BACKGROUND In patients with myocardial infarction (MI), leaflet tethering by displaced papillary muscles induces mitral regurgitation (MR), which doubles mortality. Mitral valves (MVs) are larger in such patients but fibrosis sets in counterproductively. The investigators previously reported that experimental tethering alone increases mitral valve area in association with endothelial-to-mesenchymal transition. OBJECTIVES This study explored the clinically relevant situation of tethering and MI, testing the hypothesis that ischemic milieu modifies MV adaptation. METHODS Twenty-three adult sheep were examined. Under cardiopulmonary bypass, the PM tips in 6 sheep were retracted apically to replicate tethering, short of producing MR (tethered-alone). PM retraction was combined with apical MI created by coronary ligation in another 6 sheep (tethered + MI), and left ventricular (LV) remodeling was limited by external constraint in 5 additional sheep (LV constraint). Six sham-operated sheep were controls. Diastolic MV surface area was quantified by 3-dimensional echocardiography at baseline and after 58 ± 5 days, followed by histopathology and flow cytometry of excised leaflets. RESULTS Tethered + MI leaflets were markedly thicker than tethered-alone valves and sham controls. Leaflet area also increased significantly. EMT, detected as α-smooth muscle actin-positive endothelial cells, significantly exceeded that in tethered-alone and control valves. Transforming growth factor-β, matrix metalloproteinase expression, and cellular proliferation were markedly increased. Uniquely, tethering + MI showed endothelial activation with vascular adhesion molecule expression, neovascularization, and cells positive for CD45, considered a hematopoietic cell marker. Tethered + MI findings were comparable with external ventricular constraint. CONCLUSIONS MI altered leaflet adaptation, including a profibrotic increase in valvular cell activation, CD45-positive cells, and matrix turnover. Understanding cellular and molecular mechanisms underlying leaflet adaptation and fibrosis could yield new therapeutic opportunities for reducing ischemic MR.

Heightened interest in tricuspid regurgitation (TR) stems from the consistent association of mortality with greater severity of TR, and a low use of surgical solutions in the setting of high in-hospital mortality attributed to the late presentation of the disease. The delay in intervention is likely related to a limited understanding of the valvular/ventricular anatomy and disease pathophysiology, along with an underestimation of TR severity by standard imaging modalities. With the rapid development of transcatheter solutions which have shown early safety and efficacy, there is a growing need to understand and accurately diagnose the valvular disease process in order to determine appropriate management solutions. The current review will describe both normal and pathologic tricuspid valvular anatomy, the classification of these anatomic substrates of TR, the strengths and limitations of the current guidelines-recommended multi-parametric echocardiographic approach and the role of multi-modality imaging, as well as the role of transcatheter device therapy in the management of the disease.

Rationale Ischemic mitral regurgitation (IMR), a complication after myocardial infarction (MI), induces adaptive mitral valve (MV) responses that may be initially beneficial, but eventually lead to leaflet fibrosis and MV dysfunction. We sought to examine the MV endothelial response and its potential contribution to IMR. Objective Endothelial, interstitial and hematopoietic cells in MVs from post-MI sheep were quantified. MV endothelial CD45, found post-MI, was analyzed in vitro. Methods and Results Ovine MVs, harvested 6 months after inferior MI (IMI), showed CD45, a protein tyrosine phosphatase, co-localized with von Willebrand factor, an endothelial marker. Flow cytometry of MV cells revealed significant increases in CD45-positive endothelial cells (VE-Cadherin+/CD45+/α-smooth muscle actin (SMA)+ and VE-cadherin+/CD45+/αSMA- cells) and possible fibrocytes (VE-Cadherin-/CD45+/ αSMA+) in IMI compared to sham-operated and normal sheep. CD45+ cells correlated with MV fibrosis and MR severity. VE-cadherin+/CD45+/αSMA+ cells suggested CD45 may be linked to endothelial-to-mesenchymal transition (EndMT). MV endothelial cells treated with TGFβ1 to induce EndMT expressed CD45 and fibrosis markers collagen 1 and 3 and TGFβ1–3, not observed in TGFβ1-treated arterial endothelial cells. A CD45 protein tyrosine phosphatase inhibitor blocked induction of EndMT and fibrosis markers, and inhibited EndMT-associated migration of MV endothelial cells. Conclusions MV endothelial cells express CD45, both in vivo post-MI and in vitro in response to TGFβ1. A CD45 phosphatase inhibitor blocked hallmarks of EndMT in MV endothelial cells. These results point to a novel, functional requirement for CD45 phosphatase activity in EndMT. The contribution of CD45+ endothelial cells to MV adaptation and fibrosis post-MI warrants investigation.

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 The authors tested the hypothesis that profibrotic MV changes post-MI are therapeutically accessible, specifically by losartan-mediated TGF-β inhibition. Methods We studied 17 sheep, including 6 sham-operated controls and 11 with apical MI and papillary muscle retraction short of producing MR: 6 treated with daily losartan, and 5 untreated, with flexible epicardial mesh comparably limiting left ventricular (LV) remodeling. LV volumes, tethering, and MV area were quantified by 3-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-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% 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. 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.