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From the Departments of Molecular Genetics and Cell Biology* and Human Genetics, and the Department of Medicine, Section of Cardiology, University of Chicago, Chicago Illinois
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 
-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 -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 -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, -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.
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