Cardiac Dysfunction in Hypertrophic Cardiomyopathy Mutant Tropomyosin Mice Is Transgene-Dependent, Hypertrophy-Independent, and Improved by β-Blockade

Abstract

Abstract-Familial hypertrophic cardiomyopathy (FHC) has been linked to mutations in proteins of the cardiac contractile apparatus, including ␣-tropomyosin (Tm). Mice expressing ␣Tm in the heart were developed to determine the effects of FHC mutant Tm on cardiac structure and function from single cardiac myocytes to whole organ function in vivo. Expression of E180G mutant Tm did not produce cardiac hypertrophy or detectable changes in cardiac muscle morphology. However, E180G mutant Tm expression increased the Ca 2ϩ sensitivity of force production in single cardiac myocytes in a transgene expression-dependent manner. Contractile dysfunction in single myocytes manifested organ level dysfunction, as conductance-micromanometry showed E180G Tm mice had significantly slowed relaxation (diastolic dysfunction) under physiological conditions. The diastolic dysfunction in E180G Tm mice was no longer evident during ␤-blockade because propranolol eliminated the effect of E180G Tm to slow myocardial relaxation. Cellular and organ level dysfunction were evident in E180G Tm mice in the absence of significant cardiac structural abnormalities normally associated with FHC. These findings therefore suggest that diastolic dysfunction in FHC may be a direct consequence of FHC mutant protein expression. In addition, because diastolic dysfunction in E180G Tm mice is dependent on inotropic status, cardiovascular stress may play an important role in FHC pathogenesis.

Designing Heart Performance by Gene Transfer

“…Additionally, E180G Tm, when expressed on an FVB/N mouse genetic background, resulted in marked histopathology and hypertrophy closely mimicking HCM (706). In contrast, E180G Tm when expressed on C57BL/6 background did not show altered myocyte morphology or any histopathology (567). These reported compensatory adaptations in E180G transgenic mice underscore the important difference between acute and long-term genetic strategies and the contribution of background strain effects on organ-level phenotype.…”

“…8B) (565). Transgenic mouse models corroborate this model of stoichiometric myofilament replacement as transgenic animals also maintain myofilament protein stoichiometry despite an overabundance of sarcomeric transgene transcripts (151, 258,403,567,621,735,872,874,903,999).…”

“…Notably, the development of E180G and D175N rat transgenic models (955) yielded different results from those described previously in mouse (567,623) or acute gene transfer studies (564). Extremely low levels of E180G or D175N Tm replacement had no effect on myofilament Ca 2ϩ sensitivity or relaxation function in E180G rat myocytes, while D175N Tm desensitized the myofilaments to Ca 2ϩ and accelerated relaxation rates (955).…”

“…The E180G and D175N mutant Tms have been expressed in transgenic mice (567,623,706,707) and more recently in rats (955). The direct effects of the E180G Tm mutation in transgenic mice closely paralleled that of acute gene transfer, but the compensatory changes varied between E180G transgenic mouse models.…”

Influence of genetic background on ex vivo and in vivo cardiac function in several commonly used inbred mouse strains

“…Previous reports have also demonstrated the potent effects of genetic background on modifying the cardiac phenotype of genetically modified mice (20,21,50). For instance, two distinct transgenic lines expressing hypertrophic cardiomyopathy-linked mutant tropomyosin E180G showed drastically different phenotypes, one displaying relatively mild diastolic dysfunction (29) and the other developing overt hypertrophic cardiomyopathy and heart failure (36). Excluding possible differences in animal care and housing, the main difference between these transgenic mice is their genetic background; one mouse was created on the FVB/N background, the other on the C57BL/6 background.…”