DEFINITION AND CLASSIFICATION
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 2013, cardiomyopathies are defined as “disorders characterized by morphologically and functionally abnormal myocardium in the absence of any other disease that is sufficient, by itself, to cause the observed phenotype.” It was further specified that many cardiomyopathies will be attributable to genetic disease.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 254-1).
TABLE 254-1Presentation with Symptomatic Cardiomyopathy ||Download (.pdf) TABLE 254-1 Presentation with Symptomatic Cardiomyopathy
| ||Dilated ||Restrictive ||Hypertrophic |
|Ejection fraction (normal >55%) ||Usually <30% when symptoms severe ||25–50% ||>60% |
|Left ventricular diastolic dimension (normal <55 mm) ||≥60 mm ||<60 mm (may be decreased) ||Often decreased |
|Left ventricular wall thickness ||Normal or decreased ||Normal or increased ||Markedly increased |
|Atrial size ||Increased, may also be primarily affected ||Increased; may be massive ||Increased; related to elevated filling pressures |
|Valvular regurgitation ||Related to annular dilation; mitral appears earlier during decompensation; tricuspid regurgitation with right ventricular dysfunction ||Related to endocardial involvement; frequent mitral and tricuspid regurgitation, rarely severe ||Related to valve-septum interaction; mitral regurgitation |
|Common first symptoms ||Exertional intolerance ||Exertional intolerance, fluid retention early, may have dominant right-sided symptoms ||Exertional intolerance; may have chest pain |
|Congestive symptomsa ||Left before right, except right prominent in young adults ||Right often dominates ||Left-sided congestion at rest may develop late |
|Arrhythmias ||Ventricular tachyarrhythmia; conduction block in Chagas’ disease, and some families. Atrial fibrillation. ||Ventricular uncommon except in sarcoidosis, conduction block in sarcoidosis and amyloidosis. Atrial fibrillation. ||Ventricular tachyarrhythmias; atrial fibrillation |
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. In practice however, genetic information is rarely available at initial presentation, the phenotypic expression of a given mutation varies widely, and genetic predisposition also influences acquired cardiomyopathies. 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 be unnoticed or attributed to other causes, commonly lung disease or “getting older.” 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 (AV) valve regurgitation, typical and atypical chest pain, atrial and ventricular tachyarrhythmias, and embolic events (Table 254-1). Initial evaluation begins with a detailed clinical history and examination, looking for clues to cardiac, extracardiac, and familial disease (Table 254-2).
TABLE 254-2Initial Evaluation of Cardiomyopathy ||Download (.pdf) TABLE 254-2 Initial Evaluation of Cardiomyopathy
|Clinical Evaluation |
|Thorough history and physical examination to identify cardiac and noncardiac disordersa |
|Detailed family history of heart failure, cardiomyopathy, skeletal myopathy, conduction disorders, tachyarrhythmias, and sudden death |
|History of alcohol, illicit drugs, chemotherapy or radiation therapya |
|Assessment of ability to perform routine and desired activitiesa |
|Assessment of volume status, orthostatic blood pressure, body mass indexa |
|Laboratory Evaluation |
|Chest radiographa |
|Two-dimensional and Doppler echocardiograma |
|Magnetic resonance imaging for evidence of myocardial inflammation and fibrosis |
| Serum sodium,a potassium,a calcium,a magnesiuma |
| Fasting glucose (glycohemoglobin in diabetes mellitus) |
| Creatinine,a blood urea nitrogena |
| Albumin,a total protein,a liver function testsa |
| Lipid profile |
| Thyroid-stimulating hormonea |
| Serum iron, transferrin saturation |
| Urinalysis |
| Creatine kinase isoforms |
| Cardiac troponin levels |
| Hemoglobin/hematocrita |
| White blood cell count with differential,a including eosinophils |
| Erythrocyte sedimentation rate |
|Initial Evaluation When Specific Diagnoses Are Suspected |
|DNA sequencing for genetic disease, panel selection based on phenotype |
|Titers for infection in the setting of clinical suspicion: |
| Acute viral (coxsackie, echovirus, influenza) |
| Human immunodeficiency virus |
| Chagas’ (Trypanosoma cruzi), Lyme (Borrelia burgdorferi), toxoplasmosis |
|Catheterization with coronary angiography in patients with angina who are candidates for interventiona |
|Serologies for active rheumatologic disease |
|Endomyocardial biopsy including sample for electron microscopy when suspecting specific diagnosis with therapeutic implications |
|Screening for sleep-disordered breathing |
GENETIC CAUSES OF CARDIOMYOPATHY
Estimates for the prevalence of genetic etiology of cardiomyopathy continue to rise, with increasing availability of genetic testing and attention to the family history. Well-recognized in hypertrophic cardiomyopathy, heritability is also present in at least 30% of dilated cardiomyopathy (DCM) 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 254-3). 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.
TABLE 254-3Selected Genetic Defects Associated with Cardiomyopathy ||Download (.pdf) TABLE 254-3 Selected Genetic Defects Associated with Cardiomyopathy
| ||Gene Product ||Inheritance ||Cardiac Phenotype ||Isolated Cardiac Phenotypea ||Extracardiac Manifestations |
|Sarcomere ||MYH7 (β myosin heavy chain) ||AD ||HCM, DCM, LVNC ||Yes ||Skeletal myopathy |
|MYBPC3 (myosin binding protein C) ||AD ||HCM ||Yes || |
|TNNT2 (cardiac troponin T) ||AD ||HCM, DCM, LVNC ||Yes || |
|TNNI3 (cardiac troponin I) ||AD, AR ||HCM, DCM, RCM ||Yes || |
|TTN (Titin) ||AD ||DCM ||Yes || |
|TPM1 (α-tropomyosin) ||AD ||HCM, DCM ||Yes || |
|TNNC1 (cardiac troponin C) ||AD ||DCM ||Yes || |
|MYL2 (myosin regulatory light chain) ||AD ||HCM ||Yes ||Skeletal myopathy |
|MYL3 (myosin essential light chain) ||AD ||HCM ||Yes || |
|Z-disk and Cytoskeleton ||DES (Desmin) ||AD ||DCM, RCM ||Yes ||Skeletal myopathy |
|ANKRD1 (CARP) ||AD ||HCM, (DCM) ||Yes || |
|CSRP3 (MLP) ||AD ||DCM, (HCM) ||Yes || |
|ACTN2 (α-actinin-2) ||AD ||DCM ||Yes || |
|CRYAB (αB-crystallin) ||AD ||DCM ||Yes || |
|FLNC (Filamin C) ||AD ||DCM ||Yes ||Skeletal myopathy |
|Nuclear Membrane ||LMNA (Lamin A/C) ||AD, AR ||CDDC ||Yes ||Skeletal myopathy |
|EMD (Emerin) ||X-linked ||CDDC ||No ||Skeletal myopathy, contractures |
|Excitation-Contraction Coupling ||PLN (Phospholamban) ||AD ||DCM ||Yes || |
|SCN5A (NAV 1.5) ||AD ||CDDC ||Yes ||Note other mutations associated with Brugada syndrome |
|RYR2 (cardiac ryanodine receptor) ||AD ||ARVC ||Yes || |
|CASQ2 (calsequestrin 2) ||AR ||ARVC ||Yes || |
|Cellular Metabolism ||PRKAG2 (γ-subunit of AMP kinase) ||AD ||HCM+ ||Yes || |
|LAMP2 (lysosomal associated membrane protein) ||X-linked ||HCM+ ||Noa ||Danon’s disease: skeletal myopathy, cognitive impairment |
|TAZ (Tafazzin) ||X-linked ||DCM, LVNC ||No ||Barth’s syndrome: skeletal myopathy, cognitive impairment, neutropenia |
|FXN (Frataxin) ||AR ||HCM ||No ||Friedreich’s ataxia: ataxia, diabetes mellitus type 2 |
|TMEM43 (transmembrane protein 43) ||AD ||ARVC ||Yes || |
|GLA (α-galactosidase-A) ||X-linked ||HCM+ ||Yes ||Fabry’s disease: renal failure, angiokeratomas and painful neuropathy |
|Mitochondria ||Mitochondrial DNA ||Maternal transmission ||DCM, HCM ||No ||MELAS, MERRF, Kearns-Sayre syndrome, ocular myopathy |
|Sarcolemmal Membrane ||DMD (Dystrophin) ||X-linked ||DCM ||Noa ||Duchenne’s and Becker’s muscular dystrophy |
|DMPK (dystrophica myotonica protein kinase) ||AD ||DCM ||No ||Myotonic dystrophy type 1 |
|SGCD (δ-sarcoglycan) ||AD ||DCM ||Yes || |
|Desmosome ||DSP (Desmoplakin) JUP (Plakoglobin) ||AD, AR ||ARVC ||Yes ||Carvajal syndrome (AR), Naxos syndrome (AR), “woolly hair” and hyperkeratosis of palms and soles |
|DSG2 (Desmoglein 2) DSC2 (Desmocollin 2) PKP2 (Plakophilin 2) ||AD ||ARVC ||Yes || |
|Other Examples ||RBM20 (RNA binding motif 20) ||AD ||DCM ||Yes || |
|PSEN1 (Presenilin-1,2) ||AD ||DCM ||Yes ||Dementia |
|BAG3 (BCL2-associated athanogene 3) ||AD ||DCM ||Yes || |
|ALPK3 (Alpha-kinase 3) ||AR ||HCM ||Yes || |
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-dependent 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 and rate of progression of cardiac dysfunction and associated rhythm disorders, 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 DCM, and some in left ventricular noncompaction. The most commonly recognized genetic causes of DCM are truncating mutations of the giant protein titin, encoded by 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. 254-1). 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.
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 Tennessee Health Science Center, with permission.)
Defects in the sarcolemmal membrane proteins are associated with DCM. 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 DCM. 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 DCM 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 cardiomyopathy), this condition can affect both ventricles and has also been termed “arrhythmogenic cardiomyopathy.”
As many signaling pathways are conserved over multiple systems, we anticipate discovering extracardiac manifestations of abnormal proteins initially considered restricted to 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 reduced systolic function as measured by left ventricular ejection fraction characterizes DCM (Figs. 254-2, 254-3, and 254-4). Systolic failure is more prominent than diastolic dysfunction. Although the syndrome of DCM has many disparate etiologies (Table 254-4), many converge to 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 directly from the initial injury, but more often develops later in response to elevated afterload presented by secondary pulmonary hypertension and in relation to mechanical interactions with the failing left ventricle.
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 >800 g (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. RA, right atrium; RV, right ventricle. (Image courtesy of Justina Wu, MD, Brigham and Women’s Hospital, Boston.)
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.)
TABLE 254-4Major Causes of Dilated Cardiomyopathy (with Common Examples) ||Download (.pdf) TABLE 254-4 Major Causes of Dilated Cardiomyopathy (with Common Examples)
|Inflammatory Myocarditis |
| Viral (coxsackie,a adenovirus,a HIV, hepatitis C) |
| Parasitic (T. cruzi—Chagas’ disease, trypanosomiasis, toxoplasmosis) |
| Bacterial (diphtheria) |
| Spirochetal (Borrelia burgdorferi—Lyme disease) |
| Rickettsial (Q fever) |
| Fungal (with systemic infection) |
| Granulomatous inflammatory disease |
| Sarcoidosis |
| Giant cell myocarditis |
| Eosinophilic myocarditis |
| Polymyositis, dermatomyositis |
| Collagen vascular disease |
| Checkpoint inhibitor chemotherapy |
| Transplant rejection |
|Catecholamines: amphetamines, cocaine |
|Chemotherapeutic agents (anthracyclines, trastuzumab) |
|Other therapeutic agents (hydroxychloroquine, chloroquine) |
|Drugs of misuse (emetine, anabolic steroids) |
|Heavy metals: lead, mercury |
|Occupational exposure: hydrocarbons, arsenicals |
|Nutritional deficiencies: thiamine, selenium, carnitine |
|Electrolyte deficiencies: calcium, phosphate, magnesium |
| Thyroid disease |
| Pheochromocytoma |
| Diabetes |
|Inherited Metabolic Pathway Defectsa |
|Familiala (See Table 254-3) |
|Skeletal and cardiac myopathy |
|Dystrophin-related dystrophy (Duchenne’s, Becker’s) |
|Mitochondrial myopathies (e.g., Kearns-Sayre syndrome) |
|Arrhythmogenic ventricular cardiomyopathy |
|Associated with other systemic diseases |
|Susceptibility to immune-mediated myocarditis |
|Overlap with Nondilated Cardiomyopathy |
|“Minimally dilated cardiomyopathy” |
|Hypertrophic cardiomyopathya (“burned-out”) |
|Miscellaneous (Shared Elements of Above Etiologies) |
|Peripartum cardiomyopathy |
|Left ventricular noncompactiona |
|Tachycardia-related cardiomyopathy |
| Supraventricular arrhythmias with uncontrolled rate |
| Very frequent nonsustained ventricular tachycardia or high premature ventricular complex burden |
Regardless of the nature and degree of direct cell injury, the resulting functional impairment often reflects 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 current evaluation and therapy for DCM is generally dictated by the stage of heart failure (Chap. 252), with specific aspects discussed for relevant etiologies below.
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.
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 ongoing autoimmune injury to the host.
The secondary acquired immune response is 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 pro-fibrotic 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 DCM, 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. 254-5).
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.
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 within hours 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 DCM can be identified. However, many cases assumed to result from “silent” myocarditis will later be recognized as due to genetic causes or consumption of excess alcohol or illicit stimulant drugs. The proportion of chronic, DCM due to viral infection remains a subject of controversy.
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 but not proven by evidence of increased tissue edema and gadolinium enhancement (Fig. 254-6), particularly in the mid-wall (as distinct from usual coronary artery territories).
Magnetic resonance image of myocarditis showing the typical mid-wall location (arrow) for late gadolinium enhancement from cardiac inflammation and scarring. (Image courtesy of Ron Blankstein, MD, and Marcelo Di Carli, MD, Division of Nuclear Medicine, Brigham and Women’s Hospital, Boston.)
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, yield, and benefit of endomyocardial biopsy for evaluation of myocarditis or new-onset cardiomyopathy are not well-established. When biopsy is performed, the Dallas Criteria for myocarditis include lymphocytic infiltrate with evidence of myocyte necrosis (Fig. 254-7) 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.
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.)
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 have been classified into three levels of myocarditis diagnosis. (1) Possible subclinical acute myocarditis is diagnosed when a typical viral syndrome occurs without cardiac symptoms, but with elevated biomarkers of cardiac injury, ECG suggestive of acute injury, reduced left ventricular ejection fraction or regional wall motion abnormality. (2) Probable acute myocarditis is diagnosed when the above criteria are met and accompanied by cardiac symptoms, such as shortness of breath or chest pain, which can result from pericarditis or myocarditis. When clinical findings of pericarditis 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. These have not been revised to include findings from MRI.
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 DCM, 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 DCM 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. The effect of new treatments for hepatitis C on cardiac function has not yet been well-studied. 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.
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 phases of viral myocarditis and the effects of targeted therapies, treatment will continue to be guided by general recommendations for DCM.
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 <10 million in South America, cases are increasingly recognized in Western developed countries (see Global Perspectives below).
Multiple pathogenic mechanisms are implicated. The parasite itself can cause myocyte lysis and primary neuronal damage. 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. 254-5). 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 for >10–30 years in almost half of patients to manifest chronically in the cardiac and gastrointestinal systems. Features typical of Chagas’ disease are conduction system abnormalities, particularly sinus node and 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, 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. The most common antiparasitic therapies are benznidazole and nifurtimox which have been effective in children with chronic T. cruzi infection. Both drugs are associated with multiple severe reactions, including dermatitis, gastrointestinal distress, and neuropathy. Moreover, in a large trial of adults with established Chagas’ cardiomyopathy, benznidazole did not prevent disease progression, leaving the role of antiparasitic therapy unclear. Survival is <30% at 5 years after the onset of overt clinical heart failure. Patients without major extracardiac disease have occasionally undergone transplantation, after which they require surveillance testing and recurrent antiparasitic 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, 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.
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.
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.
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, as discussed in Chap. 360, 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 cardiomyopathy. 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. 254-8).
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. 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 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 often of rapid deterioration requiring urgent mechanical support or 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 considered idiopathic, although in Mediterranean and African countries, is associated with 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. A severe lymphocytic myocarditis has been seen with combination of immune checkpoint inhibitors (see toxic cardiomyopathy below).
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, affecting between 1:2000 and 1:4000 deliveries in the United Sates. Risk factors are increased maternal age, increased parity, twin pregnancy, malnutrition, use of tocolytic therapy for premature labor, and preeclampsia or toxemia of pregnancy. Several of these risk factors contribute to anti-angiogenic signaling through secreted vascular endothelial growth factor (VEGF) inhibitors, such as soluble FLT1 (sFLT1). Recent animal and human studies have confirmed the role of decreased angiogenic reserve in the pathogenesis of PPCM, which may be rescued by correcting the angiogenic imbalance. Another recently proposed mechanism invokes an abnormal prolactin cleavage fragment, which is induced by oxidative stress and also affects angiogenesis; this observation has led to preliminary investigation of bromocriptine as possible therapy.
However, other processes also contribute to PPCM. 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.
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 DCM. As in familial and sporadic DCM, truncating mutations in TTN are present in 15% of patients with PPCM and are associated with systolic dysfunction that persists. Pregnancy may, thus, represent an environmental trigger for accelerated phenotypic expression of genetic and other cardiomyopathies.
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 DCM. 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 may influence the likelihood of alcoholic cardiomyopathy in an individual with excess consumption. Superimposed vitamin deficiencies and toxic alcohol additives are rarely implicated currently. 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 (e.g., doxorubicin) 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. Risk for cardiotoxicity increases with higher doses, preexisting cardiac disease, extremes of age, concomitant chemotherapy, or chest irradiation and in women. Although cardiomyopathy has frequently been considered to occur late after exposure, a recent study shows that systolic dysfunction is usually evident within 1 year after anthracycline exposure among adult patients who develop cardiomyopathy. Doxorubicin cardiotoxicity generally results in minimal ventricular dilation, perhaps due to accompanying fibrosis. Thus, the stroke volume may be severely reduced with an ejection fraction of 30–40%, in contrast to the hemodynamic compensation possible in a dilated ventricle typical of other heart failure with reduced ejection fraction. Therapy includes angiotensin-converting enzyme inhibitors and β-adrenergic blocking agents, 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, many patients with doxorubicin cardiotoxicity improve with careful management to near-normal clinical function, particularly if additional insults such as hypertension or supraventricular tachycardias can be avoided. The course differs for patients receiving these drugs before puberty, in whom inadequate growth of the heart may lead to inexorable heart failure by the time the patient reaches the early twenties.
Trastuzumab (Herceptin) is a monoclonal antibody that interferes with human epidermal growth receptor 2 (HER2) 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. The cardiotoxic effects of other recently introduced anti-HER2 therapies (e.g., pertuzumab) are similar to that caused by trastuzumab.
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 that affect VEGF are under use 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 cardiovascular system and as a group are associated with a ~2.7-fold increased risk of heart failure. 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.
Proteasome inhibitors used to treat multiple myeloma are associated with an increased risk of heart failure. The more potent agent, carfilzomib, appears more cardiotoxic than bortezomib.
Immune checkpoint inhibitors, such as ipilimumab and nivolumab, are associated with multisystem autoimmune inflammatory toxicities (e.g., thyroiditis, hypophysitis, pancreatitis, and pneumonitis) and rarely myocarditis. However, combination therapy with two checkpoint inhibitors can cause fulminant myocarditis with associated systolic dysfunction, AV block, and ventricular tachycardia within weeks after initial chemotherapy. This presentation has been accompanied by acute skeletal myocarditis and rapid progression to death.
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 create 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 (Chap. 380). 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 DCM 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 (Chap. 407). It is included among the causes of restrictive cardiomyopathy, but the clinical presentation is often that of a DCM. 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 such as alcoholism affecting 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. 254-9), 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.
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.)
Inborn disorders of metabolism occasionally present with DCM, although they are most often associated with restrictive cardiomyopathy (Table 254-4).
The genetic basis for cardiomyopathy is discussed in the section “Genetic Etiologies of Cardiomyopathy.” The recognized frequency of familial involvement in DCM has increased to over 30%. Mutations in TTN, encoding the giant sarcomeric protein titin, are the most common cause of DCM, 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 DCM 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 dystrophies result from abnormalities in the X-linked dystrophin gene of the sarcolemmal membrane. Skeletal myopathy is present in multiple other genetic cardiomyopathies (Table 254-3), some of which are associated with creatine kinase elevations.
Patients and families with a history of arrhythmias and/or conduction system disease which precede or supersede 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. 254-10). Originally described as affecting the right ventricle (arrhythmogenic right ventricular cardiomyopathy [ARVC]), this disorder (arrhythmogenic cardiomyopathy) 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.
Arrhythmogenic right ventricular cardiomyopathy. A. Cross-sectional slice of a pathology specimen removed at transplantation, showing severe dilation and thinning of the right ventricle (RV) with extensive fatty replacement of right ventricular myocardium. B. The remarkably thin right ventricular free wall is revealed by transillumination. LV, left ventricle. (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 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, but are increasingly recognized as non-specific findings in other cardiac diseases. 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 of ventricular arrhythmias, embolic events, and heart failure are largely restricted to patients with concomitant systolic dysfunction. 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 DCM 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 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.
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 octopuses. 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 DCM 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.
OVERLAPPING TYPES OF CARDIOMYOPATHY
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 DCM, “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. 254-4).
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 Tables 254-3, and 254-4). Hypertrophic cardiomyopathy may be mimicked by the myocardium thickened with these abnormal products causing “pseudohypertrophy,” usually with an abnormally short PR interval. The pseudo-hypertrophic phenotype is most common, but restrictive and DCM may occur. 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 in GLA. This disorder of glycosphingolipid metabolism is an X-linked disorder that may also cause clinical disease in female carriers. Glycolipid accumulation may be limited to the cardiac tissues but usually also involves the skin, peripheral nerve, and kidney. Electron microscopy of endomyocardial biopsy tissue shows diagnostic vesicles containing concentric lamellar figures (Fig. 254-11). Diagnosis can be made through assessment of enzyme activity and/or GLA sequencing and 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 >$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.
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 >10 types of mucopolysaccharidoses, in which autosomal recessive 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 DCM, 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 cause markedly 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. 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.
Restrictive cardiomyopathy 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 DCM 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 254-5). The differential diagnosis should include constrictive pericardial disease, which may also be dominated by right-sided heart failure.
TABLE 254-5Causes of Restrictive Cardiomyopathies ||Download (.pdf) TABLE 254-5 Causes of Restrictive Cardiomyopathies
|Infiltrative (Between Myocytes) |
| Primary (light chain amyloid) |
| Familial (abnormal transthyretin)a |
| Senile (normal transthyretin or atrial peptides) |
|Inherited metabolic defectsa |
|Storage (Within Myocytes) |
|Hemochromatosis (iron)a |
|Inherited metabolic defectsa |
| Fabry’s disease |
| Glycogen storage disease (II, III) |
|Possibly related fibrotic diseases |
| Tropical endomyocardial fibrosis |
| Hypereosinophilic syndrome (Löffler’s endocarditis) |
|Carcinoid syndrome |
|Drugs: e.g., serotonin, ergotamine |
|Overlap with Other Cardiomyopathies |
|Hypertrophic cardiomyopathy/“pseudohypertrophic”a |
|“Minimally dilated” cardiomyopathy |
| Early-stage dilated cardiomyopathy |
| Partial recovery from dilated cardiomyopathy |
Amyloidosis is the major cause of restrictive cardiomyopathy (Figs. 254-12, 254-13, and 254-14). Several proteins can self-assemble to form the beta-sheets of amyloid proteins, which deposit with different consequences depending on the type of protein. The systemic amyloidoses are discussed in Chap. 108. 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 >100 identified mutations in transthyretin on chromosome 13, among which the V122I transthyretin mutation has been identified in ~4% of African Americans in whom it is associated with a 50% increased risk of heart failure. However, penetrance of the V122I mutation is incomplete with most mutation carriers free of heart failure at 70 years of age.
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 hyperrefractile “glittering” of the myocardium typical of amyloid infiltration, which is a non-specific finding with contemporary echocardiography. The mitral and tricuspid valves are thickened. A pacing lead is visible in the right ventricle (RV), and a pericardial effusion is evident. Note that the echocardiographic and pathologic images are vertically opposite, such that the left ventricle (LV) is by convention on the top right in the echocardiographic image and bottom right in the pathologic images. LA, left atrium; RA, right atrium. (Image courtesy of Justina Wu, MD, Brigham and Women’s Hospital, Boston.)
Amyloidosis—microscopic images of amyloid involving the myocardium. The left panel (hematoxylin and 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.)
Organ dysfunction in amyloidosis was once 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 aged >80 years and half of those aged >90 years but often without apparent clinical disease. Men show a greater burden of amyloid deposition and twentyfold 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. Technetium pyrophosphate imaging is sensitive and specific for TTR amyloidosis as opposed to AL amyloidosis. 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. 254-14). 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 presentation, but that has improved substantially with the use of the proteasome inhibitor bortezomib. 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. Novel therapies including RNA interference and small molecules are being studied in TTR amyloidosis.
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.
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/μL 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. 254-15 and 254-16). 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, Africa, and Asia 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.
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 (MV) 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.)
The clustering of hypertrophic cardiomyopathy within families has been appreciated since recognition of the disease ~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 >1400 mutations have been implicated, although ~80% of patients have a mutation in either MYH7 or MYBPC3 (Table 254-3).
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. 254-17), 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.
Hypertrophic cardiomyopathy. Microscopic image of hypertrophic cardiomyopathy showing the characteristic disarrayed 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.)
Macroscopically, hypertrophy is typically manifest as nonuniform ventricular thickening (Fig. 254-15). 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.
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. 254-16) 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 (VO2max >50 mL/kg per min), mild ventricular dilation, and normal diastolic function.
TREATMENT Hypertrophic Cardiomyopathy
Management focuses on treatment of symptoms and prevention of sudden death and stroke (Fig. 254-18). Left ventricular outflow tract obstruction can be controlled medically in the majority of patients. β-Adrenergic blocking agents and L-type calcium channel blockers (e.g., verapamil) are first-line agents that reduce the severity of obstruction by slowing heart rate, enhancing diastolic filling, and decreasing contractility. Persistent symptoms of exertional dyspnea or chest pain can sometimes be controlled with the addition of disopyramide, an antiarrhythmic agent with potent negative inotropic properties.
Patients with or without obstruction may develop heart failure symptoms due to fluid retention and require diuretic therapies for venous congestion. Severe medically refractory symptoms develop in ~5% of patients, for whom surgical myectomy or alcohol septal ablation may be effective. Developed over 50 years ago, surgical myectomy effectively relieves outflow tract obstruction by excising part of the septal myocardium involved in the dynamic obstruction. In selected patients, perioperative mortality is extremely low with excellent long-term survival free from recurrent obstruction and symptoms. Mitral valve repair or replacement is usually unnecessary as associated eccentric mitral regurgitation resolves with myectomy alone. Alcohol septal ablation in patients with suitable coronary anatomy can relieve outflow tract obstruction via a controlled infarction of the proximal septum, which produces similar periprocedural outcomes and gradient reduction as surgical myomectomy. Until long-term outcomes are demonstrated for this procedure, it is relegated primarily to patients who wish to avoid surgery or who have limiting comorbidities. Neither procedure has been shown to improve outcomes other than symptoms. With both procedures, the most common complication is the development of complete heart block necessitating permanent pacing. However, ventricular pacing as a primary therapy for outflow tract obstruction is ineffective and not generally advised.
Patients with hypertrophic cardiomyopathy have an increased risk of sudden cardiac death from ventricular tachyarrhythmias. Vigorous physical activity and competitive sport are prohibited. Factors that increase the risk of sudden death from a baseline of 0.5% per year are presented in Table 254-6. As sudden death has not been reduced by medical or procedural interventions, an implantable cardioverter-defibrillator is advised for patients with two or more risk factors and is advised on a selected basis for patient with one risk factor. Nevertheless, the positive predictive value of most risk factors is low, and many patients receiving a defibrillator never receive an appropriate therapy. Long-term use of a defibrillator may be associated with serious device-related complications, particularly in young active patients. Refinement of sudden death risk through the application of contemporary technologies such as cardiac MRI is ongoing.
Atrial fibrillation is common in patients with hypertrophic cardiomyopathy and may lead to hemodynamic deterioration and embolic stroke. Rapid ventricular response is poorly tolerated and may worsen outflow tract obstruction. β-Adrenergic blocking agents and L-type calcium channel blockers slow AV nodal conduction and improve symptoms; cardiac glycosides should be avoided, as they may increase contractility and worsen obstruction. Symptoms exacerbated by atrial fibrillation may persist despite adequate rate control due to loss of AV synchrony and may require restoration of sinus rhythm. Disopyramide and amiodarone are the preferred antiarrhythmic agents, with radiofrequency ablation considered for medically refractory cases. Anticoagulation to prevent embolic stroke in atrial fibrillation is recommended.
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 atrial fibrillation and risk of sudden death, whether or not they require treatment for symptoms. ICD, implantable cardioverter-defibrillator; LV, left ventricular.
TABLE 254-6Risk Factors for Sudden Death in Hypertrophic Cardiomyopathy ||Download (.pdf) TABLE 254-6 Risk Factors for Sudden Death in Hypertrophic Cardiomyopathy
|Major Risk Factor || ||Screening Technique |
|History of cardiac arrest or spontaneous sustained ventricular tachycardiaa || ||History |
|Syncope ||Nonvagal, often with or after exertion ||History |
|Family history of sudden cardiac death || ||Family history |
|Spontaneous nonsustained ventricular tachycardiab ||>3 beats at rate >120 ||Exercise or 24- to 48-h ambulatory recording |
|LV thickness >30 mm ||Present in <10% of patients ||Echocardiography |
|Abnormal blood pressure response to exerciseb ||Systolic blood pressure fall or failure to increase at peak exercise ||Maximal upright exercise testing |
The general prognosis for hypertrophic cardiomyopathy is 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 <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.
Comparison of myocardial diseases across eras and countries is complicated by differences in techniques for diagnosis, such as endomyocardial biopsy, testing for viral genomes, and specific antibodies. Deaths attributed to cardiomyopathy/myocarditis in the Global Burden of Disease study have increased by 51% between 1990 and 2013 while the age-adjusted mortality rates have declined by 12.6% and the disability-adjusted life years lost have declined by almost 4%. For comparison, the current mortality rates are comparable to those of rheumatic heart disease, which has declined overall by 26.5 and by 55% after adjustment for age. Deaths from Chagas’ cardiomyopathy worldwide have declined from 12.7 thousand to 10.6 thousand, with a reduction of 51.7% in the age-adjusted rates per 100,000 population to 0.2, attributable in major part to improved health conditions in rural areas of South and Central America. By contrast, there has been an increase in the prevalence of Chagas’ disease to an estimated 300,000 in the United States, detected largely through blood donation. It is no longer limited to patients from known endemic areas as de novo infection is increasingly recognized in warmer regions of the country.
Health care for other diseases affects myocarditis and cardiomyopathy. Developed nations will see a higher prevalence of cardiomyopathy due to chemotherapy. However, vaccination has reduced deaths from diphtheria myocarditis to <50 per 100 million population, currently most common in Russia. World regions providing highly active antiviral therapy for HIV have decreased not only transmission but also the rate of associated cardiomyopathy by several-fold. Increasing availability of clinical genetic testing is expected to shift the apparent epidemiology of cardiomyopathy away from acquired causes toward causative and facilitating genetic factors. For instance, heart failure with preserved ejection fraction attributed to hypertension and diabetes is increasingly recognized to represent amyloidosis from mutant transthyretin, with distinct recognized mutations in Portugal, Japan, and the African-Caribbean population.
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