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Comparison of two murine models of familial hypertrophic cardiomyopathy
B K McConnell1, D Fatkin, C Semsarian
1Cardiovascular Division and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Insights
Familial hypertrophic cardiomyopathy (FHC) mouse models show that beta-cardiac myosin heavy chain (MHC) mutations cause more severe disease than cardiac myosin binding protein C (MyBP-C) mutations, impacting cardiac function and hypertrophy differently.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Animal Models of Disease
Background:
- Familial hypertrophic cardiomyopathy (FHC) is caused by sarcomere protein gene mutations.
- Mutations in beta-cardiac myosin heavy chain (MHC) genes are generally associated with a worse prognosis than cardiac myosin binding protein C (MyBP-C) gene mutations.
Purpose of the Study:
- To compare the cardiac structure and function of murine models with alphaMHC(403/+) and MyBP-C(t/+) mutations.
- To define mechanisms determining FHC severity using these genetic models.
Main Methods:
- Construction of heterozygous mice with alphaMHC(403/+) or MyBP-C(t/+) mutations via homologous recombination.
- Assessment of cardiac structure and function using multiple methods, including electrophysiological evaluation and molecular marker analysis.
Main Results:
- Both mouse strains exhibited progressive left ventricular (LV) hypertrophy, but alphaMHC(403/+) mice showed significantly more LV hypertrophy and earlier onset of molecular markers of cardiac hypertrophy.
- alphaMHC(403/+) mice displayed impaired cardiac function before LV hypertrophy development and a higher incidence of inducible ventricular tachycardia compared to MyBP-C(t/+) mice.
- MyBP-C(t/+) mice showed delayed hypertrophy progression, no significant cardiac dysfunction even after hypertrophy, and lower susceptibility to ventricular tachycardia.
Conclusions:
- Murine models of FHC with alphaMHC and MyBP-C mutations accurately reflect human disease severity.
- These models can predict clinical outcomes for other FHC-causing mutations.
- Electrophysiological and cardiac function studies are crucial for risk stratification in FHC patients.
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 beta-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (alphaMHC(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, alphaMHC(403/+) mice demonstrated considerably more LV hypertrophy than MyBP-C(t/+) mice. In older heterozygous mice, hypertrophy continued to be more severe in the alphaMHC(403/+) mice than in the MyBP-C(t/+) mice. Consistent with this finding, hearts from 50-week-old alphaMHC(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 alphaMHC(403/+) mice. In addition, cardiac function of alphaMHC(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.
