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）： 心肌梗塞（MI）后的心肌重塑（MI）通过一系列细胞，体液和血液动力学事件导致左心室（LV）的进行性增大和衰竭，预后较差。 MI后不良预后也与二尖瓣反流（MR）有关，这是一种频繁的并发症，本身可能导致LV扩张和失败，进而在恶性循环中增加MR，例如通过早期瓣膜修复来治疗MR。因此，重要的是确定重塑和反流是否相互影响。该提案将检验以下假设：MRTYPE体积超负荷增加了MI的重塑，以及修复MR限制或逆转重塑的推论。重塑将评估为LV扩张和功能障碍，以及相关的细胞和分子变化，包括细胞形状和收缩性的改变，凋亡增加，肥厚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时间的流逝，随着时间的流逝，整体和分段LV重塑作为LV变形。测试与MR型体积超负荷和MI重塑有关的结合解剖学和分子假设需要改变MR独立于MI。由于它们倾向于在下部MI中一起发生，因此将使用前MI模型，MR型体积超负荷由左心室到四方分流产生，这是一种已发表的方法。随着时间的流逝，有和没有MR MR的动物（开放式分流量与假手术）将比较重塑的超声心动图测量，并与心肌衰竭和重塑，神经肿瘤激活和凋亡的细胞和分子标记有关。 LV-LA分流器将被关闭以模拟二尖瓣修复，并测试与持续的分流器相比，这是否逆转或限制了重塑和相关的分子变化。还将在具有和没有遗传过表达的分子过表达的心脏中进行比较，从而影响细胞收缩力，细胞存活和细胞外基质重塑的关键要素，并假设有利地修改这些相互作用靶标的任何一种都会减少LV膨胀和功能障碍。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影响。