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

• Published in: American journal of physiology. Heart and circulatory physiology 2001-01, Vol.280 (1), p.H151-H159
• Main Authors: Freeman, Kalev, Colon-Rivera, Cynthia, Olsson, M. Charlotte, Moore, Russell L, Weinberger, Howard D, Grupp, Ingrid L, Vikstrom, Karen L, Iaccarino, Guido, Koch, Walter J, Leinwand, Leslie A
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Agonists - pharmacology; Animals; beta-Adrenergic Receptor Kinases; Cardiomegaly - diagnostic imaging; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomyopathy, Dilated - diagnostic imaging; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - metabolism; Cardiomyopathy, Dilated - pathology; Cyclic AMP-Dependent Protein Kinases - metabolism; Disease Progression; Genetic Markers; Hemodynamics; In Vitro Techniques; Isoproterenol - pharmacology; Male; Mice; Mice, Inbred C57BL; Mutation; Myosins - genetics; Myosins - metabolism; Physical Conditioning, Animal; Transgenes; Ultrasonography
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.2001.280.1.H151

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 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 -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