doi: 10.1161/hc0402.102990
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(Circulation. 2002;105:446.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Sarcomere Protein Gene Mutations in Hypertrophic Cardiomyopathy of the Elderly
From the Howard Hughes Medical Institute and Department of Genetics (H.N., K.K.P., J.S., J.G.S., C.E.S.) and Cardiac Unit, Massachusetts General Hospital and Department of Medicine (K.K.P.), Harvard Medical School, Boston, Mass; First Department of Internal Medicine (H.N.), Kagoshima University, Kagoshima, Japan; Cardiological Sciences (W.J.M.), St George’s Hospital Medical School, London, UK; Minneapolis Heart Institute Foundation (B.J.M.), Minneapolis, Minn; and Howard Hughes Medical Institute and Cardiovascular Division (C.E.S.), Brigham and Women’s Hospital, Boston, Mass. J. Soults currently is at Millennium Pharmaceuticals, Inc, Cambridge, Mass.
Correspondence to Christine Seidman, MD, Department of Genetics, Harvard Medical School, 200 Longwood Ave, Boston, MA 02115. E-mail cseidman{at}rascal.med.harvard.edu
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 
-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 ß-cardiac myosin heavy chain, cardiac troponin T, and -tropomyosin account for >45% of familial hypertrophic cardiomyopathy, none were found here. Rather, mutations in cardiac myosin binding protein-C, troponin I, and -cardiac myosin heavy chain caused elderly-onset hypertrophic cardiomyopathy.
Key Words: cardiomyopathy • genes • aging • hypertrophy
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