Improving Mitral Compensation In Ischemic Regurgitation

改善缺血性反流的二尖瓣代偿

• 批准号: 9898446
• 负责人: Elena Aikawa
• 金额: $ 138.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898446
• 关键词: Address; Aldosterone Antagonists; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Animals; Area; Automobile Driving; Biological; Blood; CRISPR/Cas technology; Cardiac Surgery procedures; Cell Adhesion; Cells; Clinical; Collagen; Complication; Conditioned Culture Media; Coronary sinus structure; Data; Enalapril; Endothelial Cells; Endothelium; Event; Extracellular Fluid; Fibrosis; Financial compensation; Gene Expression; Growth; Heart; Heart Valves; Heart failure; Histology; Human; In Vitro; Inferior; Inflammatory; Interruption; Left; Left Ventricular Remodeling; Leukocytes; Losartan; Mechanics; Mediating; Mesenchymal; Mitral Valve; Mitral Valve Insufficiency; Modeling; Myocardial Infarction; Myocardium; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Organ; PTPRC gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphoric Monoester Hydrolases; Plasma; Preventive therapy; Process; Protein Tyrosine Phosphatase; Proteins; Recurrence; Rest; Role; Sheep; Signal Transduction; Smooth Muscle Actin Staining Method; Stretching; Surface; Testing; Therapeutic; Thick; Tissues; Transforming Growth Factors; Translations; Vascular Cell Adhesion Molecule-1; Ventricular; Whole Blood; base; biobank; cell motility; clinically relevant; cytokine; early onset; flexibility; healing; heart damage; improved; inhibitor/antagonist; interstitial cell; mortality; myocardial infarct sizing; novel; overexpression; papillary muscle; phosphodiesterase V; phosphoric diester hydrolase; prevent; promoter; receptor; repaired; seal; src-Family Kinases; tadalafil; therapeutic candidate; therapeutic evaluation; therapeutic target; translational study; treatment optimization; trend; wound healing

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.

缺血性二尖瓣返流(IMR)是一种常见的疾病，它会增加心力衰竭并使死亡率加倍。 心肌梗死(MI)后。这是由于二尖瓣(MV)受左室(LV)重塑所致。 传单，并限制其关闭。有效的修复一直难以用标准的治疗方法来解决 固有的瓣膜变化；我们的目标是缩小这一实质性的治疗差距。我们展示了在没有MI的情况下进行系留 自适应地增加小叶面积，伴随着内皮到间质的转变(EMT)。但是，在 我们的下壁心肌梗死(IMI)模型，是IMR最常见的原因，随着左室在六个月内逐渐扩张， MV表面积增加，但随后停滞，相对于LV变得不足，因此MR增加。 进行性纤维化改变与适应性叶的生长相反：膜厚度和胶原增加 使用转化生长因子-β，一种促纤维化的子宫内膜间质转化激活剂。血管细胞黏附分子-1 提示心肌梗塞后炎性细胞因子的影响。内皮细胞意外接受内皮细胞移植 表达调节细胞迁移的蛋白酪氨酸磷酸酶CD45。CD45激活和 转化生长因子-β启动促纤维化内皮细胞基因表达。间接转化生长因子-β抑制剂氯沙坦降低 心肌梗死模型中CD45+上皮细胞转化和纤维化小叶的增厚；它通过阻断转化生长因子-β介导的转化生长因子抑制体外转化 福利激活。用他达拉非阻断磷酸二酯酶5(PDE5)也可减少CD45+EMT，纤维化细胞 和MI后的先生。我们的中心假设是，心肌梗死后MV的变化可以通过预防或晚些时候来改善 中断细胞变化的渐进周期，小叶纤维化和Aim先生1将检验这一假说 存在机械上不同的早期和晚期治疗窗口，以改善叶适应以减少 IMR.我们将比较3种临床相关的药物：氯沙坦和依那普利，根据它们的不同减少量。 和PDE5抑制，这是一种新的途径，我们的初步研究也是在这一背景下进行的 显示出适应小叶生长的潜力。在心肌梗死后6个月，我们将比较所有6个月治疗的绵羊， 仅限前2个月，或仅限2至6个月。目标2将探索早期激发事件来检验该假说 从梗死心肌释放的循环物质在数天内刺激MV纤维化过程 密西西比。除组织学外，全血、冠状静脉窦血浆和条件培养液均来自于脑梗塞 将测试心肌是否诱导MV内皮细胞转化为CD45+纤维细胞 内源性转化生长因子-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 CD45蛋白酪氨酸磷酸酶的下游靶点，潜在的Src激酶(HCK)及其底物， 旨在寻找瓣膜特异性靶点，以防止MV内皮向产生胶原的收缩细胞转化 可能会使MV僵硬，并导致小叶区域平坦。辅助生物信息库研究包括组织学和 CTSN IMR患者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的未得到满足的临床需求。