Comparison of Two Murine Models of Familial Hypertrophic Cardiomyopathy

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.

Hypertrophic cardiomyopathy: from gene defect to clinical disease

“…This mimics the human disease very closely. Further studies in a second mouse model of HCM in which the myosin-binding protein C gene is truncated using a targeted construct with a Neo cassette, confirms the human finding that disease occurs much later in life, with the myosin-binding protein C mice showing hypertrophy in only 30% of mice at age 30 weeks (versus 100% with hypertrophy in Arg403Gln myosin mice at the same age) but all mice developing disease by age 2 years [60]. Such comparison between models will be invaluable in addressing the issues of disease heterogeneity and penetrance, as well as the effects of aging in the progression of cardiomyopathy.…”

“…Analysis of the phenotype in these heterozygous Arg403Gln mice has revealed features which parallel the human disease (summarised in Tab 2). In brief, Arg403Gln mice develop classical histopathological changes of HCM (myocyte hypertrophy, disarray and fibrosis) by age 15 weeks, and echocardiographically detectable left ventricular hypertrophy by 30 weeks [60]. This mimics the human disease very closely.…”

“…Longitudinal studies of murine models have also demonstrated that haemodynamic dysfunction precedes histopathology, suggesting that the hypertrophic phenotype occurs as a compensatory response to sarcomere mutation [60]. Elucidation of intracellular signals that trigger myocyte growth and death are therefore likely to provide novel avenues for intervention and prevention.…”

Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats

“…The increase in HW/ BW ratio in post-MI rats was consistent with the presence of enlarged cardiomyocytes (cross-sectional width 32.1±0.8µm to compare with sham: 23.5 ± 0.6 µm; P<0.05, Fig.3b), next to interstitial collagen deposits in the noninfarcted LV. Fibrosis (Fig.3c) and re-expression of fetal atrial natriuretic peptide (ANP) and myosin heavy chain (MHC)-ß isoform genes (Fig.3d) attested to pathological hypertrophy [36][37][38][39]. One-month NAC treatment did not lessen hypertrophy (Fig.3a).…”

Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia

“…Initial studies of genetically outbred MHC 403/ϩ mice demonstrated variable degrees of hypertrophy and histopathology (19)(20)(21)(22). To control for the influence of background genotype on disease expression, we bred the MHC 403/ϩ allele into the inbred 129SvEv genetic background and investigated the relationship between histopathology and arrhythmia vulnerability in hypertrophic mice using in vivo and ex vivo electrophysiological studies (23,24).…”