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(Circulation. 2002;105:1837.)
© 2002 American Heart Association, Inc.

Basic Science Reports

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; 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.

Correspondence to Jeffrey S. Borer, MD, New York Presbyterian Hospital–Weill Cornell Center, 525 East 68th Street, New York, NY 10021. 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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