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. 1997 Feb 15;99(4):570–576. doi: 10.1172/JCI119197

Electrophysiological abnormalities and arrhythmias in alpha MHC mutant familial hypertrophic cardiomyopathy mice.

C I Berul 1, M E Christe 1, M J Aronovitz 1, C E Seidman 1, J G Seidman 1, M E Mendelsohn 1
PMCID: PMC507836  PMID: 9045856

Abstract

A new mouse cardiac electrophysiology method was used to study mice harboring an alpha-myosin heavy chain Arg403Gln missense mutation (alpha-MHC403/+), which results in histological and hemodynamic abnormalities characteristic of familial hypertrophic cardiomyopathy (FHC) and sudden death of uncertain etiology during exercise. Wild-type animals had completely normal cardiac electrophysiology. In contrast, FHC mice demonstrated (a) electrocardiographic abnormalities including prolonged repolarization intervals and rightward axis; (b) electrophysiological abnormalities including heterogeneous ventricular conduction properties and prolonged sinus node recovery time; and (c) inducible ventricular ectopy. These data identify distinct electrophysiologic abnormalities in FHC mice with a specific alpha-myosin mutation, and also validate a novel method to explore in vivo the relationship between specific genotypes and their electrophysiologic phenotypes.

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Selected References

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  1. Berul C. I., Aronovitz M. J., Wang P. J., Mendelsohn M. E. In vivo cardiac electrophysiology studies in the mouse. Circulation. 1996 Nov 15;94(10):2641–2648. doi: 10.1161/01.cir.94.10.2641. [DOI] [PubMed] [Google Scholar]
  2. Berul C. I., Sweeten T. L., Dubin A. M., Shah M. J., Vetter V. L. Use of the rate-corrected JT interval for prediction of repolarization abnormalities in children. Am J Cardiol. 1994 Dec 15;74(12):1254–1257. doi: 10.1016/0002-9149(94)90558-4. [DOI] [PubMed] [Google Scholar]
  3. Buja G., Miorelli M., Turrini P., Melacini P., Nava A. Comparison of QT dispersion in hypertrophic cardiomyopathy between patients with and without ventricular arrhythmias and sudden death. Am J Cardiol. 1993 Oct 15;72(12):973–976. doi: 10.1016/0002-9149(93)91118-2. [DOI] [PubMed] [Google Scholar]
  4. Cannan C. R., Reeder G. S., Bailey K. R., Melton L. J., 3rd, Gersh B. J. Natural history of hypertrophic cardiomyopathy. A population-based study, 1976 through 1990. Circulation. 1995 Nov 1;92(9):2488–2495. doi: 10.1161/01.cir.92.9.2488. [DOI] [PubMed] [Google Scholar]
  5. Epstein N. D., Cohn G. M., Cyran F., Fananapazir L. Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the beta-myosin heavy chain gene. A 908Leu----Val mutation and a 403Arg----Gln mutation. Circulation. 1992 Aug;86(2):345–352. doi: 10.1161/01.cir.86.2.345. [DOI] [PubMed] [Google Scholar]
  6. Fananapazir L., Chang A. C., Epstein S. E., McAreavey D. Prognostic determinants in hypertrophic cardiomyopathy. Prospective evaluation of a therapeutic strategy based on clinical, Holter, hemodynamic, and electrophysiological findings. Circulation. 1992 Sep;86(3):730–740. doi: 10.1161/01.cir.86.3.730. [DOI] [PubMed] [Google Scholar]
  7. Fananapazir L., Epstein S. E. Hemodynamic and electrophysiologic evaluation of patients with hypertrophic cardiomyopathy surviving cardiac arrest. Am J Cardiol. 1991 Feb 1;67(4):280–287. doi: 10.1016/0002-9149(91)90560-8. [DOI] [PubMed] [Google Scholar]
  8. Geisterfer-Lowrance A. A., Christe M., Conner D. A., Ingwall J. S., Schoen F. J., Seidman C. E., Seidman J. G. A mouse model of familial hypertrophic cardiomyopathy. Science. 1996 May 3;272(5262):731–734. doi: 10.1126/science.272.5262.731. [DOI] [PubMed] [Google Scholar]
  9. Lin M. C., Rockman H. A., Chien K. R. Heart and lung disease in engineered mice. Nat Med. 1995 Aug;1(8):749–751. doi: 10.1038/nm0895-749. [DOI] [PubMed] [Google Scholar]
  10. Mandel W., Hayakawa H., Danzig R., Marcus H. S. Evaluation of sino-atrial node function in man by overdrive suppression. Circulation. 1971 Jul;44(1):59–66. doi: 10.1161/01.cir.44.1.59. [DOI] [PubMed] [Google Scholar]
  11. Maron B. J., Fananapazir L. Sudden cardiac death in hypertrophic cardiomyopathy. Circulation. 1992 Jan;85(1 Suppl):I57–I63. [PubMed] [Google Scholar]
  12. McKenna W. J., Sadoul N., Slade A. K., Saumarez R. C. The prognostic significance of nonsustained ventricular tachycardia in hypertrophic cardiomyopathy. Circulation. 1994 Dec;90(6):3115–3117. doi: 10.1161/01.cir.90.6.3115. [DOI] [PubMed] [Google Scholar]
  13. Paigen K. A miracle enough: the power of mice. Nat Med. 1995 Mar;1(3):215–220. doi: 10.1038/nm0395-215. [DOI] [PubMed] [Google Scholar]
  14. Roberts N. K., Gillette P. C. Electrophysiologic study of the condition system in normal children. Pediatrics. 1977 Dec;60(6):858–863. [PubMed] [Google Scholar]
  15. Scheidt S. Basic electrocardiography: abnormalities of electrocardiographic patterns. Clin Symp. 1984;36(6):2–32. [PubMed] [Google Scholar]
  16. Solomon S. D., Wolff S., Watkins H., Ridker P. M., Come P., McKenna W. J., Seidman C. E., Lee R. T. Left ventricular hypertrophy and morphology in familial hypertrophic cardiomyopathy associated with mutations of the beta-myosin heavy chain gene. J Am Coll Cardiol. 1993 Aug;22(2):498–505. doi: 10.1016/0735-1097(93)90055-6. [DOI] [PubMed] [Google Scholar]
  17. Spirito P., Rapezzi C., Autore C., Bruzzi P., Bellone P., Ortolani P., Fragola P. V., Chiarella F., Zoni-Berisso M., Branzi A. Prognosis of asymptomatic patients with hypertrophic cardiomyopathy and nonsustained ventricular tachycardia. Circulation. 1994 Dec;90(6):2743–2747. doi: 10.1161/01.cir.90.6.2743. [DOI] [PubMed] [Google Scholar]
  18. Thierfelder L., Watkins H., MacRae C., Lamas R., McKenna W., Vosberg H. P., Seidman J. G., Seidman C. E. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994 Jun 3;77(5):701–712. doi: 10.1016/0092-8674(94)90054-x. [DOI] [PubMed] [Google Scholar]
  19. Watkins H., Anan R., Coviello D. A., Spirito P., Seidman J. G., Seidman C. E. A de novo mutation in alpha-tropomyosin that causes hypertrophic cardiomyopathy. Circulation. 1995 May 1;91(9):2302–2305. doi: 10.1161/01.cir.91.9.2302. [DOI] [PubMed] [Google Scholar]
  20. Watkins H., McKenna W. J., Thierfelder L., Suk H. J., Anan R., O'Donoghue A., Spirito P., Matsumori A., Moravec C. S., Seidman J. G. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med. 1995 Apr 20;332(16):1058–1064. doi: 10.1056/NEJM199504203321603. [DOI] [PubMed] [Google Scholar]
  21. Watkins H., Rosenzweig A., Hwang D. S., Levi T., McKenna W., Seidman C. E., Seidman J. G. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med. 1992 Apr 23;326(17):1108–1114. doi: 10.1056/NEJM199204233261703. [DOI] [PubMed] [Google Scholar]
  22. Watson R. M., Schwartz J. L., Maron B. J., Tucker E., Rosing D. R., Josephson M. E. Inducible polymorphic ventricular tachycardia and ventricular fibrillation in a subgroup of patients with hypertrophic cardiomyopathy at high risk for sudden death. J Am Coll Cardiol. 1987 Oct;10(4):761–774. doi: 10.1016/s0735-1097(87)80268-1. [DOI] [PubMed] [Google Scholar]
  23. Wigle E. D., Rakowski H., Kimball B. P., Williams W. G. Hypertrophic cardiomyopathy. Clinical spectrum and treatment. Circulation. 1995 Oct 1;92(7):1680–1692. doi: 10.1161/01.cir.92.7.1680. [DOI] [PubMed] [Google Scholar]
  24. Wit A. L., Weiss M. B., Berkowitz W. D., Rosen K. M., Steiner C., Damato A. N. Patterns of atrioventricular conduction in the human heart. Circ Res. 1970 Sep;27(3):345–359. doi: 10.1161/01.res.27.3.345. [DOI] [PubMed] [Google Scholar]

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