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1 Department of Molecular Cellular and Developmental Biology and 2 Department of Kinesiology and Applied Physiology, University of Colorado, Boulder 80309-0347; 3 Division of Cardiology, University of Colorado Health Sciences Center, Denver, Colorado 80262; 4 Department of Pharmacology, University of Cincinnati Medical Center, Cincinnati, Ohio 45267; 5 Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210; and 6 Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710
A mouse model of
hypertrophic cardiomyopathy (HCM) was created by expression of a
cardiac 
-myosin transgene including the R403Q mutation
and a deletion of a segment of the actin-binding domain. HCM mice show
early histopathology and hypertrophy, with progressive hypertrophy in
females and ventricular dilation in older males. To test the hypothesis
that dilated cardiomyopathy (DCM) is part of the pathological spectrum
of HCM, we studied chamber 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 relaxation
parameters of isolated hearts were also decreased, and lusitropic
responsiveness to the 
-adrenergic agonist isoproterenol was modestly
reduced. Myocardial levels of the G protein-coupled -adrenergic
receptor kinase 1 (-ARK1) were increased by more than twofold over
controls, and total -ARK1 activity was also significantly elevated.
Induction of fetal gene expression was also observed in transgenic
hearts. We conclude that 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.
myosin heavy chain; cardiac decompensation; exercise
intolerance; -adrenergic receptor kinase 1
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