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Effect of Losartan on Mitral Valve Changes After Myocardial Infarction.

ABSTRACT: 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)-? overexpression. In vitro, losartan-mediated TGF-? 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-? 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-?, and downstream phosphorylated extracellular-signal-regulated kinase and EMT (27.2 ± 12.0% vs. 51.6 ± 11.7% ?-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.

SUBMITTER: Bartko PE

PROVIDER: S-EPMC5679094 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Effect of Losartan on Mitral Valve Changes After Myocardial Infarction.

Bartko Philipp E PE Dal-Bianco Jacob P JP Guerrero J Luis JL Beaudoin Jonathan J Szymanski Catherine C Kim Dae-Hee DH Seybolt Margo M MM Handschumacher Mark D MD Sullivan Suzanne S Garcia Michael L ML Titus James S JS Wylie-Sears Jill J Irvin Whitney S WS Messas Emmanuel E Hagège Albert A AA Carpentier Alain A Aikawa Elena E Bischoff Joyce J Levine Robert A RA

Journal of the American College of Cardiology 20170901 10

<h4>Background</h4>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)-β overexpression. In vitro, losartan-mediated TGF-β inhibition reduces EMT of MV endothelial cells.<h4>Objectives</h4>T ...[more]

PMID: 28859786

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Project description:In patients with myocardial infarction (MI), leaflet tethering by displaced papillary muscles induces mitral regurgitation (MR), which doubles mortality. Mitral valves (MVs) are larger in such patients but fibrosis sets in counterproductively. The investigators previously reported that experimental tethering alone increases mitral valve area in association with endothelial-to-mesenchymal transition.The aim of this study was to explore the clinically relevant situation of tethering and MI, testing the hypothesis that ischemic milieu modifies mitral valve adaptation.Twenty-three adult sheep were examined. Under cardiopulmonary bypass, the papillary muscle tips in 6 sheep were retracted apically to replicate tethering, short of producing MR (tethered alone). Papillary muscle retraction was combined with apical MI created by coronary ligation in another 6 sheep (tethered plus MI), and left ventricular remodeling was limited by external constraint in 5 additional sheep (left ventricular constraint). Six sham-operated sheep were control subjects. Diastolic mitral valve surface area was quantified by 3-dimensional echocardiography at baseline and after 58 ± 5 days, followed by histopathology and flow cytometry of excised leaflets.Tethered plus MI leaflets were markedly thicker than tethered-alone valves and sham control subjects. Leaflet area also increased significantly. Endothelial-to-mesenchymal transition, detected as ?-smooth muscle actin-positive endothelial cells, significantly exceeded that in tethered-alone and control valves. Transforming growth factor-?, matrix metalloproteinase expression, and cellular proliferation were markedly increased. Uniquely, tethering plus MI showed endothelial activation with vascular adhesion molecule expression, neovascularization, and cells positive for CD45, considered a hematopoietic cell marker. Tethered plus MI findings were comparable with external ventricular constraint.MI altered leaflet adaptation, including a profibrotic increase in valvular cell activation, CD45-positive cells, and matrix turnover. Understanding cellular and molecular mechanisms underlying leaflet adaptation and fibrosis could yield new therapeutic opportunities for reducing ischemic MR.

Dataset Information

Effect of Losartan on Mitral Valve Changes After Myocardial Infarction.

Publications

Effect of Losartan on Mitral Valve Changes After Myocardial Infarction.

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