Author + information
- Received March 31, 2017
- Revision received May 26, 2017
- Accepted July 4, 2017
- Published online August 28, 2017.
- Philipp E. Bartko, MD, PhDa,
- Jacob P. Dal-Bianco, MDa,
- J. Luis Guerrero, BSb,
- Jonathan Beaudoin, MDa,c,
- Catherine Szymanski, MDa,d,
- Dae-Hee Kim, MD, PhDa,e,
- Margo M. Seybolt, BSb,
- Mark D. Handschumacher, BSa,
- Suzanne Sullivan, BSb,
- Michael L. Garcia, MAb,
- James S. Titus, BSb,
- Jill Wylie-Sears, MSf,
- Whitney S. Irvin, MSg,
- Emmanuel Messas, MD, PhDd,
- Albert A. Hagège, MD, PhDd,
- Alain Carpentier, MD, PhDd,
- Elena Aikawa, MD, PhDg,
- Joyce Bischoff, PhDf,
- Robert A. Levine, MDa,d,∗ (, )
- Leducq Transatlantic Mitral Network
- aCardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- bSurgical Cardiovascular Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- cDepartment of Medicine, Université Laval, Quebec City, Quebec, Canada
- dDepartments of Cardiology and Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, University Paris Descartes, INSERM Unit 633, Paris, France
- eDivision of Cardiology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
- fVascular Biology Program and Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
- gCenter for Excellence in Vascular Biology, Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Robert A. Levine, Massachusetts General Hospital, Cardiac Ultrasound Laboratory, 55 Fruit Street, Yawkey 5068, Boston, Massachusetts 02114.
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.
This work was supported in part by grant 07CVD04 from the Fondation Leducq for the Transatlantic MITRAL Network of Excellence. Research reported in this paper was also supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number R01HL109506 to Drs. Levine, Aikawa, and Bischoff. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support was from the Ellison Foundation, Boston, MA, from D. Reid Weedon, Jr. and his family, from grants R01 HL128099 and K24 HL67434 from the National Institutes of Health, an American Society of Echocardiography Career Development Award, and an Erwin-Schrödinger Stipend (FWF Austrian Science Fund). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Bartko and Dal-Bianco contributed equally to this work and are joint first authors. Drs. Aikawa, Bischoff, and Levine contributed equally to this work and are joint last authors.
- Received March 31, 2017.
- Revision received May 26, 2017.
- Accepted July 4, 2017.
- 2017 American College of Cardiology Foundation