Copyright © 1995 by the European Society of Cardiology.
© 1995 The European Society of Cardiology
Sudden cardiac death in hypertrophic cardiomyopathy
*Baylor College of Medicine Houston, Texas
Washington University St. Louis, Missouri, U.S.A
accepted 16 August 1994.
Correspondence- Robert Roberts, MD, Chief of Cardiology, Professor of Medicine and Cell Biology, Baylor College of Medicine, 6535 Fannin, MS F905, Houston. TX 77030, U.S A.
Abstract
Background: Recent identification of mutations in the ß-myosin heavy chain gene (MYH7), a major responsible gene for HCM, has provided the opportunity to characterize genotype-phenotype correlation in HCM families. In this study we analysed the phenotypic expression of two ß-myosin heavy chain (ßMHC) mutations in three unrelated HCM families.
Methods: Living individuals from three unrelated HCM families (Families 1, 2, and 3) were screened by history, physical examination, electrocardiography, and two-dimensional echocardiography. Blood was collected from all individuals for DNA extraction. Polymerase chain reaction (PCR), restriction endonuclease digestion and chemical cleavage were utilized for detection of mutations. All mutations were confirmed by sequence analysis. Results: Identification of mutations: A missense mutation in exon 13 of the ßMHC gene (Arg403Gln) was detected in HCM patients from Families 1 and 2. PCR amplification of the exon 13 DNA, followed by Ddel digestion of the PCR product and gel electrophoresis, showed two fragments of 84 and 70 bp in normal individuals and four fragments of 84, 70, 52 and 32 bp in HCM patients. Sequence analysis showed substitution of an adenine for guanine at coding position 1208. In Family 3, a missense mutation in exon 16 of the ßMHC gene (Val606Met) was detected in HCM patients. Chemical cleavage of the PCR products showed an uncleaved product of 337 bp in the normal individuals, while in the affected individuals, in addition to the uncleaved product, a 90 bp cleaved product was also detected, indicating the presence of a mismatch in one allele. Sequence analysis showed substitution of an adenine for guanine in coding position 1817.
Clinical Characteristics: Seven members of Family 1 had HCM, of whom five are alive. One patient died from sudden cardiac death (SCD) and another from recurrent cerebral embolL In Family 2, 15 individuals had HCM of whom nine have died, seven from SCD. The mean age at the time of SCD was 33 years. The third family is comprised of 11 affected individuals and one obligate carrier, of whom one patient died at age 17 from progressive heart failure. Two additional individuals in this family have also succumbed to SCD to age 60. A variety of clinical and echocardiographic manifestations of HCM were present in each family.
Logrank test of Kaplan-Meier survival curves indicates that Arg403Gln mutation was associated with a poor prognosis in HCM families as compared to Val606Met (P=0.034).
Conclusions: ßMHC mutations despite showing variable clinical and echocardiographic manifestations of HCM are predictors of survival in HCM families.
Key Words: Hypertrophic cardiomyopathy • sudden cardiac death • missense mutation • ß-myosin heavy chain
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. E. Epstein, J. P. DiMarco, K. A. Ellenbogen, N.A. M. Estes III, R. A. Freedman, L. S. Gettes, A. M. Gillinov, G. Gregoratos, S. C. Hammill, D. L. Hayes, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic Surgeons J. Am. Coll. Cardiol., May 27, 2008; 51(21): e1 - e62. [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. Epstein, J. P. DiMarco, K. A. Ellenbogen, N.A. M. Estes III, R. A. Freedman, L. S. Gettes, A. M. Gillinov, G. Gregoratos, S. C. Hammill, D. L. Hayes, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): Developed in Collaboration With the American Association for Thoracic Surgery and Society of Thoracic Surgeons Circulation, May 27, 2008; 117(21): e350 - e408. [Full Text] [PDF]
|
|
|
|
|
|
Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]
|
|
|
|
 |
|
 Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Perkins, S. L. Van Driest, E. G. Ellsworth, M. L. Will, B. J. Gersh, S. R. Ommen, and M. J. Ackerman Gene-specific modifying effects of pro-LVH polymorphisms involving the renin-angiotensin-aldosterone system among 389 unrelated patients with hypertrophic cardiomyopathy Eur. Heart J., November 2, 2005; 26(22): 2457 - 2462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S L Van Driest, B J Maron, and M J Ackerman From malignant mutations to malignant domains: the continuing search for prognostic significance in the mutant genes causing hypertrophic cardiomyopathy Heart, January 1, 2004; 90(1): 7 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Dzau Risk assessment in cardiovascular disease: from traditional risk factors to genomics Eur. Heart J. Suppl., August 1, 2003; 5(suppl_F): F48 - F55. [Abstract] [PDF]
|
|
|
|
|
|
S. L. Van Driest, M. J. Ackerman, S. R. Ommen, R. Shakur, M. L. Will, R. A. Nishimura, A. J. Tajik, and B. J. Gersh Prevalence and Severity of "Benign" Mutations in the {beta}-Myosin Heavy Chain, Cardiac Troponin T, and {alpha}-Tropomyosin Genes in Hypertrophic Cardiomyopathy Circulation, December 10, 2002; 106(24): 3085 - 3090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Roberts Disrobing the Emperor (Heart) Without Destroying the Dignity of Super-Normality Circulation, June 25, 2002; 105(25): 2934 - 2936. [Full Text] [PDF]
|
|
|
|
|
|
R. Roberts and U. Sigwart New Concepts in Hypertrophic Cardiomyopathies, Part I Circulation, October 23, 2001; 104(17): 2113 - 2116. [Full Text] [PDF]
|
|
|
|
|
|
H. Kokado, M. Shimizu, H. Yoshio, H. Ino, K. Okeie, Y. Emoto, T. Matsuyama, M. Yamaguchi, T. Yasuda, N. Fujino, et al. Clinical Features of Hypertrophic Cardiomyopathy Caused by a Lys183 Deletion Mutation in the Cardiac Troponin I Gene Circulation, August 8, 2000; 102(6): 663 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sorajja, P.M. Elliott, and W.J. Mckenna The molecular genetics of hypertrophic cardiomyopathy: prognostic implications Europace, January 1, 2000; 2(1): 4 - 14. [PDF]
|
|
|
|
 |
|
 C. S. Redwood, J. C. Moolman-Smook, and H. Watkins Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy Cardiovasc Res, October 1, 1999; 44(1): 20 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D P Dutka, J E Donnelly, P Nihoyannopoulos, C M Oakley, and D J Nunez Marked variation in the cardiomyopathy associated with Friedreich's ataxia Heart, February 1, 1999; 81(2): 141 - 147. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. P. R. M. Osterop, M. J. M. Kofflard, L. A. Sandkuijl, F. J. t. Cate, R. Krams, M. A. D. H. Schalekamp, and A. H. J. Danser AT1 Receptor A/C1166 Polymorphism Contributes to Cardiac Hypertrophy in Subjects With Hypertrophic Cardiomyopathy Hypertension, November 1, 1998; 32(5): 825 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Maron, J. H. Moller, C. E. Seidman, G. M. Vincent, H. C. Dietz, A. J. Moss, J. A. Towbin, H. M. Sondheimer, R. E. Pyeritz, G. McGee, et al. Impact of Laboratory Molecular Diagnosis on Contemporary Diagnostic Criteria for Genetically Transmitted Cardiovascular Diseases: Hypertrophic Cardiomyopathy, Long-QT Syndrome, and Marfan Syndrome : A Statement for Healthcare Professionals From the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association Circulation, October 6, 1998; 98(14): 1460 - 1471. [Full Text] [PDF]
|
|
|
|
|
|
R. Coronel, T. Opthof, P. Taggart, J. Tytgat, and M. Veldkamp Differential electrophysiology of repolarisation from clone to clinic Cardiovasc Res, March 1, 1997; 33(3): 503 - 517. [PDF]
|
|
|
|
|
|
M. L. Schwartz, G. F. Cox, A. E. Lin, M. S. Korson, A. Perez-Atayde, R. V. Lacro, and S. E. Lipshultz Clinical Approach to Genetic Cardiomyopathy in Children Circulation, October 15, 1996; 94(8): 2021 - 2038. [Abstract] [Full Text]
|
|
|
|
|
|
M. Lechin, M. A. Quinones, A. Omran, R. Hill, Q.-T. Yu, H. Rakowski, D. Wigle, C.C. Liew, M. Sole, R. Roberts, et al. Angiotensin-I Converting Enzyme Genotypes and Left Ventricular Hypertrophy in Patients With Hypertrophic Cardiomyopathy Circulation, October 1, 1995; 92(7): 1808 - 1812. [Abstract] [Full Text]
|
|
|
|
|
|
A.J. Marian and R. Roberts Recent Advances in the Molecular Genetics of Hypertrophic Cardiomyopathy Circulation, September 1, 1995; 92(5): 1336 - 1347. [Full Text]
|
|