Progression from hypertrophic to dilated cardiomyopathy in mice that express a mutant myosin transgene.
A mouse model of hypertrophic cardiomyopathy (HCM) was created by expression 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 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 beta-adrenergic agonist isoproterenol was modestly reduced. Myocardial levels of the G protein-coupled beta-adrenergic receptor kinase 1 (beta-ARK1) were increased by more than twofold over controls, and total beta-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.
Freeman
K
K
Department of Molecular Cellular and Developmental Biology, University of Colorado, Boulder 80309-0347, Colorado, USA.
Colon-Rivera
C
C
Olsson
M C
MC
Moore
R L
RL
Weinberger
H D
HD
Grupp
I L
IL
Vikstrom
K L
KL
Iaccarino
G
G
Koch
W J
WJ
Leinwand
L A
LA
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018450:Disease Progression; D005819:Genetic Markers; D006439:Hemodynamics; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009218:Myosins / Q000235:genetics* / Q000378:metabolism; D010805:Physical Conditioning, Animal; D019076:Transgenes; D014463:Ultrasonography; D051552:beta-Adrenergic Receptor Kinases
D000318:Adrenergic beta-Agonists; D005819:Genetic Markers; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D009218:Myosins; D007545:Isoproterenol