Published Online
on April 1, 2002

A more recent version of this article appeared on April 16, 2002

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Submitted on January 9, 2002
Revised on February 4, 2002
Accepted on February 5, 2002

Myocardial Fibrosis in Chronic Aortic Regurgitation. Molecular and Cellular Responses to Volume Overload

Jeffrey S. Borer MD^*, Sharada Truter PhD, Edmund M. Herrold MD, PhD, Domenick J. Falcone PhD, Magda Pena BS, John N. Carter PhD, Themy F. Dumlao BA, Jennifer A. Lee BS, and Phyllis G. Supino EdD

From the Division of Cardiovascular Pathophysiology, the Howard Gilman Institute for Valvular Heart Diseases, Department of Anatomy and Cell Biology, Department of Pathology, and Vascular Biology Center, Weill Medical College of Cornell University, New York, NY.

^* To whom correspondence should be addressed. E-mail: memontal{at}med.cornell.edu.

Background—Myocardial fibrosis is common in patients with chronic aortic regurgitation (AR). Experimentally, fibrosis with disproportionate noncollagen extracellular matrix (ECM) elements precedes and contributes to heart failure in AR.

Method and Results—We assessed [³H]-glucosamine and [³H]-proline incorporation in ECM, variations in cardiac fibroblast (CF) gene expression, and synthesis of specific ECM proteins in CF cultured from rabbits with surgically induced chronic AR versus controls. To determine whether these variations are primary responses to AR, normal CF were exposed to mechanical strain that mimicked that of AR. Compared with normal CF, AR CF incorporated more glucosamine (1.8:1, P=0.001) into ECM, showed fibronectin gene upregulation (2.0:1, P=0.02), and synthesized more fibronectin (2:1 by Western blot, P<0.06; 1.5:1 by affinity chromatography, P=0.02). Proline incorporation was unchanged by AR (1.1:1, NS); collagen synthesis was unaffected (type I, 0.9:1; type III, 1.0:1, NS). Normal CF exposed to cyclical mechanical strain during culture showed parallel results: glucosamine incorporation increased with strain (2.1:1, P<0.001), proline incorporation was unaffected (1.1:1, NS), fibronectin gene expression (1.6:1, P=0.07) and fibronectin synthesis (Western analysis, 1.3:1, P<0.01; chromatography, 1.9:1, NS) were upregulated.

Conclusions—In AR, CF produce abnormal proportions of noncollagen ECM, specifically fibronectin, with relatively little change in collagen synthesis. At least in part, this is a primary response to strain imposed on CF by AR. Further study must relate these findings to the pathogenesis of heart failure in AR.

Key words: valves • heart failure • regurgitation • molecular biology • myocardium

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