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

 描述（由申请人提供）：心力衰竭（HF）是心肌梗死（MI）患者死亡的主要原因，在20-25%的MI后缺血性二尖瓣返流（IMR）患者中尤其进展。IMR导致左心室（LV）扩张和二尖瓣返流的恶性循环，二尖瓣返流由瓣叶栓系到LV壁上引起。持续的重塑驱动导致标准瓣膜成形环治疗频繁失败，表明需要治疗心室和瓣膜。我们之前的工作表明，MI后LV重构因MR诱导的容量超负荷而加剧，SERCA 2a（一种关键的钙循环泵）下调，纤维化增加。用冠状动脉内腺相关病毒（AAV）上调SERCA 2a在早期给予时以及在晚期MR修复时减少重塑。AAV. CCN 5可以减少纤维化，其逆转由压力超负荷诱导的HF中的功能恶化。该提案考虑了两种临床情况：急性MI，有可能限制早期重塑作为进行性重塑和IMR的刺激;以及后期重塑，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诱导的进行性心力衰竭伴IMR模型中，通过改善心力衰竭的心肌和间质组分的协同方法，可以在早期和晚期减少LV重塑。我们将测试以下假设：1）在缺血-再灌注损伤时早期施用SERCA 2a、CCN 5或两者可以预防尽管血管重建但发生的重塑。这是支持的转基因摄取在这种情况下，最近的证据，我们的初步证据表明，早期预防性治疗与组合载体安全地减少局部梗死变形和随后的MR和全球重塑的周期。该目的模拟急性心肌梗死患者接受直接经皮介入治疗（PCI）的情况。2)上调SERCA 2a、CCN 5或两者可预防或逆转产生重要MR的已建立下壁MI模型中的重塑，从而模拟重塑发生后的治疗临床情况，相对于代偿途径激活或衰竭而言为早期或晚期。3)在下壁MI模型中，在瓣环成形术修复期间给予SERCA 2a、CCN 5或两者均可预防持续性重塑导致复发性二尖瓣返流。将比较单独使用成形环、单独使用心肌治疗（目标2）和联合使用的LV重塑和MR。在这些目标中，我们将解决关于CCN 5通过减少MI后内皮细胞向间充质细胞转化和促纤维化肌成纤维细胞形成来抑制纤维化的机制假说; SERCA 2a通过增加收缩性和减少凋亡来减少重塑;以及除了减少整体重塑的进展之外，通过早期治疗来减少局部梗死变形。该合作团队结合了外科生理学建模、纤维化成像和病理学以及心肌生物学与基因治疗方面的优势。结果可以支持这些策略在因缺血性MR接受二尖瓣修复术和因急性MI接受直接PCI的患者中的临床研究。

 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.