Improving Mitral Compensation In Ischemic Regurgitation

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Ischemic mitral regurgitation (IMR) is a common condition that increases heart failure and doubles mortality after myocardial infarction (MI). It is caused by left ventricular (LV) remodeling that tethers the mitral valve (MV) leaflets and restricts their closure. Effective repair has been elusive with standard therapies that do not address intrinsic valve changes; we aim to reduce this substantial therapeutic gap. We showed that tethering without MI adaptively increases leaflet area with associated endothelial-to-mesenchymal transition (EMT). However, in our model of inferior MI (IMI), the most common cause of IMR, as the LV progressively dilates over six months, MV surface area increases but then plateaus and becomes deficient relative to the LV, so MR increases. Adaptive leaflet growth is opposed by progressive fibrotic changes: MV thickness and collagen increase along with transforming growth factor (TGF)-β, a pro-fibrotic EMT activator. Vascular cell adhesion molecule-1 suggests the influence of post-MI inflammatory cytokines. Endothelial cells undergoing EMT unexpectedly express the protein tyrosine phosphatase CD45, which modulates cell migration. Both CD45 activation and TGF-β turn on pro-fibrotic endothelial cell gene expression. Losartan, an indirect TGF-β inhibitor, reduces CD45+ EMT and fibrotic leaflet thickening in our MI models; it inhibits EMT in vitro by blocking TGF-β-mediated pERK activation. Blocking phosphodiesterase 5 (PDE5) with Tadalafil also reduces CD45+ EMT, fibrotic cells and MR post-MI. Our central hypothesis is that MV changes post-MI can be improved by preventing or later interrupting the progressive cycle of cellular changes, leaflet fibrosis and MR. Aim 1 will test the hypothesis that mechanistically different early and late therapeutic windows exist for improving leaflet adaptation to decrease IMR. We will compare 3 clinically relevant agents: Losartan and Enalapril, based on their differential reduction of TGF-β signaling; and PDE5 inhibition, a new pathway in this context for which our preliminary studies also show adaptive leaflet growth potential. At 6 months post-MI, we will compare sheep treated for all 6 months, only the first 2 months, or only from 2 to 6 months. Aim 2 will explore early inciting events to test the hypothesis that circulating substances released from infarcted myocardium stimulate MV fibrotic processes within days of MI. In addition to histology, whole blood and coronary sinus plasma and conditioned medium from infarcted myocardium will be tested for induction of MV endothelial transformation to CD45+ fibrocytes producing intrinsic TGF-β, cytokines and collagen in a self-reinforcing cycle of progressive fibrosis. Aim 3 will identify downstream targets of CD45 protein tyrosine phosphatase, potentially Src kinases (HCK) and their substrates, aiming to find valve-specific targets to prevent MV endothelial transition to collagen-producing contractile cells that likely stiffen the MV and cause the leaflet area plateau. Ancillary biorepository studies include histology and pro-fibrotic plasma effects in CTSN IMR patients. The aims have the potential to expand therapeutic opportunities and promote translation to address unmet clinical needs for this common heart failure driving factor.