Improving Mitral Compensation In Ischemic Regurgitation

缺血性二尖瓣反流（IMR）是一种常见的疾病，可增加心力衰竭和死亡率 心肌梗死（MI）后。它是由左心室（LV）重塑，束缚二尖瓣（MV） 并限制其关闭。有效的修复一直是难以捉摸的标准疗法，不解决 内在的瓣膜变化;我们的目标是减少这种实质性的治疗差距。我们证明了没有MI的Tethering 适应性地增加小叶面积，伴随相关的内皮-间充质转化（EMT）。但在 我们的下壁心肌梗死（IMI）模型是IMR的最常见原因，因为LV在6个月内进行性扩张， MV表面积增加，但随后趋于稳定，相对于LV变得不足，因此MR增加。 适应性瓣叶生长与进行性纤维化变化相反：MV厚度和胶原沿着增加 转化生长因子（TGF）-β，一种促纤维化EMT激活剂。血管细胞黏附分子-1 提示心肌梗死后炎性细胞因子的影响。内皮细胞意外发生EMT 表达调节细胞迁移的蛋白酪氨酸磷酸酶CD 45。CD 45活化和 TGF-β调节促纤维化内皮细胞基因表达。Losartan是一种间接TGF-β抑制剂， 在我们的MI模型中，CD 45 + EMT和纤维化小叶增厚;它通过阻断TGF-β介导的 pERK激活。用他达拉非阻断磷酸二酯酶5（PDE 5）也可减少CD 45 + EMT、纤维化细胞 和心肌梗死后二尖瓣返流我们的中心假设是，心肌梗死后的MV变化可以通过预防或延迟治疗来改善。 中断细胞变化、瓣叶纤维化和MR的进行性周期，目的1将检验以下假设： 存在机制上不同的早期和晚期治疗窗口，以改善瓣叶适应性， IMR。我们将比较3种临床相关药物：氯沙坦和依那普利，基于它们的差异减少 TGF-β信号传导;和PDE 5抑制，在这种情况下，我们的初步研究也 显示适应性小叶生长潜力。在MI后6个月，我们将比较所有6个月治疗的绵羊， 仅前2个月，或仅2至6个月。目标2将探讨早期的刺激事件来检验假设 从梗死心肌释放的循环物质在心肌梗死后数天内刺激MV纤维化过程。 MI.除组织学检查外，还检测了梗死灶的全血、冠状窦血浆和条件培养基。 将检测心肌诱导MV内皮细胞转化为CD 45+纤维细胞， 内源性TGF-β、细胞因子和胶原在进行性纤维化的自我强化循环中的作用。目标3将确定 CD 45蛋白酪氨酸磷酸酶的下游靶标，潜在的Src激酶（HCK）及其底物， 目的是寻找瓣膜特异性靶点，以防止MV内皮细胞转变为产生胶原的收缩细胞， 可能会使二尖瓣扩张并导致瓣叶面积稳定。辅助生物储存库研究包括组织学和 CTSN IMR患者中的促纤维化血浆效应。这些目标有可能扩大治疗 机会和促进翻译，以解决这一常见心力衰竭驱动因素未满足的临床需求。

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.