Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly

Background: Hypertrophic cardiomyopathy, a familial myocardial condition caused by sarcomere protein mutations, is usually recognized by early adulthood. Hypertrophic cardiomyopathy of the elderly has similar clinical features but, notably, a later age of onset and noncontributory family history. Causes of elderly-onset hypertrophic cardiomyopathy are unknown.

Methods and results: Eighteen women and 13 men diagnosed with late-onset hypertrophic cardiomyopathy were studied. Initial symptoms occurred at 59.3 (+/-12.3) years, and diagnosis was made at 62.8 (+/-10.8) years. None had family histories of cardiomyopathy. Echocardiography demonstrated maximal left ventricular wall thickness of 19.9+/-3.8 mm, systolic anterior motion of the mitral valve (58%), and, in 11 individuals, left ventricular outflow tract gradients (average, 63+/-42.8 mm). Sarcomere protein gene analyses revealed 8 sequence variants in cardiac Myosin binding protein-C (1 nonsense, 1 splice acceptor site, and 3 missense), cardiac troponin I (2 missense), and alpha-cardiac Myosin heavy chain (1 missense). Seven variants were not found in over 170 normal chromosomes; 1 variant (cardiac Myosin binding protein-C Arg326Gln) also occurred in a healthy adult.

Conclusions: Hypertrophic cardiomyopathy of the elderly can be a genetic disorder caused by dominant sarcomere protein mutations. The distribution of mutations in elderly-onset disease is strikingly different (P<0.00001) from that of familial, early onset hypertrophic cardiomyopathy. Whereas defects in beta-cardiac Myosin heavy chain, cardiac troponin T, and alpha-tropomyosin account for > 45% of familial hypertrophic cardiomyopathy, none were found here. Rather, mutations in cardiac Myosin binding protein-C, troponin I, and alpha-cardiac Myosin heavy chain caused elderly-onset hypertrophic cardiomyopathy.