Hypertrophic cardiomyopathy (HCM) is a phenotypically heterogeneous condition that affects individuals of all ages. The disease is typically inherited in an autosomal dominant fashion with variable clinical penetrance. In adults, the majority of cases are caused by mutations in one of 12 cardiac sarcomeric protein genes; in infants and children, left ventricular hypertrophy is often associated with congenital malformations and syndromes, inherited disorders of metabolism, and neuromuscular diseases.

The disease is characterized by myocardial hypertrophy, most commonly affecting the interventricular septum, disorganization (“disarray”) of cardiac myocytes and myofibrils, myocardial fibrosis, and small-vessel disease. Twenty-five percent of patients have resting left ventricular outflow tract obstruction.

Patients present throughout life with chest pain, dyspnea, palpitations, and syncope; the most important complication of the disease is sudden death, which occurs with an annual incidence of approximately 1%. Other complications include atrial arrhythmia, thromboembolism, infective endocarditis, and congestive cardiac failure. Symptoms can be improved with pharmacologic therapy or relief of left ventricular outflow tract obstruction using alcohol ablation or surgery; cardiac transplantation is required in a small minority of cases. Sudden death prevention is based on the identification of clinical risk markers; patients with multiple risk factors are treated with implantable cardioverter defibrillators.

Asymmetric hypertrophy of the interventricular septum was first described in 1869 by Liouville (1) and Hallopeau (2), but it was only in the 1950s that hypertrophic cardiomyopathy was established as a discrete clinical entity with the description of “functional obstruction of the left ventricle” by Sir Russell Brock (3) and asymmetric septal hypertrophy by Donald Teare (4). There followed a period of intense clinical investigation in which the characteristic morphologic and hemodynamic features of the disease were defined. In the 1960s (5,6,7,8,9), reliance on stethoscope and cardiac catheterization meant that left ventricular outflow tract obstruction was considered to be the diagnostic hallmark of HCM, a fact reflected in the many pseudonyms for the disease used during this period (e.g., idiopathic hypertrophic subaortic stenosis [IHSS]); in the 1970s, M-mode echocardiography (10,11,12) reemphasized asymmetric septal hypertrophy (ASH) as the diagnostic hallmark of the disease, but the advent of two-dimensional echocardiographic imaging demonstrated that virtually any pattern of unexplained myocardial hypertrophy is consistent with the diagnosis (13,14).

In the 1980s, work on the clinical pathophysiology of the disease continued, but the growing recognition that the majority of cases were familial led to the identification of the first genetic mutation in the gene encoding the β-myosin heavy chain (15). Since then, numerous mutations in this and other sarcomeric proteins have been reported, leading to the modern concept of the disease as a disorder of the myocyte contractile apparatus. This remains the current view, but genetic characterization has illustrated the diversity of clinical expression and is beginning to show that similar mutations can cause dilated and restrictive cardiomyopathy in the absence of hypertrophy (16,17).

Many cases of left ventricular hypertrophy in infants and young children are associated with congenital malformations and syndromes, inherited metabolic disorders, and neuromuscular diseases (Table 29.1) (18,19,26,29,30,37,38,39,40,41,42,43). The majority of adolescents and adults with HCM have familial disease with an autosomal dominant pattern of inheritance; approximately 50% to 60% of patients have mutations in one of eight genes that encode different components of the cardiac sarcomere (Fig. 29.4): β-myosin heavy chain (chromosome 14); cardiac troponin T (chromosome 1); cardiac troponin I (chromosome 19);
α-tropomyosin (chromosome 15); cardiac myosin-binding protein C (chromosome 11); the essential and regulatory myosin light chains (chromosomes 3 and 12, respectively); and cardiac actin (chromosome 15). Mutations in three other sarcomeric protein genes have been reported: titin (62), troponin C (63), and α-cardiac myosin heavy chain (19,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62). Some adult patients with apparently unexplained ventricular hypertrophy have diseases such as Anderson-Fabry disease (63), mitochondrial disease (64), and a rare phenotype comprising HCM, Wolff-Parkinson-White syndrome, and premature conduction disease caused by mutations in the gene encoding the γ-subunit of AMP kinase, an important regulator of cellular energy homeostasis (65,66,67). Other examples of nonsarcomeric gene mutations that can result in HCM phenocopies include LAMP-2 (Danon disease) (67,68), human muscle LIM protein (69), and phospholamban promoter (70).