1. Effect of Losartan on Mitral Valve Changes After Myocardial Infarction.
- Author
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Bartko, Philipp E., Dal-Bianco, Jacob P., Guerrero, J. Luis, Beaudoin, Jonathan, Szymanski, Catherine, Kim, Dae-Hee, Seybolt, Margo M., Handschumacher, Mark D., Sullivan, Suzanne, Garcia, Michael L., Titus, James S., Wylie-Sears, Jill, Irvin, Whitney S., Messas, Emmanuel, Hagège, Albert A., Carpentier, Alain, Aikawa, Elena, Bischoff, Joyce, Levine, Robert A., and Leducq Transatlantic Mitral Network
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MITRAL valve insufficiency , *TRANSFORMING growth factors , *LOSARTAN , *THERAPEUTICS , *DISEASE risk factors , *MYOCARDIAL infarction complications , *ANIMAL experimentation , *ANIMALS , *BIOLOGICAL models , *ECHOCARDIOGRAPHY , *EPITHELIAL cells , *GROWTH factors , *MITRAL valve , *MYOCARDIAL infarction , *MYOCARDIUM , *RESEARCH funding , *SHEEP , *FIBROSIS , *VENTRICULAR remodeling , *ANGIOTENSIN receptors , *PHARMACODYNAMICS , *DIAGNOSIS ,MYOCARDIAL infarction diagnosis ,ANIMAL models of 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)-β overexpression. In vitro, losartan-mediated TGF-β 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-β 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-β, and downstream phosphorylated extracellular-signal-regulated kinase and EMT (27.2 ± 12.0% vs. 51.6 ± 11.7% α-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. [ABSTRACT FROM AUTHOR]- Published
- 2017
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