Effect of Mitral Regurgitation on Ischemic LV Remodeling

二尖瓣反流对缺血性左室重构的影响

• 批准号: 7093175
• 负责人: ROBERT A LEVINE
• 金额: $ 41.74万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7093175
• 关键词: apoptosis; biological signal transduction; biomarker; cardiovascular surgery; cell morphology; echocardiography; extracellular matrix; gene expression; heart failure; mitral valve insufficiency; myocardial infarction; neurotransmitters; nonhuman therapy evaluation; pathologic process; prognosis; sheep; ventricular hypertrophy

DESCRIPTION (provided by applicant): Myocardial remodeling after myocardial infarction (MI) leads, through a cascade of cellular, humoral and hemodynamic events, to progressive enlargement and failure of the left ventricle (LV), with poorer prognosis. Adverse prognosis post-MI is also associated with mitral regurgitation (MR), a frequent complication which itself could potentially lead to LV dilatation and failure, in turn increasing MR in a vicious cycle that could be interrupted by treating the MR, for example, by early valve repair. It is therefore important to determine whether remodeling and regurgitation influence one another. This proposal will test the hypothesis that MRtype volume overload augments remodeling post-MI, and the corollary that repairing MR limits or reverses remodeling. Remodeling will be assessed as LV dilatation and dysfunction, and associated cellular and molecular changes, including altered cell shape and contractility, increased apoptosis, changes in hypertrophic signaling pathways, and altered extracellular matrix support. Three-dimensional echocardiography is well-suited for quantifying and comparing global and segmental LV remodeling over time as the LV deforms. Testing the combined anatomic and molecular hypothesis relating MR-type volume overload and post-MI remodeling requires varying MR independent of MI. Because they tend to occur together in inferior MI, a model of anterior MI will be used, with MR-type volume overload created by a left ventricular-to-atrial shunt, a published approach. Echocardiographic measures of remodeling will be compared over time between animals with and without MR post-MI (open shunt vs sham), and correlated with cellular and molecular markers of myocardial failure and remodeling, neurohumoral activation, and apoptosis. The LV-LA shunt will be closed to simulate mitral valve repair and test whether this reverses or limits both the remodeling and associated molecular changes compared with persistent shunt patency. Remodeling will also be compared in hearts with and without genetic overexpression of molecules affecting the key elements of cell contractility, cell survival, and extracellular matrix remodeling, with the hypothesis that favorably modifying any one of these interacting targets will diminish both LV dilatation and dysfunction. These studies have implications for potential therapeutic strategies and for guiding decision-making regarding mitral valve repair in patients with myocardial infarction.

描述（由申请人提供）： 心肌梗死（MI）后的心肌重塑通过一系列细胞、体液和血流动力学事件导致左心室（LV）进行性扩大和衰竭，预后较差。 MI 后的不良预后还与二尖瓣反流 (MR) 有关，这是一种常见的并发症，其本身可能导致左心室扩张和衰竭，进而增加 MR，形成恶性循环，而这种恶性循环可以通过治疗 MR 来中断，例如，及早修复阀门。因此，确定重塑和反流是否相互影响非常重要。该提案将检验 MR 型容量超载会增强 MI 后重塑的假设，以及修复 MR 限制或逆转重塑的推论。重塑将通过左心室扩张和功能障碍以及相关的细胞和分子变化来评估，包括细胞形状和收缩性的改变、细胞凋亡的增加、肥大信号通路的变化以及细胞外基质支持的改变。三维超声心动图非常适合量化和比较随着 LV 变形而随时间推移的整体和节段 LV 重塑。测试与 MR 型容量超负荷和 MI 后重塑相关的组合解剖学和分子假说需要独立于 MI 的不同 MR。由于它们往往在下壁 MI 中同时发生，因此将使用前壁 MI 模型，并通过左心室至心房分流（一种已发表的方法）产生 MR 型容量超负荷。将随着时间的推移，对有和没有 MR 后 MI 的动物（开放分流与假手术）之间的超声心动图重塑测量进行比较，并与心肌衰竭和重塑、神经体液激活和细胞凋亡的细胞和分子标志物相关。将关闭 LV-LA 分流器以模拟二尖瓣修复，并测试与持续分流通畅相比，这是否会逆转或限制重塑和相关的分子变化。还将在心脏中比较有或没有影响细胞收缩力、细胞存活和细胞外基质重塑关键要素的分子基因过度表达的心脏中的重塑，并假设有利地修改这些相互作用目标中的任何一个都将减少左心室扩张和功能障碍。这些研究对潜在的治疗策略和指导心肌梗死患者二尖瓣修复的决策具有重要意义。