Cardiomyopathy.pdf

1954 may also present initially with atypical chest pain, with palpitations or 259 Cardiomyopathy...

1954 may also present initially with atypical chest pain, with palpitations or 259 Cardiomyopathy Myocarditis and syncope related to associated rhythm disorders, or with an embolism from an intracardiac thrombus. Acute cardiogenic shock is the primary presentation for fulminant myocarditis, which can occur in otherwise healthy young adults and require rapid diagnosis and aggressive sup- Neal K. Lakdawala, Lynne Warner Stevenson, port, after which cardiac function may improve to near-normal levels. PART 6 Joseph Loscalzo The nonspecific term congestive heart failure describes only the resulting syndrome of fluid retention, which is common to all three structural phenotypes of cardiomyopathy and also to other cardiac DEFINITION AND CLASSIFICATION structural diseases, such as mitral valve disease, that are associated with Disorders of the Cardiovascular System Cardiomyopathy is disease of the heart muscle. It is estimated that elevated intracardiac filling pressures. Initial evaluation begins with cardiomyopathy accounts for 5–10% of the heart failure in the a detailed clinical history and examination seeking clues to cardiac, 5–6 million patients carrying that diagnosis in the United States. This extracardiac, and genetic causes of heart disease (Tables 259-1 and term is intended to exclude cardiac dysfunction that results from other 259-2). Echocardiography remains the initial imaging modality, with structural heart disease, such as coronary artery disease, primary valve increasing use of MRI to provide further information on myocardial disease, or severe hypertension; however, in general usage, the phrase tissue characterization and evidence of focal and diffuse inflammation ischemic cardiomyopathy is sometimes applied to describe diffuse and abnormal interstitium. dysfunction attributed to multivessel coronary artery disease, and nonischemic cardiomyopathy is used to describe cardiomyopathy from GENETIC CAUSES OF CARDIOMYOPATHY other causes. As of 2013, cardiomyopathies are defined as “disorders Estimates for the prevalence of a genetic etiology for cardiomyo- characterized by morphologically and functionally abnormal myo- pathy continue to rise, with increasing availability of genetic cardium in the absence of any other disease that is sufficient, by itself, testing and attention to the family history. Well-recognized in to cause the observed phenotype.” It was further specified that many hypertrophic cardiomyopathy, heritability is also present in at least 30% cardiomyopathies will be attributable to genetic disease.1 of dilated cardiomyopathy (DCM) without other clear etiology. Careful The traditional classification of cardiomyopathies into a triad of family history should elicit information about not only known cardio- dilated, restrictive, and hypertrophic was based initially on autopsy myopathy and heart failure, but also family members who have had specimens and later on echocardiographic findings. Dilated and sudden death, often incorrectly attributed to “a massive heart attack,” hypertrophic cardiomyopathies can be distinguished on the basis of who have had atrial fibrillation or pacemaker implantation by middle left ventricular wall thickness and cavity dimension; however, restric- age, or who have muscular dystrophy. tive cardiomyopathy can have variably increased wall thickness and Most familial cardiomyopathies are inherited in an autosomal chamber dimensions that range from reduced to slightly increased, dominant pattern, with occasional autosomal recessive, matrilineal with prominent atrial enlargement. Restrictive cardiomyopathy is now (mitochondrial), and X-linked inheritance (Table 259-3). Missense defined more on the basis of abnormal diastolic function, which is also mutations with amino acid substitutions and truncating variants are present but initially less prominent in dilated and hypertrophic car- the most common genetic abnormalities in cardiomyopathy. Expressed diomyopathy. Restrictive cardiomyopathy can overlap in presentation, mutant proteins may interfere with function of the normal allele gross morphology, and etiology with both hypertrophic and dilated through a dominant negative mechanism. Mutations introducing a cardiomyopathies (Table 259-1). premature stop codon (nonsense) or shift in the reading frame (frame- Expanding information renders this classification triad based on shift) may create a truncated or unstable protein, the lack of which phenotype increasingly inadequate to define disease or therapy. While causes cardiomyopathy (haploinsufficiency). Deletions or duplications dilated cardiomyopathy is associated with low left ventricular ejection of an entire exon or gene are uncommon causes of cardiomyopathy, fraction and hypertrophic cardiomyopathy with normal or high ejec- except for the dystrophinopathies. tion fraction, efforts to define intermediate phenotypes based on arbi- Many different genes have been implicated in human cardiomyo- trary thresholds for mid-range ejection fraction are confounded by the pathy (locus heterogeneity), and many mutations within those genes increasing prevalence of patients whose low ejection has improved with have been associated with disease (allelic heterogeneity). Although contemporary therapies. Identification of more genetic determinants most identified mutations are “private” to individual families, several of cardiomyopathy has suggested a four-way classification scheme specific mutations are found repeatedly, either due to a founder effect of etiology as primary (affecting primarily the heart) and secondary or recurrent mutations at a common residue. to other systemic disease. The primary causes are then divided into Genetic cardiomyopathy is characterized by age-dependent and genetic, mixed genetic and acquired, and acquired. In practice, how- incomplete penetrance. The defining phenotype of cardiomyopathy is ever, genetic information is rarely available at initial presentation, the rarely present at birth and, in some individuals, may never manifest. phenotypic expression of a given mutation varies widely, and acquired Related individuals who carry the same mutation may differ in the cardiomyopathies may also be influenced by genetic predisposition, severity and rate of progression of cardiac dysfunction and associated which can be monogenic or polygenic, to establish a “two-hit” etiol- rhythm disorders, indicating the important role of other genetic, ogy. Identification of genetic causes of cardiomyopathy will become epigenetic, and environmental modifiers in disease expression. Sex increasingly relevant as classification moves beyond morphology to appears to play a role, as penetrance and clinical severity may be identify specific molecular targets for intervention. greater in men for most cardiomyopathies. Clinical disease expression is generally more severe in the ~1% of individuals who harbor two or GENERAL PRESENTATION more mutations linked to cardiomyopathy. However, the clinical course The early symptoms of cardiomyopathy often reflect exertional intol- of a patient usually cannot be predicted based on which mutation is erance with breathlessness or fatigue. As filling pressures become ele- present; thus, current therapy is based on the phenotype rather than vated at rest, shortness of breath may occur during routine activity or the genetic defect. Currently, the greatest utility of genetic testing for when lying down at night. Although often considered the hallmark of cardiomyopathy is to inform family evaluations. However, genetic test- congestion, peripheral edema may be absent despite severe fluid reten- ing occasionally enables the detection of a disease for which specific tion, particularly in younger patients in whom abdominal discomfort therapy is indicated, such as the replacements for defective metabolic from hepato-splanchnic congestion and ascites may dominate. Patients enzymes in Fabry’s disease and Gaucher’s disease. GENES AND PATHWAYS IN CARDIOMYOPATHY Mutations in sarcomeric genes, encoding the thick and thin myo- From E Arbustini et al: J Am Coll Cardiol 62:2046, 2013. 1 filament proteins, are the best characterized. While the majority are HPIM21e_Part6_p1797-p2130.indd 1954 21/01/22 6:22 PM  1955 TABLE 259-1 Typical Presentation with Symptomatic Cardiomyopathy DILATED RESTRICTIVE HYPERTROPHIC Ejection fraction (normal >55%) Usually 40–50% >60% Left ventricular diastolic ≥60 mm if chronic 800 g (upper MYOCARDITIS 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 Myocarditis (inflammation of the heart) is most often attributable to of Pathology, Brigham and Women’s Hospital, Boston.) infective agents but can also arise from other causes of inflammation. Infectious myocarditis cannot be assumed from a presentation of decreased systolic function in the setting of an acute infection, as any severe condition causing systemic cytokine release can depress cardiac function transiently, as seen frequently in medical intensive care units. Myocardial inflammation without obvious infection is seen in sarcoi- dosis and giant cell myocarditis, with checkpoint inhibitor therapy, in eosinophilic myocarditis, or in association with autoimmune diseases such as polymyositis and systemic lupus erythematosus. Fulminant myocarditis can result from viral infection, checkpoint inhibitor ther- apy, giant cell myocarditis, or necrotizing eosinophilic myocarditis, and is often complicated by recurrent arrhythmias. Early recognition of fulminant myocarditis is crucial as recovery to near-normal cardiac function can occur during aggressive circulatory support. LV INFECTIVE MYOCARDITIS Infections can injure the myocardium through direct invasion, disrup- tion of normal cellular processes, production of cardiotoxic substances, or stimulation of chronic inflammation with or without persistent RV infection. 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 as divided into three phases. For the direct viral invasion phase, viruses gain entry through LA the respiratory or gastrointestinal tract and infect organs possessing specific receptors, such as the coxsackie-adenovirus receptors on the RA heart, which are prominent around intercalated disks and the atrioven- tricular (AV) node. Viral infection and replication can cause myocar- dial injury and lysis. For example, the enteroviral protease 2A degrades the myocyte structural protein dystrophin and interacts with other host proteins to induce apoptosis, inhibit the host serum response factor, and interfere with autophagy of protein aggregates. FIGURE 259-3 Dilated cardiomyopathy. This echocardiogram of a young man with The second phase is the nonspecific (innate) host response to infec- dilated cardiomyopathy shows massive global dilation and thinning of the walls of tion, which is heavily dependent on Toll-like receptors that recognize 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 common antigenic patterns. Cytokine release is rapid, followed by trig- the LV is by convention on the top right in the echocardiographic image and bottom gered activation and expansion of specific T- and B-cell populations. right in the pathologic images. RA, right atrium; RV, right ventricle. (Image courtesy This initial response appears to be crucial, as early immunosuppression of Justina Wu, MD, Brigham and Women’s Hospital, Boston.) in animal models can increase viral replication and worsen cardiac HPIM21e_Part6_p1797-p2130.indd 1958 21/01/22 6:22 PM  TABLE 259-4 Major Causes of Dilated Cardiomyopathy (with Common injury. However, successful recovery from viral infection depends not 1959 Examples) only on the efficacy of the immune response to limit viral infection, Inflammatory Myocarditis but also on timely downregulation to prevent ongoing autoimmune injury to the host. Infective The secondary acquired (adaptive) immune response is specifically CHAPTER 259 Cardiomyopathy and Myocarditis Viral (coxsackie,a adenovirus,a HIV, hepatitis C) addressed against the viral proteins and can include both T-cell infil- Parasitic (T. cruzi—Chagas’ disease, trypanosomiasis, toxoplasmosis) tration and antibodies to viral proteins. If unchecked, the acquired Bacterial (diphtheria) immune response can perpetuate secondary cardiac damage. Ongoing Spirochetal (Borrelia burgdorferi—Lyme disease) cytokine release activates matrix metalloproteinases that can disrupt Rickettsial (Q fever) the collagen and elastin scaffolding of the heart, potentiating ventric- Fungal (with systemic infection) ular dilation. Stimulation of profibrotic factors leads to pathologic Noninfective interstitial fibrosis. Some antibodies triggered through co-stimulation Granulomatous inflammatory disease or molecular mimicry also recognize targets within the host myocyte,   Sarcoidosis such as the β-adrenergic receptor, α-myosin, and troponin, but it    Giant cell myocarditis remains unclear as to whether or not these antibodies contribute to Eosinophilic myocarditis cardiac dysfunction in humans or merely serve as markers of cardiac Polymyositis, dermatomyositis injury. It is not known how long the viruses persist in the human heart, Collagen vascular disease whether late persistence of the viral genome continues to be delete- Checkpoint inhibitor chemotherapy rious, or how often a dormant virus can be reactivated. Genomes of Transplant rejection common viruses are often present in patients with clinical diagnoses of Toxic myocarditis or DCM, but there is little information on how often these Alcohol are present in patients without cardiac disease (see below). Further Catecholamines: amphetamines, cocaine information is needed to understand the relative timing and contribu- Chemotherapeutic agents (anthracyclines, trastuzumab) tion of infection, immune responses, and secondary adaptations in the Interferon progression of heart failure after viral myocarditis (Fig. 259-5). Other therapeutic agents (hydroxychloroquine, chloroquine) Clinical Presentation of Viral Myocarditis Acute viral myocarditis Drugs of misuse (emetine, anabolic steroids) often presents with symptoms and signs of heart failure, but may Heavy metals: lead, mercury present with chest pain and ECG changes suggestive of pericarditis or Occupational exposure: hydrocarbons, arsenicals acute myocardial infarction, and occasionally with atrial or ventricular Metabolica tachyarrhythmias. The typical patient with presumed viral myocarditis is a young to middle-aged adult who develops progressive dyspnea and Nutritional deficiencies: thiamine, selenium, carnitine weakness within a few days to weeks after a viral syndrome that was Electrolyte deficiencies: calcium, phosphate, magnesium accompanied by fever and myalgias. Subacute presentation may occur Endocrinopathy within a few weeks or months of a viral infection. As viral infections Thyroid disease are common and the resulting cytokine activation can depress cardiac Pheochromocytoma function, it is often difficult to determine whether viral infection caused Diabetes myocarditis or unmasked a previously unrecognized cardiomyopathy. Obesity A small number of patients present with fulminant myocarditis, Hemochromatosis with rapid progression within hours from a severe febrile respiratory Inherited Metabolic Pathway Defectsa syndrome to cardiogenic shock that may involve multiple organ sys- tems, leading to renal failure, hepatic failure, and coagulopathy. These Familiala (See Table 259-3) patients are typically young adults who have recently been dismissed Skeletal and cardiac myopathy from urgent care settings with antibiotics for bronchitis, only to return Dystrophin-related dystrophy (Duchenne’s, Becker’s) within a few days in rapidly progressive cardiogenic shock. Recogni- Mitochondrial myopathies (e.g., Kearns-Sayre syndrome) tion of patients with this fulminant presentation is potentially life-saving Hemochromatosis as more than half can survive with aggressive support, which may Associated with other systemic diseases include high-dose intravenous catecholamine therapy and sometimes Susceptibility to immune-mediated myocarditis temporary mechanical circulatory support. The ejection fraction func- Overlap with Nondilated Cardiomyopathy tion of these patients often recovers to near-normal, although residual diastolic dysfunction may limit vigorous exercise for some survivors. “Minimally dilated cardiomyopathy” Chronic viral myocarditis is often invoked, but rarely proven, as a Hemochromatosisa diagnosis when no other cause of DCM can be identified. Many cases Amyloidosisa attributed to previous viral infection will later be recognized as due Hypertrophic cardiomyopathya (“burned-out”) to genetic causes or consumption of excess alcohol or illicit stimulant “Idiopathic”a drugs. The proportion of chronic DCM due to viral infection remains a subject of controversy. Miscellaneous (Shared Elements of Above Etiologies) Arrhythmogenic ventricular cardiomyopathy Laboratory Evaluation for Myocarditis The initial evaluation Peripartum cardiomyopathy for suspected myocarditis includes an ECG, an echocardiogram, and Left ventricular noncompactiona serum levels of troponin and creatine phosphokinase, of which both Tachycardia-related cardiomyopathy cardiac and skeletal muscle fractions may be elevated. Magnetic res- onance imaging is increasingly used for the diagnosis of myocarditis, Supraventricular arrhythmias with uncontrolled rate which is supported but not proven by evidence of increased tissue  Very frequent nonsustained ventricular tachycardia or high premature edema and gadolinium enhancement (Fig. 259-6), particularly in the ventricular complex burden mid-wall (as distinct from usual coronary artery territories). a Some specific cases can be linked now to specific genetic mutation in a familial Endomyocardial biopsy is indicated when a new presentation of cardiomyopathy; others with similar phenotypes that appear to be acquired or idiopathic may represent genetic factors not yet identified. heart failure is accompanied by conduction blocks or ventricular tachyarrhythmias, which suggest possible etiologies of noninfectious HPIM21e_Part6_p1797-p2130.indd 1959 21/01/22 6:22 PM  1960 Chronic An increase in circulating viral titers Infection Immune Responses Dilated cardiomyopathy between acute and convalescent blood samples supports a diagnosis of acute viral myocardi- Macrophages tis with potential spontaneous improvement. Natural killer T cells Ab anti-myocyte surface proteins Respiratory virus panels can detect adenovirus, Specific T cell respones Ab anti-myocyte cellular proteins influenza, and coronavirus. There is no estab- PART 6 Ab anti-pathogen Ab anti-pathogen lished role for measuring circulating anti-heart antibodies, which may be the result, rather than Cytokines a cause, of myocardial injury and have also been Chronic dilated found in patients with coronary artery disease Entry into myocytes cardiomyopathy Disorders of the Cardiovascular System and genetic cardiomyopathy. Viral replication Patients with recent or ongoing viral syn- and protein expression Persistent or latent Viremia dromes have been classified into three levels of Delayed apoptosis infection myocarditis diagnosis. (1) Possible subclinical Myocyte lysis acute myocarditis is diagnosed when a typical viral syndrome occurs without cardiac symp- toms, but with elevated biomarkers of cardiac injury, ECG suggestive of acute injury, and/ or reduced left ventricular ejection fraction or regional wall motion abnormality. (2) Probable Alterations in acute myocarditis is diagnosed when the above extracellular matrix criteria are met and accompanied by cardiac symptoms, such as shortness of breath or chest pain, which can result from pericarditis or FIGURE 259-5 Schematic diagram demonstrating the possible progression from infection through direct, myocarditis. When clinical findings of peri- secondary, and autoimmune responses to dilated cardiomyopathy. Most of the supporting evidence for this carditis are accompanied by elevated troponin sequence is derived from animal models. It is not known to what degree persistent infection and/or ongoing or CK-MB or abnormal cardiac wall motion, immune responses contribute to ongoing myocardial injury in the chronic phase. the terms perimyocarditis or myopericarditis are sometimes used. (3) Definite myocarditis inflammatory causes that warrant aggressive immunosuppression, is diagnosed when there is histologic or immunohistologic evidence such as sarcoidosis or giant cell myocarditis. The indications, yield, of inflammation on endomyocardial biopsy (see below) and does not and benefit of endomyocardial biopsy for evaluation of myocarditis or require any other laboratory or clinical criteria. Magnetic resonance new-onset cardiomyopathy are not well established. When biopsy is imaging is increasingly employed early in the evaluation for possible performed, the key Dallas criteria for myocarditis include lymphocytic myocarditis. With the original 2009 Lake Louise criteria for myocar- infiltrate with evidence of myocyte necrosis (Fig. 259-7) and are neg- ditis, a positive study required any two of three findings: abnormal ative in 80–90% of patients with clinical myocarditis. Negative Dallas T2-weighted imaging or early or late gadolinium enhancement. criteria can reflect sampling error or early resolution of lymphocytic Revised criteria for specificity require both a T2-weighted criterion infiltrates, but may also be influenced by the insensitivity of the test indicating edema and one T1-based criterion consistent with inflam- when inflammation results from cytokines and antibody-mediated matory injury, although more liberal diagnostic criteria allowing for injury. Routine histologic examination of endomyocardial biopsy the presence of either one yields higher sensitivity. The presence of rarely reveals a specific infective etiology, such as toxoplasmosis or pericardial effusion supports the diagnosis of inflammation, although cytomegalovirus subsets. Immunohistochemistry of myocardial biopsy it is not specific. 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 specific- ity and significance of these findings are uncertain. FIGURE 259-7 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 FIGURE 259-6 Magnetic resonance image of myocarditis showing the typical mid- replacement fibrosis even if the inflammatory response could be suppressed. wall location (arrow) for late gadolinium enhancement from cardiac inflammation Hematoxylin and eosin–stained section, 200× original magnification. (Image and scarring. (Image courtesy of Ron Blankstein, MD, and Marcelo Di Carli, MD, courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Division of Nuclear Medicine, Brigham and Women’s Hospital, Boston.) Women’s Hospital, Boston.) HPIM21e_Part6_p1797-p2130.indd 1960 21/01/22 6:22 PM  SPECIFIC VIRUSES IMPLICATED IN MYOCARDITIS encouraging results and ongoing investigations with immunosuppres- 1961 In humans, viruses are rarely proven to be the direct cause of clinical sive therapy for immune-mediated myocarditis defined by immuno- myocarditis. First implicated was the picornavirus family of RNA histologic criteria on biopsy or circulating antimyocardial antibodies viruses, principally the enteroviruses, coxsackie virus, echovirus, and in the absence of myocardial viral genomes. However, neither antiviral poliovirus. Influenza, another RNA virus, is implicated with varying nor anti-inflammatory therapies are currently recommended. Until we CHAPTER 259 Cardiomyopathy and Myocarditis frequency every winter and spring as epitopes change. Of the DNA have a better understanding of the phases of viral myocarditis and the viruses, adenovirus, vaccinia, and the herpesviruses (varicella-zoster effects of targeted therapies, treatment will continue to be guided by virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus general recommendations for DCM. 6 [HHV6]) are well recognized to cause myocarditis but also occur commonly in the healthy population. Polymerase chain reaction (PCR) OTHER INFECTIOUS CAUSES detects viral genomes in the majority of patients with DCM, but also in normal “control” hearts. Most often detected are parvovirus B19 and Parasitic Myocarditis Chagas’ disease is the third most common HHV6, which may affect the cardiovascular system, in part, through parasitic infection in the world and the most common infective cause infection of vascular endothelial cells. However, their contribution to of cardiomyopathy. The protozoan T. cruzi is transmitted by the bite chronic cardiomyopathy is uncertain, as serologic evidence of exposure of the reduviid bug, endemic in the rural areas of South and Central is present in many children and most adults. America. Transmission can also occur through blood transfusion, Human immunodeficiency virus (HIV) was associated with an organ donation, from mother to fetus, and occasionally orally. While incidence of DCM of 1–2%. However, with the advent of highly active programs to eradicate the insect vector have decreased the prevalence antiretroviral therapy (HAART), HIV has been associated with a sig- from about 16 million to 10–30 years in almost half of patients to manifest chronically in the mumps, respiratory syncytial virus, the arboviruses (dengue fever and cardiac and gastrointestinal systems. Features typical of Chagas’ disease yellow fever), and arenaviruses (Lassa fever). For any serious infection, are conduction system abnormalities, particularly sinus node and AV the systemic inflammatory response can cause nonspecific depression node dysfunction and right bundle branch block. Atrial fibrillation and of cardiac function, which is generally reversible if the patient survives. ventricular tachyarrhythmias also occur. Small ventricular aneurysms This nonspecific inflammatory response is likely responsible for most are common, particularly at the ventricular apex. These dilated ventri- of the cardiac findings with SARS-CoV-2, for which clinical informa- cles are particularly thrombogenic, giving rise to pulmonary and sys- tion is accumulating rapidly. There is some evidence for direct cardio- temic emboli. Xenodiagnosis, detection of the parasite itself, is rarely myocyte invasion by the virus, consistent with an early model of acute performed. The serologic tests for specific IgG antibodies against the myocarditis in rabbits caused by rabbit coronavirus. Some patients do trypanosome lack sufficient specificity and sensitivity, requiring two present with ECG changes mimicking acute myocardial infarction. separate positive tests to make a diagnosis. The endothelium is also a distinct cellular target of SARS-CoV-2, and Treatment of the advanced stages focuses on clinical manifestations the resulting vasoconstrictive and prothrombotic endotheliopathy may of the disease and includes heart failure medications, pacemaker- contribute to myocardial ischemia (and stroke). The dominant injury defibrillators, and anticoagulation. The most common antiparasitic is to the lungs, where adult respiratory distress syndrome can develop, therapies are benznidazole and nifurtimox, which have been effective particularly in older patients and those with underlying comorbidities. in children with chronic T. cruzi infection. Both drugs are associated When heart failure develops later in the course, it is usually in the set- with multiple severe reactions, including dermatitis, gastrointestinal ting of refractory respiratory failure and other organ failure from which distress, and neuropathy. Moreover, in a large trial of adults with estab- survival is unlikely. lished Chagas’ cardiomyopathy, benznidazole did not prevent disease progression, leaving the role of antiparasitic therapy unclear. Survival THERAPY OF VIRAL MYOCARDITIS is 60% for adaptive neurohumoral responses. Fluid retention may be aggravated men and >45–50% for women. MRI can help to quantitate iron stores by large fluid intake and the rapid clearance of natriuretic peptides by in the liver and heart, and endomyocardial biopsy tissue can be stained adipose tissue. In the absence of another obvious cause of cardiomy- for iron (Fig. 259-9), which is particularly important if the patient has opathy in an obese patient with systolic dysfunction without marked another cause for cardiomyopathy. If diagnosed early, hemochromato- ventricular dilation, effective weight reduction is often associated sis can often be managed by repeated phlebotomy to remove iron. For with major improvement in ejection fraction and clinical function. more severe iron overload, iron chelation therapy with desferrioxamine Improvement in cardiac function has been described after successful (deferoxamine) or deferasirox can help to improve cardiac function if bariatric surgery, although all major surgical therapy poses increased myocyte loss and replacement fibrosis are not too severe. risk for patients with heart failure. Postoperative malabsorption and Inborn disorders of metabolism occasionally present with DCM, nutritional deficiencies, such as calcium and phosphate deficiencies, although they are most often associated with restrictive cardiomyop- may be particularly deleterious for patients with cardiomyopathy. athy (Table 259-4). Nutritional deficiencies can occasionally cause DCM but are not commonly implicated in developed countries. Beri-beri heart disease FAMILIAL DILATED CARDIOMYOPATHY due to thiamine deficiency can result from poor nutrition in under- The genetic basis for cardiomyopathy is discussed above in the section, nourished populations and in patients deriving most of their calories “Genetic Etiologies of Cardiomyopathy.” The recognized frequency from alcohol and has been reported in teenagers subsisting only on of familial involvement in DCM has increased to >30%. Mutations in highly processed foods. This disease is initially a vasodilated state with TTN, encoding the giant sarcomeric protein titin, are the most com- very-high-output heart failure that can later progress to a low-output mon cause of DCM, accounting for up to 25% of familial disease. On state; thiamine repletion can lead to prompt recovery of cardiovascular average, men with TTN mutations develop cardiomyopathy a decade function. Abnormalities in carnitine metabolism can cause dilated before women, without distinctive clinical features. Mutations in thick or restrictive cardiomyopathies, usually in children. Deficiency of and thin filament genes account for ~8% of DCM and may manifest in trace elements such as selenium can cause cardiomyopathy (Keshan’s early childhood. disease). The most recognizable familial cardiomyopathy syndromes with Calcium is essential for excitation-contraction coupling. Chronic extracardiac manifestations are the muscular dystrophies. Both Duch- deficiencies of calcium, such as can occur with hypoparathyroidism enne’s and the milder Becker’s dystrophies result from abnormalities in (particularly postsurgical) or intestinal dysfunction (from diarrheal the X-linked dystrophin gene of the sarcolemmal membrane. Skeletal syndromes and following extensive resection), can cause severe chronic myopathy is present in multiple other genetic cardiomyopathies heart failure that responds over days or weeks to vigorous calcium (Table 259-3), some of which are associated with creatine kinase elevations. HPIM21e_Part6_p1797-p2130.indd 1965 21/01/22 6:22 PM  1966 Patients and families with a history of arrhyth- mias and/or conduction system disease that pre- cede or supersede cardiomyopathy may have abnormalities of the nuclear membrane lamin proteins, which are present in ~5% of patients LV with DCM. While all DCMs carry a risk of sudden PART 6 death, a family history of cardiomyopathy with sudden death raises suspicion for a particularly arrhythmogenic mutation; affected family mem- bers may be considered for implantable defibrilla- RV Disorders of the Cardiovascular System tors to prevent sudden death even without meeting the reduced ejection fraction threshold. A prominent family history of sudden death or ventricular tachycardia before clinical cardiomyo- A B pathy suggests genetic defects in the desmosomal FIGURE 259-10 Arrhythmogenic right ventricular cardiomyopathy. A. Cross-sectional slice of a pathology proteins (Fig. 259-10). Originally described as specimen removed at transplantation, showing severe dilation and thinning of the right ventricle (RV) with affecting the right ventricle (arrhythmogenic right 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 ventricular cardiomyopathy [ARVC]), this disorder Mitchell, MD, PhD, Division of Pathology, Brigham and Women’s Hospital, Boston.) (arrhythmogenic cardiomyopathy) can affect either or both ventricles. Patients often present first with ventricular tachycardia. Genetic defects in proteins of the desmosomal extends beyond a specific coronary artery distribution and generally complex disrupt myocyte junctions and adhesions, leading to replace- resolves within days to weeks. Animal models and ventricular biop- ment of myocardium by deposits of fat. Thin ventricular walls may sies suggest that this acute cardiomyopathy may result from intense be recognized on echocardiography but are better visualized on MRI. sympathetic activation with heterogeneity of myocardial autonomic Because desmosomes are also important for elasticity of hair and skin, innervation, diffuse microvascular spasm, and/or direct catecholamine some of the defective desmosomal proteins are associated with striking toxicity. Cardiac MRI demonstrates diffuse myocardial edema without “woolly hair” and thickened skin on the palms and soles. Implantable necrosis. Coronary angiography may be required to rule out acute defibrillators are usually indicated to prevent sudden death. There is coronary occlusion. No therapies have been proven beneficial, but variable progression to right, left, or biventricular failure. reasonable strategies include nitrates for pulmonary edema; intraaortic Left ventricular noncompaction is a condition of unknown preva- balloon pump if needed for low output, provided transient left ven- lence that is increasingly suspected with the refinement of imaging tricular outflow tract obstruction is absent; combined alpha and beta techniques. The diagnostic criteria include the presence of multiple blockers rather than selective beta blockade if hemodynamically stable; trabeculations in the left ventricle distal to the papillary muscles, creat- and magnesium for arrhythmias related to QT prolongation. The long- ing a “spongy” appearance of the apex, but are increasingly recognized term prognosis is generally good, with the lowest mortality associated as nonspecific findings in other cardiac diseases. Noncompaction has with episodes triggered by emotional rather than physical triggers. been associated with multiple genetic variants in the sarcomeric and In-hospital complications and mortality are similar to acute myocardial other genes, such as TAZ (encoding tafazzin). The diagnosis may be infarction. Recurrences have been described in up to 10% of patients. made incidentally or in patients previously diagnosed with cardio- myopathy, in whom the criteria for noncompaction may appear and IDIOPATHIC DCM disappear with changing left ventricular size and function. The three Idiopathic DCM is a diagnosis of exclusion, when all other known fac- cardinal clinical features of ventricular arrhythmias, embolic events, tors have been excluded. Approximately two-thirds of DCMs are still and heart failure are largely restricted to noncompaction with con- labeled as idiopathic; however, a substantial proportion of these may comitant systolic dysfunction. Treatment generally includes antico- reflect unrecognized genetic disease. Continued reconsideration of agulation and early consideration for an implantable defibrillator, in etiology during chronic heart failure management often reveals specific addition to neurohormonal antagonists as indicated by stage of disease. causes later in a patient’s course. Some families inherit a susceptibility to viral-induced myocarditis. This propensity may relate to abnormalities in cell surface receptors, OVERLAPPING TYPES OF such as the coxsackie-adenovirus receptor, that bind viral proteins. CARDIOMYOPATHY Some may have partial homology with viral proteins such that an auto- The limitations of our phenotypic classification are revealed through immune response is triggered against the myocardium. the multiple overlaps between the etiologies and presentations of the three Prognosis and therapy of familial DCM are dictated primarily by the types. Cardiomyopathy with reduced systolic function but without stage of clinical disease and the risk for sudden death. In some cases, the severe dilation can represent early DCM, “minimally dilated cardiomy- familial etiology facilitates prognostic decisions, particularly regarding the opathy,” or restrictive diseases without marked increases in ventricular likelihood of recovery after a new diagnosis, which is unlikely for familial wall thickness. For example, sarcoidosis and hemochromatosis can disease. The rate of progression of disease is to some extent heritable, present as dilated or restrictive disease. Early stages of amyloidosis although marked variation can be seen. However, there have been cases are often mistaken for hypertrophic cardiomyopathy. Progression of of remarkable clinical remission after acute presentation, likely after a hypertrophic cardiomyopathy into a “burned-out” phase occurs occa- reversible “second hit,” such as prolonged tachycardia or viral myocarditis. sionally, with decreased contractility and modest ventricular dilation. Overlaps are particularly common with the inherited metabolic disor- TAKOTSUBO CARDIOMYOPATHY ders, which can present as any of the three major phenotypes (Fig. 259-4). The apical ballooning syndrome, or acute stress-induced cardiomyop- athy, occurs typically in older women after sudden intense emotional DISORDERS OF METABOLIC PATHWAYS or physical stress. The ventricle shows global ventricular dilation with Multiple genetic disorders of metabolic pathways can cause myocardial basal contraction, forming the shape of the narrow-necked jar (takotsubo) disease, due to infiltration of abnormal products or cells containing used in Japan to trap octopuses. Originally described in Japan, it is well them between the myocytes, and storage disease, due to their accu- recognized elsewhere during emergency cardiac catheterization and mulation within cells (Tables 259-3 and 259-4). Hypertrophic car- intensive care unit admissions for noncardiac conditions. Presentations diomyopathy may be mimicked by the myocardium thickened with include pulmonary edema, hypotension, and chest pain with ECG these abnormal products causing “pseudohypertrophy,” usually with changes mimicking an acute infarction. The left ventricular dysfunction an abnormally short PR interval. The pseudohypertrophic phenotype HPIM21e_Part6_p1797-p2130.indd 1966 21/01/22 6:22 PM  been associated with a high prevalence of conduction abnormalities, 1967 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 CHAPTER 259 Cardiomyopathy and Myocarditis a syndrome of skeletal myopathy, mental retardation, and hepatic dys- function referred to as Danon’s disease. Extreme left ventricular hyper- trophy 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 Restrictive cardiomyopathy is dominated by abnormal diastolic func- tion, 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- FIGURE 259-11 Fabry’s disease. Transmission electron micrograph of a right diastolic dimension $100,000 a year. The that infiltrate between cells of target organs (Figs. 259-12, 259-13, and oral chaperone therapy, migalastat, stabilizes mutant forms of alpha- 259-14). Almost all amyloid that affects the heart is caused by assembly galactosidase, increases enzymatic activity, and was approved for use either of immunoglobulin light chains from clonal plasma cells (AL or in a subset of patients with Fabry’s disease bearing mutations amenable “primary” amyloid) or of transthyretin (ATTR), which is made in the to this therapy. Enzyme replacement can also improve the course of liver and can either be an inherited mutant protein (ATTRm) or the Gaucher’s disease, in which cerebroside-rich cells accumulate in mul- normal protein (ATTRwt [wild-type], which accumulates with age, tiple organs due to a deficiency of beta-glucosidase. Cerebroside-rich leading to cardiac amyloid in half of people >90 years old, but clini- cells infiltrate the heart, which can also lead to a hemorrhagic pericar- cally much more common in men than women). There are multiple dial effusion and valvular disease. mutations in the transthyretin molecule, of which the most common is Glycogen storage diseases lead to accumulation of lysosomal stor- V1221, which confers a 50% increased risk of heart failure in the 3-4% age products and intracellular glycogen accumulation, particularly of African Americans who are heterozygous, but it is often clinically with glycogen storage disease type III, due to a defective debranching silent. enzyme. There are >10 types of mucopolysaccharidoses, in which auto- Right heart failure often dominates the clinical presentation of car- somal recessive or X-linked deficiencies of lysosomal enzymes lead diac amyloidosis, although both ventricles are affected. Conduction to the accumulation of glycosaminoglycans in the skeleton, nervous system disease and atrial fibrillation are common. Nephrotic syndrome system, and occasionally the heart. With characteristic facies, short is common in AL amyloid, which may also cause angina as the amy- stature, and frequent cognitive impairment, most individuals are diag- loid encircles the coronary arteries. Because the ventricular cavity is nosed early in childhood and die before adulthood. diminished by amyloid infiltration, cardiac output may be very low Carnitine is an essential cofactor in long-chain fatty acid metab- with a modest ejection fraction reduction. Peripheral and autonomic olism. Multiple defects have been described that lead to carnitine neuropathy are common in both AL amyloidosis and ATTRm amyloi- deficiency, causing intracellular lipid inclusions and restrictive cardio- dosis. A history of carpal tunnel syndrome is common in ATTRm and myopathy or DCM, often presenting in children. Fatty acid oxidation ATTRwt, often preceding cardiac symptoms by many years. ATTRwt requires many metabolic steps with specific enzymes that can be is also associated with spinal stenosis. deficient, with complex interactions with carnitine. Depending on the Amyloidosis should be suspected when ventricular myocardium defect, cardiac and skeletal myopathy can be ameliorated with replace- appears thick on imaging with low ECG voltage, but this mismatch is ment of fatty acid intermediates and carnitine. more common with AL than TTR amyloidosis. Atrial enlargement is Two monogenic metabolic cardiomyopathies cause markedly prominent and diastolic dysfunction more severe than that of other increased ventricular wall thickness without an increase of muscle causes of hypertrophy. Longitudinal strain is frequently more pre- subunits or an increase in contractility. Mutations in the gamma-2 served at the apex, creating a “bull’s-eye” pattern. MRI shows diffuse regulatory subunit of the adenosine monophosphate (AMP)-activated late gadolinium enhancement. Technetium-pyrophosphate scanning protein kinase important for glucose metabolism (PRKAG2) have reliably highlights TTR amyloidosis but does not detect AL amyloid. HPIM21e_Part6_p1797-p2130.indd 1967 21/01/22 6:22 PM  1968 TABLE 259-5 Causes of Restrictive Cardiomyopathies Infiltrative (Between Myocytes) Amyloidosis Primary (light chain amyloid) Familial (abnormal transthyretin)a PART 6 Senile (normal transthyretin or atrial peptides) Inherited metabolic defectsa Storage (Within Myocytes) Disorders of the Cardiovascular System Hemochromatosis (iron)a Inherited metabolic defectsa Fabry’s disease Glycogen storage disease (II, III) Fibrotic Radiation Scleroderma Endomyocardial Possibly related fibrotic diseases Tropical endomyocardial fibrosis Hypereosinophilic syndrome (Löffler’s endocarditis) Carcinoid syndrome Radiation Drugs: e.g., serotonin, ergotamine Overlap with Other Cardiomyopathies Hypertrophic cardiomyopathy/”pseudohypertrophic”a FIGURE 259-12 Restrictive cardiomyopathy—amyloidosis. Gross specimen of a heart “Minimally dilated” cardiomyopathy 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 Early-stage dilated cardiomyopathy amyloid deposits that give texture to the surface. (Image courtesy of Robert Padera, Partial recovery from dilated cardiomyopathy MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) Sarcoidosis Idiopathica cardiomyopathy. Patients with radiation cardiomyopathy may present with a possible diagnosis of constrictive pericarditis, as the two con- Can be familial. a ditions often coexist. Careful hemodynamic evaluation and, often, endomyocardial biopsy should be performed if considering pericardial Endomyocardial biopsy is virtually 100% reliable for the diagnosis of all amyloid due to the characteristic birefringence pattern of Congo red staining of the amyloid fibrils under polarized light, but immu- nohistochemistry may be necessary to confirm the amyloid type, as serum or urine electrophoresis may be misleading. Until recently, the Pacing Pericardial therapy of amyloidosis was limited to the treatment of congestion and lead in effusion arrhythmias. There is no evidence for benefit from neurohormonal RV antagonists, which may complicate the postural hypotension and fixed low stroke volume of amyloid disease. However, specific therapies for amyloidosis are changing the prognosis. Median survival with AL amy- LV Lateral loidosis was previously 6–12 months but has markedly improved with RV wall of the use of the proteasome inhibitor bortezomib. If present, multiple LV myeloma may be treated with conventional chemotherapy, if not lim- Septum ited by cardiac dysfunction. AL amyloid can sometimes be treated with heart transplantation followed by delayed stem cell transplantation, with some risk of recurrence of amyloid in the transplanted heart. The course of TTR amyloidosis is measured in years even after the typical RA delay in diagnosis and may be affected by new therapies. Stabilizers of LA the normal transthyretin structure, tafamidis and diflusinal, have been approved for therapy of the associated neuropathy and are now being studied for effect on cardiac outcomes. Expression of transthyretin can be decreased by patisiran, a small interfering RNA that decreases message production, or inotersen, an antisense mRNA that enhances FIGURE 259-13 Restrictive cardiomyopathy—amyloidosis. Echocardiogram showing mRNA degradation. Both have been approved as treatment for the thickened walls of both ventricles without major chamber dilation. The atria are polyneuropathy of TTR amyloid, with possible benefit on long-term markedly dilated, consistent with chronically elevated ventricular filling pressures. In outcomes. These therapies have not yet been approved for a cardiac this example, there is a characteristic hyperrefractile “glittering” of the myocardium indication. typical of amyloid infiltration, which is a nonspecific 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 FIBROTIC RESTRICTIVE CARDIOMYOPATHY the echocardiographic and pathologic images are vertically opposite, such that the Progressive fibrosis can cause restrictive myocardial disease without left ventricle (LV) is by convention on the top right in the echocardiographic image ventricular dilation. Thoracic radiation, common for breast and lung and bottom right in the pathologic images. LA, left atrium; RA, right atrium. (Image cancer or mediastinal lymphoma, can produce early or late restrictive courtesy of Justina Wu, MD, Brigham and Women’s Hospital, Boston.) HPIM21e_Part6_p1797-p2130.indd 1968 21/01/22 6:22 PM  recommended. Atrial fibrillation is associated with 1969 worse symptoms and prognosis but may be diffi- cult to suppress. Surgical resection of the apices and replacement of the fibrotic valves can improve symptoms, but surgical morbidity and mortality CHAPTER 259 Cardiomyopathy and Myocarditis 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 sero- tonin to reach the venous circulation. FIGURE 259-14 Amyloidosis—microscopic images of amyloid involving the myocardium. The left panel (hematoxylin and eosin stain) shows glassy, gray-pink amorphous material infiltrating between cardiomyocytes, which stain a darker pink. The right panel shows a sulfated blue stain that highlights the HYPERTROPHIC amyloid green and stains the cardiac myocytes yellow. (The Congo red stain can also be used to highlight CARDIOMYOPATHY amyloid; under polarized light, amyloid will have an apple-green birefringence when stained with Congo Hypertrophic cardiomyopathy is defined as left red.) Images at 100× original magnification. (Image courtesy of Robert Padera, MD, PhD, Department of ventricular hypertrophy that develops in the Pathology, Brigham and Women’s Hospital, Boston.) absence of causative hemodynamic factors, such as hypertension, aortic valve disease, or systemic stripping surgery, which is unlikely to be successful in the presence of infiltrative or storage diseases (Figs. 259-15 and 259-16). It has previ- underlying restrictive cardiomyopathy. Scleroderma causes small vessel ously been termed hypertrophic obstructive cardiomyopathy (HOCM), spasm and ischemia that can lead to a small, stiff heart with reduced asymmetric septal hypertrophy (ASH), and idiopathic hypertrophic subaor- ejection fraction without dilation. The pulmonary hypertension asso- tic stenosis (IHSS). However, the accepted terminology is now hypertro- ciated with scleroderma may lead to more clinical right heart failure phic cardiomyopathy with or without obstruction. Prevalence in North because of concomitant fibrotic disease of the right ventricle. America, Africa, and Asia is about 1:500. It is a leading cause of sudden death in the young and is an important cause of heart failure. Although ENDOMYOCARDIAL DISEASE pediatric presentation is associated with increased early morbidity and The physiologic picture of elevated filling pressures with atrial enlarge- mortality, the prognosis for patients diagnosed as adults is generally ment and preserved ventricular contractility with normal or reduced favorable, although worse than for age-matched individuals without ventricular volumes can result from extensive fibrosis of the endocar- hypertrophic cardiomyopathy. dium, without transmural myocardial disease. For patients who have A sarcomere mutation is present in ~50% of patients with hypertro- not lived in the equatorial regions, this picture is rare, and when seen is phic cardiomyopathy and is more common in those with familial disease often associated with a history of chronic hypereosinophilic syndrome and characteristic asymmetric septal hypertrophy. More than nine differ- (Löffler’s endocarditis), which is more common in men than women. ent genes with >1500 mutations have been implicated, although ~80% of In this disease, persistent hypereosinophilia of >1500 eosinophils/μL patients have a mutation in either MYH7 or MYBPC3 (Table 259-3). for at least 6 months can cause an acute phase of eosinophilic injury in the endocardium (see earlier discussion of eosinophilic myocarditis), Mitral valve Tricuspid valve with systemic illness and injury to other organs. Hypereosinophilic syndromes can occasionally be explained by allergic or parasitic dis- ease, but are increasingly being recognized as due to myeloproliferative variants. 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 leaf- lets. 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 endomyocar- dial fibrosis has not been clearly demonstrated. RV free In tropical countries, up to one-quarter of heart failure may be due wall to endomyocardial fibrosis, affecting either or both ventricles. This condition shares with the previous condition the partial obliteration LV free of the ventricular apex with fibrosis extending into the valvular inflow wall tract and leaflets; however, it is not clear that the etiologies are the same for all cases. Pericardial effusions frequently accompany end- RV Chamber omyocardial fibrosis but are not common in Löffler’s endocarditis. For LV Chamber IVS endomyocardial fibrosis, there is no gender difference, but there is a FIGURE 259-15 Hypertrophic cardiomyopathy. Gross specimen of a heart with higher prevalence in African-American populations. While tropical hypertrophic cardiomyopathy removed at the time of transplantation, showing endomyocardial fibrosis could represent the end-stage of previous asymmetric septal hypertrophy (septum much thicker than left ventricular free wall) hypereosinophilic disease triggered by endemic parasites, neither prior with the septum bulging into the left ventricular outflow tract causing obstruction. parasitic infection nor hypereosinophilia is usually documented. Geo- The forceps are retracting the anterior leaflet of the mitral valve, demonstrating the graphic nutritional deficiencies have also been proposed as an etiology. 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 Clonal proliferation with specific mutations may respond to mono- patchy replacement fibrosis, and small thick-walled arterioles can be appreciated clonal antibody therapy. Other treatment includes glucocorticoids grossly, especially in the interventricular septum. IVS, interventricular septum; to suppress hypereosinophilia when present. Fluid retention may LV, left ventricle; RV, right ventricle. (Image courtesy of Robert Padera, MD, PhD, become increasingly resistant to diuretic therapy. Anticoagulation is Department of Pathology, Brigham and Women’s Hospital, Boston.) HPIM21e_Part6_p1797-p2130.indd 1969 21/01/22 6:22 PM  1970 PART 6 LV Disorders of the Cardiovascular System Septum MV FIGURE 259-17 Hypertrophic cardiomyopathy. Microscopic image of hypertrophic LA 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.) ischemia and angina. Microinfarction of hypertrophied myocardium is a hypothesized mechanism for replacement scar formation. Macroscopically, hypertrophy is typically manifest as nonuniform ventricular thickening (Fig. 259-15). The interventricular septum is the FIGURE 259-16 Hypertrophic cardiomyopathy. This echocardiogram of hypertrophic typical location of maximal hypertrophy, although other patterns of hyper- cardiomyopathy shows asymmetric hypertrophy of the septum compared to the trophic remodeling include concentric and midventricular. Hypertrophy lateral wall of the left ventricle (LV). The mitral valve (MV) is moving anteriorly confined to the ventricular apex (apical hypertrophic cardiomyopathy) is toward the hypertrophied septum in systole. The left atrium (LA) is enlarged. Note that the echocardiographic and pathologic images are vertically opposite, such that less often familial and has a different genetic substrate, with sarcomere the LV is by convention on the top right in the echocardiographic image and bottom mutations present in only ~15%. Left ventricular outflow tract obstruc- right in the pathologic images. (Image courtesy of Justina Wu, MD, Brigham and tion represents the most common focus of diagnosis and intervention, Women’s Hospital, Boston.) although diastolic dysfunction, myocardial fibrosis, and microvascular