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Losartan and Mitral Valve Changes After MI
Study Questions:
Are pro-fibrotic mitral valve (MV) changes after myocardial infarction (MI) affected by losartan-mediated transforming growth factor (TGF)-ß inhibition?
Methods:
A group of 17 sheep was studied, including six sham-operated controls and 11 with apical MI and papillary muscle retraction short of producing mitral regurgitation (MR). Of the 11 sheep with apical MI, eight were treated with losartan 50 mg daily; and five underwent implantation of a flexible epicardial mesh-limiting left ventricular (LV) remodeling, with no losartan therapy. LV volumes, MV tethering, and MV area were quantified by 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 losartan-treated and untreated LV-constraint sheep. Telemetered sensors (n = 6) showed no significant losartan-induced arterial pressure changes. Losartan strongly reduced leaflet thickness (0.9 ± 0.2 mm vs. 1.6 ± 0.2 mm; p < 0.05; 0.4 ± 0.1 mm shams); TGF-ß; and downstream phosphorylated extracellular-signal – regulated kinase and endothelial-to-mesenchymal transition (27.2% ± 12.0% vs. 51.6% ± 11.7% α-smooth-muscle-actin-positive endothelial cells, p < 0.05; 7.2% ± 3.5% shams); 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. MV leaflet area increased comparably (17%) in constrained and losartan-treated sheep.
Conclusions:
Pro-fibrotic changes of tethered MV leaflets post-MI can be modulated by losartan without eliminating adaptive growth.
Perspective:
Following acute MI, MV leaflet tethering stimulates adaptive leaflet growth; however, leaflet thickening and fibrosis augment ischemic MR, potentially contributing to heart failure and mortality. MV fibrosis after MI is associated with excessive endothelial-to-mesenchymal transition, driven by TGF-ß overexpression. In vitro, losartan-mediated TGF-ß inhibition reduces endothelial-to-mesenchymal transition of MV endothelial cells. This study, performed in sheep, suggests that therapy with losartan can modulate pro-fibrotic changes of tethered MV leaflets after MI without eliminating adaptive growth. Understanding the cellular and molecular mechanisms of this effect could provide new opportunities to mitigate the development of ischemic MR.
Keywords: Actins, Arterial Pressure, Cell Differentiation, Cell Proliferation, Dilatation, Echocardiography, Three-Dimensional, Endothelial Cells, Extracellular Signal-Regulated MAP Kinases, Flow Cytometry, Heart Failure, Heart Valve Diseases, Losartan, Mitral Valve Insufficiency, Muscle, Smooth, Myocardial Infarction, Myocardial Ischemia, Papillary Muscles, Phosphorylation, Transforming Growth Factors, Vascular Cell Adhesion Molecule-1, Ventricular Remodeling
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