transmission. The familial variety often occurs as part of a
syndrome complex (Carney complex) that includes (1) myxomas (car-
diac, skin, and/or breast), (2) lentigines and/or pigmented nevi, and
(3) endocrine overactivity (primary nodular adrenal cortical disease
with or without Cushing’s syndrome, testicular tumors, and/or pitu-
itary adenomas with gigantism or acromegaly). Certain constellations
of findings have been referred to as the NAME syndrome (nevi, atrial
myxoma, myxoid neurofibroma, and ephelides) or the LAMB syndrome
(lentigines, atrial myxoma, and blue nevi), although these syndromes
probably represent subsets of the Carney complex. The genetic basis of
this complex has not been elucidated completely; however, inactivating
mutations in the tumor-suppressor gene PRKAR1A, which encodes the
protein kinase A type I-α regulatory subunit, have been identified in
~70% of patients with Carney complex.
Pathologically, myxomas are gelatinous structures that consist of
myxoma cells embedded in a stroma rich in glycosaminoglycans.
Most sporadic tumors are solitary, arise from the interatrial septum
in the vicinity of the fossa ovalis (particularly in the left atrium), and
are often pedunculated on a fibrovascular stalk. In contrast, familial
or syndromic tumors tend to occur in younger individuals, are often
multiple, may be ventricular in location, and are more likely to recur
after initial resection.
Myxomas commonly present with obstructive signs and symptoms.
The most common clinical presentation mimics that of mitral valve dis-
ease: either stenosis owing to tumor prolapse into the mitral orifice or
regurgitation resulting from tumor-induced valvular trauma or distor-
tion. Ventricular myxomas may cause outflow tract obstruction similar
to that caused by subaortic or subpulmonic stenosis. The symptoms
and signs of myxoma may be sudden in onset or positional in nature,
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