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| TEXT BOOK of MEDICINE |
Section VIII Cardiovascular Disease
| 59 DISEASES OF THE MYOCARDIUM AND ENDOCARDIUM William McKenna • |
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▪ MYOCARDIAL DISEASE
Although descriptive rather than etiologic, the usual designation of cardiomyopathy as hypertrophic, dilated, or restrictive has provided a useful clinical and prognostic framework for diagnosis and management (Table 59-1). Many infectious, metabolic, toxic, inflammatory, and other causes have been implicated, but most patients who present with symptoms or incidental abnormalities on routine cardiac evaluation in the absence of significant systemic hypertension, valvular heart disease, or atherosclerotic coronary artery disease have cardiomyopathies that have historically been considered idiopathic (Fig. 59-1). However, most of these patients actually have familial disease involving the sarcomere (hypertrophic cardiomyopathy), the cytoskeleton (dilated cardiomyopathy), or cell adhesion (arrhythmogenic right ventricular cardiomyopathy), although most family members have incomplete gene expression and do not fulfill conventional clinical diagnostic criteria.
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| FIGURE 59-1 Initial approach to classification of cardiomyopathy. The evaluation of symptoms or signs consistent with heart failure first includes confirmation that they can be attributed to a cardiac cause. Although this conclusion is often apparent from routine physical examination and electrocardiography, echocardiography serves to confirm cardiac disease and provides clues to the presence of other cardiac disease, such as focal abnormalities, suggesting primary valve disease or congenital heart disease. Having excluded these conditions, cardiomyopathy is generally considered to be dilated, restrictive, or hypertrophic, as shown in Table 59-1. Patients with apparently normal cardiac structure and contraction are occasionally found to demonstrate abnormal intracardiac flow patterns consistent with diastolic dysfunction but should also be evaluated carefully for other causes of their symptoms. Most patients with so-called diastolic dysfunction also demonstrate at least borderline criteria for left ventricular hypertrophy, frequently in the setting of chronic hypertension and diabetes. A moderately decreased ejection fraction without marked dilation or a pattern of restrictive cardiomyopathy is sometimes referred to as “minimally dilated cardiomyopathy,” which may represent either a distinct entity or a transition between acute and chronic disease. |
▪ Hypertrophic Cardiomyopathy
Definition and Epidemiology
Hypertrophic cardiomyopathy is a genetically determined myocardial disease, which is defined clinically by the presence of unexplained left ventricular hypertrophy and pathologically by the presence of myocyte disarray surrounding increased areas of loose connective tissue. The disease occurs in all racial groups, with a prevalence of between 0.2 and 0.5% in the general population, based on an unexplained left ventricular wall thickness in excess of 1.5 cm.
Pathobiology
Genetics
Hypertrophic cardiomyopathy is usually familial, with autosomal dominant inheritance. Abnormalities in sarcomeric contractile protein genes (Table 59-2) account for approximately 50 to 60% of cases. A similar clinical phenotype is seen in association with several rare genetically determined disorders, including Noonan's syndrome (Chapter 68), Friedreich's ataxia (Chapter 447), neurofibromatosis (Chapter 444), hereditary spherocytosis (Chapter 165), aniridia with catalase deficiency, mitochondrial disease, and several of the glycogen storage diseases (Table 59-3). The available genotype/phenotype studies do not provide a ready explanation for the marked clinical heterogeneity of hypertrophic cardiomyopathy. Studies of families in whom disease-causing genes have been identified do, however, suggest that different genes are associated with particular phenotypes, such as the following: myosin-binding protein C, late-onset expression; troponin T, premature sudden death; and troponin I, variable expression from generation to generation (see later).
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Pathology
Typically, heart weight is increased and the interventricular septum is hypertrophic, although virtually any pattern of thickening may occur. In the normal heart, the true apex is often relatively thinner than other segments. Apical variants characterized by relative or absolute thickening are rare, although hypertrophy commonly is predominantly in the distal ventricle below the papillary muscles. Macroscopically, one often sees a characteristic patch of endocardial thickening on the septum as a consequence of contact with the anterior leaflet of the mitral valve, which is correspondingly thickened.
Histologically, the hallmark of hypertrophic cardiomyopathy is myocyte disarray. This appearance results from the loss of the normal parallel arrangement of myocytes, with cells forming in whorls around foci of connective tissue. Marked variation in the diameter of myocytes and in nuclear size may be noted, as well as abnormal intercellular connections. Myofibrillar architecture within the cells is also disorganized. Myocyte and myofibrillar disarray may be seen in patients with aortic stenosis, long-standing hypertension, and some forms of congenital heart disease, but the extent and severity in hypertrophic cardiomyopathy are typically far greater. The distinction may be problematic from a single myocardial biopsy but rarely is difficult at post mortem, when 5 to 40% of the myocardium may be involved in hypertrophic cardiomyopathy. Myocytolysis with replacement fibrosis and interstitial fibrosis are also common, and abnormal small intramural arteries are typically seen within the fibrotic areas. Patients with extensive fibrosis may have ventricular dilation and reduced systolic function.
Pathophysiology
Left ventricular hypertrophy is usually associated with hyperdynamic indices of systolic performance, impaired diastolic function, and clinical features suggestive of ischemia. Typically, ejection velocity is increased, and a high proportion of stroke volume is ejected early in systole. This appearance of supranormal systolic function is misleading, because indices of systolic performance taken from the long axis of the left ventricle, rather than the short axis, often demonstrate impairment of systolic performance.
Diastolic dysfunction is common, although variable. Many of the characteristic pathophysiologic features of hypertrophic cardiomyopathy, including abnormal ventricular geometry, wall thickening, myocyte hypertrophy, myocyte and myofibrillar disarray, myocardial fibrosis, and ischemia would be expected to impair diastolic function. In most cases, relaxation is slow and prolonged, with elevation of diastolic pressures. A few patients have rapid early filling with restrictive hemodynamic physiology, markedly elevated filling pressures, and atrial dilation, with evidence of right-sided congestion, which may occur in the absence of significant myocardial hypertrophy or impairment of systolic performance. How the recognized genetic mutations cause these histologic and pathophysiologic changes is poorly understood, but inefficient utilization of adenosine triphosphatase by the sarcomere may be the final common pathway, because many of the mitochondrial and metabolic disorders and congenital syndromes that may mimic hypertrophic cardiomyopathy are associated with changes in adenosine triphosphatase synthesis and/or regulation.
Clinical Manifestations
The clinical expression of left ventricular hypertrophy usually occurs during periods of rapid somatic growth, which may be during the first year of life or childhood but more typically during adolescence and, occasionally, in the early 20s. The de novo development of myocardial hypertrophy later in life is uncommon but typically is associated with the development of mild to moderate systolic hypertension in patients with mutations in myosin-binding protein C.
Most patients are asymptomatic or have only mild or intermittent symptoms. Symptomatic progression is usually slow, age related, and associated with a gradual deterioration in left ventricular function over decades. Fewer than 5% of patients may have rapid, symptomatic deterioration in association with progressive myocardial wall thinning, increased left ventricular end-systolic dimensions, and an overall reduction in systolic performance. Such a rapid course is not associated with any particular genetic abnormality.
Symptoms and Signs
Symptoms may develop at any age, even many years after the appearance of electrocardiographic (ECG) or echocardiographic manifestations of left ventricular hypertrophy. Occasionally, sudden death may be the initial presentation. Experience from evaluating families suggests, however, that most affected individuals have few or only paroxysmal symptoms. Approximately 30% of adults develop exertional chest pain (Chapters 48 and 70), which may be atypical, prolonged, and noted at rest or nocturnally. Postprandial angina associated with mild exertion is typical. Mild to moderate dyspnea is common in adults and may relate to left ventricular outflow tract obstruction and/or mitral regurgitation; it probably develops as a consequence of ventricular diastolic dysfunction and raised pulmonary venous pressures.
Occasionally, patients without significant symptoms present with or develop paroxysmal nocturnal dyspnea. Such episodes suggest transient myocardial ischemia or arrhythmias, although evaluations often fail to identify the mechanism.
Approximately 20% of patients experience syncope (Chapter 427), and a similar proportion complain of presyncope. Such symptoms are often attributed to arrhythmias, but documentation may require prolonged ECG monitoring or implantation of an ECG recorder (Chapter 61); in many cases, no underlying cause is identified. Exertion-related syncope or presyncope raises the suspicion of labile left ventricular outflow tract obstruction, exertion-related mitral regurgitation, or ischemia.
Palpitations are a frequent complaint and are usually attributable to supraventricular or ventricular ectopy or to forceful cardiac contractions. Sustained palpitations are usually caused by supraventricular tachyarrhythmias. Initial presentation with a symptomatic arrhythmia, usually atrial fibrillation, is uncommon.
Patients with distal or apical hypertrophy have fewer symptoms, better exercise capacity, no arrhythmias, and good prognosis. Occasionally, however, patients with distal or apical hypertrophy may have severe refractory chest pain or may present with troublesome supraventricular arrhythmias.
Diagnosis
The initial diagnostic evaluation includes a family history focusing on premature cardiac disease or death, a comprehensive medical history focusing on cardiovascular symptoms, a careful physical examination, a 12-lead ECG study, and a two-dimensional echocardiogram. In patients with resting left ventricular outflow tract obstruction (∼20%), the physical examination may demonstrate a rapid upstroke of the arterial pulse, often followed by a second late systolic peak (spike and dome). The left ventricular impulse is forceful, and the typical murmur is heard in late systole, loudest at the left sternal edge, and radiating to the aortic and mitral areas but not into the neck or axilla (Chapter 48). Physiologic and pharmacologic maneuvers that decrease afterload or venous return (e.g., standing, Valsalva maneuver, inhalation of amyl nitrite) or contractility (e.g., a post-extrasystole beat) will increase the intensity of the murmur, whereas interventions that increase afterload and venous return (e.g., squatting or handgrip) will reduce it (see Table 48-2). In contrast, in the majority of patients who do not have left ventricular outflow tract obstruction, the physical signs are subtle and are limited to features reflecting the hyperdynamic contraction (rapid upstroke pulse) and poorly compliant right (prominent a wave in jugular venous pressure) and left (S4 gallop, double-apex beat) ventricles (Chapter 48).
More than 90% of patients have abnormal ECG findings, but no changes are disease specific. The most common abnormalities are left axis deviation (15 to 20%), abnormal Q waves (25 to 30%, most commonly in inferolateral leads), and ST segment or T wave changes (>50%). An isolated increase in the QRS voltage without ST segment changes or T wave inversion is rare in hypertrophic cardiomyopathy. The presence of predominantly distal or apical thickening is associated with giant negative T wave inversion on the ECG tracing.
Two-dimensional echocardiography (Chapter 53) is the mainstay of diagnostic imaging, although magnetic resonance imaging (Chapter 55) and computed tomography (Chapter 54) provide alternatives if the echocardiogram is of poor quality. A wall thickness of more than two standard deviations above the mean, corrected for age, gender, and height, is generally accepted as diagnostic: in adults, this value is typically 1.5 cm or greater in men and 1.3 cm or greater in women. In most patients, the hypertrophy is asymmetrical and involves the anterior and posterior intraventricular septum (Fig. 59-2). The hypertrophy, however, may be more generalized and may involve the free wall of the left ventricle, or it may be localized and confined to areas other than the septum, such as the free wall or posterior wall of the left ventricle.
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| FIGURE 59-2 Hypertrophic obstructive cardiomyopathy. A, The two-dimensional long-axis parasternal view shows the chambers of the heart. The left ventricle posterior wall (LVPW) is thickened, and the most striking abnormality is the hypertrophy of the interventricular septum (IVS). Another characteristic feature is a Venturi effect: as blood leaves the left ventricle (LV), it sucks the anterior leaflet of the mitral valve forward, a phenomenon called systolic anterior motion (SAM). This phenomenon is more clearly shown in the parasternal long-axis M-mode echocardiogram (B). The massive thickening of the septum is also obvious in the M-mode image (IVS). AO = aorta; LA = left atrium; RV = right ventricle. (From Forbes CD, Jackson WF: Color Atlas and Text of Clinical Medicine, 3rd ed. London, Mosby, 2003.) |
The echocardiogram can measure left ventricular outflow tract obstruction, both at rest and after maneuvers (e.g., amyl nitrite, Valsalva) that may worsen or provoke obstruction. Patients with 30 mm Hg or more of left ventricular outflow tract obstruction typically have systolic anterior motion of the mitral valve, with contact of either the anterior (or less commonly) the posterior mitral leaflet with the intraventricular septum during systole, in association with a posteriorly directed jet of mitral regurgitation, the severity of which is usually proportionate to the severity of the obstruction. Most patients with hypertrophic cardiomyopathy have mild to moderate left atrial enlargement as well as echocardiographic evidence of diastolic dysfunction.
Diagnostic Criteria in Patients and First-Degree Relatives
Because genetic analysis is not routinely available outside of research centers, the diagnosis in first-degree relatives relies on the echocardiographic features of unexplained left ventricular hypertrophy. When genetic testing is available, it is at best confirmatory in individuals who meet echocardiographic criteria because the recognized sarcomeric contractile protein gene abnormalities account for only 60% of the cases of hypertrophic cardiomyopathy. Genetic testing is most helpful in first-degree relatives who do not meet conventional echocardiographic criteria but who may, nonetheless, be at risk of the complications of hypertrophic cardiomyopathy. Given the 50% probability of disease in a first-degree relative of a patient with hypertrophic cardiomyopathy, modified diagnostic criteria (Table 59-4) consider the high probability that their otherwise unexplained ECG and echocardiographic findings reflect incomplete disease expression, with the corresponding risks of complications and of passing the gene to their children.
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When available, cardiopulmonary exercise testing with metabolic gas exchange measurements provides an accurate and reproducible assessment of exercise capacity, which can be followed serially. Cardiac catheterization is rarely required for diagnosis or management, but it may be indicated when measurement of intracardiac pressures is required to guide therapeutic decisions (e.g., in patients with severe mitral regurgitation) and for the exclusion of coexistent coronary artery disease in patients with chest pain.
Differential Diagnosis
In the presence of other causes of left ventricular hypertrophy, such as long-standing systemic hypertension or aortic stenosis, the diagnosis of hypertrophic cardiomyopathy may be problematic. However, secondary hypertrophy from other causes rarely exceeds 1.8 cm. Hypertrophy in the highly trained athlete is usually less than 1.6 cm and typically occurs in association with an increased left ventricular end-diastolic dimension and stroke volume, rather than at the expense of the size of the left ventricular cavity. An ECG tracing showing Q waves or inferolateral repolarization changes favors the diagnosis of hypertrophic cardiomyopathy.
Treatment
The aims of management are to improve symptoms and prevent disease-related complications (Fig. 59-3).
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| FIGURE 59-3 Approach to the management of hypertrophic cardiomyopathy (HCM). ICD = implantable cardioverter-defibrillator. (Adapted from Maron BJ, McKenna WJ, Danielson GK, et al: American College of Cardiology/European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy. J Am Coll Cardiol 2003;42:1687-1713.) |
Medical Therapy
Symptomatic therapy is influenced by left ventricular morphology and hemodynamics. Patients with left ventricular outflow tract gradients and those with mitral regurgitation have higher rates of endocarditis and should undergo antibiotic prophylaxis whenever the risk of bacteremia exists (Chapter 76).
Therapeutic options in patients without left ventricular outflow gradients are limited predominantly to pharmacologic therapy. β-Blockade (starting at a dose equivalent to propranolol, 120 mg/day) may improve chest pain and dyspnea, but patients' responses are variable. The dose should be titrated to achieve a target heart rate of 50 to 70 beats per minute at rest and 130 to 140 beats per minute at peak exercise. The calcium antagonists, verapamil (starting at a dose of 120 mg/day) and diltiazem (starting at a dose of 180 mg/day), provide useful alternatives, particularly in patients with refractory chest pain, but high doses (e.g., verapamil ≥480 mg/day, diltiazem ≥360 mg/day) may be required. In patients with paroxysmal nocturnal dyspnea despite no evidence of ventricular outflow obstruction, a transient mechanism such as myocardial ischemia or arrhythmia may be the cause, although investigations usually fail to identify the precise mechanism. Such patients, as well as those with chronically raised pulmonary pressures, may require diuretics. The dose (typically starting with furosemide, 20 to 40 mg orally as needed, followed by 20 mg/day if required) and duration of diuretic therapy should be minimized because injudicious use of these drugs can be dangerous, particularly in patients with severe diastolic impairment or labile obstruction.
In patients with symptoms associated with significant left ventricular outflow tract obstruction, the main aim of treatment is to reduce the gradient. Options include negative inotropic drugs, surgery, atrioventricular sequential pacing, and percutaneous alcohol ablation. Approximately 60 to 70% of patients improve with β-blockers, although high doses (equivalent to propranolol at 480 mg/day) are frequently required, and side effects are often limiting. When β-blockade alone is ineffective, disopyramide, titrated to the maximum tolerated dose (usually between 400 and 600 mg/day), may be effective in up to two thirds of patients, but side effects, principally related to the anticholinergic effects (e.g., dry eyes and mouth) limit this drug's use. Disopyramide should be given concomitantly with a small to medium dose of a β-blocker (e.g., propranolol, 120 to 240 mg/day), which will slow the heart rate and also blunt rapid atrioventricular nodal conduction should supraventricular arrhythmias develop. In patients who have left ventricular outflow tract obstruction and who are receiving a β-blocker and disopyramide, other antiarrhythmic drugs that alter repolarization (e.g., sotalol or amiodarone) must be avoided because of the potential pro-arrhythmic effect. In patients with outflow tract gradients, verapamil's effects are unpredictable, and acute hemodynamic collapse has been described, particularly in patients with substantial gradients or elevated pulmonary pressures.
Invasive Treatments
Surgery should be considered for significant outflow obstruction (gradient >50 mm Hg) in patients who have symptoms refractory to medical therapy or an exercise capacity less than 70% of predicted. The most commonly performed surgical procedure, ventricular septal myectomy, either abolishes or significantly reduces the gradient in 95% of cases, reduces mitral regurgitation, and improves exercise capacity and symptoms; benefits are maintained long term in 70 to 80% of patients. Surgery should be performed in an experienced center, where mortality rates should be less than 2%. The main complications (atrioventricular block, ventricular septal defects) are rare with intraoperative transesophageal echocardiography and current surgical techniques. In some patients, concomitant mitral valve repair or replacement may be required.
In experienced centers, the selective injection of alcohol into a targeted septal perforator branch of the left anterior descending coronary artery to create a localized septal scar yields outcomes similar to surgery in terms of reducing the outflow gradient and improving symptoms and exercise capacity. The main complication is damage to the conduction system, with a resulting need for a pacemaker in 5 to 10% of patients. In contrast to myectomy, most patients develop right, rather than left, bundle branch block after the procedure. Patients whose outflow tract obstruction predominantly relates to the anatomy of the mitral valve and papillary muscle, rather than to upper septal hypertrophy, will not benefit from alcohol ablation. Dual-chamber pacing using a short-programmed atrial ventricular delay that provides maximum preexcitation while also maintaining effective atrial transport can reduce the outflow gradient by 30 to 50%, but it provides little objective improvement in exercise capacity.
Specific Treatment Situations
Supraventricular Arrhythmia
Palpitations are common; when sustained, they are usually the result of a supraventricular tachyarrhythmia. Atrial fibrillation in hypertrophic cardiomyopathy is associated with significant risk of systemic embolization, so anticoagulation (international normalized ratio in the range of 2.0 to 3.0) should be considered in all patients with sustained or paroxysmal atrial fibrillation (Chapter 63). Treatment with low-dose amiodarone, 1000 to 1400 mg/week, is effective in maintaining sinus rhythm and in controlling the ventricular response during breakthrough episodes. The addition of a low-dose β-blocker (equivalent to propranolol, 120 mg/day), verapamil (120 mg/day) or diltiazem (180 mg/day) may be required for rate control. Serious side effects on low-dose amiodarone are uncommon. β-Blockers, particularly those with class III action (e.g., sotalol, 160 to 240 mg/day) are less effective alternatives. In general, the principles of managing atrial fibrillation in patients with hypertrophic cardiomyopathy are similar to those in other conditions (Chapter 63), with the proviso that the threshold to use anticoagulation should be low because of the significant embolic risk.
Patients at Risk of Sudden Death
Patients with a prior sustained ventricular arrhythmia have fatal events at rates of up to 10% per year, but many sudden deaths occur in patients who have not previously experienced arrhythmic symptoms. Clinical features associated with an increased risk of sudden death include a family history of premature sudden death from hypertrophic cardiomyopathy, unexplained syncope, the presence of nonsustained ventricular tachycardia during ambulatory ECG monitoring, the finding of an abnormal blood pressure response during upright exercise, and severe left ventricular hypertrophy (≥3.0 cm). The presence of two or more of these risk markers is associated with annual sudden death rates of 3 to 6%, and the consensus is that such individuals, as well as those who have experienced symptomatic sustained ventricular arrhythmias, should receive an implantable cardioverter-defibrillator (ICD; Chapter 65). In such patients, the subsequent primary and secondary prevention discharge rates of 5 and 11%, respectively, support the benefit of the approach. Current clinical practice also supports consideration of an ICD in adolescents and young adults with any one of these risk factors. Patients with hypertrophic cardiomyopathy should be advised to avoid competitive sports and intense physical exertion. However, this advice arises from consensus guidelines, although no data prove that abstention from vigorous physical activity modifies risk or prevents sudden death.
Family Screening
First-degree relatives should undergo 12-lead ECG and two-dimensional echocardiographic studies annually during puberty and adolescence and then every 5 years as adults. Family evaluation should include genetic counseling regarding the risk of developing hypertrophic cardiomyopathy and its complications. Efforts to identify early markers of disease expression in adolescents who are known to carry disease-causing genes have focused on echocardiographic Doppler indices of impaired relaxation, which may be abnormal in the absence of left ventricular hypertrophy. The earliest changes are usually seen in the 12-lead ECG tracing: pathologic Q waves, left axis deviation, and inferolateral T wave inversion.
Prognosis
Population data reveal that the mortality rate in adults is approximately 1% per year from sudden death, and preliminary data suggest that patients who carry mutations in cardiac troponin T or in certain β-myosin heavy chain mutations (e.g., Arg403Glu) are at increased risk of sudden death. The rate of significant embolic events in individuals followed in tertiary referral centers is 1 to 4% per year. Embolic strokes are associated with more cardiac symptoms, left atrial enlargement, and paroxysmal supraventricular arrhythmias.
Enzymatic Deficiencies
Specific metabolic enzyme deficiencies also cause increased ventricular mass and restrictive cardiomyopathy, usually without outflow tract obstruction, through the accumulation of abnormal metabolites in the myocardium. Fabry's disease (Chapter 223) results in intracellular glycolipid accumulation in the myocardium, valves, vessel walls, skin, cornea, kidneys, gastrointestinal tract, and central nervous system. Mortality from this X-linked disorder in men results from multiple organ involvement in the fourth or fifth decade. Heterozygous women also can develop cardiomyopathy. Glycogen storage disease (Chapter 219) results from enzyme deficiencies that lead to excessive deposition of normal glycogen in the myocardium, skeletal muscle, and liver. The most common is type II, Pompe's disease, which is associated with dramatic thickening of ventricular septum and free wall, large QRS amplitude, short PR interval, and death usually within the first few years of life.
▪ Myocarditis
Definition
Myocarditis, which is an inflammatory process involving cardiac myocytes, can be caused by infections, immune-mediated damage, or toxins. It can be defined based on histopathologic or clinical criteria.
Epidemiology
Histologic diagnostic criteria for myocarditis were met in 1% of more than 12,000 unselected consecutive autopsies in a Swedish study, in up to 20% of unexpected sudden deaths in young persons, and in 40% of cases of new-onset heart failure in children. Approximately 5% of a virus-infected population have clinical evidence of cardiac involvement.
A wide range of infectious, immune-mediated, toxic, and genetic causes has been implicated (Table 59-5). Viral genome studies of myocardium obtained by endomyocardial biopsy reveal evidence of adenovirus, enterovirus, or cytomegalovirus in 35 to 40% of patients with an acute presentation and histologic features of myocarditis. Trypanosoma cruzi infection (Chagas' disease; Chapter 368) is prevalent in South America, hepatitis C (Chapter 152) myocarditis is more common in Japan, and the parvovirus (Chapter 394) genome is increasingly recognized in Europe and North America. Cardiac involvement in human immunodeficiency virus (HIV) infection (Chapter 407) is associated with a lymphocytic myocarditis and is a strong predictor of poor prognosis. Recently, smallpox vaccination (Chapter 16) has been documented to cause myopericarditis, with a reported incidence of 7.8 cases per 100,000 vaccine administrations.
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Pathobiology
Current knowledge of viral pathogenesis arises predominantly from inoculation of enterovirus (often coxsackievirus B3; Chapter 402) into various strains of mice. Direct myocardial invasion by cardiotropic virus progresses quickly (<5 to 7 days) to immunologic activation, initially with an inflammatory cellular infiltration, and later to activation of cell-mediated immunity, as well as development of autoantibodies directed against contractile (antimyosin), structural (antisarcolemmal), mitochondrial (adenine nucleotide translocator), and receptor (anti–β-adrenergic and anti-M2) proteins. In genetically predisposed mouse strains, immune-mediated myocarditis with production of serum autoantibodies develops following immunization with the relevant organ-specific autoantigens (e.g., cardiac myosin) in the absence of viral inoculation, similar to other autoimmune diseases. In humans, the detection of viral genome following presumed myocardial infection suggests that viral persistence may contribute to ongoing myocardial damage as a component of the immunologic response to infection.
Immune-mediated myocarditis is seen in association with certain systemic inflammatory disorders but is probably more common when no infectious or associated disorder is identified. So-called autoimmune myocarditis may reflect progression of undiagnosed early dilated cardiomyopathy or a response to unrecognized triggers. Antibiotics, antidepressants, anti-inflammatory agents, and diuretics may cause hypersensitivity myocarditis that is associated with peripheral eosinophilia and a myocardial infiltrate with lymphocytes and eosinophils.
Clinical Manifestations
The clinical presentation is variable, ranging from asymptomatic ECG changes, symptoms of arrhythmia, or acute coronary syndromes to the new onset of heart failure. Acute fulminant myocarditis may develop rapidly, with fever, leukocytosis, severe heart failure, and cardiogenic shock. A viral prodrome is reported in 10 to 80% of patients who fulfill histologic diagnostic criteria.
Diagnosis
Evaluation of new-onset features of possible myocarditis should include a history of cardiac symptoms or premature (<40 years of age) familial cardiac disease. A careful history and physical examination should be supplemented by both routine and targeted laboratory testing (Table 59-6). Serum biomarkers of myocardial damage (troponin I or T) have high (>80%) positive predictive value if performed within 1 month of the onset of symptoms, whereas markers of inflammation appear to have low sensitivity and specificity. Noninvasive tests including 12-lead and exercise ECG and two-dimensional echocardiographic studies are recommended. Other studies of possible value include the following: gallium-67 scintigraphy, which detects the extent of myocardial inflammation; antimyosin imaging with indium-111, which detects the extent of myocyte necrosis; and early and late gadolinium-enhanced magnetic resonance imaging, which reflects both inflammation and necrosis.
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Histologic evaluation based on endomyocardial biopsy tissue in patients with new-onset heart failure does not correlate with symptoms or prognosis, nor does it guide therapy. In addition, biopsy yields diagnostic information in only 10 to 20% of patients who present with clinical features of myocarditis. The low yield of biopsy may relate to sampling error (myocarditis is patchy), the timing of biopsy (acute versus chronic disease), interobserver variability in interpretation, and the overall low sensitivity of histologic evaluation in isolation. Biopsy is generally reserved for patients with heart failure (subacute or acute) refractory to standard management, features suggestive of associated cardiac (e.g., conduction defects, arrhythmia) or systemic disease (e.g., connective tissue disease, amyloidosis, hemochromatosis, sarcoidosis), or suspicion of giant cell myocarditis because of new-onset heart failure associated with tachyarrhythmias or conduction disease.
Treatment
Treatment of most patients with myocarditis is supportive. The severity of heart failure determines the level of pharmacologic intervention (Chapter 58) and hemodynamic support. In patients with fulminant myocarditis and severe left ventricular dysfunction, an aggressive short-term approach (e.g., left ventricular assist device, extracorporeal membrane oxygenation) is warranted because of the probability of spontaneous complete recovery. For giant cell myocarditis, which is a usually fatal disease of relatively young healthy adults, heart transplantation is the treatment of choice for most patients.
Recognition that pathogenesis involves immune-mediated damage has led to trials of immunosuppression, but data regarding benefit are unconvincing.1 In general, immunosuppression using high-dose prednisolone (tapered over 3 to 6 months from 60 mg/day down to 5 mg/day) plus azathioprine (1 mg/kg twice daily for ≤6 months) is reserved for patients who have virus-negative myocarditis and whose disease progresses despite maximal supportive therapy, for patients with systemic autoimmune disease or progressive sarcoidosis, or for patients who have idiopathic giant cell myocarditis and are not able to undergo heart transplantation.
Prognosis
Patients with acute myocarditis with mild heart failure or symptoms suggestive of myocardial ischemia/infarction typically improve within weeks without sequelae. An acute presentation of myocarditis with advanced heart failure (ejection fraction <35%) may resolve (25%) but typically (50%) leads to chronic left ventricular dysfunction (dilated cardiomyopathy) or progresses to death or cardiac transplantation (25%). Patients who present with acute fulminant myocarditis, however, have an excellent prognosis, with survival rates of more than 90%. Giant cell myocarditis is usually fatal without heart transplantation.
▪ Myocarditis Syndromes
▪ Viral Myocarditis
Viral myocarditis may be suspected from the clinical picture of recent febrile illness, often with prominent myalgias, followed by angina-like chest pain, dyspnea, or arrhythmias. Elevated troponin levels support the diagnosis, and increasing viral titers (to coxsackievirus, echovirus, adenovirus, or influenza virus) confirm recent infection. The general prognosis of truly “new-onset” heart failure attributed to recent viral infection is major improvement in left ventricular function in up to 50% of patients. If deterioration continues during the months after diagnosis, the prognosis for recovery becomes poor.
▪ Giant Cell Myocarditis
Patients with giant cell myocarditis, which accounts for 10 to 20% of biopsy-positive cases of myocarditis, present with the rapid onset of chest pain, fever, and hemodynamic compromise, often with ventricular tachycardia and/or atrioventricular block. When ventricular tachyarrhythmias are a major feature of myocarditis, particularly in a young person, endomyocardial biopsy is generally recommended to determine whether giant cell myocarditis is present, even though the diagnosis is statistically unlikely. Immunosuppression, although frequently used, does not appear to improve the clinical course, which is usually characterized by rapid deterioration and death from heart failure and refractory ventricular tachyarrhythmias unless cardiac transplantation can be performed.
▪ Human Immunodeficiency Virus Cardiomyopathy
Clinical cardiomyopathy occurs in 10 to 40% of patients infected with HIV (Chapter 407), owing to HIV itself or to coinfection with cytomegalovirus. Treatment is of the underlying HIV infection.
▪ Chagas' Disease
Chagas' disease (Chapter 368), which is caused by infection with Trypanosoma cruzi, affects up to 15% of rural populations in South America, is common in Central America, and is seen elsewhere in immigrants from these endemic areas. The acute tissue-invasive phase can present as myocarditis but is usually silent. Progressive myocardial disease and heart failure are manifested by apical aneurysms, right bundle branch block, and arrhythmias. Serologic diagnosis is made by the complement-fixation (Machado-Guerreiro) test and by immunofluorescent and immunosorbent assays. Antiparasitic agents such as nifurtimox and benzimidazole reduce parasitemia, but benefit in late-phase disease is not established. ICDs may decrease the risk of sudden death from conduction block or tachyarrhythmias. After the development of symptomatic heart failure, the 5-year survival rate is 20%.
▪ Toxoplasmosis
Toxoplasmosis (Chapter 370) myocarditis, owing to intermittent rupture of cysts in the myocardium, can cause atypical chest pain, arrhythmias, pericarditis, and symptomatic heart failure. Diagnosis is made from antibody titers. Therapy is with pyrimethamine and sulfadiazine, but relapses are common.
▪ Lyme Disease
Lyme carditis (Chapter 342) classically presents with conduction system abnormalities resulting from infection with Borrelia burgdorferi, which is diagnosed serologically. However, isolated cases of heart failure occur.
▪ Immune-Mediated Myocarditis
Myocardial inflammation can be associated with polymyositis (Chapter 290) or systemic lupus erythematosus (Chapter 287), although pericarditis and coronary artery vasculitis are more common. Hypersensitivity reactions, especially to drugs (Chapter 275), can cause myocarditis that often is associated with peripheral eosinophilia and can be confirmed by endomyocardial biopsy. Treatment includes discontinuation of the offending agent and corticosteroid therapy.
▪ Peripartum Cardiomyopathy
Peripartum cardiomyopathy appears in the last month of pregnancy or in the first 5 months after delivery in the absence of preexisting cardiac disease (Chapter 259). The incidence is between 1 in 3000 to 15,000 deliveries, with increased risk in older mothers or in the setting of twins, malnutrition, tocolytic therapy, toxemia, or hypertension. Lymphocytic myocarditis, found in 30 to 50% of biopsy specimens, suggests an immune component, perhaps cross-reactivity between uterine and cardiac myocyte proteins or an enhanced susceptibility to viral myocarditis. Presentation is usually with orthopnea and dyspnea on minimal exertion, most often within the first weeks after delivery when the excess volume of pregnancy would normally be mobilized. Preexisting cardiac disease must be excluded. Diuretics facilitate postpartum diuresis, and angiotensin-converting enzyme inhibitors improve symptoms. The prognosis is improvement to normal or near-normal ejection fraction during the next 6 months in more than 50% of patients.
▪ Dilated Cardiomyopathy
Definition and Epidemiology
Dilated cardiomyopathy is characterized by ventricular dilation and impaired contractile performance, which may involve the left or both ventricles. It may develop as a consequence of prior myocarditis or as a result of a recognized toxin, infection, predisposing cardiovascular disease (e.g., hypertension, ischemic or valvular heart disease), or systemic metabolic, neuromuscular, or inflammatory disorder (Table 59-7). For some patients, identification of the specific cause and associated disease will strongly influence diagnosis, management, and prognosis, even though the principles related to the management of heart failure are generic (Chapter 58).
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In the population, about 36 persons per 100,000 have unexplained left ventricular dysfunction with an ejection fraction of less than 40%—a finding that is indicative of advanced disease. Evidence from population data and family studies, however, indicates a higher frequency of asymptomatic left ventricular dysfunction. When no cause or associated disease is identified, dilated cardiomyopathy has been termed idiopathic, although pedigree studies revealed that 50 to 60% of such patients have familial disease, and disease-causing mutations currently can be identified in 10 to 20% of such families.
Pathobiology
In dilated cardiomyopathy, systolic dysfunction may result from a variety of causes (e.g., toxins, infection, ischemia) and pathologic states (e.g., inflammation, high output, genetic abnormalities). The altered hemodynamic parameters of decreased stroke volume and increased chamber pressures trigger the recognized neurohumoral changes of heart failure (Chapter 57) and produce ventricular remodeling with eccentric hypertrophy and cavity dilation, which is distinct from the remodeling seen in hypertrophic and restrictive cardiomyopathy but is similar for all other causes of dilated cardiomyopathy. The insult to myocyte integrity may be relatively acute and may trigger programmed cell death (apoptosis); however, insidious progression is the rule in inherited dilated cardiomyopathy and is also seen with viral persistence, anthracycline toxicity, and autoimmune dilated cardiomyopathy. The systolic dysfunction may reflect a combination of irreversible cell death and reversible dysfunction from inflammatory mediators. Current conventional treatment aims to minimize myocardial stress and triggers of ongoing inflammatory damage. Examples of significant improvement in systolic function raise the possibility of myocardial regenerative capacity, which is being investigated in the context of stem cell and myoblast therapies.
Dilated cardiomyopathy that develops in the absence of significant valvular, hypertensive, or ischemic heart disease is usually familial. Endomyocardial biopsy and long-term follow-up of asymptomatic relatives suggest a natural history of slowly progressive, immune-mediated myocardial damage, with age-related disease expression reaching 90% by the fifth decade. Symptomatic clinical presentation may be triggered by a respiratory tract infection, pregnancy, alcohol, or a salt and water load.
The concept of a trigger with immune-mediated pathogenesis in genetically predisposed individuals is supported by the finding of mutations in genes encoding important structural proteins in 20 to 30% of families with dilated cardiomyopathy; sarcomeric genes (10%) and lamin A/C (5%) are the most common (Table 59-8). One third of probands and family members develop low-titer, organ-specific autoantibodies to cardiac α-myosin, antibodies that are rare in other cardiac diseases or in physiologically normal individuals. The presence of autoantibodies is associated with markers of early disease and may reflect exposure of the immune system to the normally unseen intracytoplasmic antigens from the structurally damaged myocytes. Viral persistence has also been implicated as an ongoing trigger of immune-mediated damage. Preliminary studies do not suggest major phenotypic differences among families with mutations that affect various structural elements in the Z band (i.e., actin), in intermediate filaments (i.e., actinin), or in binding to the extracellular matrix (i.e., dystrophin). Lamin A/C mutations in the nuclear envelope, however, are associated with several distinct phenotypes, including premature conduction disease with late-onset dilated cardiomyopathy, severe early dilated cardiomyopathy with sudden death, and dilated cardiomyopathy in association with Emery-Dreifuss muscular dystrophy (Chapter 447).
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Clinical Manifestations
The classic presentation with a gradual decrease in exercise capacity may be appreciated only in retrospect. The initial presentation is often with acute decompensation triggered by an unrelated problem, such as anemia, thyrotoxicosis, or infection (Chapter 57). Atypical chest pain may be prominent, perhaps reflecting myopericarditis. Presentation with an embolic event from the left ventricle or left atrium or with a sustained arrhythmia is less common. Symptoms relating to raised filling pressures (e.g., orthopnea, nocturnal cough, paroxysmal nocturnal dyspnea, peripheral edema) often precede symptoms of low cardiac output (e.g., dyspnea on exertion). An obvious family history of dilated cardiomyopathy is present in 5 to 10% of patients, although pedigree evaluation elicits suggestive evidence of unexplained premature cardiac disease or embolic events in up to 30% of patients.
Diagnosis
The diagnosis of dilated cardiomyopathy historically has relied on signs or symptoms of heart failure accompanied by indices of advanced left ventricular impairment and dilation. Unexplained less severe abnormalities on physical examination, 12-lead ECG tracings, or two-dimensional echocardiographic study, however, may reflect an early stage of disease with the opportunity to intervene and attenuate or prevent disease progression.
An early diagnosis of dilated cardiomyopathy requires consideration of the common recognized causes: systemic hypertension, valvular heart disease, associated systemic disorders, high-output states, and the muscular dystrophies, each of which is often suggested by the history, physical examination, 12-lead ECG study, and two-dimensional echocardiogram. Coronary angiography may be required, however, to exclude ischemic heart disease in patients with chest pain, risk factors for coronary disease, or age greater than 40 years. Recommended tests (see Table 59-6) include the following: a complete blood count; tests of renal, thyroid, and hepatic function; a chest radiograph to exclude infection; iron and transferrin levels to exclude hemochromatosis; and creatine kinase levels to exclude subclinical skeletal myopathy. Specific viral titers may be required if evidence suggests myocarditis (see Table 59-8).
The ECG changes of early disease are not specific and may include left axis deviation and T wave abnormalities. With progressive and advanced disease, conduction abnormalities develop: PR prolongation, QRS widening, and left bundle branch block. The rapid development of conduction disease in association with left ventricular dysfunction may suggest giant cell myocarditis, whereas progressive conduction disease in the absence of significant left ventricular dysfunction should raise suspicion of sarcoidosis (Chapter 95), myotonic dystrophy (Chapter 447), or disease caused by a mutation in lamin A/C.
As a baseline and for serial assessment to monitor disease progression and the effect of treatment, patients should have a two-dimensional echocardiogram (with measurement of chamber dimensions and calculated indices of systolic function) and a maximal exercise test (ideally with metabolic gas exchange measurements) to provide structural and functional characterization of their disease. Cardiac magnetic resonance imaging (Chapter 55) may provide more accurate measurements of ventricular volume but is generally less practical for serial evaluation. Gadolinium-enhanced magnetic resonance imaging, however, may be very helpful in differentiating segmental wall motion abnormalities in dilated cardiomyopathy from previous myocardial infarction. A myocardial biopsy occasionally should be considered in patients with potential unexplained myocarditis.
Treatment
In the absence of a specific underlying cause or aggravating factor, treatment is as described for the various stages of heart failure (Chapter 58). Supportive therapy includes sodium and fluid restriction, avoidance of alcohol and other toxins, and use of established heart failure medications. Although older recommendations emphasized rest and avoidance of exercise, this advice should be limited to patients with myocarditis or peripartum cardiomyopathy; for other patients, a submaximal exercise regimen is desirable to sustain mobility, to avoid deconditioning, and to maintain physical and psychological well-being. Patients with atrial fibrillation or with echocardiographic evidence of a left atrial or left ventricular mural thrombosis should be anticoagulated to an international normalized ratio of 2.0 to 3.0. An ICD is preferred over medication for ventricular arrhythmias, 2 and some patients require management for advanced heart failure (Chapter 58) with biventricular pacing, inotropic medications, ventricular assist devices, and cardiac transplantation (Chapter 82).
Prevention
Familial evaluation of first-degree relatives by history, by physical examination, and with 12-lead ECG and two-dimensional echocardiographic studies is warranted at the time of diagnosis and serially thereafter. Precise algorithms to determine the interval of evaluation remain to be determined; in the absence of acute myocarditis, disease progression is usually slow, and evaluation about every 5 years until age 50 years appears appropriate. The detection of early disease in a family member offers an opportunity to initiate treatment, usually with an angiotensin-converting enzyme inhibitor or β-blocker, but the efficacy of such therapy remains to be proven.
Prognosis
Prognosis relates to specific treatable causes (e.g., valvular heart disease) and to the overall prognosis of any associated disease (e.g., scleroderma). The prognosis of idiopathic and genetically determined dilated cardiomyopathy is related to the severity of disease at the time of presentation and the response to initial treatment. Most patients improve with treatment, but 5-year survival is less than 50% in patients who present with severe disease (e.g., ejection fraction <25%, left ventricular end-diastolic dimension >65 mm, peak oxygen consumption <12 mL/kg/minute).
▪ Specific Causes of Dilated Cardiomyopathy
Alcoholic Cardiomyopathy
In the United States, excess alcohol consumption (Chapter 31) contributes to more than 10% of cases of heart failure. Alcohol and its metabolite, acetaldehyde, are cardiotoxins acutely and chronically. Myocardial depression is initially reversible but, if sustained, can lead to irreversible vacuolization, mitochondrial abnormalities, and fibrosis. Even in chronic stages, however, the heart failure represents a sum of both reversible and irreversible depression. The amount of alcohol necessary to produce symptomatic cardiomyopathy in susceptible individuals is not known but has been estimated to be six drinks (∼4 oz of pure ethanol) a day for 5 to 10 years. Frequent binging without heavy daily consumption may also be sufficient. Alcoholic cardiomyopathy can develop in patients without social evidence of an alcohol problem. Abstinence leads to improvement in at least 50% of patients with severe symptoms, some of whom normalize their left ventricular ejection fractions. Patients with other causes of heart failure should also limit alcohol consumption.
Chemotherapy
Doxorubicin (Adriamycin) cardiotoxicity (Chapter 192) causes characteristic histologic changes on endomyocardial biopsy, with overt heart failure in 5 to 10% of patients who receive doses greater than or equal to 450 mg/m2 of body surface area. Patients who have received anthracyclines in the prepubertal period without apparent cardiotoxicity may develop cardiac failure in young adulthood. The risk is higher in patients who have lower baseline ejection fractions, concomitant radiation therapy, or higher doses of doxorubicin. Cyclophosphamide and ifosfamide can cause acute severe heart failure and malignant ventricular arrhythmias. Imatinib (Chapter 195) therapy has recently been associated with decreased left ventricular function. 5-Fluorouracil can cause coronary artery spasm and depressed left ventricular contractility. Trastuzumab has been associated with an increased incidence of heart failure, particularly in patients who have received previous chemotherapy for breast cancer (Chapter 208). Interferon-α may be associated with hypotension and arrhythmias in up to 10% of patients, and interleukin-2 rarely has been associated with cardiotoxicity. Treatment consists of discontinuation of chemotherapy and, usually, standard therapy for heart failure (Chapter 58).
Metabolic Causes
Excess catecholamines, as in pheochromocytoma (Chapter 246), may injure the heart by compromising the coronary microcirculation or by direct toxic effects on myocytes. Cocaine (Chapter 32) increases synaptic concentrations of catecholamines by inhibiting reuptake at nerve terminals; the result may be an acute coronary syndrome or chronic cardiomyopathy.
Thiamine deficiency from poor nutrition or alcoholism (Chapter 237) can cause beriberi heart disease, with vasodilation and high cardiac output followed by low output. Calcium deficiency resulting from hypoparathyroidism, gastrointestinal abnormalities, or chelation directly compromises myocardial contractility. Hypophosphatemia (Chapter 120), which may occur in alcoholism, during recovery from malnutrition, and in hyperalimentation, also reduces myocardial contractility. Patients with magnesium depletion owing to impaired absorption or increased renal excretion (Chapter 120) also may present with left ventricular dysfunction.
Hypothyroidism (Chapter 244) depresses contractility and conduction and may cause pericardial effusions, whereas hyperthyroidism increases cardiac output, can worsen underlying heart failure, and may rarely be the sole cause of heart failure. The presenting sign of diabetes (Chapter 247) can be cardiomyopathy, especially with diastolic dysfunction, independent of epicardial coronary atherosclerosis, for which it is a major risk factor. Obesity (Chapter 239) can cause cardiomyopathy with increased ventricular mass and decreased contractility, which improve after weight loss, or it can aggravate underlying heart failure from other causes.
Skeletal Myopathies
Duchenne's muscular dystrophy and Becker's X-linked skeletal muscle dystrophy (Chapter 447) typically include cardiac dysfunction. Emery-Dreifuss muscular dystrophy with abnormalities of the anchoring protein emerin occurs in an X-linked pattern, whereas the same phenotype in an autosomal dominant pattern results from abnormalities of nuclear laminar proteins. Maternally transmitted mitochondrial myopathies such as Kearns-Sayre syndrome (Chapter 447) frequently cause cardiac myopathic changes that can be rapidly progressive in young adulthood.
Overlap with Restrictive Cardiomyopathy
Diseases causing primarily restrictive cardiomyopathies (see later) can occasionally overlap to cause a picture consistent with dilated cardiomyopathy. For example, hemochromatosis (Chapter 231) and sarcoidosis (Chapter 95) should be considered when evaluating any patient with a cardiomyopathy, although these conditions are more often considered with the restrictive diseases. Amyloidosis (Chapter 296) is less commonly confused with dilated than with hypertrophic cardiomyopathy but should be considered in a patient with a thick-walled ventricle with moderately depressed contractile function.
▪ Arrhythmogenic Right Ventricular Cardiomyopathy
Definition and Epidemiology
Arrhythmogenic right ventricular cardiomyopathy (Chapter 64) is a genetically determined heart muscle disorder characterized by fibrofatty replacement of right ventricular myocardium. It is associated with arrhythmia, heart failure, and premature sudden death. The disease is seen in patients of European, African, and Asian descent, with an estimated prevalence in adults of between 1 in 1000 and 1 in 5000.
Pathobiology
Genetics
Arrhythmogenic right ventricular cardiomyopathy is inherited as an autosomal dominant disease, usually with incomplete penetrance, although recessive forms with cutaneous manifestations are recognized (Table 59-9). To date, recognized mutations account for approximately 40% of cases. Mutations in the cardiac ryanodine receptor produce a clinical picture with a closer resemblance to familial catecholaminergic polymorphic ventricular tachycardia (Chapter 64).
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Pathology
The main pathologic feature is progressive loss of right ventricular myocardium, which is replaced by adipose and fibrous tissue. These changes, which are localized, begin in the inflow, outflow, and apical regions of the right ventricle. Aneurysm formation in these areas is typical. Progressive myocardial involvement may lead to global right ventricular dilation. Severe right ventricular disease is usually associated with fibrofatty substitution of the left ventricular myocardium, with the posterolateral wall preferentially affected.
The impairment of desmosomal function under conditions of mechanical stress is hypothesized to cause myocyte detachment and cell death. The acute phase of myocardial injury may be accompanied by inflammation; repair by fibrofatty replacement occurs because regeneration in cardiomyocytes is limited. The increased distensibility of the thin-walled right ventricle appears to confer vulnerability to cell adhesion defects. Early disease shows predilection for the thinnest portions of the right ventricle, whereas left ventricular involvement is often initially in the relatively thin posterolateral wall with sparing of the thicker septum and free wall.
Clinical Manifestations
In general, four phases of disease relate to age. In the early phase, patients are usually asymptomatic, but resuscitated cardiac arrest and sudden death may be the initial manifestations, particularly in children, adolescents, and young adults. The overt arrhythmic phase most often first occurs in adolescents and young adults, when patients note palpitations or syncope. Symptomatic sustained arrhythmias are usually accompanied by morphologic and functional abnormalities of the right ventricle. The third phase, characterized by diffuse right ventricular disease, usually is recognized in the middle and later decades; patients may present with right-sided heart failure despite relatively preserved left ventricular function. In the advanced stage, obvious left ventricular involvement and biventricular heart failure are seen. More than 75% of deaths occur in patients with prior arrhythmic events and/or clinical heart failure.
Diagnosis
Clinical evaluation includes inquiry for symptoms of arrhythmia (syncope, presyncope, sustained palpitation), a family history of premature cardiac symptoms and/or sudden death, 12-lead, 24-hour, and maximal exercise ECG testing, and two-dimensional echocardiography with specific right ventricular views. Contrast echocardiography may be required to obtain better endocardial definition of the right ventricular myocardium and apex of the left ventricle. Magnetic resonance imaging may provide accurate assessment of ventricular volumes as well as noninvasive characterization of fibrous tissue and fat.
Ventricular arrhythmias with a left bundle branch block morphology, consistent with a right ventricular origin, are characteristic. Presentation during the arrhythmic phase may be with an arrhythmia of right ventricular outflow tract origin (left bundle branch block with inferior axis). However, the ECG and arrhythmic manifestations are not specific to arrhythmogenic right ventricular cardiomyopathy and overlap with many other disease states, so standard criteria are recommended for diagnosis (Table 59-10). Because these criteria are highly specific but lack sensitivity for detecting early disease, more sensitive criteria are recommended for first-degree relatives of known cases (Table 59-11). The diagnosis of arrhythmogenic right ventricular cardiomyopathy in a proband also raises the possibility of mutation analysis throughout the family to identify those at risk and in need of serial evaluation, as well as those who need no specific follow-up.
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Differential Diagnosis
The differential diagnosis includes other inherited cardiomyopathies (e.g., hypertrophic, dilated), the inherited arrhythmias (long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia; Chapter 64) as well as anomalous coronary arteries (Chapter 56). The differentiation from so-called benign right ventricular outflow tract tachycardia may be problematic, although in the latter the 12-lead ECG and right ventricular imaging studies are typically normal, and no familial disease is present.
Treatment
Treatment of patients with symptomatic ventricular arrhythmias is with an ICD, with supplemental metoprolol (50 to 200 mg/day), sotalol (160 to 240 mg/day), or even amiodarone (maintenance dose of 200 mg/day) if needed because of atrial fibrillation or frequent shocks.
▪ Restrictive Cardiomyopathy
Definition and Epidemiology
Restrictive cardiomyopathies are characterized by impaired filling and reduced diastolic volume of the left and/or right ventricle despite normal or near-normal systolic function and wall thickness. Primary forms are uncommon, whereas secondary forms, in which the heart is affected as part of a multisystem disorder, usually present at the advanced stage of an infiltrative disease (e.g., amyloidosis or sarcoidosis) or a systemic storage disease (e.g., hemochromatosis). Idiopathic restrictive cardiomyopathy affects both male and female patients and may manifest in children and young adults.
Pathobiology
Genetics
Restrictive cardiomyopathy may be familial. Of the secondary forms, transthyretin amyloidosis (Chapter 296), hemochromatosis, several of the glycogen storage diseases (Chapter 219), and Fabry's disease (Chapter 223) all have a genetic basis (Table 59-12). Familial idiopathic restrictive cardiomyopathy also is part of the genetic and phenotypic expression of hypertrophic cardiomyopathy caused by sarcomeric contractile protein gene abnormalities. Restrictive cardiomyopathy has also been reported in association with skeletal myopathy and conduction system disease as part of the phenotypic spectrum caused by mutations in lamin A or C.
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Pathophysiology
The characteristic dip and plateau (or square root) hemodynamic pattern (Fig. 59-4) during diastole, which is caused by an increased stiffness of the endocardium or myocardium, induces ventricular pressures to rise disproportionately to small changes in volume until a maximum is reached. In infiltrative diseases such as amyloidosis or sarcoidosis, the increased stiffness results from infiltrates within the interstitium between myocardial cells. In the storage disorders, the deposits are within the cells.
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| FIGURE 59-4 Idiopathic restrictive cardiomyopathy. Right ventricular (RV) and left ventricular (LV) pressure electrocardiographic (ECG) tracings in a patient with idiopathic restrictive cardiomyopathy. A dip-and-plateau pattern is seen in both ventricles, and diastolic filling pressures are elevated. The plateaus occur at different pressures, approximately 16 mm Hg for the RV tracing compared with 20 mm Hg for the LV tracing. The diagnosis of restrictive disease was confirmed by thoracotomy. (Redrawn from Benofti JR, Grossman W, Cohn PF: The clinical profile of restrictive cardiomyopathy. Circulation 1980;61:1206.) |
Clinical Manifestations
The presenting clinical features develop as a consequence of raised ventricular filling pressures and are generally not distinguishable from those of heart failure resulting from systolic impairment. In the early stages, the patient may have a decrease in exercise capacity, whereas advanced disease is typically associated with extreme fatigue and dyspnea at rest as part of a low cardiac output state. Atrial dilation and atrial fibrillation are common. Pulmonary congestion, hepatic engorgement, ascites, and peripheral edema develop with advanced disease.
Diagnosis
Diagnosis is based on the demonstration of the abnormal filling pattern and can most usefully be achieved by Doppler echocardiographic evaluation (Chapter 53). Contrast echocardiography or magnetic resonance imaging is useful to delineate the distribution of disease and the extent of mitral and tricuspid valve involvement.
The diagnostic evaluation aims to exclude potentially reversible conditions (e.g., most of the secondary causes of restrictive cardiomyopathy). In such cases, the cardiac manifestations may provide the clues, but definitive diagnosis relies on the demonstration of disease-specific features, such as the following: the presence of abnormal amyloid protein in amyloidosis (Chapter 296), a noncaseating granuloma in sarcoidosis (Chapter 95), abnormal iron studies in hemochromatosis (Chapter 231), and reduced α1-galactosidase levels in Fabry's disease (Chapter 223). Endomyocardial biopsy, although potentially definitive, is rarely required to make these diagnoses. It is often important to exclude constrictive pericarditis (Chapter 77), which is also characterized by rapid early diastolic filling.
Differential Diagnosis
In pericardial constriction, the capacity of the heart to expand is limited by the rigid pericardium, so increases in filling pressures will not result in an increased cardiac volume (Chapter 77). In restrictive cardiomyopathy, by comparison, increases in volume will increase filling pressures and, as a result, increase systemic blood pressure; by the same principle, patients with restrictive cardiomyopathy may be very sensitive to volume depletion.
Although the strictest definition of a restrictive cardiomyopathy requires normal or near-normal left ventricular systolic function and wall thickness with the dip and plateau hemodynamic pattern, diastolic impairment with or without restrictive physiology is also part of the spectrum of the clinical presentation of both hypertrophic and dilated cardiomyopathies. Patients with hypertension (Chapter 66) also may first present with diastolic dysfunction and mild left ventricular hypertrophy before progressing to more marked left ventricular hypertrophy or dilation.
Treatment
In patients with secondary restrictive cardiomyopathies, treatment must address both the underlying systemic disease and the heart failure itself (Chapter 58; Tables 58-2 through 58-5). Diuresis is key but must be undertaken carefully so as not to reduce left ventricular filling pressures to the point of causing hypotension. Angiotensin-converting enzyme inhibitors and β-blockers are commonly recommended despite fewer data on their benefit than in dilated cardiomyopathy. For idiopathic restrictive cardiomyopathy, treatment of heart failure is the only option.
Prognosis
In restrictive cardiomyopathy, the clinical course is usually slow and protracted with an antecedent history that, in retrospect, may go back 5 years or more. Survival from the time of diagnosis is often 10 years or more, except for amyloidosis, which progresses much more rapidly. Symptoms of heart failure with mitral and tricuspid regurgitation are generally progressive and respond poorly to treatments for heart failure. Referral for transplant assessment should be considered early because pulmonary hypertension may develop and necessitate heart and lung transplantation.
▪ Specific Clinical Syndromes
▪ Sarcoidosis
Although cardiac involvement is found in up to 50% of patients with sarcoidosis (Chapter 95) at autopsy, clinical cardiac involvement occurs in fewer than 10% of patients. The presentation is often with conduction defects or ventricular tachyarrhythmias, although granulomas can also compromise the coronary circulation and cause ischemia or infarction. On echocardiogram, the cardiomyopathy may be dilated or restrictive. Biopsy of extracardiac sites is usually adequate for the diagnosis, but a gallium scan often demonstrates cardiac inflammation. A myocardial biopsy may show granulomas or, because of the focal distribution of the lesions, may be nondiagnostic. Corticosteroid therapy may improve arrhythmias, but heart failure may worsen despite such therapy. An ICD is generally indicated for ventricular arrhythmias.
▪ Amyloidosis
Amyloidosis (Chapter 296), which is the most common cause of restrictive cardiomyopathy, can result from either primary amyloidosis in patients with multiple myeloma (Chapter 215) or familial amyloidosis in patients in whom an abnormal transthyretin is deposited in the kidney, liver, and sometimes the heart (Chapter 296). By comparison, secondary amyloidosis rarely involves the heart. Senile amyloidosis, involving normal transthyretin, occasionally causes clinical heart failure in elderly patients but progresses quite slowly compared with primary amyloidosis. Amyloid fibrils infiltrate into the interstitium, stiffen the ventricles, replace some contractile elements, and frequently affect the conduction system, thereby leading to bradyarrhythmias. When amyloid also surrounds the arterioles, it may lead to anginal chest pain and even myocardial infarction. Some patients may present with orthostatic hypotension resulting from amyloid autonomic neuropathy. Macroglossia, carpal tunnel syndrome with hypothenar wasting, skin friability, nephrotic syndrome, or multiple myeloma may also suggest the diagnosis of amyloidosis.
The ECG tracing characteristically shows markedly decreased voltage despite increased wall thickness on echocardiography. Specific diagnosis in some cases can be made from a characteristic sparkling refractile pattern on echocardiography (Fig. 59-5). Up to 80% of patients have a monoclonal protein identified from either serum or urine. Biopsy of subcutaneous fat or the rectum frequently reveals amyloidosis, so endomyocardial biopsy is rarely required.
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| FIGURE 59-5 Amyloidosis. A, Parasternal long-axis echocardiographic image shows a “sparkling” granular myocardial texture in the interventricular septum in a patient with biopsy-proved amyloidosis. LA = left atrium; LV = left ventricle. B, An apical four-chamber echocardiographic image demonstrates biventricular hypertrophy in a patient with biopsy-proved amyloidosis. RA = right atrium; RV = right ventricle. (From Levine RA: Echocardiographic assessment of the cardiomyopathies. In Weyman AE [ed]: Principles and Practice of Echocardiography, 2nd ed. Philadelphia: Lea & Febiger, 1994, p 810.) |
Therapy with colchicine or with combined melphalan and prednisone provides a 20 to 30% response rate in patients with monoclonal gammopathy. Vasodilator therapy is less effective than in dilated cardiomyopathy, owing to less pronounced systolic dysfunction, greater reliance on high filling pressures, and the frequently accompanying autonomic neuropathy, which predisposes to postural hypotension. Amyloidosis is usually a contraindication to cardiac transplantation because it recurs in the donor heart and can progress rapidly in other organs.
Patients with amyloidosis with heart failure have a median survival of less than 1 year and a 5-year survival of less than 5%. Most deaths occur suddenly. Patients with familial amyloidosis have a slower course than do patients with a monoclonal gammopathy.
▪ Hemochromatosis
In hemochromatosis (Chapter 231), which can result from a genetic defect in iron regulation or from iron overload related to hemolytic anemia and transfusions, iron in the perinuclear areas of myocytes disrupts cellular architecture and mitochondrial function, thereby leading to cell death and replacement fibrosis. The atrioventricular node may be involved. Restrictive physiologic features dominate earlier in the course, followed by dilation generally to a left ventricular diastolic dimension less than 60 mm; ejection fractions in severe cases are often less than 30%. The diagnosis is generally made from the clinical picture, an elevated serum iron level, and high transferrin saturation (≥50%). Genetic testing may be helpful, and the diagnosis can be confirmed by endomyocardial biopsy. Phlebotomy and iron chelation therapy with deferoxamine (Chapter 231) may improve cardiac function before cell injury becomes irreversible. Standard heart failure treatment (Chapter 58) is generally recommended. Deaths from hemochromatosis result more often from cirrhosis and liver carcinoma than from cardiac disease.
▪ Fabry's Disease
In Fabry's disease and glycogen storage diseases, restrictive physiology is associated with increases in left ventricular mass (see Hypertrophic Cardiomyopathy). Treatment is for the underlying systemic disease, with careful treatment of the heart failure caused by the restrictive myopathy (Chapter 58).
Fibrotic Restrictive Cardiomyopathies
Radiation therapy for thoracic malignant disease (Chapters 18 and 201) can produce restrictive cardiomyopathy, usually within several years, although occasionally up to 15 years later, and sometimes with constrictive pericarditis (Chapter 77). In the scleroderma-affected heart (Chapter 288), interstitial fibrosis is common, perhaps related to small vessel ischemia with microinfarction; left ventricular dilation is uncommon, and the congestive symptoms may be refractory to therapy.
▪ Unclassified Cardiomyopathies
▪ Left Ventricular Noncompaction
Failure of the trabecular or spongiform layer of the myocardium to compact may occur with congenital heart disease, including atrial and ventricular septal defects and coarctation of the aorta (Chapter 68), and with the rare X-linked multisystem disorder, Barth's syndrome. With recent improvements in imaging technology, it has also been recognized in patients with hypertrophic and dilated cardiomyopathy. The prevalence of localized areas of noncompaction is unknown, but clinically significant, isolated left ventricular noncompaction in the absence of other cardiac abnormalities is uncommon.
Areas of noncompacted myocardium may be best delineated from normal myocardium by the demonstration of flow within the myocardium by Doppler or contrast echocardiography. When extensive areas are involved, systolic performance may be impaired, and there is a risk of ventricular arrhythmias and systemic emboli. Treatment, when necessary, is for associated heart failure (Chapter 58), arrhythmias (Chapter 61), and the risk of emboli (Chapter 99. Natural history and prognosis are not well established.
▪ Tako-Tsubo Cardiomyopathy
Tako-Tsubo cardiomyopathy is a syndrome of transient apical left ventricular dysfunction that mimics myocardial infarction. Postulated mechanisms include coronary artery spasm, myocarditis, and dynamic midcavity obstruction. Analogous permanent apical outpouchings develop in patients with hypertrophic cardiomyopathy and midventricular obstruction.
The clinical syndrome classically includes chest pain, ST segment elevation, and raised cardiac biomarkers in association with emotional or physical stress. Coronary arteriography reveals normal epicardial vessels. Conservative treatment with rehydration and removal of the determinants of stress usually results in rapid resolution within hours of the symptoms, ECG changes, and wall motion abnormalities.
▪ DISEASES OF THE ENDOCARDIUM
▪ Löffler's Endocarditis and Endocardial Fibroelastosis
In equatorial Africa, endomyocardial fibrosis accounts for 15 to 25% of cardiac deaths. It can cause dense thickening of the ventricular inflow tracts and atrioventricular valves and of one or more commonly both ventricles. However, the underlying myocardium is usually spared, and systolic function is normal. The atria may be very large, and pericardial effusions may be present. Endocardial disease can also cause a clinical syndrome similar to restrictive cardiomyopathy.
In Löffler's endocarditis, which is seen as part of hypereosinophilic syndrome (Chapter 176), degranulated eosinophils are involved in an inflammatory endocardial process that predominantly involves the left ventricle. The mechanism of the fibrotic response, which develops in either or both ventricles, is unknown. Löffler's endocarditis occurs in temperate climates and is characterized by older age, male predominance, and a more aggressive course than endomyocardial fibrosis. Persistent eosinophilia of more than 1500 eosinophils/mm3 without other causes leads to dysfunction of the heart, lungs, and other organs.
Diagnosis
In Löffler's endocarditis and endocardial fibrosis, the apices of the ventricle typically are obliterated, and immobility of the posterior leaflet of the mitral valve with mitral regurgitation are noted. Cardiac catheterization, which typically shows the dip and plateau hemodynamic profile of restrictive cardiomyopathy (see Fig. 59-4), usually is not necessary unless the quality of noninvasive studies is suboptimal. Endomyocardial biopsy in Löffler's endocarditis and endocardial fibrosis is important for diagnosis, although it may be difficult to obtain adequate tissue.
Treatment
In Löffler's endocarditis, treatment depends on the stage of disease and the activity of degranulating lymphocytes; anecdotal success has been reported with corticosteroids, hydroxyurea, and interferon. For both endomyocardial fibrosis and Löffler's endocarditis, diuretics and anticoagulation are important adjuncts to therapy. Surgical débridement of the fibrous plague with repair or replacement of the mitral or tricuspid valves may dramatically improve symptoms, albeit with significant perioperative mortality of 10 to 20%. In endomyocardial fibrosis, the prognosis is poor because progressive disease leads to death from heart failure, embolism, or ventricular arrhythmia.
▪ Carcinoid Syndrome
Epidemiology and Pathobiology
Once a carcinoid tumor (Chapter 251) has metastasized to the liver, up to two thirds of patients will have endocardial involvement, usually with thickening and scarring of the right atrial and right ventricular endocardium as well as of the tricuspid and/or pulmonary valves. Valvular involvement may result in both stenosis and regurgitation, with tricuspid regurgitation oftentimes predominating. In patients with a patent foramen ovale, left-sided valvular involvement is common. Occasional patients may have concomitant myocardial metastases and pericardial effusions from direct tumor invasion, but the endocardial changes are typically related to the vasoactive substances produced by the tumor in the liver, rather than by actual tumor involvement.
Clinical Manifestations
The most common presentation is with dyspnea and signs and symptoms of right-sided heart failure. Cardiac involvement may be a major contributor to death in many patients.
Treatment
Treatment of the underlying carcinoid with a somatostatin analogue can improve systemic symptoms (Chapter 251). Valve replacement has occasionally been performed, but the operative mortality rate is markedly higher than is typical for valve replacement, and the advisability of such surgery must be weighed against the natural history of the noncardiac extent of disease (Chapter 251).
▪ Endocardial Manifestations of Cancer
▪ Nonbacterial Thrombotic (Marantic) Endocarditis
Epidemiology and Pathobiology
Platelet-fiber masses that are adherent to the mitral and/or aortic valves are seen in about 20% of patients with malignant tumors, especially mucin-producing adenocarcinomas, melanomas, leukemias, and lymphomas. The lesions are sterile, commonly verruciform, and without accompanying inflammation.
Clinical Manifestations
Nonbacterial thrombotic endocarditis is virtually always asymptomatic but occasionally is a source of systemic emboli. Because of the small size of many of the emboli, the first presentation is often with cerebral symptoms.
Diagnosis
Larger lesions are detectable by echocardiography, but even transesophageal echocardiography is not sufficiently sensitive to identify lesions that may be found at autopsy and that may have been the source of systemic emboli.
Treatment
No treatment has proven efficacious. However, systemic anticoagulation similar to that used in patients with tumor-associated deep venous thrombosis is often tried (Chapters 81 and 189).
▪ CARDIAC TUMORS
▪ Myocardial Tumors
Most primary cardiac tumors are benign. However, all tumors that extend from other tissues into the heart are malignant, as are metastatic lesions.
Epidemiology and Pathobiology
Primary tumors of the heart are unusual, with a prevalence of 1 in 2000 to 1 in 4000 in autopsy series. Nearly all these primary tumors are benign myxomas, although fibromas, lipomas, and fibroelastomas also occur. Rhabdomyomas are seen in children, especially with tuberous sclerosis (Chapter 444). The rare primary malignant tumors include sarcomas, especially angiosarcomas (Table 59-13). Rarely, a primary mesothelioma or lymphoma may originate in the heart.
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Up to 20% of advanced cancers may involve the pericardium, epicardium, or cardiac chambers either by direct extension of the primary tumor or by metastatic disease. Direct extension occurs principally from cancers of the lung, breast, esophagus, and mediastinum. Extension through the inferior vena cava to the right atrium and even to the right ventricle occurs with cancers of the kidney, adrenal gland, and liver. Metastatic spread is most common with melanomas or lymphomas.
▪ Pericardial Tumors
Clinical Manifestations
Pericardial tumors almost always result from direct extension of tumors, principally lung and breast, which produce a pericardial effusion that can progress to cardiac tamponade (Chapter 77). Patients typically are asymptomatic or minimally symptomatic in terms of the cardiac involvement until the effusion is very large, although they often may be very ill owing to progressive tumor elsewhere.
Diagnosis
The diagnosis is often suspected in a patient with advanced malignant disease based on evidence of heart failure, hypertension, or arrhythmia and is confirmed by echocardiography. The differentiation between pericardial involvement by tumor as compared with postradiation pericarditis depends on pericardiocentesis, often guided by echocardiography, and cytologic examination.
Treatment
Cardiac tamponade must be treated with urgent pericardiocentesis, preferably under echocardiographic or radiologic guidance (Chapter 77). Although such a procedure can be life-saving and provide short-term to immediate-term palliation, control of the effusion often requires prolonged drainage, administration of intrapericardial chemotherapeutic agents, or limited or full pericardiectomy (Chapter 77). Some patients with pericardial tumors may respond to aggressive systemic chemotherapy, but recurrent accumulation of fluid is sufficiently likely that creation of a pericardial window should be considered before hospital discharge.
Prognosis
In many cases, a tumor that is causing pericarditis has extended or will eventually extend through the pericardial space and into the myocardium, so no therapy is likely to be successful. The prognosis is very poor, except in unusual cases when the tumor responds dramatically to systemic therapy.
▪ Intracavitary Tumors
▪ Myxoma
Definition and Epidemiology
A myxoma is a benign polypoid neoplasm that originates from endocardial cells and is attached to the interatrial septum, usually protruding into the left atrium but occasionally into the right atrium and rarely into the ventricles. Myxomas are more common in women, especially between the ages of 30 and 60 years, than in men. These tumors can be familial and are rarely associated with other systemic abnormalities.
Clinical Manifestations
Myxomas are slow growing and usually do not produce symptoms or signs until they enlarge. The typical presentation is with a tumor embolus, whereby usually small portions of the myxoma break loose and cause a single embolism or a shower of emboli. However, a large embolism from a myxoma can be of sufficient size to obstruct a medium-size artery. Some patients have systemic symptoms including fever, malaise, and arthralgias as part of a clinical syndrome that may be confused with bacterial endocarditis (Chapter 76) or a collagen vascular disease. Large myxomas can prolapse into the mitral valve orifice during diastole, or they may obstruct blood flow from the left atrium to the left ventricle and mimic rheumatic mitral stenosis.
Diagnosis
A myxoma large enough to obstruct the mitral orifice can produce an audible “tumor plop” when the myxoma prolapses and obstructs blood flow during diastole, at the same time that the opening snap of mitral stenosis would typically be heard. If obstruction is incomplete, the tumor plop may be followed by a diastolic rumble. As obstruction becomes more severe, cardiac output may fall precipitously. Echocardiography (Chapter 53) is usually definitive; transesophageal echocardiography provides a higher sensitivity than does transthoracic echocardiography.
Treatment
Surgical removal is generally curative, although myxomas can be multiple or recur in about 5% of cases. Follow-up postoperative echocardiography is generally recommended. However, the optimal frequency and duration for follow-up screening are uncertain.
▪ Other Primary Intracavitary Tumors
Papillary fibroelastomas are rare, typically frondlike tumors that may arise from a cardiac valve, often the mitral valve, and are generally detected incidentally by echocardiography. However, like myxomas, they can manifest with systemic or even coronary emboli. Surgical excision is usually successful.
Angiosarcomas, which are more frequent in men than in women, typically involve the pericardium and right atrium. They cause obstruction with clinical signs and symptoms of right-sided heart failure. These sarcomas are generally not amenable to therapy.
▪ Extension of Tumor into the Cardiac Cavities
Direct extension of tumor up the inferior vena cava into the right atrium can be seen with renal cell carcinomas and less commonly with liver and adrenal cancers. In some cases, tumor extension will be accompanied by adherent clot, and either the tumor or the clot may cause obstruction or pulmonary emboli (Chapter 99). No treatments are generally successful, and the prognosis is grim.
▪ Intramyocardial Tumors
Benign tumors in the myocardium include lipomas, fibromas, and rhabdomyomas. Primary malignant tumors include sarcomas, lymphomas, and mesotheliomas. Metastatic tumors include melanomas, lymphomas, and leukemias. The tumors may be clinically silent, or they may produce arrhythmias or even impinge on coronary arteries, thereby causing ischemic syndromes. Large tumors may protrude into the cardiac chamber and cause obstruction. Therapies are not successful, except for occasional patients whose metastatic tumors may respond to systemic chemotherapy or whose primary tumors have been cured by heart transplantation.
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