Progression from hypertrophic to dilated cardiomyopathy in mice that express a mutant myosin transgene

A mouse model of hypertrophic cardiomyopathy (HCM) was created by expressio n of a cardiac alpha -myosin transgene including the R(403)Q mutation and a deletion of a segment of the actin-binding domain. HCM mice show early his topathology and hypertrophy, with progressive hypertrophy in females and ve ntricular dilation in older males. To test the hypothesis that dilated card iomyopathy (DCM) is part of the pathological spectrum of HCM, we studied ch amber morphology, exercise tolerance, hemodynamics, isolated heart function , adrenergic sensitivity, and embryonic gene expression in 8- to 11-mo-old male transgenic animals. Significantly impaired exercise tolerance and both systolic and diastolic dysfunction were seen in vivo. Contraction and rela xation parameters of isolated hearts were also decreased, and lusitropic re sponsiveness to the beta -adrenergic agonist isoproterenol was modestly red uced. Myocardial levels of the G protein-coupled beta -adrenergic receptor kinase 1 (beta -ARK1) were increased by more than twofold over controls, an d total beta -ARK1 activity was also significantly elevated. Induction of f etal gene expression was also observed in transgenic hearts. We conclude th at transgenic male animals have undergone cardiac decompensation resulting in a DCM phenotype. This supports the idea that HCM and DCM may be part of a pathological continuum rather than independent diseases.