Effect of Losartan on Mitral Valve Changes After Myocardial Infarction

BACKGROUND After myocardial infarction (MI), mitral valve (MV) tethering stimulates adaptive leaflet growth, but counterproductive leaflet thickening and fibrosis augment mitral regurgitation (MR), doubling heart failure and mortality. MV fibrosis post-MI is associated with excessive endothelial-to-mesenchymal transition (EMT), driven by transforming growth factor (TGF)-beta overexpression. In vitro, losartan-mediated TGF-beta inhibition reduces EMT of MV endothelial cells. OBJECTIVES This study tested the hypothesis that profibrotic MV changes post-MI are therapeutically accessible, specifically by losartan-mediated TGF-beta inhibition. METHODS The study assessed 17 sheep, including 6 sham-operated control animals and 11 with apical MI and papillary muscle retraction short of producing MR; 6 of the 11 were treated with daily losartan, and 5 were untreated, with flexible epicardial mesh comparably limiting left ventricular (LV) remodeling. LV volumes, tethering, and MV area were quantified by using three-dimensional echocardiography at baseline and at 60 +/- 6 days, and excised leaflets were analyzed by histopathology and flow cytometry. RESULTS Post-MI LV dilation and tethering were comparable in the losartan-treated and untreated LV constraint sheep. Telemetered sensors (n = 6) showed no significant losartan-induced changes in arterial pressure. Losartan strongly reduced leaflet thickness (0.9 +/- 0.2 mm vs. 1.6 +/- 0.2 mm; p < 0.05; 0.4 +/- 0.1 mm sham animals), TGF-beta, and downstream phosphorylated extracellular-signal-regulated kinase and EMT (27.2 +/- 12.0% vs. 51.6 +/- 11.7% alpha-smooth muscle actin-positive endothelial cells, p < 0.05; 7.2 +/- 3.5% sham animals), cellular proliferation, collagen deposition, endothelial cell activation (vascular cell adhesion molecule-1 expression), neovascularization, and cells positive for cluster of differentiation (CD) 45, a hematopoietic marker associated with post-MI valve fibrosis. Leaflet area increased comparably (17%) in constrained and losartan-treated sheep. CONCLUSIONS Profibrotic changes of tethered MV leaflets post-MI can be modulated by losartan without eliminating adaptive growth. Understanding the cellular and molecular mechanisms could provide new opportunities to reduce ischemic MR. (C) 2017 by the American College of Cardiology Foundation.