Comparison of two murine models of familial hypertrophic cardiomyopathy

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

Research output: Contribution to journalArticle

80 Citations (Scopus)

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 β-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (αMHC403/+ or a cardiac MyBP-C mutation (MyBP-C1/+) 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, αMHC403/+ mice demonstrated considerably more LV hypertrophy than MyBP-C1/+ mice. In older heterozygous mice, hypertrophy continued to be more severe in the αMHC403/+ mice than in the MyBP-C1/+ mice. Consistent with this finding, hearts from 50-week-old αMHC403/+ mice demonstrated increased expression of molecular markers of cardiac hypertrophy, but MyBP-C1/+ hearts did not demonstrate expression of these molecular markers until the mice were >125 weeks old. Electrophysiological evaluation indicated that MyBP-C1/+ mice are not as likely to have inducible ventricular tachycardia as αMHC403/+ mice. In addition, cardiac function of αMHC403/+ mice is significantly impaired before the development of LV hypertrophy, whereas cardiac function of MyBP-C1/+ 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.

Original languageEnglish (US)
Pages (from-to)383-389
Number of pages7
JournalCirculation Research
Volume88
Issue number4
StatePublished - Mar 2 2001
Externally publishedYes

Fingerprint

Familial Hypertrophic Cardiomyopathy
Cardiac Myosins
Left Ventricular Hypertrophy
Mutation
Myosin Heavy Chains
Cardiomegaly
Sarcomeres
Homologous Recombination
Missense Mutation
Ventricular Tachycardia
Embryonic Stem Cells

Keywords

  • Cardiac myosin binding protein C
  • Cardiomyopathy
  • Genetics
  • Hypertrophy
  • Myosin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

McConnell, B. K., Fatkin, D., Semsarian, C., Jones, K. A., Georgakopoulos, D., Maguire, C. T., ... Seidman, J. G. (2001). Comparison of two murine models of familial hypertrophic cardiomyopathy. Circulation Research, 88(4), 383-389.

Comparison of two murine models of familial hypertrophic cardiomyopathy. / McConnell, Bradley K.; Fatkin, Diane; Semsarian, Christopher; Jones, Karen A.; Georgakopoulos, Dimitrios; Maguire, Colin T.; Healey, Michael J.; Mudd, James; Moskowitz, Ivan P G; Conner, David A.; Giewat, Michael; Wakimoto, Hiroko; Berul, Charles I.; Schoen, Frederick J.; Kass, David A.; Seidman, Christine E.; Seidman, Jonathan G.

In: Circulation Research, Vol. 88, No. 4, 02.03.2001, p. 383-389.

Research output: Contribution to journalArticle

McConnell, BK, Fatkin, D, Semsarian, C, Jones, KA, Georgakopoulos, D, Maguire, CT, Healey, MJ, Mudd, J, Moskowitz, IPG, Conner, DA, Giewat, M, Wakimoto, H, Berul, CI, Schoen, FJ, Kass, DA, Seidman, CE & Seidman, JG 2001, 'Comparison of two murine models of familial hypertrophic cardiomyopathy', Circulation Research, vol. 88, no. 4, pp. 383-389.
McConnell BK, Fatkin D, Semsarian C, Jones KA, Georgakopoulos D, Maguire CT et al. Comparison of two murine models of familial hypertrophic cardiomyopathy. Circulation Research. 2001 Mar 2;88(4):383-389.
McConnell, Bradley K. ; Fatkin, Diane ; Semsarian, Christopher ; Jones, Karen A. ; Georgakopoulos, Dimitrios ; Maguire, Colin T. ; Healey, Michael J. ; Mudd, James ; Moskowitz, Ivan P G ; Conner, David A. ; Giewat, Michael ; Wakimoto, Hiroko ; Berul, Charles I. ; Schoen, Frederick J. ; Kass, David A. ; Seidman, Christine E. ; Seidman, Jonathan G. / Comparison of two murine models of familial hypertrophic cardiomyopathy. In: Circulation Research. 2001 ; Vol. 88, No. 4. pp. 383-389.
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