Lynne Warner Stevenson Joseph Loscalzo
DEFINITION AND CLASSIFICATION
Cardiomyopathy is a disease of the heart muscle. It is estimated that cardiomyopathy accounts for 5–10% of the 5–6 million patients already diagnosed with heart failure in the United States. This term is intended to exclude cardiac dysfunction that results from other structural heart disease, such as coronary artery disease, primary valve disease, or severe hypertension; however, in general usage the phrase ischemic cardiomyopathy is sometimes applied to describe diffuse dysfunction occurring in the presence of multivessel coronary artery disease, and nonischemic cardiomyopathy to describe cardiomyopathy from other causes. As of 2006, cardiomyopathies are defined as “a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic.”1
The traditional classification of cardiomyopathies into a triad of dilated, restrictive, and hypertrophic was based initially on autopsy specimens and later on echocardio-graphic findings. Dilated and hypertrophic cardiomyopathies can be distinguished on the basis of left ventricular wall thickness and cavity dimension; however, restrictive cardiomyopathy can have variably increased wall thickness and chamber dimensions that range from reduced to slightly increased, with prominent atrial enlargement. Restrictive cardiomyopathy is now defined more on the basis of abnormal diastolic function, which is also present but initially less prominent in dilated and hypertrophic cardiomyopathy. Restrictive cardiomyopathy can overlap in presentation, gross morphology, and etiology with both hypertrophic and dilated cardiomyopathies (Table 21-1).
PRESENTATION WITH SYMPTOMATIC CARDIOMYOPATHY
Expanding information renders this classification triad based on phenotype increasingly inadequate to define disease or therapy. Identification of more genetic determinants of cardiomyopathy has suggested a four-way classification scheme of etiology as primary (affecting primarily the heart) and secondary to other systemic disease. The primary causes are then divided into genetic, mixed genetic and acquired, and acquired; however, in current practice the genetic information is often unavailable at the time of initial presentation, particularly in the absence of extracardiac manifestations. Many mutated genes can be associated with the same general phenotype, and one defective gene may manifest as multiple phenotypes. In addition, the bases of evidence for most therapies are still driven by clinical phenotypes. Although the proposed genetic classification does not yet guide many current clinical strategies, it will become increasingly relevant as classification of disease moves beyond individual organ pathology to more integrated systems approaches.
For all cardiomyopathies, the early symptoms often relate to exertional intolerance with breathlessness or fatigue, usually from inadequate cardiac reserve during exercise. These symptoms may initially go unnoticed or be attributed to other causes, commonly pulmonary. As fluid retention leads to elevation of resting filling pressures, shortness of breath may occur during routine daily activity, such as dressing, and may manifest as dyspnea or cough in the supine position. Although often considered the hallmark of congestion, peripheral edema may not appear despite severe fluid retention, particularly in younger patients. The nonspecific term congestive heart failure describes only the resulting syndrome of fluid retention, which is common to the three types of cardiomyopathy and also to other cardiac diseases associated with elevated filling pressures. Despite the different structural basis, all three types of cardiomyopathy can be associated with atrioventricular valve regurgitation, typical and atypical chest pain, atrial and ventricular tachyarrhythmias, and embolic events (Table 21-1). Initial evaluation begins with a detailed clinical history and examination, looking for clues to cardiac, extracardiac, and familial disease (Table 21-2). The initial evaluation, prognosis, and therapy are generally defined by the severity of cardiac and clinical dysfunction, with some distinctive features according to etiology.
INITIAL EVALUATION OF CARDIOMYOPATHY
GENETIC ETIOLOGIES OF CARDIOMYOPATHY
The estimated prevalence of a genetic etiology for cardiomyopathy continues to increase with increasing awareness of the importance of the family history and the availability of genetic testing. Well recognized in hypertrophic cardiomyopathy, heritability is present in at least 30% of dilated cardiomyopathies without other clear etiology. Careful family history should elicit not only known cardiomyopathy and heart failure, but also family members who have had sudden death, often incorrectly attributed to “a massive heart attack,” who have had atrial fibrillation or pacemaker implantation by middle age, or who have muscular dystrophy. The family history should be reviewed at subsequent intervals particularly regarding siblings and cousins, who may tend to manifest disease at similar ages.
Most familial cardiomyopathies are inherited in an autosomal dominant pattern, with occasional autosomal recessive and X-linked inheritance (Table 21-3). The penetrance and phenotype of a given mutation varies with other genetic, epigenetic, and environmental determinants. Some mutations are associated with primary conduction system disease as well as dilated cardiomyopathy (CDDC). With rare exceptions, such as the replacements for defective metabolic enzymes, current therapy is based on the phenotype rather than the genetic defect. However, knowledge of the genetic defect may influence prognosis and in some cases provide indication for implantable defibrillators.
Defects in sarcomeric proteins of myosin, actin, and troponin are the best characterized. While the majority of these are associated with hypertrophic cardiomyopathy, an increasing number of sarcomeric mutations have now been implicated in dilated cardiomyopathy, and some have also been associated with left ventricular noncompaction. Thus far, few mutations have been identified in excitation-contraction coupling proteins, perhaps because they are too crucial for survival to allow variation.
Many of the proteins encoded by abnormal structural genes span more than one functional area of the myocyte (Fig. 21-1). Proteins contributing to the Z-disk organize and stabilize the sarcomeres. Multiple other proteins are involved in connecting and maintaining the cytoskeleton of the myocyte. For example, desmin forms intermediate filaments that connect the nuclear and plasma membranes, Z-lines, and the intercalated disks between muscle cells. Desmin mutations impair the transmission of force and signaling for both cardiac and skeletal muscle, and are, thus, associated with a peripheral myopathy as well as a dilated cardiomyopathy. Most of the identified genetic defects in the Z-disk and cytoskeleton are associated with dilated cardiomyopathy.
Drawing of myocyte indicating multiple sites of abnormal gene products associated with cardiomyopathy. Major functional groups include the sarcomeric proteins (actin, myosin, tropomyosin, and the associated regulatory proteins), the dystrophin complex stabilizing and connecting the cell membrane to intracellular structures, the desmosome complexes associated with cell-cell connections and stability, and multiple cytoskeletal proteins that integrate and stabilize the myocyte. ATP, adenosine triphosphate. (Figure adapted from Jeffrey A. Towbin, MD, University of Cincinnati, with permission.)
Proteins in the sarcolemmal membrane are associated with dilated cardiomyopathy. The best known is the X-linked dystrophin, abnormalities of which cause Duchenne’s and Becker’s muscle dystrophy. (Interestingly, abnormal dystrophin can be acquired when the coxsackievirus cleaves dystrophin during viral myocarditis.) This protein provides a network that supports the sarcolemma and also connects to the sarcomere. The progressive functional defect in both cardiac and skeletal muscle reflects vulnerability to mechanical stress. Dystrophin is associated at the membrane with a complex of other proteins, such as metavinculin, abnormalities of which cause dilated cardiomyopathy with autosomal dominant inheritance. Defects in the sarcolemmal channel proteins (channelopathies) are generally associated with primary arrhythmias, but mutations in SCN5A, distinct from those which cause the Brugada or long-QT syndromes, have been implicated in dilated cardiomyopathy.
Nuclear membrane protein defects in the myocyte can also cause skeletal myopathy in either autosomal dominant (lamin proteins) or X-linked (emerin) patterns. These are associated with a high prevalence of atrial arrhythmias and conduction system disease which, in some family members, occur without detectable cardiomyopathy.
Intercalated disks between cardiac myocytes allow mechanical and electrical coupling between cells and also connect to desmin filaments within the cell. Mutations in proteins of the desmosomal complex compromise attachment of the myocytes, which can become disconnected and die, to be replaced by fat and fibrous tissue. These areas are highly arrhythmogenic and may go on to aneurysm formation. Although it is more noticeable in the thinner right ventricle, this condition often affects both ventricles. As desmosomes are also important for elasticity of hair and skin, some defective desmosomal proteins are associated with striking “woolly hair” and thickened skin on the palms and soles.
Owing to the conservation of signaling pathways in multiple systems, we may expect to discover more extracardiac manifestations of genetic abnormalities initially considered to manifest exclusively in the heart. In contrast, the monogenic disorders of metabolism that affect the heart are already clearly recognized to affect multiple organ systems (Table 21-4). The most important currently are those defective enzymes for which specific enzyme replacement therapy can now ameliorate the course of disease, as with alpha-galactosidase-A (Fabry’s disease). Abnormalities of mitochondrial DNA (maternally transmitted) impair energy production with multiple clinical manifestations, including impaired cognitive function and skeletal myopathy. The phenotypic expression is highly variable depending on the distribution of the maternal mitochondria during embryonic development. Heritable systemic diseases, such as familial amyloidosis and hemochromatosis, can affect the heart without abnormal expression of specific cardiac genes.
For any patient with suspected or proven genetic disease, family members should be considered and evaluated in a longitudinal fashion. Screening includes an echocardiogram and electrocardiogram (ECG). The indications and implications for confirmatory specific genetic testing vary depending upon the specific mutation. The profound questions raised by families about diseases shared and passed down merit serious and sensitive discussion, ideally provided by a trained genetic counselor.
An enlarged left ventricle with decreased systolic function as measured by left ventricular ejection fraction characterizes dilated cardiomyopathy (Figs. 21-2, 21-3, and 21-4). Systolic failure is more marked than the frequently accompanying diastolic dysfunction, although the latter may be functionally severe in the setting of marked volume overload. The syndrome of dilated cardiomyopathy has multiple etiologies (Table 21-5). Up to one-third of cases may be familial, as discussed later. Acquired cardiomyopathy is often attributed to a brief primary injury such as infection or toxin exposure. Some myocytes may die during the initial injury, while others survive only to have later programmed cell death, (apoptosis). As the surviving myocytes hypertrophy to accommodate the increased burden of wall stress, local and circulating factors stimulate deleterious responses that contribute to progression of disease, even in the absence of further primary injury. Dynamic remodeling of the interstitial scaffolding affects diastolic function and the amount of ventricular dilation. Mitral regurgitation commonly develops as the valvular apparatus is distorted by ventricular dilation and sometimes by focal injury to underlying myocardium and is usually substantial by the time heart failure is severe. Many cases that present “acutely” have progressed silently through these stages over months to years.
Dilated cardiomyopathy. This gross specimen of a heart removed at the time of transplantation shows massive left ventricular dilation and moderate right ventricular dilation. Although the left ventricular wall in particular appears thinned, there is significant hypertrophy of this heart, which weighs more than 800 gm (upper limit of normal = 360 g). A defibrillator lead is seen traversing the tricuspid valve into the right ventricular apex. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)
Dilated cardiomyopathy. This echocardiogram of a young man with dilated cardiomyopathy shows massive global dilation and thinning of the walls of the left ventricle (LV). The left atrium (LA) is also enlarged compared to normal. Note that the echocardiographic and pathologic images are vertically opposite, such that the LV is by convention on the top right in the echocardiographic image and bottom right in the pathologic images. (Image courtesy of Justina Wu, MD, Brigham and Women’s Hospital, Boston.)
Regardless of the nature and degree of direct cell injury, the resulting functional impairment often includes some contribution from secondary responses that may be reversible. The potential reversibility of cardiomyopathy in the absence of ongoing injury remains a subject of active controversy. Almost half of all patients with truly recent onset cardiomyopathy demonstrate substantial spontaneous recovery. Some patients have dramatic improvement to near-normal ejection fractions during pharmacologic therapy, particularly notable with the β-adrenergic antagonists coupled with renin-angiotensin system inhibition. Interest in the potential for recovery of cardiomyopathy in the absence of coronary artery disease has been further stimulated by occasional “recovery” of left ventricular function in young patients after a year or more of mechanical circulatory support. The diagnosis and therapy for dilated cardiomyopathy is generally dictated by the stage of heart failure (Chap. 17), with specific aspects discussed with the relevant etiology later in this chapter.
MAJOR CAUSES OF DILATED CARDIOMYOPATHY (WITH COMMON EXAMPLES)
Myocarditis is an inflammatory process, most commonly attributed to infectious organisms that can invade the myocardium directly, produce cardiotoxins, and trigger chronic inflammatory responses. Infective myocarditis has been reported with almost all types of infectious agents, but is most commonly associated with viral infections, the protozoan Trypanosoma cruzi in South America, and endomyocardial fibrosis in equatorial Africa.
Viral myocarditis in murine models begins with acute infection. After viruses enter the circulation through the respiratory or gastrointestinal tract, they can infect other organs possessing specific receptors, such as the coxsackie-adenovirus receptor on the heart. Viral invasion and replication can lead directly to myocardial injury and lysis. Viral proteases have multiple actions, of which one is to degrade the protein, dystrophin, in the myocyte membrane complex that is genetically abnormal in some muscular dystrophies. Viral antigens activate immune responses that help to contain the initial infection but may persist into later phases. Components include nonspecific cytokines, specific antibodies, and cytotoxic T-lymphocytes, which in some cases recognize myocyte proteins. There is varying evidence for a latent phase of ongoing infection with persistence of the viral genome and some viral proteins. The relative contributions of viral persistence and deleterious host immune responses to progressive dysfunction have not been clearly delineated in human disease (Fig. 21-5). The late stages are dominated by nonspecific secondary changes in gene expression, and by local and systemic neurohormonal responses, as seen for other etiologies of heart failure.
Schematic diagram demonstrating the possible progression from infection through direct, secondary, and autoimmune responses to dilated cardiomyopathy. Most of the supporting evidence for this sequence is derived from animal models. It is not known to what degree persistent infection and/or ongoing immune responses contribute to ongoing myocardial injury in the chronic phase.
Although viral myocarditis is generally considered to be an acquired cardiomyopathy, families have been reported whose clinical disease appeared after a syndrome consistent with viral myocarditis. One possible explanation for this apparent mixed etiology is that some genetic variants of myocardial cell surface receptors bind more avidly to certain viruses, particularly coxsackievirus and adenovirus.
The typical clinical picture of myocarditis is a young adult with progressive dyspnea and weakness over a few days to weeks after a recent viral syndrome with fevers and often myalgias indicative of skeletal muscle inflammation. Some patients present with atypical or anginal-type chest pain, or with pleuritic, positional chest pain due to pericarditis with some degree of underlying myocarditis. Patients in whom ventricular tachyarrhythmias dominate the presentation may have viral myocarditis but should be evaluated for sarcoidosis or giant cell myocarditis. Patients presenting with pulmonary or systemic embolic events from intracardiac thrombi generally already have chronic, severe cardiac dysfunction.
A small number of patients present with acute fulminant myocarditis, with rapid progression from a severe febrile respiratory syndrome to cardiogenic shock from which multiple organ system failure, including coagulopathy, may develop. Such patients have often been discharged from the emergency department with antibiotic therapy only to return in extremis. Prompt triage is vital to provide aggressive support with high-level intravenous inotropic therapy and on occasion, mechanical circulatory support; importantly, more than half of patients with this acute presentation can survive with marked improvement within the first few weeks, often returning to near-normal systolic function.
Many patients presenting with heart failure after a viral illness actually have a long-standing cardiomyopathy that was acutely exacerbated but not caused by the new viral illness. Heart failure from any cause often worsens transiently during infection, presumably due to the myocardial depressant effects of circulating cytokines. Marked left ventricular dilation and the presence of severely elevated left-ventricular filling pressures without frank pulmonary edema suggest chronic, slowly progressive disease, which is often further supported by a history of gradual changes in exercise tolerance before the viral syndrome.
For the usual subacute presentation, the diagnosis of cardiomyopathy is confirmed by echocardiography, and further evaluation is directed to ascertain whether myocarditis is present. Troponin is often mildly elevated, and creatine kinase may be released from the cardiac injury or skeletal muscle involvement. In some cases, cardiac catheterization is performed to rule out acute ischemia. Magnetic resonance imaging is increasingly used for the diagnosis of myocarditis, which is supported by evidence of increased tissue edema and gadolinium enhancement, particularly in the mid-wall distinct from the usual coronary artery territories. Endomyocardial biopsy criteria for myocarditis require lymphocytic infiltration with evidence of myocyte necrosis (Fig. 21-6), but are met in only about 10–20% of classic presentations. Most biopsies in fulminant myocarditis show only marked tissue edema without a cellular infiltrate, and it is likely that many less acute cases may similarly be characterized by tissue edema and cytokine depression of myocardial function, possibly including some antibody-mediated endothelial injury, without marked cellular infiltrates. Acute and convalescent viral titers are usually sent but are more likely to be important from the public health standpoint than for the individual.
Acute myocarditis. Microscopic image of an endomyocardial biopsy showing massive infiltration with mononuclear cells and occasional eosinophils associated with clear myocyte damage. The myocyte nuclei are enlarged and reactive. Such extensive involvement of the myocardium would lead to extensive replacement fibrosis even if the inflammatory response could be suppressed. Hematoxylin and eosin stained section, 200× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)
Viral myocarditis treatment is initially directed toward stabilizing the hemodynamic status and then toward adjusting neurohormonal antagonists for the treatment of heart failure as tolerated. Presentation with fulminant disease requires rapid evaluation and therapy as discussed earlier. For patients with subacute presentation, randomized trials have shown no benefit of immunosuppression with glucocorticoid combinations or intravenous immunoglobulin, even when the biopsy is positive for lymphocytic infiltrates; yet, immunosuppression is often used even in the absence of evidence of benefit, in part due to perceived analogy to acute cardiac transplant rejection. Animal models have shown that viral replication and myocardial injury can be worsened by immunosuppression during the early phase of infection; however, patients with persistent inflammatory myocarditis and a progressive downhill course over weeks may be treated empirically with glucocorticoids in an attempt to avoid the need for cardiac transplantation.
The true prognosis of viral myocarditis is not known, as most unrecognized cases probably resolve spontaneously, while others progress to cardiomyopathy without other obvious cause. However, among patients who have truly recent onset cardiomyopathy of less than 3–6 months’ duration without other apparent etiology, almost half will have major improvement in left ventricular ejection fraction during the subsequent 6–12 months. Those patients in whom left ventricular ejection fraction and dimensions return to normal are usually considered to have residual subclinical cardiomyopathy. Neurohormonal antagonist therapy is usually continued indefinitely as tolerated, with dose adjustments to avoid side effects.
In humans, viruses are often suspected but rarely confirmed as the direct cause of myocarditis. Often implicated is the picornavirus family of RNA viruses, with the enteroviruses Coxsackie, echovirus, and poliovirus. Influenza,another RNA virus, is implicated in myocarditis with varying frequency from year to year as the epitopes change. Of the DNA viruses, adenovirus, variola (smallpox) and vaccinia(smallpox vaccine), and the herpesviruses(Varicella zoster, Cytomegalovirus, and Epstein-Barr virus) are well recognized as causes of myocarditis. From genetic analyses of biopsy tissue, parvovirus B19, coxsackie, adenovirus, and Epstein-Barr virus are the agents most often implicated. The role of parvovirus B19 as a cause of myocarditis or cardiomyopathy is difficult to determine, as almost half of individuals show evidence of prior infection with this small DNA virus that causes “fifth disease” in children.
Human immunodeficiency virus (HIV) has been associated with echocardiographic abnormalities in 10–40% patients with clinical disease. Cardiomyopathy in HIV may result from cardiac involvement with other associated viruses, such as cytomegalovirus and hepatitis C. Antiviral drugs to treat chronic HIV can cause cardiomyopathy, both directly as cardiotoxins and through drug hypersensitivity. The clinical picture may be complicated by pericardial effusions and pulmonary hypertension. There is a high frequency of lymphocytic myocarditis found at autopsy, and viral particles have been demonstrated in the myocardium in some cases, consistent with direct causation.
Hepatitis C has been repeatedly implicated in cardiomyopathy, particularly in Germany and Asia. Cardiac function may improve after interferon therapy. As this cytokine itself often depresses cardiac function transiently, careful coordination of administration and ongoing clinical evaluation are critical. Involvement of the heart with hepatitis B is uncommon but can be seen when associated with systemic vasculitis (polyarteritis nodosa).
Other viral infections in which cardiac involvement is specifically implicated, beyond the depression of cardiac function during any systemic cytokine activation, include mumps, respiratory syncytial virus,the arboviruses (dengue fever and yellow fever), and arenaviruses (Lassa fever).
Chagas’ disease is the third most common parasitic infection in the world and the most common cause of cardiomyopathy. The protozoan Trypanosoma cruzi (T. cruzi) is usually transmitted by the bite of the reduviid bug, endemic in the rural areas of South and Central America. Transmission can also occur through blood transfusion, organ donation, from mother to fetus, and occasionally orally. While programs to eradicate the insect vector have decreased the prevalence from about 16 million to less than 10 million in South America, cases are increasingly recognized in Western developed countries. Approximately 100,000 affected individuals are currently living in the United States, most of whom contracted the disease in endemic areas.
The acute phase of Chagas’ disease with parasitemia is usually unrecognized, but in fewer than 5% of cases presents clinically within a few weeks of infection, with nonspecific symptoms or occasionally with acute myocarditis and meningoencephalitis. In the absence of anti-parasitic therapy, the silent stage progresses slowly over 10–30 years in almost half of patients to manifest in the cardiac and gastrointestinal systems in the chronic stages. Survival is less than 30% at 5 years after the onset of overt clinical heart failure.
Multiple pathogenetic mechanisms are implicated. The parasite itself can cause myocyte lysis and primary neuronal damage, and specific immune responses may recognize the parasites or related antigens and lead to chronic immune activation in the absence of detectable parasites. Molecular techniques have revealed persistent parasite DNA fragments in infected individuals. Further evidence for persistent infection is the eruption of parasitic skin lesions during immunosuppression after cardiac transplantation. As in postviral myocarditis, the relative roles of persistent infection and of secondary autoimmune injury have not been resolved (Fig. 21-5). An additional factor in progression of Chagas’ disease is the autonomic dysfunction and microvascular damage that may contribute to cardiac and gastrointestinal disease.
Features typical of Chagas’ disease are conduction system abnormalities, particularly sinus node and atrioventricular (AV) node dysfunction and right bundle branch block. Atrial fibrillation and ventricular tachyarrhythmias also occur. Small ventricular aneurysms are common, particularly at the apex. The dilated ventricles are particularly thrombogenic, giving rise to pulmonary and systemic emboli. The serologic enzyme-linked immunosorbent assay (ELISA) for the IgM has largely replaced the previous complement fixation test for diagnosis.
Treatment of the advanced stages focused on the clinical manifestations of the disease, with heart failure regimens, pacemaker-defibrillators, and anticoagulation; however, increasing emphasis is placed on antiparasitic therapy even in chronic disease. The most common effective anti-parasitic therapies are benznidazole and nifurtimox, both associated with multiple severe reactions, including dermatitis, gastrointestinal distress, and neuropathy. Patients without major extracardiac disease have occasionally undergone transplantation, after which they require lifelong therapy to suppress reactivation of infection.
African trypanosomiasis infection results from the tsetse fly bite and can occur in travelers exposed during trips to Africa. The West African form is caused by Trypanosoma brucei gambiense and progresses silently over years. The East African form caused by T. brucei rhodesiense can progress rapidly through perivascular infiltration to myocarditis and heart failure, with frequent arrhythmias. The diagnosis is made by identification of trypanosomes in blood, lymph nodes, or other affected sites. Development of optimal drug regimens remains limited, and depends on the type and the stage (hemolymphatic or neurologic).
Toxoplasmosis is contracted through undercooked infected beef or pork, transmission from feline feces, organ transplantation, transfusion, or maternal-fetal transmission. Immunocompromised hosts are at greatest risk for reactivation of latent infection from cysts. The cysts have been found in up to 40% of autopsies of patients dying from HIV infection. Toxoplasmosis may present with encephalitis or chorioretinitis, and in the heart can cause myocarditis, pericardial effusion, constrictive pericarditis, and heart failure. The diagnosis may be suspected in an immunocompromised patient with myocarditis and serologic evidence of toxoplasmosis. Fortuitous sampling may reveal the cysts in the myocardium. Combination therapy can include pyrimethamine and sulfadiazine or clindamycin.
Trichinellosis is caused by Trichinella spiralis larva ingested with undercooked meat. Larva migrating into skeletal muscles cause myalgias, weakness, and fever. Periorbital and facial edema, and conjunctival and retinal hemorrhage may also be seen. Although the larva may occasionally invade the myocardium, clinical heart failure is rare, and when observed, attributed to the eosinophilic inflammatory response. The diagnosis is made from the specific serum antibody and is further supported by the presence of eosinophilia. Treatment includes antihelminthic drugs and glucocorticoids if inflammation is severe.
Cardiac involvement with Echinococcus is rare, but cysts can form and rupture in the myocardium and pericardium.
Most bacterial infections can involve the heart occasionally through direct invasion and abscess formation, but do so rarely. More commonly, contractility is depressed globally in severe infection and sepsis through systemic inflammatory responses. Diphtheria specifically affects the heart in almost one-half of cases and is the most common cause of death in patients with this infection. Once a disease of children, the prevalence of vaccines has shifted the incidence of this disease to countries where immunization is not routine and to older populations who have lost their immunity. The bacillus releases a toxin that impairs protein synthesis and may particularly affect the conduction system. The specific antitoxin should be administered as soon as possible, with higher priority than antibiotic therapy. Other systemic bacterial infections that can involve the heart include brucellosis, chlamydophila, legionella, meningococcus, mycoplasma, psittacosis, and salmonellosis, for which treatment is directed at the systemic infection.
Clostridial infections cause myocardial damage from the released toxin. Gas bubbles can be detected in the myocardium, and occasionally abscesses can form in the myocardium and pericardium. Streptococcal infection with β-hemolytic streptococci is most commonly associated with acute rheumatic fever, and is characterized by inflammation and fibrosis of cardiac valves and systemic connective tissue, but can also lead to a myocarditis with focal or diffuse infiltrates of mononuclear cells.
Tuberculosis can involve the myocardium directly as well as through tuberculous pericarditis, but rarely does so when the disease is treated with antibiotics. Whipple’s disease is caused by Tropheryma whippleii. The usual manifestations are in the gastrointestinal tract, but pericarditis, coronary arteritis, valvular lesions, and occasionally clinical heart failure may also occur. Multidrug antituberculous regimens are effective, but the disease tends to relapse even with appropriate treatment.
Spirochetal myocarditis has been diagnosed from myocardial biopsies containing Borrelia burgdorferi that causes Lyme disease. Lyme carditis most often presents with arthritis and conduction system disease that resolves within 1–2 weeks of antibiotic treatment, only rarely causing clinical heart failure.
Fungal myocarditis can occur due to hematogenous or direct spread of infection from other sites, as has been described for aspergillosis, actinomycosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, and mucormycosis. However, cardiac infection is rarely the dominant clinical feature of these infections.
The rickettsial infections, Q fever, Rocky Mountain spotted fever, and scrub typhus, are frequently accompanied by ECG changes, but most clinical manifestations relate to systemic vascular involvement.
Myocardial inflammation can occur without apparent preceding infection. The paradigm of noninfectious inflammation without infection is cardiac transplant rejection, from which we have learned that myocardial depression can develop and reverse quickly, that non-cellular mediators such as antibodies and cytokines play a major role in addition to lymphocytes, and that myocardial antigens are exposed by prior physical injury and viral infection.
The most commonly diagnosed noninfectious inflammation is granulomatous myocarditis, including both sarcoidosis and giant cell myocarditis. Sarcoidosis is a multisystem disease most commonly affecting the lungs, presenting in young adults with higher prevalence in African-American males. Patients with pulmonary sarcoid are at high risk for cardiac involvement, but cardiac sarcoidosis may also occur without clinical lung disease in middle-aged whites of both genders. Regional clustering of the disease supports the suspicion that the granulomatous reaction is triggered by an infectious or environmental allergen not yet identified.
The sites and density of cardiac granulomata, the time course, and the degree of extracardiac involvement are remarkably variable. Patients may present with rapid onset heart failure and ventricular tachyarrhythmias, conduction block, chest pain syndromes, or minor cardiac findings in the setting of ocular involvement, an infiltrative skin rash, or a nonspecific febrile illness. They may also present less acutely after months to years of fluctuating cardiac symptoms. When ventricular tachycardia or conduction block dominate the initial presentation of heart failure without coronary artery disease, suspicion should be high for these granulomatous myocarditides.
Depending on the time course, the ventricles may appear restrictive or dilated, at times with right ventricular predominance. Small ventricular aneurysms are common. Computed tomography of the chest often reveals pulmonary lymphadenopathy even in the absence of clinical lung disease. Metabolic imaging (positron emission tomography [PET]) of the whole chest can highlight active sarcoid lesions that are avid for glucose. Magnetic resonance imaging (MRI) of the heart can identify areas likely to be inflammatory. To rule out chronic granulomatous infections, the diagnosis usually requires pathologic confirmation. Biopsy of enlarged mediastinal nodes may provide the highest yield. The scattered granulomata of sarcoidosis can be missed on cardiac biopsy (Fig. 21-7).
Sarcoidosis. Microscopic image of an endomyocardial biopsy showing a noncaseating granuloma and associated interstitial fibrosis typical of sarcoidosis. No microorganisms were present on special stains, and no foreign material was identified. Hematoxylin and eosin stained section, 200× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)
Immunosuppressive treatment for sarcoidosis is initiated with high-dose glucocorticoids, which are often more effective for arrhythmias than for the heart failure. Pacemakers and implantable defibrillators are generally indicated to prevent life-threatening heart block or ventricular tachycardia, respectively. Because the inflammation often resolves into extensive fibrosis that impairs cardiac function and provides pathways for reentrant arrhythmias, the prognosis is best when the granulomata are not extensive.
Giant cell myocarditis is less common than sarcoidosis, but accounts for 10–20% of biopsy-positive cases of myocarditis. Giant cell myocarditis typically presents with rapidly progressive heart failure and tachyarrhythmias. Diffuse granulomatous lesions are surrounded by extensive inflammatory infiltrate unlikely to be missed on endomyocardial biopsy. Associated conditions are thymomas, thyroiditis, pernicious anemia, other autoimmune diseases, and occasionally recent infections. Glucocorticoid therapy is less effective than for sarcoidosis, and is sometimes combined with other immunosuppressive agents. The course is generally of rapid deterioration requiring urgent transplantation. Although the severity of presentation and myocardial histology are more fulminant than sarcoidosis, the occasional finding of giant cell myocarditis after sarcoidosis suggests that they may in some cases represent different stages of a similar disease.
Hypersensitivity myocarditis is usually an unexpected diagnosis, made when the biopsy reveals infiltration with lymphocytes and mononuclear cells with a high proportion of eosinophils. (Sometimes called eosinophilic myocarditis, this should not be confused with hypereosinophilic syndrome in which very high circulating, often clonal populations of eosinophils cause endomyocardial fibrosis.) Most commonly the reaction is attributed to antibiotics, particularly those taken chronically, but thiazides, anticonvulsants, indomethacin, and methyldopa have also been implicated. High-dose glucocorticoids can be curative.
Myocarditis can be associated with systemic inflammatory diseases such as polymyositis and dermatomyositis. While sometimes considered as an explanation for cardiac findings in patients with other inflammatory disease, such as systemic lupus erythematosus, the more common causes are pericarditis, vasculitis, pulmonary hypertension, or accelerated coronary artery disease.
Peripartum cardiomyopathy develops during the last trimester or within the first 6 months after pregnancy, with a frequency between 1:3000 and 1:15,000 deliveries. The mechanisms remain controversial, but inflammation has been implicated. Risk factors are increased maternal age, increased parity, twin pregnancy, malnutrition, use of tocolytic therapy for premature labor, and preeclampsia or toxemia of pregnancy. As the increased circulatory demand of pregnancy can aggravate other cardiac disease that was clinically unrecognized, it is crucial to the diagnosis that there be no evidence for preexisting cardiac disorder.
Heart failure early after delivery was previously common in Nigeria, when the custom for new mothers included salt ingestion while reclining on a warm bed, which likely impaired mobilization of the excess circulating volume after delivery. In the Western world, lymphocytic myocarditis has often been found on myocardial biopsy. This inflammation has been hypothesized to reflect increased susceptibility to viral myocarditis or an autoimmune myocarditis due to cross-reactivity of anti-uterine antibodies against cardiac muscle. Another mechanism involving a prolactin cleavage fragment has been proposed based on an animal model.
Cardiotoxicity has been reported with multiple environmental and pharmacologic agents. Often these associations are seen only with very high levels of exposure or acute overdoses, respectively, in which acute electrocardiographic and hemodynamic abnormalities may reflect both direct drug effect and systemic toxicity.
Alcohol is the most common toxin implicated in chronic dilated cardiomyopathy. Excess consumption may contribute to more than 10% of cases of heart failure, including exacerbation of cases with other primary etiologies such as valvular disease or previous infarction. Toxicity is attributed both to alcohol and to its primary metabolite acetaldehyde. Polymorphisms of the genes encoding alcohol dehydrogenase and the angiotensin-converting enzyme increase the likelihood of alcoholic cardiomyopathy. Superimposed vitamin deficiencies and toxic alcohol additives are rarely implicated. The alcohol consumption necessary to produce cardiomyopathy in an otherwise normal heart has been estimated to be six drinks (about 4 ounces of pure ethanol) daily for 5–10 years, but frequent binge drinking may also be sufficient. Many patients with alcoholic cardiomyopathy are fully functional without apparent stigmata of alcoholism.
Diastolic dysfunction, mild ventricular dilation, and subclinical depression of contractility can be seen before the development of clinical heart failure. Atrial fibrillation occurs commonly. The cardiac impairment in severe alcoholic cardiomyopathy is the sum of both permanent damage and a substantial component that is reversible after cessation of alcohol consumption. Medical therapy includes neurohormonal antagonists and diuretics as needed for fluid management. Withdrawal should be supervised to avoid exacerbations of heart failure or arrhythmias, and ongoing support arranged. Even with severe disease, marked improvement can occur within 3–6 months of abstinence. Implantable defibrillators are generally deferred until an adequate period of abstinence, after which they may not be necessary if the ejection fraction has improved. With continued consumption, the prognosis is grim.
Cocaine, amphetamines, and related catecholaminergic stimulants can produce chronic cardiomyopathy as well as acute ischemia and tachyarrhythmias. Pathology reveals tiny microinfarcts consistent with small vessel ischemia. Similar findings can be seen with pheochromocytoma.
Chemotherapy agents are the most common drugs implicated in cardiomyopathy. Judicious use of these drugs requires balancing the risks of the malignancy and the risks of cardiotoxicity, as many cancers have a chronic course with prognosis no worse than heart failure.
Anthracyclines cause characteristic histologic changes of vacuolar degeneration and myofibrillar loss. Generation of reactive oxygen species involving heme compounds is currently the favored explanation for myocyte injury and fibrosis. Disruption of the large titin protein may contribute to loss of sarcomere organization. There are three different presentations of anthracycline-induced cardiomyopathy. Acute heart failure developing during administration of a single dose can be severe, but may clinically resolve in a few weeks. Early onset doxorubicin cardiotoxicity develops in about 3% of patients during or shortly after a chronic course, relating closely to total dose. It may be rapidly progressive, but may also improve to restore reasonable ventricular function. The chronic presentation differs according to whether therapy was given before or after puberty. Patients who received doxorubicin while still growing may have inadequate development of the heart to support cardiac function into the early twenties. Late after adult exposure, patients may develop the gradual onset of symptoms or an acute onset precipitated by a reversible insult, such as influenza or atrial fibrillation. Doxorubicin cardiotoxicity leads to a relatively nondilated ventricle, perhaps due to the accompanying fibrosis. Thus, the stroke volume may be severely reduced with an ejection fraction of 30–40%, which would be well tolerated in a patient with a more dilated ventricle typical of other cardiomyopathies. Therapy is that for heart failure, with careful suppression of “inappropriate” sinus tachycardia, and attention to postural hypotension that can occur in these patients. Once thought to have an inexorable downward course, some patients with doxorubicin cardiotoxicity improve under careful management to near-normal clinical function for many years.
Trastuzumab is a monoclonal antibody that interferes with cell surface receptors crucial for some tumor growth and for cardiac adaptation. The incidence of cardiotoxicity is lower than for anthracyclines but enhanced by coadministration with them. Although considered to be more often reversible, trastuzumab cardiotoxicity does not always resolve, and some patients progress to clinical heart failure and death. As with anthracycline cardiotoxicity, therapy is as usual for heart failure, but it is not clear whether or not the spontaneous rate of improvement is enhanced by neurohormonal antagonists.
Cardiotoxicity with cyclophosphamide and ifosfamide generally occurs acutely and with very high doses. 5-Fluorouracil, cisplatin, and some other alkylating agents can cause recurrent coronary spasm that occasionally leads to depressed contractility. Many small molecule tyrosine kinase inhibitors are under development for different malignancies. Although these agents are “targeted” at specific tumor receptors or pathways, the biologic conservation of signaling pathways can cause inhibitors to have “off-target” effects that include the heart and vasculature. Acute administration of interferon-α can cause hypotension and arrhythmias. Clinical heart failure occurring during repeated chronic administration usually resolves after discontinuation.
Other therapeutic drugs that can cause cardiotoxicity during chronic use include hydroxychloroquine, chloroquine, emetine, and antiretroviral therapies.
Toxic exposures are most commonly implicated in arrhythmias or respiratory injury acutely during accidents. Chronic exposures that can cause cardiotoxicity include hydrocarbons, fluorocarbons, arsenicals, lead, and mercury.
METABOLIC CAUSES OF DILATED CARDIOMYOPATHY
Endocrine disorders affect multiple organ systems, including the heart. Hyperthyroidism and hypothyroidism do not often cause clinical heart failure in an otherwise normal heart, but commonly exacerbate heart failure. The most common, current reason for thyroid abnormalities in the heart failure population is the use of amiodarone, a drug with substantial iodine content. Clinical signs of thyroid disease may be masked, so tests of thyroid function are part of the routine evaluation of cardiomyopathy. Hypothyroidism should be treated with very slow escalation of doses to avoid exacerbating tachyarrhythmias and heart failure. Hyperthyroidism should always be considered with new onset atrial fibrillation or ventricular tachycardia, or atrial fibrillation in which the rapid ventricular response is difficult to control. Hyperthyroidism and heart failure are a dangerous combination that merits very close supervision, often hospitalization, during titration of antithyroid medications, which may lead to precipitous worsening of heart failure. Pheochromocytoma is rare, but should be considered when a patient has heart failure and very labile blood pressure and heart rate, sometimes with episodic palpitations. Most patients with pheochromocytoma have postural hypotension. In addition to α-adrenergic receptor antagonists, definitive therapy requires surgical extirpation. Very high renin states, such as those caused by renal artery stenosis, can lead to modest depression in ejection fraction with little or no ventricular dilation and markedly labile symptoms with flash pulmonary edema, related to sudden shifts in vascular tone and intravascular volume.
Controversies remain regarding whether diabetes and obesity are sufficient to cause cardiomyopathy. Most heart failure in diabetes results from epicardial coronary disease, with further increase in coronary artery risk due to accompanying hypertension and renal dysfunction. Cardiomyopathy may result in part from insulin resistance and increased advanced-glycosylation end products, which impair both systolic and diastolic function. However, much of the dysfunction can be attributed to scattered focal ischemia resulting from distal coronary artery tapering and limited microvascular perfusion even without proximal focal stenoses. Diabetes is a typical factor, along with hypertension, advanced age, and female gender, in heart failure with “preserved” ejection fraction.
The existence of a cardiomyopathy due to obesity is generally accepted. In addition to cardiac involvement from associated diabetes, hypertension, and vascular inflammation of the metabolic syndrome, obesity alone is associated with impaired excretion of excess volume load, which, over time, can lead to increased wall stress and secondary adaptive neurohumoral responses. The rapid clearance of natriuretic peptides by adipose tissue may contribute to fluid retention. In the absence of another obvious cause of cardiomyopathy in an obese patient with systolic dysfunction without marked ventricular dilation, effective weight reduction is often associated with major improvement in ejection fraction and clinical function.
Nutritional deficiencies can occasionally cause dilated cardiomyopathy but are not commonly implicated in developed Western countries. Beri-beri heart disease due to thiamine deficiency can result from poor nutrition in undernourished populations, and in patients deriving most of their calories from alcohol, and has been reported in teenagers subsisting only on highly processed foods. This disease is initially a vasodilated state with very high output heart failure that can later progress to a low output state; thiamine repletion can lead to prompt recovery of cardiovascular function. Abnormalities in carnitinemetabolism can cause dilated or restrictive cardiomyopathies, usually in children. Deficiency of trace elements such as selenium can cause cardiomyopathy (Keshan’s disease).
Calcium is essential for excitation-contraction coupling, serving as an inotrope when administered. Chronic deficiencies of calcium, such as can occur with hypoparathyroidism (particularly postsurgical) or intestinal dysfunction (from diarrheal syndromes and following extensive resection), can cause severe chronic heart failure that responds over days or weeks to vigorous calcium repletion. Phosphate is a component of high-energy compounds needed for efficient energy transfer and multiple signaling pathways. Hypophosphatemia can develop during starvation and early refeeding following a prolonged fast, and occasionally during hyper-alimentation. Magnesium is a cofactor for thiamine-dependent reactions and for the sodium-potassium adenosine triphosphatase (ATPase), but hypomagnesemia rarely becomes sufficiently profound to cause clinical cardiomyopathy.
Hemochromatosis is variably classified as a metabolic or storage disease. It is included among the causes of restrictive cardiomyopathy, but the clinical presentation is often that of a dilated cardiomyopathy. The autosomal recessive form is related to the HFE gene. With up to 10% of the population heterozygous for one mutation, the clinical prevalence might be as high as 1 in 500. The lower rates observed highlight the limited penetrance of the disease, suggesting the role of additional genetic and environmental factors for clinical expression. The clinical syndrome includes cirrhosis, diabetes, and hypogonadism. Hemochromatosis can also be acquired from iron overload due to hemolytic anemia and transfusions. Excess iron is deposited in the perinuclear compartment of cardiomyocytes, with resulting disruption of intracellular architecture and mitochondrial function. Diagnosis is easily made from measurement of serum iron and transferrin saturation, with a threshold of >60% for men, and >45–50% for women. Magnetic resonance imaging can help to quantitate iron stores in the liver and heart, and endomyocardial biopsy tissue can be stained for iron (Fig. 21-8). If diagnosed early, hemochromatosis can often be managed by repeated phlebotomy to remove iron. For more severe iron overload, iron chelation therapy with desferrioxamine (deferoxamine) or deferasirox can help to improve cardiac function if myocyte loss and replacement fibrosis are not too severe. Inborn disorders of metabolism occasionally present with dilated cardiomyopathy, although are most often associated with restrictive cardiomyopathy (Table 21-4).
Hemochromatosis. Microscopic image of an endomyocardial biopsy showing extensive iron deposition within the cardiac myocytes with the Prussian blue stain (400× original magnification). (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)
FAMILIAL DILATED CARDIOMYOPATHY
The recognized frequency of familial involvement in dilated cardiomyopathy has now increased to an estimated 30% (Table 21-3). The most recognizable familial syndromes are the muscular dystrophies.Both Duchenne’s and the milder Becker’s dystrophy result from abnormalities in the X-linked dystrophin gene of the sarcolemmal membrane. Skeletal myopathy is present in multiple other genetic cardiomyopathies (Table 21-3), some of which are associated with creatine kinase elevations. Mitochondrial myopathies are associated with varying degrees of skeletal involvement, biopsies of which show the characteristic “ragged red fiber” appearance. Some patients with mitochondrial myopathy have characteristic drooping eyelids. The energy deficits associated with mitochondrial abnormalities lead to multiple systemic syndromes. Other familial metabolic defects more often present as restrictive disease, but can sometimes be identified on electron microscopy of endomyocardial biopsies.
INHERITED GENETIC DEFECTS ASSOCIATED WITH CARDIOMYOPATHY
Families with a history of atrial arrhythmias, conduction system disease, and cardiomyopathy may have abnormalities of the nuclear membrane lamin proteins. While all dilated cardiomyopathies carry a risk of sudden death, a family history of cardiomyopathy with sudden death raises suspicion for a particularly arrhythmogenic mutation; affected family members may be considered for implantable defibrillators even before meeting the reduced ejection fraction threshold for primary prevention of sudden death.
A prominent family history of sudden death or ventricular tachycardia before clinical cardiomyopathy suggests genetic defects in the desmosomal proteins causing arrhythmogenic ventricular dysplasia(Fig. 21-9). Originally described as affecting the right ventricle (arrhythmogenic right ventricular dysplasia [ARVD]), this disorder can affect either or both ventricles. Patients often present first with ventricular tachycardia. Genetic defects in proteins of the desmosomal complex disrupt myocyte junctions and adhesions, leading to replacement of myocardium by deposits of fat. Thin ventricular walls may be recognized on echocardiography but are better visualized on MRI. The same protein also affects hair and skin, leading in some cases to a distinct syndrome of “woolly hair,” and thickened palms and soles. Implantable defibrillators are usually indicated to prevent sudden death. There is variable progression to right, left, or biventricular failure.
Arrhythmogenic right ventricular dysplasia. (A) Cross-sectional slice of a pathology specimen removed at transplantation, showing severe dysplasia of the right ventricle (RV) with extensive fatty replacement of right ventricular myocardium. The remarkably thin right ventricular free wall is revealed by transillumination (B). (Images courtesy of Gayle Winters, MD, and Richard Mitchell, MD, PhD, Division of Pathology, Brigham and Women’s Hospital, Boston.)
Left ventricular noncompaction is a condition of unknown prevalence that is increasingly revealed by better imaging techniques, first by two-dimensional echocardiography and more recently by magnetic resonance imaging. The diagnostic criteria includes the presence of multiple trabeculations in the left ventricle distal to the papillary muscles, creating a “spongy” appearance of the apex; it has been associated with multiple genetic variants in the sarcomeric and other proteins such as tafazzin. The condition may be diagnosed incidentally or in patients carrying previous diagnoses of dilated, restrictive, or hypertrophic cardiomyopathy. The three cardinal clinical features are ventricular arrhythmias, embolic events, and heart failure. Treatment generally includes anticoagulation and consideration for an implantable defibrillator.
Some families inherit a susceptibility to viral-induced myocarditis. This propensity may relate to abnormalities in cell surface receptors, such as the coxsackie-adenovirus receptor, that bind viral proteins. Some may have partial homology with viral proteins such that an autoimmune response is triggered against the myocardium.
The therapy of familial dilated cardiomyopathy is dictated primarily by the stage of clinical disease and the risk for sudden death. In some cases, the familial etiology facilitates prognostic decisions, particularly regarding the likelihood of recovery after a new diagnosis, which is unlikely for familial disease and frequent if the disease is acquired. The rate of progression of disease is to some extent heritable, although marked variation can be seen; however, there have been cases of remarkable clinical remission after acute presentation, likely after a reversible insult, such as infective myocarditis.
Genetic testing is less robust for dilated cardiomyopathy, for which our current understanding is similar to that for hypertrophic cardiomyopathy a decade ago. Newer molecular techniques, animal models, and data banks of cardiomyopathy patients are all contributing to the rapid expansion of the data presented in Table 21-3. However, serendipitous identification of inherited cardiomyopathy, its systemic signature, and clinical course remain crucial to continue to advance the field, one family and one gene at a time.
The apical ballooning syndrome, or stress-induced cardiomyopathy, occurs typically in older women after sudden intense emotional or physical stress. The ventricle shows global ventricular dilation with basal contraction, forming the shape of the narrow-necked jar (takotsubo) used in Japan to trap octopi. Originally described there, it is increasingly recognized in other countries and may go unrecognized during intensive care unit (ICU) admission for noncardiac conditions. Presentations include pulmonary edema, hypotension, and chest pain with ECG changes mimicking an acute infarction. The left ventricular dysfunction extends beyond a specific coronary artery distribution and generally resolves within days to weeks, but may recur in up to 10% of patients. Animal models and ventricular biopsies suggest that this acute cardiomyopathy may result from intense sympathetic activation with heterogeneity of myocardial autonomic innervation, diffuse microvascular spasm, and/or direct catecholamine toxicity. Coronary angiography may be required to rule out acute coronary occlusion. No therapies have been proven beneficial, but reasonable strategies include nitrates for pulmonary edema, intraaortic balloon pump if needed for low output, combined alpha and beta blockers rather than selective beta blockade if hemodynamically stable, and magnesium for arrhythmias related to QT prolongation. Anticoagulation is generally withheld due to the occasional occurrence of ventricular rupture.
IDIOPATHIC DILATED CARDIOMYOPATHY
Idiopathic dilated cardiomyopathy is a diagnosis of exclusion, when all other known factors have been excluded. Approximately two-thirds of dilated cardiomyopathies are still labeled as idiopathic; however, a substantial proportion of these may reflect unrecognized genetic disease. Continued reconsideration of etiology often reveals specific causes later in a patient’s course.
OVERLAP BETWEEN CARDIOMYOPATHIES
The limitations of our phenotypic classification are revealed through the multiple overlaps between the etiologies and presentations of the three types. Cardiomyopathy with reduced systolic function but without severe dilation can represent early dilated cardiomyopathy, “minimally dilated cardiomyopathy,” or restrictive diseases without marked increases in ventricular wall thickness. For example, sarcoidosis and hemochromatosis can present as dilated or restrictive disease. Early stages of amyloidosis sometimes appear as dilated cardiomyopathy, but can also be mistaken for hypertrophic cardiomyopathy. Progression of hypertrophic cardiomyopathy into a “burned-out” phase occurs occasionally, with decreased contractility and modest ventricular dilation. Overlaps are particularly common with the inherited metabolic disorders, which can present as any of the three major phenotypes (Fig. 21-4).
Dilated cardiomyopathy. Microscopic specimen of a dilated cardiomyopathy showing the nonspecific changes of interstitial fibrosis and myocyte hypertrophy characterized by increased myocyte size and enlarged, irregular nuclei. Hematoxylin and eosin stained section, 100× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)
The least common of the triad of cardiomyopathies is restrictive cardiomyopathy, which is dominated by abnormal diastolic function, often with mildly decreased contractility and ejection fraction (usually >30–50%). Both atria are enlarged, sometimes massively. Modest left ventricular dilation can be present, usually with an end-diastolic dimension <6 cm. End-diastolic pressures are elevated in both ventricles, with preservation of cardiac output until late in the disease. Subtle exercise intolerance is usually the first symptom but is often not recognized until after clinical presentation with congestive symptoms. The restrictive diseases often present with relatively more right-sided symptoms, such as edema, abdominal discomfort, and ascites, although filling pressures are elevated in both ventricles. The cardiac impulse is less displaced than in dilated cardiomyopathy and less dynamic than in hypertrophic cardiomyopathy. A fourth heart sound is more common than a third heart sound in sinus rhythm, but atrial fibrillation is common. Jugular venous pressures often show rapid Y descents, and may increase during inspiration (positive Kussmaul’s sign). Most restrictive cardiomyopathies are due to infiltration of abnormal substances between myocytes, storage of abnormal metabolic products within myocytes, or fibrotic injury (Table 21-6).
CAUSES OF RESTRICTIVE CARDIOMYOPATHIES
Amyloidosis is the major cause of restrictive cardiomyopathy (Figs. 21-10, 21-11, and 21-12), most often due to “primary amyloidosis” caused by abnormal production of immunoglobulin light chains. Familial amyloidosis results from an autosomal dominant mutation in transthyretin, a carrier protein for thyroxine and retinol, that is more common in African Americans than whites. Amyloidosis secondary to other chronic diseases rarely involves the heart. Senile amyloidosis with deposition of normal transthyretin or atrial natriuretic peptide usually has an indolent course and is very common beyond the seventh decade.
Restrictive cardiomyopathy—amyloidosis. Gross specimen of a heart with amyloidosis. The heart is firm and rubbery with a waxy cut surface. The atria are markedly dilated and the left atrial endocardium, normally smooth, has yellow-brown amyloid deposits that give texture to the surface. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)
Restrictive cardiomyopathy—amyloidosis. Echocardiogram showing thickened walls of both ventricles without major chamber dilation. The atria are markedly dilated, consistent with chronically elevated ventricular filling pressures. In this example, there is a characteristic hyper-refractile “glittering” of the myocardium typical of amyloid infiltration, which is often absent (especially with more recent echocardiographic systems of better resolution). The mitral and tricuspid valves are thickened. A pacing lead is visible in the right ventricle and a pericardial effusion is evident. Note that the echocardiographic and pathologic images are vertically opposite, such that the LV is by convention on the top right in the echocardiographic image and bottom right in the pathologic images. (Image courtesy of Justina Wu, MD, Brigham and Women’s Hospital, Boston.)
Amyloid fibrils infiltrate the myocardium, especially around the conduction system and coronary vessels. Typical clinical features are conduction block, autonomic neuropathy, renal involvement, and occasionally thickened skin lesions. Cardiac amyloid is suspected from thickened ventricular walls in conjunction with an electrocardiogram that shows low voltage. A characteristic refractile brightness in the septum on echocardiography is suggestive, but neither sensitive nor specific. Both atria are dilated, often dramatically so. The diagnosis of primary or familial can be made from biopsies of an abdominal fat pad or the rectum, but cardiac amyloidosis is most reliably identified from the myocardium (Fig. 21-12). Therapy is largely symptomatic, using diuretics as needed to treat fluid retention, which often requires high doses. Digoxin bound to the amyloid fibrils can reach toxic levels, and should therefore be used only in very low doses, if at all. There is no evidence regarding use of neurohormonal antagonists in amyloid heart disease, where the possible theoretical benefit has to be balanced against their potential side effects in light of frequent autonomic neuropathy and dependence on heart rate reserve. The risk of intracardiac thrombi may warrant chronic anticoagulation. Once heart failure develops, the median survival is 6–12 months in primary amyloidosis. Multiple myeloma is treated with chemotherapy (prednisone, melphalan, bortezomib), the extent of which is usually limited by the potential of worsening cardiac dysfunction. Colchicine can be of some benefit in inflammation-associated (AA) amyloid. Transthyretin-associated cardiac amyloid requires heart and liver transplantation, while senile cardiac amyloid is treated with conventional heart failure regimens. Immunoglobulin-associated amyloid has occasionally been treated with sequential heart transplantation and delayed bone marrow transplant, with frequent recurrence of amyloid in the transplanted heart.
Amyloidosis—microscopic images of amyloid involving the myocardium. The left panel (hematoxylin-eosin stain) shows glassy, grey-pink amorphous material infiltrating between cardiomyocytes, which stain a darker pink. The right panel shows a sulfated blue stain that highlights the amyloid green and stains the cardiac myocytes yellow. (The Congo red stain can also be used to highlight amyloid; under polarized light, amyloid will have an apple-green birefringence when stained with Congo red.) Images at 100× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)
DISORDERS OF METABOLIC PATHWAYS
Multiple genetic disorders of metabolic pathways can cause myocardial disease, due to infiltration of abnormal products or cells containing them between the myocytes, and storage disease, due to their accumulation within cells (Tables 21-4 and 21-6). The restrictive phenotype is most common but mildly dilated cardiomyopathy may occur. Hypertrophic cardiomyopathy may be mimicked by the myocardium thickened with these abnormal products causing “pseudohypertrophy.” Most of these diseases are diagnosed during childhood.
EXAMPLES OF INHERITED DEFECTS IN METABOLIC PATHWAYS ASSOCIATED WITH CARDIOMYOPATHY, USUALLY RESTRICTIVE OR PSEUDOHYPERTROPHIC PHENOTYPE
Fabry’s disease results from a deficiency of the lysosomal enzyme alpha-galactosidase A caused by one of more than 160 mutations. This disorder of glycosphingolipid metabolism is an X-linked recessive disorder that may also cause clinical disease in female carriers. Glycolipid accumulation may be limited to the cardiac tissues or may also involve the skin and kidney. Electron microscopy of endomyocardial biopsy tissue shows diagnostic vesicles containing concentric lamellar figures (Fig. 21-13). Diagnosis is crucial because enzyme replacement can reduce abnormal deposits and improve cardiac and clinical function. Enzyme replacement can also improve the course of Gaucher’s disease, in which cerebroside-rich cells accumulate in multiple organs due to a deficiency of beta-glucosidase. Cerebroside-rich cells infiltrate the heart, which can also lead to a hemorrhagic pericardial effusion and valvular disease.
Fabry’s disease. Transmission electron micrograph of a right ventricular endomyocardial biopsy specimen at high magnification showing the characteristic concentric lamellar inclusions of glycosphingolipids accumulating as a result of deficiency of the lysosomal enzyme alpha-galactosidase A. Image taken at 15,000× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)
Glycogen storage diseases lead to accumulation of lysosomal storage products and intracellular glycogen accumulation, particularly with glycogen storage disease type III, due to a defective debranching enzyme. There are more than 10 types of mucopolysaccharidoses, in which autosomal dominant or X-linked deficiencies of lysosomal enzymes lead to the accumulation of glycosaminoglycans in the skeleton, nervous system, and heart. With characteristic facies, short stature, and frequent cognitive impairment, most individuals are diagnosed early in childhood and die before adulthood.
Carnitine is an essential cofactor in long-chain fatty acid metabolism. Multiple defects have been described that lead to carnitine deficiency, causing intracellular lipid inclusions and restrictive or dilated cardiomyopathy, often presenting in children. Fatty acid oxidation requires many metabolic steps with specific enzymes that can be deficient, with complex interactions with carnitine. Depending on the defect, cardiac and skeletal myopathy can be ameliorated with replacement of fatty acid intermediates and carnitine.
Two monogenic metabolic cardiomyopathies have recently been described as causes of increased ventricular wall thickness without an increase of muscle subunits or an increase in contractility. Mutations in the gamma-2 regulatory subunit of the adenosine mono-phosphate (AMP)-activated protein kinase important for glucose metabolism (PRKAG2) have been associated with a high prevalence of conduction abnormalities, such as AV block and ventricular preexcitation (Wolff-Parkinson-White syndrome). Several defects have been reported in an X-linked lysosome-associated membrane protein (LAMP2). This defect can be maternally transmitted or sporadic and has occasionally been isolated to the heart, although it often leads to a syndrome of skeletal myopathy, mental retardation, and hepatic dysfunction referred to as Danon’s disease. Left ventricular hypertrophy appears early, often in childhood, and can progress rapidly to end-stage heart failure with low ejection fraction. Electron microscopy of these metabolic disorders shows that the myocytes are enlarged by multiple intracellular vacuoles of metabolic by-products.
FIBROTIC RESTRICTIVE CARDIOMYOPATHY
Progressive fibrosis can cause restrictive myocardial disease without dilation. Thoracic radiation, common for breast and lung cancer or mediastinal lymphoma, can produce early or late restrictive cardiomyopathy. Patients with radiation cardiomyopathy may present with a possible diagnosis of constrictive pericarditis, as the two conditions often coexist. Careful hemodynamic evaluation and, often, endomyocardial biopsy should be performed if considering pericardial stripping surgery, which is unlikely to be successful in the presence of underlying restrictive cardiomyopathy.
Scleroderma causes small vessel spasm and ischemia that can lead to a small, stiff heart with reduced ejection fraction without dilation. Doxorubicin causes direct myocyte injury usually leading to dilated cardiomyopathy, but the limited degree of dilation may result from increased fibrosis, which restricts remodeling.
The physiologic picture of elevated filling pressures with atrial enlargement and preserved ventricular contractility with normal or reduced ventricular volumes can also result from extensive fibrosis of the endocardium, without transmural myocardial disease. For patients who have not lived in the equatorial regions, this picture is rare, and when seen is usually associated with a history of chronic hypereosinophilic syndrome (Löffler’s endocarditis), which is more common in men than women. In this disease, persistent hypereosinophilia of >1500 eos/mm3 for at least 6 months can cause an acute phase of eosinophilic injury in the endocardium, with systemic illness and injury to other organs. There is usually no obvious cause, but the hypereosinophilia can occasionally be explained by allergic, parasitic, or malignant disease. It is postulated to be followed by a period in which cardiac inflammation is replaced by evidence of fibrosis with superimposed thrombosis. In severe disease, the dense fibrotic layer can obliterate the ventricular apices and extend to thicken and tether the atrioventricular valve leaflets. The clinical disease may present with heart failure, embolic events, and atrial arrhythmias. While plausible, the sequence of transition has not been clearly demonstrated.
In tropical countries, up to one-quarter of heart failure may be due to endomyocardial fibrosis, affecting either or both ventricles. This condition shares with the previous condition the partial obliteration of the ventricular apex with fibrosis extending into the valvular inflow tract and leaflets; however, it is not clear that the etiologies are the same for all cases. Pericardial effusions frequently accompany endomyocardial fibrosis but are not common in Löffler’s endocarditis. For endomyocardial fibrosis, there is no gender difference, but a higher prevalence in African-American populations. While tropical endomyocardial fibrosis could represent the end stage of previous hypereosinophilic disease triggered by endemic parasites, neither prior parasitic infection nor hypereosinophilia is usually documented. Geographic nutritional deficiencies have also been proposed as an etiology.
Medical treatment focuses on glucocorticoids and chemotherapy to suppress hypereosinophilia when present. Fluid retention may become increasingly resistant to diuretic therapy. Anticoagulation is recommended. Atrial fibrillation is associated with worse symptoms and prognosis, but may be difficult to suppress. Surgical resection of the apices and replacement of the fibrotic valves can improve symptoms, but surgical morbidity and mortality and later recurrence rates are high.
The serotonin secreted by carcinoid tumors can produce fibrous plaques in the endocardium and right-sided cardiac valves, occasionally affecting left-sided valves, as well. Valvular lesions may be stenotic or regurgitant. Systemic symptoms include flushing and diarrhea. Liver disease from hepatic metastases may play a role by limiting hepatic function and thereby allowing more serotonin to reach the venous circulation.
Hypertrophic cardiomyopathy is characterized by marked left ventricular hypertrophy in the absence of other causes, such as hypertension or valve disease (Figs. 21-14 and 21-15). The systolic function as measured by ejection fraction is often supranormal, at times with virtual obliteration of the left ventricular cavity during systole. The hypertrophy may be asymmetric, involving the septum more than the free wall of the ventricle. Approximately one-third of symptomatic patients demonstrate a resting intraventricular gradient that impedes outflow during systole and is exacerbated by increased contractility. This was previously termed hypertrophic obstructive cardiomyopathy(HOCM), as distinguished from nonobstructive hypertrophic cardiomyopathy. Other terms that have been used include asymmetric septal hypertrophy (ASH) and idiopathic hypertrophic subaortic stenosis (IHSS). However, the accepted terminology is now hypertrophic cardiomyopathy with or without an obstructive gradient. Classically, the microscopic picture shows marked disarray of individual fibers in a characteristic whorled pattern and disarray, also at the level of the larger bundles, interspersed with fibrosis (Fig. 21-16).
Hypertrophic cardiomyopathy. Gross specimen of a heart with hypertrophic cardiomyopathy removed at the time of transplantation, showing asymmetric septal hypertrophy (septum much thicker than left ventricular free wall) with the septum bulging into the left ventricular outflow tract causing obstruction. The forceps are retracting the anterior leaflet of the mitral valve, demonstrating the characteristic plaque of systolic anterior motion, manifest as endocardial fibrosis on the interventricular septum in a mirror-image pattern to the valve leaflet. There is patchy replacement fibrosis, and small thick walled arterioles can be appreciated grossly, especially in the interventricular septum. IVS, interventricular septum; LV, left ventricle; RV, right ventricle. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)
Hypertrophic cardiomyopathy. This echocardiogram of hypertrophic cardiomyopathy shows asymmetric hypertrophy of the septum compared to the lateral wall of the left ventricle (LV). The mitral valve is moving anteriorly toward the hypertrophied septum in systole. The left atrium (LA) is enlarged. Note that the echocardiographic and pathologic images are vertically opposite, such that the LV is by convention on the top right in the echocardiographic image and bottom right in the pathologic images. (Image courtesy of Justina Wu, MD, Brigham and Women’s Hospital, Boston.)
Hypertrophic cardiomyopathy. Microscopic image of hypertrophic cardiomyopathy showing the characteristic disordered myocyte architecture with swirling and branching rather than the usual parallel arrangement of myocyte fibers. Myocyte nuclei vary markedly in size and interstitial fibrosis is present. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.)
The prevalence of hypertrophic cardiomyopathy is 1:500 adults. Approximately one-half of these cases occur in a recognizable autosomal dominant pattern, and spontaneous mutations also arise. This is the best characterized genetic cardiomyopathy, for which more than 400 individual mutations have been identified in 11 sarcomeric genes. More than 80% of the mutations are in the beta-myosin heavy chain, the cardiac myosin-binding protein C, or cardiac troponin T. Some families may demonstrate a higher incidence of early progression to end-stage heart failure or death, suggesting that their mutations are more “malignant.” However, the heterogeneity of phenotypic expression within and between families confirms the influence of modifying factors from other genes and the environment.
Hypertrophic cardiomyopathy is characterized hemodynamically by diastolic dysfunction, originally attributed to the hypertrophy, fibrosis, and intraventricular gradient when present. However, studies of asymptomatic family members indicate that diastolic dysfunction is a more fundamental abnormality that can precede evidence of hypertrophy. Resting ejection fraction and cardiac output are usually normal, but peak cardiac output during exercise may be reduced due to inadequate ventricular filling at high heart rates.
Hypertrophic cardiomyopathy usually presents between the ages of 20 and 40 years. Dyspnea on exertion is the most common presenting symptom, reflecting elevated intracardiac filling pressures. Chest pain with either an atypical or typical exertional pattern occurs in more than half of symptomatic patients and is attributed to myocardial ischemia from high demand and abnormal intramural coronary arteries in the hypertrophied myocardium. Palpitations may result from atrial fibrillation or ventricular arrhythmias. Much less common are episodes of presyncope or syncope, often related to heavy exertion. Of grave concern is the possibility that the first manifestation of disease may be sudden death from ventricular tachycardia or fibrillation. Hypertrophic cardiomyopathy is the most common lesion found at autopsy of young athletes dying suddenly.
The physical examination typically reveals a harsh murmur heard best at the left lower sternal border, arising from both the outflow tract turbulence during ventricular ejection and the commonly associated mitral regurgitation. The gradient and the murmur may be enhanced by maneuvers that decrease ventricular volume, such as the Valsalva maneuver, or standing after squatting. They may be decreased by increasing ventricular volume or vascular resistance, such as with squatting or hand grip. A fourth heart sound is commonly heard due to decreased ventricular compliance. In patients with a significant outflow tract gradient, palpation of the carotid pulse may reveal a bifid systolic impulse, from early and delayed ejection. Patients with chronic, severe elevations in filling pressures may show signs of systemic fluid retention.
The electrocardiogram usually shows left ventricular hypertrophy, often with prominent septal Q waves that can be misdiagnosed as indicative of infarction. The diagnosis of hypertrophic cardiomyopathy is confirmed by echocardiography demonstrating left ventricular hypertrophy, which may or may not be more marked in the septum (Fig. 21-15). Intraventricular gradients to outflow can be identified by Doppler echocardiography at rest or during provocative maneuvers, such as the Valsalva maneuver. Systolic anterior motion (SAM) of the mitral valve is a classic finding on the echocardiogram. Mitral regurgitation may become severe. Cardiac catheterization can be performed to quantify the gradient, which characteristically increases after a premature ventricular contraction.
Apical hypertrophic cardiomyopathy is a variant that is uncommon in the United States; however, this variant accounts for about one-fourth of patients with hypertrophic cardiomyopathy in Japan. The electrocardiogram shows deep T-wave inversions in the precordial leads, and the echocardiogram shows a characteristic spade-like appearance with apical obliteration. It has been associated with a specific genetic defect in cardiac actin (Glu 101 Lys), but may occur with other sarcomere mutations.
The differential diagnosis of hypertrophic cardiomyopathy is limited in most patients once other cardiovascular causes for secondary hypertrophy are excluded. However, other diseases that result in thickened myocardium can appear indistinguishable on echocardiography, and are considered “pseudohypertrophic,” particularly the inherited metabolic diseases (Table 21-4). The differential diagnosis between hypertrophic and restrictive cardiomyopathy may be particularly difficult when considering a diagnosis of “burned-out” hypertrophic cardiomyopathy in which systolic function has decreased. Overlap with infiltrative and restrictive myocardial diseases should be considered in the evaluation of increased left ventricular wall thickness on echocardiography, particularly when clinical features are atypical for classic hypertrophic cardiomyopathy. The metabolic defects in PRKAG2, alpha-galactosidase (Fabry’s disease), and LAMP2 mutations (Tables 21-3 and 21-4) should routinely be considered during evaluation of apparent hypertrophic cardiomyopathy. With late onset without a family history of hypertrophic cardiomyopathy, amyloidosis should be carefully considered.
TREATMENT Hypertrophic Cardiomyopathy
Therapy of hypertrophic cardiomyopathy is directed to symptom management and the prevention of sudden death (Fig. 21-17); it is not known whether treatment will decrease disease progression in asymptomatic family members. Exertional dyspnea and chest pain are treated by medication to reduce heart rate and ventricular contractility with hopes of improving diastolic filling patterns. Beta-adrenergic blocking drugs and verapamil are most commonly used as initial therapy. These agents both act to decrease heart rate and increase the length of time for diastolic filling, as well as to decrease the inotropic state. If there is fluid retention, diuretic therapy will usually be necessary, but requires careful titration to avoid hypovolemia, particularly in the presence of a resting or inducible obstruction to ventricular outflow. When symptoms persist and an outflow gradient is present, addition of disopyramide is sometimes effective. Amiodarone can also improve symptoms, but is usually initiated for control of arrhythmias rather than symptoms. Anticoagulation is recommended to prevent embolic events for patients who have had atrial fibrillation.
Treatment algorithm for hypertrophic cardiomyopathy depending on the presence and severity of symptoms, and the presence of an intraventricular gradient with obstruction to outflow. Note that all patients with hypertrophic cardiomyopathy should be evaluated for risk of sudden death, whether or not they require treatment for symptoms. ICD, implantable cardioverter-defibrillator; LV, left ventricular.
Symptoms that limit routine daily life despite adjustment of medical therapies develop in fewer than 5–10% of patients, generally those with substantial obstruction to ventricular outflow. Further therapies are directed to reduce this obstruction by changing ventricular mechanics. Most of the reported symptom improvement with dual chamber pacing is now attributed to placebo effect. Cardiac surgery can be directed to reduce the size of the upper septum that contributes to the obstruction (myomectomy), which generally also dominates the contribution of the anterior mitral leaflet to outflow tract obstruction. Reduction of the septum has also been accomplished by a catheter-based procedure in which ethanol is injected into a septal artery to cause a controlled septal infarction. The purpose of these interventions is to improve symptoms; none has been shown to prolong survival.
Cardiac transplantation is considered in fewer than 5% of patients with hypertrophic cardiomyopathy. It is rarely necessary to control symptoms in patients with preserved contractility and is more often considered for patients who progress to “burned-out” cardiomyopathy with decreased ejection fraction.
THERAPY TO PREVENT SUDDEN DEATH IN HYPERTROPHIC CARDIOMYOPATHY Originally reported as 3–4% in referral populations, the annual incidence of sudden death in less selected populations of hypertrophic cardiomyopathy is approximately 1%. This outcome is attributed primarily to ventricular tachyarrhythmias, for which a myocardium with abnormal disorganized myocytes with patchy fibrosis is at exceptional risk, possibly further compromised by impaired coronary perfusion and aggravated by sudden increases in wall stress. Sudden death may precede the diagnosis of the disease, as in the death of young athletes. The highest risk is in patients with previous sustained ventricular tachyarrhythmias, a family history of sudden death, or, in cases of common mutations, a genetic mutation associated with sudden death (although the association of specific genotypes with the risk of sudden death remains controversial). Septal wall thickness >30 mm, recurrent syncope, exercise-induced hypotension, and nonsustained ventricular tachycardia are also risk factors. Areas of ventricular fibrosis detected on MRI may further identify susceptibility to life-threatening arrhythmias. Implantable cardioverter-defibrillators should be considered for those at highest risk (Table 21-7). Although low-risk patients can engage in regular physical activity with casual intent, it has been recommended that all patients with hypertrophic cardiomyopathy avoid intense training and competition.
RISK FACTORS FOR SUDDEN DEATH IN HYPERTROPHIC CARDIOMYOPATHY
1From BJ Maron et al: Circulation 113:1807, 2006.