Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly

Circulation. 2002 Jan 29;105(4):446-51. doi: 10.1161/hc0402.102990.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age of Onset
  • Amino Acid Sequence
  • Animals
  • Cardiomyopathy, Hypertrophic / diagnostic imaging
  • Cardiomyopathy, Hypertrophic / genetics*
  • Carrier Proteins / genetics
  • Echocardiography
  • Female
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Muscle Proteins / genetics*
  • Mutation*
  • Myosin Heavy Chains / genetics
  • Sarcomeres / genetics*
  • Sequence Alignment
  • Troponin I / genetics

Substances

  • Carrier Proteins
  • Muscle Proteins
  • Troponin I
  • myosin-binding protein C
  • Myosin Heavy Chains