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(Circulation Research. 2001;88:383.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Comparison of Two Murine Models of Familial Hypertrophic Cardiomyopathy

Bradley K. McConnell¹, Diane Fatkin¹, Christopher Semsarian¹, Karen A. Jones, Dimitrios Georgakopoulos, Colin T. Maguire, Michael J. Healey, James O. Mudd, Ivan P. G. Moskowitz, David A. Conner, Michael Giewat, Hiroko Wakimoto, Charles I. Berul, Frederick J. Schoen, David A. Kass, Christine E. Seidman, J. G. Seidman

From the Cardiovascular Division and Howard Hughes Medical Institute (D.F., C.E.S.), Brigham and Women’s Hospital, Boston, Mass; Department of Genetics (B.K.M., C.S., K.A.J., M.J.H., J.O.M., D.A.C., M.G., J.G.S.), Howard Hughes Medical Institute and Harvard Medical School, Boston Mass; Division of Cardiology (D.G., D.A.K.), Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Md; Department of Cardiology (C.T.M., H.W., C.I.B.), Children’s Hospital and Department of Pediatrics, Harvard Medical School Boston, Mass; Department of Pathology (I.P.G.M., F.J.S.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Jonathan Seidman, PhD, Department of Genetics, Harvard Medical School, Alpert Bldg, 200 Longwood Ave, Boston, MA 02115. E-mail seidman{at}rascal.med.harvard.edu

Abstract—Although sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), individuals bearing a mutant cardiac myosin binding protein C (MyBP-C) gene usually have a better prognosis than individuals bearing ß-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (MHC^403/+ or a cardiac MyBP-C mutation (MyBP-C^t/+) were constructed as murine FHC models using homologous recombination in embryonic stem cells. We have compared cardiac structure and function of these mouse strains by several methods to further define mechanisms that determine the severity of FHC. Both strains demonstrated progressive left ventricular (LV) hypertrophy; however, by age 30 weeks, MHC^403/+ mice demonstrated considerably more LV hypertrophy than MyBP-C^t/+ mice. In older heterozygous mice, hypertrophy continued to be more severe in the MHC^403/+ mice than in the MyBP-C^t/+ mice. Consistent with this finding, hearts from 50-week-old MHC^403/+ mice demonstrated increased expression of molecular markers of cardiac hypertrophy, but MyBP-C^t/+ hearts did not demonstrate expression of these molecular markers until the mice were >125 weeks old. Electrophysiological evaluation indicated that MyBP-C^t/+ mice are not as likely to have inducible ventricular tachycardia as MHC^403/+ mice. In addition, cardiac function of MHC^403/+ mice is significantly impaired before the development of LV hypertrophy, whereas cardiac function of MyBP-C^t/+ mice is not impaired even after the development of cardiac hypertrophy. Because these murine FHC models mimic their human counterparts, we propose that similar murine models will be useful for predicting the clinical consequences of other FHC-causing mutations. These data suggest that both electrophysiological and cardiac function studies may enable more definitive risk stratification in FHC patients.

Key Words: cardiomyopathy • hypertrophy • genetics • myosin • cardiac myosin binding protein C

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