Published online before print June 27, 2002, doi: 10.1161/01.RES.0000027530.58419.82
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Cardiac Dysfunction in Hypertrophic Cardiomyopathy Mutant Tropomyosin Mice Is Transgene-Dependent, Hypertrophy-Independent, and Improved by ß-Blockade
From the Departments of Physiology (D.E.M., K.E.H., J.M.M.), Pediatric Cardiology (C.A.G.), and Surgery (M.V.W.), University of Michigan, Ann Arbor, Mich.
Correspondence to Joseph M. Metzger, PhD, 7730 Medical Science II, Dept of Physiology, University of Michigan, 1301 E. Catherine, Ann Arbor, MI 48109-0622. E-mail metzgerj{at}umich.edu
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 Ca2+ 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 ß-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.
Key Words: tropomyosin • hypertrophic cardiomyopathy • calcium • heart • mice
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