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.
Department of Molecular Genetics and Cell Biology, Section of Cardiology, University of Chicago, Chicago, Illinois, USA.
Matthew T
MT
Wheeler
Claudia E
CE
Korcarz
Keith A
KA
Collins
Karen A
KA
Lapidos
Andrew A
AA
Hack
Matthew R
MR
Lyons
Sara
S
Zarnegar
Judy U
JU
Earley
Roberto M
RM
Lang
Elizabeth M
EM
McNally
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