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（由适用提供）：心肌梗死患者（MI）死亡率的主要原因（HF）在20-25％的MI缺血性二尖瓣反流（IMR）中尤其进行。 IMR驱动了左心室（LV）扩张的恶性循环，并由小叶绑在LV壁上引起的MR。持续的重塑驱动器会导致标准的环形成形术环疗法经常失败，表明需要治疗通风和阀门。我们先前的工作表明，在MR诱导的体积过载的增加，SERCA2A的下调，一个关键的钙循环泵和纤维化增加，MI LV重塑会加剧。用冠状动脉内腺相关病毒（AAV）上调SERCA2A会在提早进行时减少重塑，并降低MR修复。纤维化可以通过AAV.CCN5降低，该提案考虑了两种临床情况：急性MI，并有可能将早期重塑作为进行性重塑和IMR的刺激；然后进行重塑，以通过解决心肌重塑来改善IMR手术修复的长期结果。中心假设是，在IMI诱导的IMR进行性心力衰竭模型中的LV重塑可以通过协同方法在早期和晚期减少，从而改善心肌衰竭的心肌组成部分。我们将检验以下假设：1）在缺血 - 再灌注损伤时早期给予SERCA2A，CCN5或两者都可以防止发生目的地血运重建的重塑。在这种情况下，最近证明了转型吸收的证据，以及我们的初步证据表明，与合并载体合并的早期预防疗法可以安全地减少局部基础设施变形以及确保MR和全球重塑的周期。此目的模拟了接受原发性经皮干预（PCI）的急性MI患者的情况。 2）上调SERCA2A，CCN5或两者都可以预防或反向重塑，该模型已确定的MI模型，该模型产生重要的MR，模拟重塑后的治疗临床状况，早期或LV重塑和LV重塑和MR将与单独的环，心肌治疗（AIM 2）以及组合进行比较。在这些目标中，我们将通过减少MI后内皮到间质细胞的转化和促纤维化的成纤维纤维细胞的形成来解决有关CCN5抑制纤维化的机理假设； SERCA2A通过增加收缩力和降低凋亡而减少重塑；除了减少全球重塑的进展外，还通过早期治疗减少局部基础设施变形。协作团队结合了手术生理建模，纤维化成像和病理学以及心肌生物学的优势与基因治疗。结果可以支持急性MI缺血性MR和原发性PCI的二尖瓣修复患者的这些策略的临床研究。