Cardiac dysfunction in hypertrophic cardiomyopathy mutant tropomyosin mice is transgene-dependent, hypertrophy-independent, and improved by beta-blockade.
Familial hypertrophic cardiomyopathy (FHC) has been linked to mutations in proteins of the cardiac contractile apparatus, including alpha-tropomyosin (Tm). Mice expressing alphaTm 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 beta-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.
Michele
Daniel E
DE
Department of Physiology, University of Michigan, Ann Arbor, Mich 48109-0622, USA.
Gomez
Carlen A
CA
Hong
Katie E
KE
Westfall
Margaret V
MV
Metzger
Joseph M
JM
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics / Q000503:physiopathology; D002478:Cells, Cultured; D003971:Diastole; D006321:Heart / Q000187:drug effects; D006331:Heart Diseases / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D011433:Propranolol / Q000494:pharmacology*; D014335:Tropomyosin / Q000235:genetics* / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D014335:Tropomyosin; D011433:Propranolol; D002118:Calcium