Secondary coronary artery vasospasm promotes cardiomyopathy progression.
Genetic defects in the plasma membrane-associated sarcoglycan complex produce cardiomyopathy characterized by focal degeneration. The infarct-like pattern of cardiac degeneration has led to the hypothesis that coronary artery vasospasm underlies cardiomyopathy in this disorder. We evaluated the coronary vasculature of gamma-sarcoglycan mutant mice and found microvascular filling defects consistent with arterial vasospasm. However, the vascular smooth muscle sarcoglycan complex was intact in the coronary arteries of gamma-sarcoglycan hearts with perturbation of the sarcoglycan complex only within the adjacent myocytes. Thus, in this model, coronary artery vasospasm derives from a vascular smooth muscle-cell extrinsic process. To reduce this secondary vasospasm, we treated gamma-sarcoglycan-deficient mice with the calcium channel antagonist verapamil. Verapamil treatment eliminated evidence of vasospasm and ameliorated histological and functional evidence of cardiomyopathic progression. Echocardiography of verapamil-treated, gamma-sarcoglycan-null mice showed an improvement in left ventricular fractional shortening (44.3 +/- 13.3% treated versus 37.4 +/- 15.3% untreated), maximal velocity at the aortic outflow tract (114.9 +/- 27.9 cm/second versus 92.8 +/- 22.7 cm/second), and cardiac index (1.06 +/- 0.30 ml/minute/g versus 0.67 +/- 0.16 ml/minute/g, P < 0.05). These data indicate that secondary vasospasm contributes to the development of cardiomyopathy and is an important therapeutic target to limit cardiomyopathy progression.
Wheeler
Matthew T
MT
Department of Molecular Genetics and Cell Biology, Section of Cardiology, University of Chicago, Chicago, Illinois, USA.
Korcarz
Claudia E
CE
Collins
Keith A
KA
Lapidos
Karen A
KA
Hack
Andrew A
AA
Lyons
Matthew R
MR
Zarnegar
Sara
S
Earley
Judy U
JU
Lang
Roberto M
RM
McNally
Elizabeth M
EM
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D009202:Cardiomyopathies / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D003329:Coronary Vasospasm / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology*; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004452:Echocardiography; D005455:Fluorescent Antibody Technique; D006321:Heart / Q000187:drug effects; D006334:Heart Function Tests / Q000187:drug effects; D015151:Immunoblotting; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D049031:Sarcoglycans; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D003598:Cytoskeletal Proteins; D008562:Membrane Glycoproteins; D049031:Sarcoglycans; D014700:Verapamil