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

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 C...