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: 6771846
• 负责人: ROBERT A LEVINE
• 金额: $ 42.74万
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6771846
• 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）后的心肌重构通过细胞、体液和血液动力学事件的级联反应导致左心室（LV）进行性增大和衰竭，预后较差。MI后的不良预后还与二尖瓣返流（MR）相关，这是一种常见的并发症，其本身可能导致LV扩张和衰竭，进而在恶性循环中增加MR，该恶性循环可通过治疗MR（例如，通过早期瓣膜修复）中断。因此，重要的是要确定重构和反流是否相互影响。本提案将检验MR型容量超负荷增加MI后重构的假设，以及修复MR限制或逆转重构的推论。重塑将被评估为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力改变、细胞凋亡增加、肥大信号通路变化和细胞外基质支持改变。三维超声心动图非常适合于量化和比较LV变形时随时间推移的整体和节段LV重构。检验MR型容量超负荷和心肌梗死后重构相关的解剖学和分子学联合假设，需要改变与心肌梗死无关的MR。由于它们往往在下壁心肌梗死中一起发生，因此将使用前壁心肌梗死模型，并使用已发表的左心室-心房分流术产生的MR型容量超负荷。将比较MI后有和无MR的动物（开放分流vs假手术）随时间推移的重构超声心动图测量值，并将其与心肌衰竭和重构、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分流管以模拟二尖瓣修复，并测试与持续分流管通畅性相比，这是否逆转或限制了重塑和相关分子变化。还将比较心脏中有和没有影响细胞收缩性、细胞存活和细胞外基质重塑的关键因素的分子的遗传过表达的重塑，假设有利地修饰这些相互作用靶点中的任何一个将减少LV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术的决策具有意义。