Temporal repolarization lability in hypertrophic cardiomyopathy caused by beta-myosin heavy-chain gene mutations.

BACKGROUND Certain genetic mutations associated with hypertrophic cardiomyopathy (HCM) carry an increased risk of sudden death. QT variability identifies patients at a high risk for sudden death from ventricular arrhythmias. We tested whether patients with HCM caused by beta-myosin heavy-chain (beta-MHC) gene mutations exhibit labile ventricular repolarization using beat-to-beat QT variability analysis. METHODS AND RESULTS We measured the QT variability index and heart rate-QT interval coherence from Holter monitor recordings in 36 patients with HCM caused by known beta-MHC gene mutations and in 26 age- and sex-matched controls. There were 7 distinct beta-MHC gene mutations in these 36 patients; 9 patients had HCM caused by the malignant Arg(403)Gln mutation and 8 patients had HCM caused by the more benign Leu(908)Val mutation. The QT variability index was higher in HCM patients than in controls (-1.24+/-0.17 versus -1. 58+/-0.38, P<0.01), and the greatest abnormality was detected in patients with the Arg(403)Gln mutation (-0.99+/-0.49 versus -1. 46+/-0.43 in controls, P<0.05). In keeping with this finding, coherence was lower for the entire HCM group than for controls (P<0. 001). Coherence was also significantly lower in patients with the Arg(403)Gln mutation compared with controls (P<0.05). CONCLUSIONS These findings suggest that (1) patients with HCM caused by beta-MHC gene mutations exhibit labile repolarization quantified by QT variability analysis and, hence, may be more at risk for sudden death from ventricular arrhythmias, and (2) indices of QT variability may be particularly abnormal in patients with beta-MHC gene mutations that are associated with a poor prognosis.

[1]  J. Seidman,et al.  Mutations in the cardiac myosin binding protein–C gene on chromosome 11 cause familial hypertrophic cardiomyopathy , 1995, Nature Genetics.

[2]  L. Fananapazir,et al.  Genetic evidence of dissociation (generational skips) of electrical from morphologic forms of hypertrophic cardiomyopathy. , 1990, The American journal of cardiology.

[3]  H. Calkins,et al.  Beat-to-beat QT interval variability: novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy. , 1997, Circulation.

[4]  J. Seidman,et al.  Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. , 1995, The New England journal of medicine.

[5]  P. Nihoyannopoulos,et al.  Autonomic function in hypertrophic cardiomyopathy. , 1993, British heart journal.

[6]  L. Fananapazir,et al.  Genotype-Phenotpe Correlations in Hypertrophic Cardiomyopathy Insights Provided by Comparisons of Kindreds With Distinct and Identical j3-Myosin Heavy Chain Gene Mutations , 2005 .

[7]  J. Saul,et al.  Transfer function analysis of autonomic regulation. I. Canine atrial rate response. , 1989, The American journal of physiology.

[8]  L. Fananapazir,et al.  Hypertrophic Cardiomyopathy: valuation and Treatment of Patients at High Risk for Sudden Death , 1997 .

[9]  M. Matsuzaki,et al.  Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy , 1997, Nature Genetics.

[10]  H Calkins,et al.  Beat‐to‐Beat Repolarization Lability Identifies Patients at Risk for Sudden Cardiac Death , 1998, Journal of cardiovascular electrophysiology.

[11]  S.M. Kay,et al.  Spectrum analysis—A modern perspective , 1981, Proceedings of the IEEE.

[12]  J. Jalife,et al.  Cardiac Electrophysiology: From Cell to Bedside , 1990 .

[13]  A. Garson,et al.  Prolonged QT interval in hypertrophic and dilated cardiomyopathy in children. , 1994, American heart journal.

[14]  W. Mckenna,et al.  Arrhythmia in hypertrophic cardiomyopathy. I: Influence on prognosis. , 1981, British heart journal.

[15]  J. Seidman,et al.  Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. , 1992, The New England journal of medicine.

[16]  L. Fananapazir,et al.  Differences in Clinical Expression of Hypertrophic Cardiomyopathy Associated With Two Distinct Mutations in the β‐Myosin Heavy Chain Gene: A 908Leu→Val Mutation and a 403Arg→gGln Mutation , 1992, Circulation.

[17]  S. Solomon,et al.  Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. , 1994, The Journal of clinical investigation.

[18]  A. Marian,et al.  Recent advances in the molecular genetics of hypertrophic cardiomyopathy. , 1995, Circulation.

[19]  A Nava,et al.  Comparison of QT dispersion in hypertrophic cardiomyopathy between patients with and without ventricular arrhythmias and sudden death. , 1993, The American journal of cardiology.

[20]  W. Mckenna,et al.  Prognosis in hypertrophic cardiomyopathy: role of age and clinical, electrocardiographic and hemodynamic features. , 1981, The American journal of cardiology.

[21]  W. Williams,et al.  Hypertrophic cardiomyopathy. Clinical spectrum and treatment. , 1995, Circulation.

[22]  S. Solomon,et al.  Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1. , 1989, The New England journal of medicine.

[23]  D. Kass,et al.  Sudden cardiac death in heart failure. The role of abnormal repolarization. , 1994, Circulation.

[24]  J Hartikainen,et al.  Exercise-induced T-wave alternans as a marker of high risk in patients with hypertrophic cardiomyopathy. , 1997, Japanese circulation journal.

[25]  S. Epstein,et al.  Prognostic Determinants in Hypertrophic Cardiomyopathy: Prospective Evaluation of a Therapeutic Strategy Based on Clinical, Holter, Hemodynamic, and Electrophysiological Findings , 1992, Circulation.

[26]  Christine E. Seidman,et al.  α-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: A disease of the sarcomere , 1994, Cell.

[27]  I. Rayment,et al.  Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle , 1996, Nature Genetics.

[28]  B. Maron,et al.  Prognostic significance of 24 hour ambulatory electrocardiographic monitoring in patients with hypertrophic cardiomyopathy: a prospective study. , 1981, The American journal of cardiology.

[29]  P. Nihoyannopoulos,et al.  QT‐interval abnormalities in hypertrophic cardiomyopathy , 1992, Clinical cardiology.

[30]  J. Rose,et al.  Large community outbreak of cryptosporidiosis due to contamination of a filtered public water supply. , 1989, The New England journal of medicine.

[31]  S. Solomon,et al.  Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease. , 1990, The Journal of clinical investigation.

[32]  A. Marian,et al.  Molecular Genetic Basis of Hypertrophic Cardiomyopathy: , 1998, Journal of cardiovascular electrophysiology.

[33]  W. Mckenna,et al.  The value of time and frequency domain, and spectral temporal mapping analysis of the signal-averaged electrocardiogram in identification of patients with hypertrophic cardiomyopathy at increased risk of sudden death. , 1993, European heart journal.

[34]  R. Cohen,et al.  An Efficient Algorithm for Spectral Analysis of Heart Rate Variability , 1986, IEEE Transactions on Biomedical Engineering.