Hypertrophic cardiomyopathy is one of the most common causes of sudden cardiac death among young adults and adolescents. Unfortunately, the first manifestation of the condition may be sudden death during exertion, such as sporting activities. Other clinical symptoms include exertional dyspnea, angina, and syncope. Postmortem examination often reveals asymmetrical septal thickening and mural plaque formation in the left ventricular outflow tract. Histologic analysis shows cardiac myocyte hypertrophy, myofiber disarray, and interstitial and replacement fibrosis. Molecular analysis for known genetic abnormalities is essential to genetic counseling of living relatives of decedents to assess and reduce the risk of sudden cardiac death from hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is a structural and functional disease of the myocardium and is the most common cause of sudden cardiac death in young athletes. It occurs with a prevalence of 1 in 500 individuals.1 The first case series was reported in 1958 by Donald Teare, MD, a British forensic pathologist, who described 8 individuals with asymmetrical hypertrophy of the heart with “bizarre and disorganized arrangement of muscle bundles associated with hypertrophy of individual muscle fibers and their nuclei.”2(p7) Since that initial systematic, pathologic description, significant advances have been made in elucidating etiologic factors, including a genetic predisposition linked to specific gene abnormalities, and the functional consequences of hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy should be considered as a cause of death when pathologists are presented with sudden, unexplained deaths, particularly in individuals younger than 40 years. Hypertrophic cardiomyopathy is the most common cause of sudden cardiovascular death in young, competitive athletes, accounting for one-third of all deaths. Subsequent causes, in order of decreasing frequency, include coronary artery anomalies, myocarditis, arrhythmogenic right ventricular cardiomyopathy, and ion channelopathies.3 The frequency of sudden death secondary to HCM varies in young, nonathletic populations from different geographic regions. Hypertrophic cardiomyopathy has been found to be the second most frequent cause of sudden cardiac death, after atherosclerotic coronary artery disease, in various studies.4 In Sydney, Australia,5 HCM was the third most frequent cause of death after myocardial infarction and myocarditis in a retrospective study of patients 5 to 35 years old. Similarly, in patients aged 14 to 35 years in Ireland,6 HCM was the third most-frequent cause of sudden cardiac death after sudden arrhythmic death syndrome and coronary artery disease.
Hypertrophic cardiomyopathy is a disease with an autosomal dominant pattern of transmission and variable penetrance. Approximately one-half of all cases are familial in origin, and the remainder are due to sporadic or de novo mutations. Up to 27 individual genes7 have been implicated in the cause of HCM, with hundreds of distinct disease-causing mutations.8–11 The implicated genes occur in cardiac myofilament/sarcomeric proteins, Z-disk proteins, and nonsarcomeric calcium-handling proteins.12 Affected cardiac sarcomere proteins include giant (titin), thick (β-myosin heavy chain, α-myosin heavy chain, regulatory myosin light chain, essential myosin light chain), intermediate (cardiac myosin-binding protein C), and thin filaments (cardiac troponin T, cardiac troponin I, α-tropomyosin, α-cardiac actin, cardiac troponin C). Mutations in β-myosin heavy chain and cardiac myosin-binding protein C are the most-common single-gene causes of HCM, with a frequency of up to 25% each. The Z-disk and nonsarcomeric calcium-handling proteins are rarer. The Z-disk proteins include α-actinin 2, cardiac ankyrin repeat protein, muscle LIM protein, LIM binding domain 3, myozenin 2, telethonin, and vinculin/metavinculin. Genetic mutations are diverse and include missense, frameshift, and truncating mutations.13,14 The clinical heterogeneity and phenotypic expression seen in this disease may be explained by other factors, such as environment and genetic modifiers: modifier alleles, epigenetic factors, microRNAs, and posttranslational protein modifications.
Despite locating hundreds of mutations within numerous genes, the pathophysiology of HCM remains poorly understood. Hypotheses have been proposed for the pathogenesis of HCM and include suggestions that causal DNA mutations give rise to structural alterations in proteins that cause various stresses on cardiac myocytes. Those stressors lead to activation of signaling molecules (trophic and mitotic factors) that mediate the induction of cardiac myocyte hypertrophy and disarray and collagen synthesis.15,16
Clinical Features
The structural, pathologic changes in HCM can cause a variety of symptoms, including exertional dyspnea and anginal pain. Stroke volume in HCM is often decreased because of impaired diastolic filling resulting from smaller chamber size and poor compliance of the hypertrophied left ventricle. Septal hypertrophy, which occurs in approximately one-third of all cases, results in obstruction to the blood outflow tract. The subsequent limited cardiac output and secondary increase in pulmonary venous pressure result in exertional dyspnea. Anginal pain occurs because of focal myocardial ischemia, resulting from myocardial hypertrophy, high left ventricular chamber pressure, and abnormal intramural arteries. The morphologic changes can also manifest as a clinically detectable sign in the form of a harsh systolic ejection murmur. The murmur is the result of ventricular outflow obstruction as the anterior mitral leaflet moves toward the ventricular septum in systole.17
Gross and Histopathologic Findings
A gross, morphologic, cardiovascular examination reveals asymmetric septal hypertrophy, as evidenced by disproportionate thickening of the ventricular septum compared with the left ventricular free wall (ratio increased by 30% or more). In approximately 10% of cases, the hypertrophy is symmetric throughout the heart. Unlike dilated cardiomyopathy, HCM is characterized by hypertrophy without dilatation (until very late in the disease process). The ventricular hypertrophy has also been documented localized at various sites along the left ventricle as HCM morphologic variants. The hypertrophy may be more prominent in the subaortic region, mid ventricle, or apex.18,19 Maron et al3 recorded maximum left ventricular wall thickness mean (SD) of 23 (5) mm (range, 15–40 mm) and heart weight of 521 (113) g, in competitive athletes 13 to 25 years old with HCM. Endocardial thickening or mural plaque formation in the left ventricular outflow tract and thickening of the anterior mitral leaflet secondary to contact of the anterior mitral leaflet with the septum during ventricular systole are also present. The anterior mitral valve and papillary muscles are displaced anteriorly and result in abnormal coaptation between the mitral leaflets. The posterior leaflet coapts with the mid portion of the anterior leaflet, leaving the distal portion of the anterior mitral leaflet within the left ventricle during systole.20
Histologically, HCM is characterized by 3 predominant features: myocyte hypertrophy, myofiber disarray, and interstitial and replacement fibrosis (Figures 1 through 3). The transverse diameter of the hypertrophied myocytes exceeds 40 μm (reference range, 10–15 μm). Myofiber disarray is displayed by disordered myocyte bundles, individual myocytes, and contractile elements within sarcomeres. The hypertrophied myocytes are often arranged perpendicularly or obliquely to each other. The myocyte nuclei are also abnormal and are frequently enlarged, pleomorphic, and hyperchromatic.21 An additional feature that is often encountered in HCM is the presence of dysplastic coronary arteries.22 The abnormal arteries exhibit thickened walls because of proliferation of the intimal and medial smooth muscle cells and collagen, which result in luminal narrowing (Figure 4). Unfortunately, none of the above features are pathognomonic of HCM individually.
Cardiac myocyte hypertrophy with enlarged and hyperchromatic nuclei (hematoxylin-eosin, original magnification ×100).
Figure 2. Cardiac myocyte disarray (hematoxylin-eosin, original magnification ×100).
Figure 3. Interstitial and replacement fibrosis of myocardium (elastic trichrome, original magnification ×400).
Figure 4. Dysplastic coronary artery with adjacent area of myocardial infarction (hematoxylin-eosin, original magnification ×100).
Cardiac myocyte hypertrophy with enlarged and hyperchromatic nuclei (hematoxylin-eosin, original magnification ×100).
Figure 2. Cardiac myocyte disarray (hematoxylin-eosin, original magnification ×100).
Figure 3. Interstitial and replacement fibrosis of myocardium (elastic trichrome, original magnification ×400).
Figure 4. Dysplastic coronary artery with adjacent area of myocardial infarction (hematoxylin-eosin, original magnification ×100).
Ancillary Studies
Genetic testing can be performed to determine the causative genes for HCM. The testing is not performed solely as a pathologic diagnostic aid, but rather, for the purpose of counseling living relatives of the decedent regarding their own personal risk of having the condition.7 Comprehensive or targeted diagnostic testing is clinically available and recommended for individuals who have been diagnosed with HCM based on their clinical history, family history, and cardiac investigations.23 Individuals with suspected HCM may also undergo an endomyocardial biopsy for diagnosis of the condition. Using this technique for diagnosis, however, is fraught with difficulties. The characteristic features of HCM are often located deep within the septum and are inaccessible to the bioptome. Hearts from individuals without HCM often have physiologic focal myocyte disarray at the junction of the posterior right ventricle and septum, which may lead to erroneous false-positive results by endomyocardial biopsy. There is some value in endomyocardial biopsy, however, in recognition and diagnosis of infiltrative or storage diseases, such as amyloidosis, sarcoidosis, Fabry disease, and glycogen-storage disease.24
During postmortem investigations for sudden cardiac death, current recommendations include collection of tissue samples (5–10 mL of whole blood in ethylenediaminetetraacetic acid tubes; blood spot card, such as fast technology for analysis of nucleic acids card; or frozen sample of heart, liver, or spleen) for further investigation including DNA analysis and genetic testing.23 Paraffin-embedded tissue samples of heart, liver, or spleen may also be used for DNA extraction and subsequent analysis, however, those samples have a lower yield and accuracy than DNA from blood and fresh or frozen tissue.25
Differential Diagnosis
Differential diagnoses for HCM include hypertensive heart disease, “athlete's heart” (a physiologic and nonpathologic left ventricular hypertrophy associated with systematic training), storage diseases, and amyloidosis. The most common cause of left ventricular hypertrophy, in particular, is hypertension. Hypertensive heart disease is the primary differential diagnosis in the nonadolescent population for cardiac hypertrophy. Based on studies26 of cardiac magnetic resonance imaging of hypertensive heart disease and HCM, it was found that there was a statistically significant difference in left ventricle maximal wall thickness between the two conditions, measured at diastole. Individuals with mild to moderate hypertension were documented to have a mean left ventricular maximal wall thickness mean (SD) of 11.4 (2.4) mm, and in individuals with gene mutation-positive HCM, it was measured at 18.5 (4.8) mm. A left ventricular maximal wall thickness 17 mm or greater gave a sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of 90%, 93%, 86%, 95%, and 91%, respectively. The individuals with hypertensive heart disease also exhibited uniformly hypertrophied left ventricles, whereas those individuals with HCM had asymmetrically enlarged ventricles (as described above). The 10% of cases of HCM that have been described to have symmetric left ventricular hypertrophy would need further examination. In those cases, a microscopic examination would be imperative to look for features of myocyte disarray. Both myocyte hypertrophy and variable interstitial fibrosis may also be found in cardiac hypertrophy secondary to hypertensive heart disease.27
In cases of sudden cardiac death, in which gross and microscopic features of HCM are not apparent, appropriate genetic analyses should be undertaken to investigate potential, heritable cardiac channelopathies and cardiomyopathies.23 Common cardiac channelopathies include long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, progressive cardiac conduction disease, and short QT syndrome. Inheritable cardiomyopathies include arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, left ventricular noncompaction, and restrictive cardiomyopathy.
Sequelae
There are numerous clinicopathologic effects of this myocardial disease. Sequelae include atrial fibrillation, palpitations, syncope, mural thrombi (which may embolize and result in cerebrovascular accidents), heart failure, ventricular arrhythmias (including nonsustained ventricular tachycardia and ventricular fibrillation), and sudden death.28 Sudden death is the most consequential of effects and is generally agreed to be a result of lethal arrhythmias. The abnormal myocardium serves as an arrhythmogenic structural substrate from which the electrical abnormalities arise.
Basso et al29 described cardiovascular ischemic changes in 19 young adults (median age, 23 years), with a pathologic diagnosis of HCM, with or without a family history of HCM, who died suddenly. All stages of ischemic injury were documented among the cases: coagulative necrosis and neutrophilic infiltrate in the acute phase, myocytolysis and granulation tissue in the subacute phase, and fibrosis in the chronic phase. They postulated that the myocardial disarray of HCM and the resultant replacement-type fibrosis of ischemia combined with the eventual outcome serving as a site for electrical instability and sudden death.
Several other mechanisms have been proposed to explain myocardial ischemia in HCM, including small vessel disease, transient compression or obstruction of coronary arteries, and excessive myocardial demand. Small vessel disease, in the form of abnormally narrowed small arteries, was proposed by Maron et al22 to compromise coronary blood flow and result in myocardial ischemia. The intramural dysplastic coronary arteries were found in more than 80% of the examined cases of HCM and were significantly associated with fibrosis. The dysplastic arteries were also noted in some infants with HCM who died suddenly, suggesting that the abnormality was present as part of the disease from birth. During coronary arteriography, transient compression of the septal perforator branches of the left anterior descending coronary artery was noted in individuals with HCM during systole.30 This was thought to result in selective ischemia and may be related to the development of fibrosis; however, coronary blood flow occurs in diastole, and thus, systolic narrowing should not affect the myocardium. Myocardial bridging and subsequent compression during systole was found in the angiographic studies of 10% of young patients with HCM.31 The compression was found to extend into diastole for up to 30% to 75% of the length of diastole and could compromise myocardial perfusion leading to ischemia. A further pathophysiologic mechanism to account for myocardial ischemia includes impairment of the coronary vasodilatory response during disproportionate myocardial oxygen demand from hypertrophied myocardium in HCM.32
Prognosis and Treatment
The prognosis of individuals with HCM varies and is strongly correlated with specific gene mutations. Symptoms may present at any age, however, and individuals may be genotype-positive but phenotype-negative and remain asymptomatic. Those who are mildly symptomatic can be managed with pharmacotherapy but are at risk of progressive heart failure symptoms with subsequent development of atrial fibrillation, arrhythmias, or sudden death. Those at high risk of sudden death may opt to have implantable cardioverter-defibrillators as prophylaxis. Risk factors for sudden death include prior cardiac arrest or spontaneous, sustained ventricular tachycardia; family history of HCM with premature cardiac death; syncope and near syncope; multiple or repetitive episodes of nonsustained ventricular tachycardia; hypotensive response to exercise; and extreme left ventricular hypertrophy (with left ventricular wall thickness exceeding 30 mm).10
Mortality rates overall are not dissimilar to that of the general adult population of 1% per year25 ; however, analysis of myosin-binding protein C-related HCM in large, multigenerational pedigrees and smaller families show evidence of increased mortality in specific age categories, particularly ages 10 to 19 years.14 Annual mortality rates in children with HCM range from 2% to 6%.10
CONCLUSION
Sudden cardiac death from hypertrophic cardiomyopathy has significant clinical implications for relatives of decedents because of its heritability. Accurate pathologic diagnosis using gross, histologic, and molecular analyses can assist in prevention of further fatalities among next of kin.
