Abstract 18043: Maladaptive Mitral Valve Changes After Myocardial Infarction Can Be Therapeutically Modulated
Introduction: In patients after myocardial infarction (MI), mitral valve (MV) tethering stimulates adaptive leaflet growth but also MV fibrosis that augments MV regurgitation (MR), doubling heart failure and mortality. PostMI MV fibrosis is associated with excessive endothelial to mesenchymal transition (EMT) and overexpression of TGFβ, which drives EMT and matrix turnover. In vitro, TGFβ inhibition with Losartan reduces MV endothelial cells EMT.
Hypothesis: To test whether profibrotic postMI MV changes are therapeutically accessible, and can be modulated by Losartan TGFβ inhibition.
Methods: 17 sheep were examined. Papillary muscles of 11 sheep were retracted, short of producing MR, followed by an apical MI. 6 were treated with daily Losartan (ARB), 5 with an epicardially sutured mesh to comparably limit left ventricular (LV) remodeling (LV constraint). 6 sheep were controls. LV volumes, tethering measures and MV area were quantified by 3D echo, followed by MV histopathology and flow cytometry.
Results: PostMI LV dilatation was similar in the ARB and LV constraint sheep, with similar leaflet tethering and tenting. Blood pressure (BP) monitoring to control for BP effects showed no changes with ARB in 6 normotensive sheep. Despite this, LV constraint leaflets were thicker than ARB leaflets (1.6±0.2mm vs 0.9±0.2mm, p<0.05). TGFβ and downstream ERK were significantly reduced in ARB vs LV constraint sheep, with reduced EMT and proliferation by Ki67. ARB MVs showed resolution of endothelial cell activation with vascular adhesion molecule expression seen postMI, and significantly reduced matrix metalloproteinase expression, neovascularization, and CD45-positive cells. Leaflet area increased to a comparable degree (17%) in the ARB and LV constraint sheep.
Conclusions: Profibrotic MV changes postMI, including excessive EMT, cellular hyperproliferation, endothelial cell activation, and matrix turnover, can be modulated using Losartan without eliminating the capacity for adaptive leaflet growth. Understanding cellular and molecular mechanisms could provide new opportunities to reduce ischemic MR.
Author Disclosures: P.E. Bartko: Research Grant; Modest; Erwin Schroedinger Stipend of the Austrian Ministry of Science. L. Guerrero: None. J. Hjortnaes: None. J. Beaudoin: None. C. Szymanski: None. M. Seybolt: None. M. Hanschumacher: None. S. Sullivan: None. M. Garcia: None. J. Titus: None. J. Wylie-Sears: None. W. Irvin: None. E. Messas: None. A. Hagege: None. A. Carpentier: None. J. Dal-Bianco: None. E. Aikawa: None. J. Bischoff: None. R.A. Levine: None.
- © 2016 by American Heart Association, Inc.