Treating Ventricle and Valve: New Synergies for Ischemic LV Remodeling with MR

治疗心室和瓣膜：MR 缺血性左室重塑的新协同作用

• 批准号: 9195751
• 负责人: Roger J. Hajjar
• 金额: $ 69.13万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-15 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195751
• 关键词: Acute myocardial infarction; Address; Affect; Aftercare; Agonist; Apical; Apoptosis; Biology; Calcium; Cardiac; Cardiomegaly; Cardiovascular system; Cause of Death; Cell Proliferation; Cells; Cicatrix; Clinical; Clinical Research; Contracts; Coronary Arteriosclerosis; Dependovirus; Deterioration; Dilatation - action; Down-Regulation; Early treatment; Extracellular Matrix; Failure; Fibrosis; Financial compensation; Functional disorder; Gene Transfer Techniques; Genes; Heart; Heart failure; Homeostasis; Image; Impairment; Infarction; Inferior; Intervention; Ischemia; Left; Left Ventricular Remodeling; Matrix Metalloproteinases; Mediating; Mesenchymal; Mitral Valve; Mitral Valve Insufficiency; Modeling; Myocardial; Myocardial Infarction; Myocardial dysfunction; Myocardium; Myofibroblast; Operative Surgical Procedures; Pathology; Pathway interactions; Patients; Population; Preventive therapy; Process; Production; Public Health; Pump; Recurrence; Reperfusion Injury; Reperfusion Therapy; Research; Resources; SERCA2a; Sheep; Shunt Device; Stimulus; Stress; Testing; Time; Transgenes; Transgenic Mice; Transgenic Organisms; Up-Regulation; Ventricular; Ventricular Remodeling; Work; base; cell transformation; connective tissue growth factor; exhaust; exhaustion; gene therapy; heart cell; heart function; improved; interstitial; interstitial cell; mortality; outcome forecast; overexpression; physiologic model; pressure; prevent; public health relevance; repaired; small molecule; synergism; therapeutic target; uptake; vector

 DESCRIPTION (provided by applicant): Heart failure (HF), a leading cause of mortality in patients with myocardial infarction (MI), is especially progressive in the 20-25% of post-MI patients with ischemic mitral regurgitation (IMR). IMR drives a vicious cycle of left ventricular (LV) dilatation and MR caused by leaflet tethering to the LV walls. Ongoing remodeling drive leads to frequent failure of standard annuloplasty ring therapy, indicating the need to treat the ventricle as well as the valve. Our prior work has shown that post-MI LV remodeling is exacerbated by the added MR-induced volume overload, with downregulation of SERCA2a, a key calcium cycling pump, and increased fibrosis. Upregulating SERCA2a with intracoronary adeno associated virus (AAV) reduces remodeling when given early and also with late MR repair. Fibrosis can be reduced by AAV.CCN5, which reverses functional deterioration in HF induced by pressure overload. This proposal considers two clinical scenarios: acute MI, with potential to limit early remodeling as stimulus for progressive remodeling and IMR; and later remodeling, to improve long- term results from surgical repair of IMR by addressing myocardial remodeling as well. The central hypothesis is that LV remodeling in an IMI-induced model of progressive heart failure with IMR can be reduced at both early and late stages through a synergistic approach improving both myocardial and interstitial components of heart failure. We will test the following hypotheses: 1) Early administration of SERCA2a, CCN5 or both at the time of ischemia-reperfusion injury can prevent the remodeling that occurs despite revascularization. This is supported by recent evidence for transgene uptake in this context, and by our preliminary evidence that early preventive therapy with the combined vectors safely reduces both local infarct deformation and the ensuing cycle of MR and global remodeling. This aim simulates the scenario of patients with acute MI undergoing primary percutaneous intervention (PCI). 2) Upregulating SERCA2a, CCN5 or both can prevent or reverse remodeling in an established inferior MI model that produces important MR, simulating the clinical situation of treatment after remodeling has occurred, either early or late relative to compensatory pathway activation or exhaustion. 3) SERCA2a, CCN5 or both can prevent ongoing remodeling leading to recurrent MR when given during annuloplasty repair in an inferior MI model. LV remodeling and MR will be compared for ring alone, myocardial therapy alone (Aim 2), and the combination. In these aims we will address mechanistic hypotheses regarding CCN5 inhibition of fibrosis by decreasing post-MI endothelial-to-mesenchymal cell transformation and pro- fibrotic myofibroblast formation; SERCA2a reduction of remodeling by increasing contractility and decreasing apoptosis; and reduction of localized infarct deformation by early therapy in addition to reduced progression of global remodeling. The collaborative team combines strengths in surgical physiologic modeling, imaging and pathology of fibrosis, and myocardial biology with gene therapy. Results can support clinical studies of these strategies in patients undergoing mitral valve repair for ischemic MR and primary PCI for acute MI.

 描述（由申请人提供）：心力衰竭 (HF) 是心肌梗塞 (MI) 患者死亡的主要原因，在 20-25% 的 MI 后缺血性二尖瓣反流 (IMR) 患者中，心力衰竭 (HF) 的进展尤为严重。导致左心室 (LV) 扩张和 MR 的恶性循环，这是由瓣叶拴在 LV 壁上引起的。持续的重塑驱动导致标准频繁失败。瓣环成形环疗法，表明需要治疗心室和瓣膜，我们之前的工作表明，MR 引起的容量超负荷会加剧 MI 后的左室重塑，同时 SERCA2a（一种关键的钙循环泵）也会下调。早期使用冠状动脉内腺相关病毒 (AAV) 上调 SERCA2a 可减少重塑，晚期 MR 修复也可减少纤维化。 AAV.CCN5，可逆转压力超负荷引起的心力衰竭的功能恶化：急性心肌梗死，有可能限制早期重塑，作为渐进性重塑和 IMR 的刺激以及后期重塑，以改善长期结果。通过解决心肌重构来进行 IMR 的手术修复，其中心假设是，通过协同方法，可以在 IMI 诱导的进行性心力衰竭伴 IMR 模型中减少左室重构。我们将测试以下假设： 1) 在缺血再灌注损伤时早期给予 SERCA2a、CCN5 或两者可以预防尽管血运重建而发生的重塑。在此背景下，我们的初步证据表明，使用组合载体进行早期预防性治疗可以安全地减少局部梗塞变形以及随后的 MR 和整体重塑周期。目的模拟急性心肌梗死患者接受初次经皮介入治疗（PCI）的场景2）上调SERCA2a、CCN5或两者可以预防或逆转已建立的产生重要MR的劣质MI模型中的重塑，模拟重塑后治疗的临床情况。 3) SERCA2a、CCN5 或两者在瓣环成形修复期间给予时，可以防止持续重塑导致复发 MR。将比较单独环、单独心肌治疗（目标 2）和联合治疗的 LV 重塑和 MR。在这些目标中，我们将通过减少 MI 后内皮间质来解决有关 CCN5 抑制纤维化的机制假设。细胞转化和促纤维化肌成纤维细胞形成；SERCA2a 通过增加收缩性和减少细胞凋亡来减少重塑，以及通过早期治疗减少局部梗塞变形；该合作团队将手术生理学模型、纤维化成像和病理学以及心肌生物学方面的优势与基因治疗相结合，结果可以支持这些策略在接受缺血性 MR 和直接 PCI 的患者中的临床研究。急性心肌梗死。