CHAPTER 27: CARDIOMYOPATHY AND MYOCARDITIS

Cardiomyopathy is disease of the heart muscle. It is estimated that cardiomyopathy accounts for 5–10% of the heart failure in the 5–6 million patients carrying that diagnosis 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 attributed to 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 echocardiographic 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 27-1).

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, genetic information is often unavailable at the time of initial presentation, the phenotypic expression of a given mutation varies widely, and genetic predisposition influences the clinical phenotype of acquired cardiomyopathies, as well. Although the proposed genetic classification does not yet guide many current clinical strategies, it will likely 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 lung disease or age-dependent exercise limitation. 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 when lying down at night. Although often considered the hallmark of congestion, peripheral edema may be absent despite severe fluid retention, particularly in younger patients in whom ascites and abdominal discomfort may dominate. The nonspecific term congestive heart failure describes only the resulting syndrome of fluid retention, which is common to all three types of cardiomyopathy and also to cardiac structural diseases associated with elevated filling pressures. 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 27-1). Initial evaluation begins with a detailed clinical history and examination, looking for clues to cardiac, extracardiac, and familial disease (Table 27-2).

Estimates for the prevalence of genetic etiology for cardiomyopathy continue to rise, with increasing attention paid to the family history and the availability of genetic testing. Well-recognized in hypertrophic cardiomyopathy, heritability is also present in at least 30% of dilated cardiomyopathy 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.

Most familial cardiomyopathies are inherited in an autosomal dominant pattern, with occasional autosomal recessive and X-linked inheritance (Table 27-3). Missense mutations with amino acid substitutions are the most common in cardiomyopathy. Expressed mutant proteins may interfere with function of the normal allele through a dominant negative mechanism. Mutations introducing a premature stop codon (nonsense) or shift in the reading frame (frameshift) may create a truncated or unstable protein the lack of which causes cardiomyopathy (haploinsufficiency). Deletions or duplications of an entire exon or gene are uncommon causes of cardiomyopathy, except for the dystrophinopathies.

Many different genes have been implicated in human cardiomyopathy (locus heterogeneity), and many mutations within those genes have been associated with disease (allelic heterogeneity). Although most identified mutations are “private” to individual families, several specific mutations are found repeatedly, either due to a founder effect or recurrent mutations at a common residue.

Genetic cardiomyopathy is characterized by age dependence and incomplete penetrance. The defining phenotype of cardiomyopathy is rarely present at birth and, in some individuals, may never manifest. Related individuals who carry the same mutation may differ in the severity of cardiomyopathy and associated consequences of rhythm disorders and need for transplantation, indicating the important role of other genetic, epigenetic, and environmental modifiers in disease expression. Sex appears to play a role, as penetrance and clinical severity may be greater in men for most cardiomyopathies. Clinical disease expression is generally more severe in the 3–5% of individuals who harbor two or more mutations linked to cardiomyopathy. However, the clinical course of a patient usually cannot be predicted based on which mutation is present; thus, current therapy is based on the phenotype rather than the genetic defect. Currently, the greatest utility of genetic testing for cardiomyopathy is to inform family evaluations. However, genetic testing occasionally enables the detection of a disease for which specific therapy is indicated, such as the replacements for defective metabolic enzymes in Fabry’s disease and Gaucher disease.

GENES AND PATHWAYS IN CARDIOMYOPATHY

Mutations in sarcomeric genes, encoding the thick and thin myofilament proteins, are the best characterized. While the majority are associated with hypertrophic cardiomyopathy, an increasing number of sarcomeric mutations have now been implicated in dilated cardiomyopathy, and some in left ventricular noncompaction. Few mutations have been identified in excitation-contraction coupling proteins, perhaps because they are too crucial for survival to allow variation. The most commonly recognized genetic causes of dilated cardiomyopathy are structural mutations of the giant protein titin, encoded TTN, which maintains sarcomere structure and acts as a key signaling molecule.

As cytoskeletal proteins play crucial roles in the structure, connection, and stability of the myocyte, multiple defects in these proteins can lead to cardiomyopathy, usually with a dilated phenotype (Fig. 27-1). 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 may cause combined cardiac and skeletal myopathy.

Sarcolemmal membrane protein defects are associated with dilated cardiomyopathy. The best known is dystrophin, encoded by the X chromosome gene DMD, abnormalities of which cause Duchenne’s and Becker’s muscle dystrophy. (Interestingly, abnormal dystrophin can be acquired when the coxsackie virus 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 also cause dilated cardiomyopathy. Defects in the sarcolemmal channel proteins (channelopathies) are generally associated with primary arrhythmias, but mutations in SCN5A, distinct from those that cause the Brugada or long-QT syndromes, have been implicated in dilated cardiomyopathy with conduction disease.

Nuclear membrane protein defects in cardiac and skeletal muscle occur in either autosomal (lamin A/C) or X-linked (emerin) patterns. These defects are associated with a high prevalence of atrial arrhythmias and conduction system disease, which can occur in some family members without or before detectable cardiomyopathy.

Intercalated disks contribute to intracellular connections, allowing mechanical and electrical coupling between cells and also connections 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 dilate to form aneurysms. Although more often noted in the right ventricle (arrhythmogenic right ventricular dysplasia), this condition can affect both ventricles and has also been termed “arrhythmogenic cardiomyopathy.”

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. Currently, it is most important to diagnose defective enzymes for which specific enzyme replacement therapy can now ameliorate the course of disease, such as with alpha-galactosidase A deficiency (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 mutation of genes expressed in the heart.

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 on 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. 27-2, 27-3, and 27-4). Systolic failure is more marked than diastolic dysfunction. Although the syndrome of dilated cardiomyopathy has multiple etiologies (Table 27-4), there appear to be common pathways of secondary response and disease progression. When myocardial injury is acquired, some myocytes may die initially, whereas others survive only to have later programmed cell death (apoptosis), and remaining myocytes hypertrophy in response to increased wall stress. Local and circulating factors stimulate deleterious secondary responses that contribute to progression of disease. 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 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. Dilation and decreased function of the right ventricle may result from the initial injury and occasionally dominate, but more commonly appear later in relation to mechanical interactions with the failing left ventricle and the elevated afterload presented by secondary pulmonary hypertension.

Regardless of the nature and degree of direct cell injury, the resulting functional impairment often includes some contribution from secondary responses that may be modifiable or reversible. Almost half of all patients with new-onset cardiomyopathy demonstrate substantial spontaneous recovery. Even with long-standing disease, 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. For patients in whom left bundle branch block precedes clinical heart failure by many years, cardiac resynchronization pacing may be particularly likely to improve ejection fraction and decrease ventricular size. Interest in the potential for recovery of cardiomyopathy has been further stimulated by occasional “recovery” of left ventricular function after prolonged mechanical circulatory support. The diagnosis and therapy for dilated cardiomyopathy are generally dictated by the stage of heart failure (Chap. 19), with specific aspects discussed for relevant etiologies below.

MYOCARDITIS

Myocarditis (inflammation of the heart) can result from multiple causes but is most commonly attributed to infective agents that can injure the myocardium through direct invasion, production of cardiotoxic substances, or chronic inflammation with or without persistent infection. Myocarditis cannot be assumed from a presentation of decreased systolic function in the setting of an acute infection, as any severe infection causing systemic cytokine release can depress cardiac function transiently. Infectious myocarditis has been reported with almost all types of infective agents but is most commonly associated with viruses and the protozoan Trypanosoma cruzi.

INFECTIVE MYOCARDITIS

The pathogenesis of viral myocarditis has been extensively studied in murine models. After viruses gain entry through the respiratory or gastrointestinal tract, they can infect organs possessing specific receptors, such as the coxsackie-adenovirus receptor on the heart. Viral infection and replication can cause myocardial injury and lysis. For example, the enteroviral protease 2A facilitates viral replication and infection through degradation of the myocyte protein dystrophin, which is crucial for myocyte stability. Activation of viral receptor proteins can also activate host tyrosine kinases, which modify the cytoskeleton to facilitate further viral entry.

The first host response to infection is the nonspecific innate immune response, heavily dependent on Toll-like receptors that recognize common antigenic patterns. Cytokine release is rapid, followed by triggered activation and expansion of specific T- and B-cell populations. This initial response appears to be crucial, as early immunosuppression in animal models can increase viral replication and worsen cardiac injury. However, successful recovery from viral infection depends not only on the efficacy of the immune response to limit viral infection, but also on timely downregulation to prevent overreaction and autoimmune injury to the host.

The secondary acquired immune response is more specifically addressed against the viral proteins and can include both T-cell infiltration and antibodies to viral proteins. If unchecked, the acquired immune response can perpetuate secondary cardiac damage. Ongoing cytokine release activates matrix metalloproteinases that can disrupt the collagen and elastin scaffolding of the heart, potentiating ventricular dilation. Stimulation of profibrotic factors leads to pathologic interstitial fibrosis. Some of the antibodies triggered through co-stimulation or molecular mimicry also recognize targets within the host myocyte, such as the β-adrenergic receptor, troponin, and Na⁺/K⁺ ATPase, but it remains unclear whether these antibodies contribute actively to cardiac dysfunction in humans or merely serve as markers of cardiac injury.

It is not known how long the viruses persist in the human heart, whether late persistence of the viral genome continues to be deleterious, or how often a dormant virus can again become pathogenic. Genomes of common viruses have frequently been detected in patients with clinical diagnoses of myocarditis or dilated cardiomyopathy, but there is little information on how often these are present in patients without cardiac disease (see below). Further information is needed to understand the relative timing and contribution of infection, immune responses, and secondary adaptations in the progression of heart failure after viral myocarditis (Fig 27-5).

Clinical presentation of viral myocarditis

Acute viral myocarditis often presents with symptoms and signs of heart failure. Some patients present with chest pain suggestive of pericarditis or acute myocardial infarction. Occasionally, the presentation is dominated by atrial or ventricular tachyarrhythmias, or by pulmonary or systemic emboli from intracardiac thrombi. Electrocardiographic or echocardiographic abnormalities may also be detected incidentally during evaluation for other diagnoses. The typical patient with presumed viral myocarditis is a young to middle-aged adult who develops progressive dyspnea and weakness within a few days to weeks after a viral syndrome that was accompanied by fever and myalgias.

A small number of patients present with fulminant myocarditis, with rapid progression from a severe febrile respiratory syndrome to cardiogenic shock that may involve multiple organ systems, leading to renal failure, hepatic failure, and coagulopathy. These patients are typically young adults who have recently been dismissed from urgent care settings with antibiotics for bronchitis or oseltamivir for viral syndromes, only to return within a few days in rapidly progressive cardiogenic shock. Prompt triage is vital to provide aggressive support with high-dose intravenous catecholamine therapy and sometimes with temporary mechanical circulatory support. Recognition of patients with this fulminant presentation is potentially life-saving as more than half can survive, with marked improvement demonstrable within the first few weeks. The ejection fraction function of these patients often recovers to near-normal, although residual diastolic dysfunction may limit vigorous exercise for some survivors.

Chronic viral myocarditis is often invoked, but rarely proven, as a diagnosis when no other cause of dilated cardiomyopathy can be identified. However, some cases of otherwise unexplained cardiomyopathy will later be recognized to have a genetic basis, or ultimately found to have resulted from excess alcohol consumption or illicit drugs. There are likely many other causes that cannot yet be identified. The prevalence of previous or persistent viral infection as the cause for chronic dilated cardiomyopathy remains highly controversial.

Laboratory evaluation for myocarditis

The initial evaluation for suspected myocarditis includes an ECG, an echocardiogram, and serum levels of troponin and creatine phosphokinase fractions. Magnetic resonance imaging is increasingly used for the diagnosis of myocarditis, which is supported by evidence of increased tissue edema and gadolinium enhancement (Fig. 27-6), particularly in the mid-wall (as distinct from usual coronary artery territories).

Endomyocardial biopsy is not often indicated for the initial evaluation of suspected viral myocarditis unless ventricular tachyarrhythmias suggest possible etiologies of sarcoidosis or giant cell myocarditis. The indications and benefit of endomyocardial biopsy for evaluation of myocarditis or new-onset cardiomyopathy remain controversial.

The Dallas Criteria for myocarditis on endomyocardial biopsy include lymphocytic infiltrate with evidence of myocyte necrosis (Fig. 27-7) and are negative in 80–90% of patients with clinical myocarditis. Negative Dallas Criteria can reflect sampling error or early resolution of lymphocytic infiltrates, but also the insensitivity of the test when inflammation results from cytokines and antibody-mediated injury. Routine histologic examination of endomyocardial biopsy rarely reveals a specific infective etiology, such as toxoplasmosis or Cytomegalovirus. Immunohistochemistry of myocardial biopsy samples is commonly used to identify active lymphocyte subtypes and may also detect upregulation of HLA antigens and the presence of complement components attributed to inflammation, but the specificity and significance of these findings are uncertain.

An increase in circulating viral titers between acute and convalescent blood samples supports a diagnosis of acute viral myocarditis with potential spontaneous improvement. There is no established role for measuring circulating anti-heart antibodies, which may be the result, rather than a cause, of myocardial injury and have been found also in patients with coronary artery disease and genetic cardiomyopathy.

Patients with recent or ongoing viral syndromes can be classified into three levels of diagnosis:

1. Possible subclinical acute myocarditis is diagnosed when a patient has a typical viral syndrome but no cardiac symptoms, with one or more of the following:

   • Elevated biomarkers of cardiac injury (troponin or CK-MB)

   • ECG findings suggestive of acute injury

   • Reduced left ventricular ejection fraction or regional wall motion

   • Abnormality on cardiac imaging, usually echocardiography

2. Probable acute myocarditis is diagnosed when the above criteria are met and accompanied also by cardiac symptoms, such as shortness of breath or chest pain, which can result from pericarditis or myocarditis. When clinical findings of pericarditis (pleuritic chest pain, ECG abnormalities, pericardial rub or effusion) are accompanied by elevated troponin or CK-MB or abnormal cardiac wall motion, the terms perimyocarditis or myopericarditis are sometimes used.

3. Definite myocarditis is diagnosed when there is histologic or immunohistologic evidence of inflammation on endomyocardial biopsy (see below) and does not require any other laboratory or clinical criteria.

SPECIFIC VIRUSES IMPLICATED IN MYOCARDITIS

In humans, viruses are often suspected but rarely proven to be the direct cause of clinical myocarditis. First implicated was the picornavirus family of RNA viruses, principally the enteroviruses, coxsackie virus, echovirus, and poliovirus. Influenza, another RNA virus, is implicated with varying frequency every winter and spring as epitopes change. Of the DNA viruses, adenovirus, vaccinia (smallpox vaccine), and the herpesviruses (varicella zoster, cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6 [HHV6]) are well-recognized to cause myocarditis but also occur commonly in the healthy population. Polymerase chain reaction (PCR) detects viral genomes in the majority of patients with dilated cardiomyopathy, but also in normal “control” hearts. Most often detected are parvovirus B19 and HHV6, which may affect the cardiovascular system, in part, through infection of vascular endothelial cells. However, their contribution to chronic cardiomyopathy is uncertain, as serologic evidence of exposure is present in many children and most adults.

Human immunodeficiency virus (HIV) was associated with an incidence of dilated cardiomyopathy of 1–2%; however, with the advent of highly active antiretroviral therapy (HAART), HIV has been associated with a significantly lower incidence of cardiac disease. Cardiomyopathy in HIV may result from cardiac involvement with other associated viruses, such as cytomegalovirus and hepatitis C, as well as by HIV directly. Antiviral drugs to treat chronic HIV can cause cardiomyopathy, both directly 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 dysfunction 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).

Additional viruses implicated specifically in myocarditis include mumps, respiratory syncytial virus, the arboviruses (dengue fever and yellow fever), and arenaviruses (Lassa fever). However, for any serious infection, the systemic inflammatory response can cause nonspecific depression of cardiac function, which is generally reversible if the patient survives.

THERAPY

There is currently no specific therapy recommended during any stage of viral myocarditis. During acute infection, therapy with anti-inflammatory or immunosuppressive medications is avoided, as their use has been shown to increase viral replication and myocardial injury in animal models. Therapy with specific antiviral agents (such as oseltamivir) has not been studied in relation to cardiac involvement. There is ongoing investigation into the impact of antiviral therapy to treat chronic viral persistence identified from endomyocardial biopsy. Large trials of immunosuppressive therapy for Dallas Criteria–positive myocarditis have been negative. There are some initial encouraging results and ongoing investigations with immunosuppressive therapy for immune-mediated myocarditis defined by immunohistologic criteria on biopsy or circulating anti-heart antibodies in the absence of myocardial viral genomes. However, neither antiviral nor anti-inflammatory therapies are currently recommended. Until we have a better understanding of the different phases of viral myocarditis and its sequelae and the effects of timed or targeted therapies, treatment will continue to be directed to the clinical cardiovascular stage of the disease, for dilated cardiomyopathy in general.

Parasitic myocarditis

Chagas’ disease is the third most common parasitic infection in the world and the most common infective cause of cardiomyopathy. The protozoan T. cruzi is 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.

Multiple pathogenic 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 with viral myocarditis, the relative roles of persistent infection and of secondary autoimmune injury have not been resolved (Fig. 27-5). An additional factor in the progression of Chagas’ disease is the autonomic dysfunction and microvascular damage that may contribute to cardiac and gastrointestinal disease.

The acute phase of Chagas’ disease with parasitemia is usually unrecognized, but in fewer than 5% of cases, it presents clinically within a few weeks of infection, with nonspecific symptoms or occasionally with acute myocarditis and meningoencephalitis. In the absence of antiparasitic 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. 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 ventricular apex. These dilated ventricles are particularly thrombogenic, giving rise to pulmonary and systemic emboli. Xenodiagnosis, detection of the parasite itself, is rarely performed. The serologic tests for specific IgG antibodies against the trypanosome lack sufficient specificity and sensitivity, thereby requiring two separate positive tests required to make a diagnosis.

Treatment of the advanced stages focuses on clinical manifestations of the disease and includes heart failure medications, pacemaker-defibrillators, and anticoagulation. Increasing attention is directed to antiparasitic therapy even in chronic disease without obvious active infection. The most common effective antiparasitic therapies are benznidazole and nifurtimox, both associated with multiple severe reactions, including dermatitis, gastrointestinal distress, and neuropathy. Survival is less than 30% at 5 years after the onset of overt clinical heart failure. Patients without major extracardiac disease have occasionally undergone transplantation, after which they may 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. Antiparasitic therapy has limited efficacy and is determined by the specific type and the stage of infection (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 most likely to experience 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 in an immunocompetent patient is made when the IgM is positive and the IgG becomes positive later. Active toxoplasmosis may be suspected in an immunocompromised patient with myocarditis and a positive IgG titer for toxoplasmosis, particularly when avidity testing identifies high specificity of the antibody. Fortuitous sampling occasionally reveals 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. Larvae 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 (albendazole, mebendazole) and glucocorticoids if inflammation is severe.

Cardiac involvement with Echinococcus is rare, but cysts can form and rupture in the myocardium and pericardium.

Bacterial infections

Most bacterial infections can involve the heart occasionally through direct invasion and abscess formation, but do so rarely. More commonly, systemic inflammatory responses depress contractility in severe infection and sepsis. Diphtheria specifically affects the heart in almost one-half of cases, and cardiac involvement is the most common cause of death in patients with this infection. The prevalence of vaccines has shifted the incidence of diphtheria from children worldwide to countries without routine immunization 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 specific 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 it 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 whipplei. 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.

Other infections

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 implicated in chronic 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 involvement 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.

NONINFECTIVE MYOCARDITIS

Myocardial inflammation can occur without apparent preceding infection. The paradigm of noninfective inflammatory myocarditis is cardiac transplant rejection, from which we have learned that myocardial depression can develop and reverse quickly, that noncellular 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 noninfective inflammation is granulomatous myocarditis, including both sarcoidosis and giant cell myocarditis. Sarcoidosis is a multisystem disease most commonly affecting the lungs. Although classically presenting with higher prevalence in young African-American men, the epidemiology appears to be changing, with increasing recognition of sarcoidosis in Caucasian patients in nonurban areas. Patients with pulmonary sarcoid are at high risk for cardiac involvement, but cardiac sarcoidosis also occurs without clinical lung disease. 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 dominates 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. There is often right ventricular predominance of both dilation and ventricular arrhythmias, sometimes initially attributed to arrhythmogenic right ventricular dysplasia. 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 infections, such as tuberculosis or histoplasmosis as the cause of adenopathy, the diagnosis usually requires pathologic confirmation. Biopsy of enlarged mediastinal nodes may provide the highest yield. The scattered granulomata of sarcoidosis can easily be missed on cardiac biopsy (Fig. 27-8).

Immunosuppressive treatment for sarcoidosis is initiated with high-dose glucocorticoids, which are often more effective for arrhythmias than for the heart failure. Patients with sarcoid lesions that persist or recur during tapering of corticosteroids are considered candidates for other immunosuppressive therapies, frequently with agents also used for cardiac transplantation. 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 for improvement is best when the granulomata are not extensive and the ejection fraction is not severely reduced.

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, often with extensive eosinophilic infiltration. 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 with sarcoidosis, the occasional finding of giant cell myocarditis after sarcoidosis suggests that they may in some cases represent different stages of the same disease spectrum.

Eosinophilic myocarditis can be an important manifestation of the hypereosinophilic syndrome, which in Western countries is often idiopathic, although in Mediterranean and African countries, it is likely a consequence of antecedent infection. It may also be seen with systemic eosinophilic syndromes such as Churg-Strauss syndrome or malignancies. Hypersensitivity myocarditis is often an unexpected diagnosis, made when the biopsy reveals infiltration with lymphocytes and mononuclear cells with a high proportion of eosinophils. Most commonly, the reaction is attributed to antibiotics, particularly those taken chronically, but thiazides, anticonvulsants, indomethacin, and methyldopa have also been implicated. Occasional associations with the smallpox vaccine have been reported. Although the circulating eosinophil count may be slightly elevated in hypersensitivity myocarditis, it does not reach the high levels of the hypereosinophilic syndrome. High-dose glucocorticoids and discontinuation of the trigger agent can be curative for hypersensitivity myocarditis.

Myocarditis is often associated with systemic inflammatory diseases, such as polymyositis and dermatomyositis, which affect skeletal and cardiac muscle. Although noninfective inflammatory myocarditis is sometimes included in the differential diagnosis of cardiac findings in patients with connective tissue disease such as systemic lupus erythematosus, pericarditis, vasculitis, pulmonary hypertension, and accelerated coronary artery disease are more common cardiac manifestations of connective tissue disease.

Peripartum cardiomyopathy (PPCM) develops during the last trimester or within the first 6 months after pregnancy, with a frequency between 1:2000 and 1:15,000 deliveries. Risk factors are increased maternal age, increased parity, twin pregnancy, malnutrition, use of tocolytic therapy for premature labor, and preeclampsia or toxemia of pregnancy. 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 sometimes 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 proposed mechanism invokes an abnormal prolactin cleavage fragment, which is induced by oxidative stress and may trigger myocardial apoptosis; this observation has led to preliminary investigation of bromocriptine as possible therapy.

Very recently, PPCM has been found to be associated with increased antiangiogenic signaling, a process that is exacerbated by preeclampsia. In animal models of this disease, proangiogenic therapies have proven curative.

As the increased circulatory demand of pregnancy can aggravate other cardiac disease that was clinically unrecognized, it is crucial to the diagnosis of PPCM that there be no evidence for a preexisting cardiac disorder. By contrast, heart failure presenting earlier in pregnancy has been termed pregnancy-associated cardiomyopathy (PACM). Both PPCM and PACM have been found in some families with other presentations of dilated cardiomyopathy, in some cases with known sarcomeric protein mutations. Pregnancy may, thus, represent an environmental trigger for accelerated phenotypic expression of genetic cardiomyopathy.

TOXIC CARDIOMYOPATHY

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, 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 in an individual with excess consumption. 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 five to 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 in their daily lives without apparent stigmata of alcoholism. 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. Atrial fibrillation occurs commonly both early in the disease (“holiday heart”) and in advanced stages. 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 microinfarcts consistent with small vessel ischemia, similar to those seen with pheochromocytoma.

Chemotherapy agents are the most common drugs implicated in toxic 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 better prognosis 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. Risk for cardiotoxicity increases with higher doses, preexisting cardiac disease, and concomitant chest irradiation. There are three different presentations of anthracycline-induced cardiomyopathy. (1) Heart failure can develop acutely during administration of a single dose, but may clinically resolve in a few weeks. (2) 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 resolve to good, but not normal, ventricular function. (3) The chronic presentation differs according to whether therapy was given before or after puberty. Patients who received doxorubicin while still growing may have impaired development of the heart, which leads to clinical heart failure by the time the patient reaches the early twenties. Late after adult exposure, patients may develop the gradual onset of symptoms or an acute onset precipitated by a reversible second 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 larger ventricle typical of other cardiomyopathies with systolic dysfunction. Therapy includes angiotensin-converting enzyme inhibitors and β-adrenergic blocking agents used for other causes of 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 (Herceptin) 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 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. Acute administration of interferon-α can cause hypotension and arrhythmias. Clinical heart failure occurring during repeated chronic administration usually resolves after discontinuation.

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 these inhibitors to have “off-target” effects that include the heart and vasculature. Recognition of cardiotoxicity during therapy with these agents is complicated because they occasionally cause peripheral fluid accumulation (ankle edema, periorbital swelling, pleural effusions) due to local factors rather than elevated central venous pressures. Therapeutic approaches include withdrawal of the tyrosine kinase inhibitor (when possible) and substitution with a congener (when available), as well as conventional treatment for heart failure. Prophylactic treatment with beta blockers and angiotensin-converting enzyme inhibitors prior to and during chemotherapy is a topic of ongoing investigation.

Other therapeutic drugs that can cause cardiotoxicity during chronic use include hydroxychloroquine, chloroquine, emetine, and antiretroviral therapies.

Toxic exposures can cause arrhythmias or respiratory injury acutely during accidents. Chronic exposures implicated in cardiotoxicity include hydrocarbons, fluorocarbons, arsenicals, lead, and mercury.

METABOLIC CAUSES OF 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. Clinical signs of thyroid disease may be masked, so tests of thyroid function are part of the routine evaluation of cardiomyopathy. 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. The most common current reason for thyroid abnormalities in the cardiac population is the treatment of tachyarrhythmias with amiodarone, a drug with substantial iodine content. Hypothyroidism should be treated with very slow escalation of thyroid supplements to avoid exacerbating tachyarrhythmias and heart failure. Hyperthyroidism and heart failure are a dangerous combination that merits very close supervision, often hospitalization, during titration of antithyroid medications, during which decompensation of heart failure may occur precipitously and fatally.

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. Patients with pheochromocytoma often 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 in heart failure with “preserved” ejection fraction, along with hypertension, advanced age, and female gender.

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. Fluid retention may be aggravated by large fluid intake and the rapid clearance of natriuretic peptides by adipose tissue. 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. Improvement in cardiac function has been described after successful bariatric surgery, although all major surgical therapy poses increased risk for patients with heart failure. Postoperative malabsorption and nutritional deficiencies, such as calcium and phosphate deficiencies, may be particularly deleterious for patients with cardiomyopathy.

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 carnitine metabolism 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. 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 hyperalimentation. 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 observed rates highlight the limited penetrance of the disease, suggesting the role of additional genetic and environmental factors for clinical expression. 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. MRI can help to quantitate iron stores in the liver and heart, and endomyocardial biopsy tissue can be stained for iron (Fig. 27-9), which is particularly important if the patient has another cause for cardiomyopathy. 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 they are most often associated with restrictive cardiomyopathy (Table 27-4).

FAMILIAL DILATED CARDIOMYOPATHY

The genetic basis for cardiomyopathy is discussed in the section, “Genetic Etiologies of Cardiomyopathy.” The recognized frequency of familial involvement in dilated cardiomyopathy has increased to over 30%. Mutations in TTN, encoding the giant sarcomeric protein titin, are the most common cause of dilated cardiomyopathy, accounting for up to 25% of familial disease. On average, men with TTN mutations develop cardiomyopathy a decade before women, without distinctive clinical features. Mutations in thick and thin filament genes account for ~8% of dilated cardiomyopathy and may manifest in early childhood.

The most recognizable familial cardiomyopathy syndromes with extracardiac manifestations 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 27-3), some of which are associated with creatine kinase elevations.

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 (Fig. 27-10). Originally described as affecting the right ventricle (arrhythmogenic right ventricular dysplasia [ARVD]), this disorder (arrhythmogenic ventricular dysplasia) 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. Because desmosomes are also important for elasticity of hair and skin, some of the defective desmosomal proteins are associated with striking “woolly hair” and thickened skin on the palms and soles. Implantable defibrillators are usually indicated to prevent sudden death. There is variable progression to right, left, or biventricular failure.

Left ventricular noncompaction is a condition of unknown prevalence that is increasingly revealed with the refinement of imaging techniques. The diagnostic criteria include the presence of multiple trabeculations in the left ventricle distal to the papillary muscles, creating a “spongy” appearance of the apex. Noncompaction has been associated with multiple genetic variants in the sarcomeric and other genes, such as TAZ (encoding tafazzin). The diagnosis may be made incidentally or in patients previously diagnosed with cardiomyopathy, in whom the criteria for noncompaction may appear and resolve with changing left ventricular size and function. The three cardinal clinical features are ventricular arrhythmias, embolic events, and heart failure. Treatment generally includes anticoagulation and early consideration for an implantable defibrillator, in addition to neurohormonal antagonists as indicated by stage of disease.

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.

Prognosis and therapy of familial dilated cardiomyopathy are 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. The rate of progression of disease, once manifest, 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 additional insult, such as prolonged tachycardia or infective myocarditis.

TAKOTSUBO CARDIOMYOPATHY

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 in Japan, it is increasingly recognized elsewhere during emergency cardiac catheterization and intensive care unit admissions 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. 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. While the prognosis is generally good, recurrences have been described in up to 10% of patients.

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 during chronic heart failure management often reveals specific causes later in a patient’s course.

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 are often 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. 27-4).

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 (see Table 27-5). 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.

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. 27-11). Diagnosis is crucial because enzyme replacement can reduce abnormal deposits and improve cardiac and clinical function. The magnitude of clinical impact has not been well-established for this therapy, which requires frequent infusions of the enzyme at a cost of over $100,000 a year. 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.

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 occasionally the 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 monophosphate (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. Extreme 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.

The least common of the physiologic 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 27-5). The differential diagnosis should include constrictive pericardial disease, which may also be dominated by right-sided heart failure.

INFILTRATIVE DISEASE

Amyloidosis is the major cause of restrictive cardiomyopathy (Figs. 27-12, 27-13, 27-14). Several proteins can self-assemble to form the beta-sheets of amyloid proteins, which deposit with different consequences depending on the type of protein. In addition to cardiac infiltration, neurologic involvement occurs commonly with primary amyloidosis (immunoglobulin light chains) and with familial amyloidosis (genetic abnormalities of transthyretin). There are over 100 identified mutations in transthyretin on chromosome 13, among which the V122I transthyretin mutation has been identified in about 4% of African Americans and in 10% of African Americans with heart failure and may contribute importantly to heart failure in general in the elderly African-American population. Organ dysfunction was previously attributed solely to physical disruption from the infiltrating amyloid fibrils, but newer information suggests additional direct toxicity from the immunoglobulin light chain and abnormal transthyretin protein aggregates themselves. In senile amyloidosis, there is abnormal accumulation of normal transthyretin or natriuretic peptide folding, detected in 10% of people over 80 years and half of those over 90 years but often without apparent clinical disease. Men show a greater burden of amyloid deposition and 20-fold greater likelihood of clinical disease with senile amyloidosis. The aging of the population will soon render senile amyloidosis the most common of the amyloidoses.

Cardiac amyloid is classically suspected from thickened ventricular walls with an ECG that shows low voltage. However, low voltage is not always present and is less common in familial or senile amyloidosis than in primary AL amyloidosis. A characteristic refractile brightness in the septum on echocardiography is suggestive of the diagnosis, but neither sensitive nor specific. Both atria are dilated, often dramatically, and diastolic dysfunction may be more obvious than in left ventricular hypertrophy from other causes. Amyloid infiltration can also be detected with gadolinium enhancement in MRI. The diagnosis of primary or familial amyloidosis can sometimes be made from biopsies of an abdominal fat pad or the rectum, but cardiac amyloidosis is most reliably identified from a biopsy of the heart, in which amyloid fibrils infiltrate the myocardium diffusely, particularly around the conduction system and coronary vessels (Fig. 27-14). Diagnosis of the type of amyloid protein requires immunohistochemistry of biopsied tissue rather than serum or urine electrophoresis, which can lead to incorrect classification.

Therapy for all types of amyloid is predominantly for symptoms of fluid retention, which often requires high doses of loop diuretics. 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 the possibility of aggravating postural hypotension and diminishing the crucial heart rate reserve. The risk of intracardiac thrombi may warrant chronic anticoagulation.

The prognosis is worst for primary amyloid, with a median survival of 6–12 months after symptoms of heart failure. If present, multiple myeloma is treated with chemotherapy, the extent of which is often limited by the potential of worsening cardiac dysfunction. 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. Abnormal transthyretin-associated cardiac amyloid has a somewhat better prognosis and can be treated in selected patients with heart and liver transplantation. Senile cardiac amyloid has the slowest progression and best overall prognosis.

FIBROTIC RESTRICTIVE CARDIOMYOPATHY

Progressive fibrosis can cause restrictive myocardial disease without ventricular 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. The pulmonary hypertension associated with scleroderma may lead to more clinical right heart failure because of concomitant fibrotic disease of the right ventricle. Doxorubicin causes direct myocyte injury usually leading to dilated cardiomyopathy, but the limited degree of dilation may result from increased fibrosis, which restricts remodeling.

ENDOMYOCARDIAL DISEASE

The physiologic picture of elevated filling pressures with atrial enlargement and preserved ventricular contractility with normal or reduced ventricular volumes can 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 often 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 (see earlier discussion of eosinophilic myocarditis), 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 AV valve leaflets. The clinical disease may present with heart failure, embolic events, and atrial arrhythmias. While plausible, the sequence of transition from eosinophilic myocarditis or Löffler’s endocarditis to endomyocardial fibrosis 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 defined as left ventricular hypertrophy that develops in the absence of causative hemodynamic factors, such as hypertension, aortic valve disease, or systemic infiltrative or storage diseases (Figs. 27-15 and 27-16). It has previously been termed hypertrophic obstructive cardiomyopathy (HOCM), asymmetric septal hypertrophy (ASH), and idiopathic hypertrophic subaortic stenosis (IHSS). However, the accepted terminology is now hypertrophic cardiomyopathy with or without obstruction. Prevalence in North America, Japan, and China is about 1:500. It is the leading cause of sudden death in the young and is an important cause of heart failure. Although pediatric presentation is associated with increased early morbidity and mortality, the prognosis for patients diagnosed as adults is generally favorable.

The clustering of hypertrophic cardiomyopathy within families has been appreciated since recognition of the disease approximately 55 years ago. Echocardiographic screening of families revealed an autosomal dominant pattern of inheritance. Initial genetic studies using linkage analysis in large families identified disease-causing mutations in sarcomeric genes. A sarcomere mutation is present in ~60% of patients with hypertrophic cardiomyopathy and is more common in those with familial disease and characteristic asymmetric septal hypertrophy. More than nine different sarcomere genes with over 1400 mutations have been implicated, although ∼80% of patients have a mutation in either MYH7 or MYBPC3 (Table 27-3), most of which are unique to individual families (“private” mutations).

Hypertrophic cardiomyopathy is characterized by age-dependent and incomplete penetrance. The defining phenotype of left ventricular hypertrophy is rarely present at birth and usually develops later in life. Accordingly, screening of family members should begin in adolescence and extend through adulthood. In MYBPC3 mutation carriers, the average age of disease development is 40 years, while 30% remain free from hypertrophy after 70 years. Related individuals who carry the same mutation may have a different extent and pattern of hypertrophy (e.g., asymmetric versus concentric), occurrence of outflow tract obstruction, and associated clinical outcomes (e.g., sudden death, atrial fibrillation).

At the level of the sarcomere, hypertrophic cardiomyopathy mutations lead to enhanced calcium sensitivity, maximal force generation, and ATPase activity. Calcium handling is affected through modification of regulatory proteins. Sarcomere mutations lead to abnormal energetics and impaired relaxation, both directly and as a result of hypertrophy. Hypertrophic cardiomyopathy is characterized by misalignment and disarray of the enlarged myofibrils and myocytes (Fig. 27-17), which can also occur to a lesser extent in other cardiac diseases. Although hypertrophy is the defining feature of hypertrophic cardiomyopathy, fibrosis and microvascular disease are also present. Interstitial fibrosis is detectable before overt hypertrophy develops and likely results from early activation of profibrotic pathways. In the majority of patients with overt cardiomyopathy, focal areas of replacement fibrosis can be readily detected with MRI. These areas of “scar” may represent substrate for the development of ventricular arrhythmias. Increased thickness and decreased luminal area of the intramural vessels in hypertrophied myocardium contribute to microvascular ischemia and angina. Microinfarction of hypertrophied myocardium is a hypothesized mechanism for replacement scar formation.

Macroscopically, hypertrophy is typically manifest as nonuniform ventricular thickening (Fig. 27-15). The interventricular septum is the typical location of maximal hypertrophy, although other patterns of hypertrophic remodeling include concentric and midventricular. Hypertrophy confined to the ventricular apex (apical hypertrophic cardiomyopathy) is less often familial and has a different genetic substrate, with sarcomere mutations present in only ~15%. Left ventricular outflow tract obstruction represents the most common focus of diagnosis and intervention, although diastolic dysfunction, myocardial fibrosis, and microvascular ischemia also contribute to contractile dysfunction and elevated intracardiac pressures. Obstruction is present in ~30% of patients at rest and can be provoked by exercise in another ~30%. Systolic obstruction is initiated by drag forces, which push an anteriorly displaced and enlarged anterior mitral leaflet into contact with the hypertrophied ventricular septum. Mitral leaflet coaptation may ensue, leading to posteriorly directed mitral regurgitation. In order to maintain stroke volume across outflow tract obstruction, the ventricle generates higher pressures, leading to higher wall stress and myocardial oxygen demand. Smaller chamber size and increased contractility exacerbate the severity of obstruction. Conditions of low preload, such as dehydration, and low afterload, such as arterial vasodilation, may lead to transient hypotension and near-syncope. The systolic ejection murmur of left ventricular outflow tract obstruction is harsh and late peaking and can be enhanced by bedside maneuvers that diminish ventricular volume and transiently worsen obstruction, such as standing from a squatting position or the Valsalva maneuver.

DIAGNOSIS

The substantial variability of hypertrophic cardiomyopathy pathology is reflected in the diversity of clinical presentations. Patients may be diagnosed after undergoing evaluations triggered by the abnormal physical findings (murmur) or symptoms of exertional dyspnea, angina, or syncope. Alternatively, diagnosis may follow evaluations prompted by the detection of disease in family members. Cardiac imaging (Fig. 27-16) is central to diagnosis due to the insensitivity of examination and ECG and the need to exclude other causes for hypertrophy. The identification of a disease-causing mutation in a proband can focus family evaluations on mutation carriers, but this strategy requires a high degree of certainty that the mutation is truly pathogenic and not a benign DNA variant. Biopsy is not needed to diagnose hypertrophic cardiomyopathy but can be used to exclude infiltrative and metabolic diseases. Rigorous athletic training (athlete’s heart) may cause intermediate degrees of physiologic hypertrophy difficult to differentiate from mild hypertrophic cardiomyopathy. Unlike hypertrophic cardiomyopathy, hypertrophy in the athlete’s heart regresses with cessation of training, and is accompanied by supernormal exercise capacity (VO_2max >50 mL/kg/min), mild ventricular dilation, and normal diastolic function.

TREATMENT

Prognosis

The general prognosis for hypertrophic cardiomyopathy is good, better than in early studies of referral populations. For patients diagnosed as adults, survival is comparable to an age-matched population without cardiomyopathy. The sudden death risk is less than 1% per year; however, up to 1 in 20 patients will progress to overt systolic dysfunction with a reduced ejection fraction with or without dilated remodeling (“burned out” or end-stage hypertrophic cardiomyopathy). These patients suffer from low cardiac output and have a high risk of death from progressive heart failure and sudden death unless they undergo cardiac transplantation.