Effect of Losartan on Mitral Valve Changes After Myocardial Infarction.

Autor:	Bartko PE; Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Dal-Bianco JP; Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Guerrero JL; Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Beaudoin J; Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medicine, Université Laval, Quebec City, Quebec, Canada., Szymanski C; Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Departments of Cardiology and Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, University Paris Descartes, INSERM Unit 633, Paris, France., Kim DH; Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Division of Cardiology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea., Seybolt MM; Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Handschumacher MD; Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Sullivan S; Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Garcia ML; Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Titus JS; Surgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Wylie-Sears J; Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts., Irvin WS; Center for Excellence in Vascular Biology, Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts., Messas E; Departments of Cardiology and Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, University Paris Descartes, INSERM Unit 633, Paris, France., Hagège AA; Departments of Cardiology and Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, University Paris Descartes, INSERM Unit 633, Paris, France., Carpentier A; Departments of Cardiology and Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, University Paris Descartes, INSERM Unit 633, Paris, France., Aikawa E; Center for Excellence in Vascular Biology, Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts., Bischoff J; Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts., Levine RA; Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Departments of Cardiology and Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, University Paris Descartes, INSERM Unit 633, Paris, France. Electronic address: Levine.Robert@mgh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Journal of the American College of Cardiology [J Am Coll Cardiol] 2017 Sep 05; Vol. 70 (10), pp. 1232-1244.
DOI:	10.1016/j.jacc.2017.07.734
Abstrakt:	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. (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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