Surgery to prevent postinfarction ventricular remodeling

描述（由申请人提供）：充血性心力衰竭（CHF）每年导致25万美国人死亡。大多数病例是由心肌梗死（MI）引起的左心室（LV）重构。重塑表现为LV扩张和收缩功能的整体丧失;至少35%的患者发生显著二尖瓣返流（缺血性二尖瓣返流- IMR），并可能加剧该现象。本项目的目标是使用良好表征和临床相关的绵羊梗死模型来阐明MI后重塑的机制，其程度在以前是不可能的。我们将集中在两个常见的机械性后遗症的MI：梗死扩大和IMR。在特定目标1中，我们检验了梗死扩展（伸展）通过增加边界区（BZ）心肌的应力来驱动LV重构的假设。增加的BZ应力通过降低该区域的收缩应变并引起肌细胞和细胞外基质生物学的固有变化而产生自我延续现象，这允许异常应力场传播到逐渐更远的心肌区域。我们开发了创新和强大的技术能力，以定量评估这种病理级联的所有组成部分。标记的MRI图像的光流映射将用于测量真正的3D心肌应变。根据MRI应变数据，使用最先进的有限元分析计算心肌应力分布。将使用双轴机械测试测量可压缩材料特性。在具体目标1中，将研究三种限制MI后早期梗死扩展的治疗方法：用Acorn CSD（R）包裹心脏、梗死再灌注和钙羟基磷灰石微球凝胶注射。在特定目标2中，使用相同的工具，我们专注于治疗慢性重塑的心脏，并测试以下假设：即使LV壁体积（由钙羟基磷灰石微球凝胶注射引起）的微小（<4.5%）变化也可以显著改善最佳位置时的心脏力学。在特定目标3中，我们重点关注IMR的慢性重塑心脏，并检验了以下假设：旨在增加二尖瓣瓣叶曲率（理论上降低瓣叶/腱索应力）的外科修复技术在改善已确立IMR的严重重塑心脏的局部和整体LV功能方面上级平环瓣环成形术。鞍形瓣环成形术和瓣叶扩张术将用于操纵瓣叶曲率。将使用基于3D超声心动图的新方法测量瓣叶几何形状。公共卫生相关性：该项目旨在确定梗死后左心室重塑的机制。将研究梗死扩大和缺血性二尖瓣返流的作用。强大的新成像和分析工具将用于阐明梗死材料特性和二尖瓣-心室相互作用的时间依赖性变化如何影响局部心肌应力分布、局部收缩功能以及局部肌细胞和细胞外基质生物学。还将评估新的早期和晚期治疗对重塑过程的影响。

DESCRIPTION (provided by applicant): Congestive heart failure (CHF) causes the death of 250,000 Americans each year. The majority of cases result from myocardial infarction (MI) induced left ventricular (LV) remodeling. Remodeling is manifest by LV dilatation and global loss of contractile function; significant mitral regurgitation (ischemic mitral regurgitation- IMR) develops in at least 35% of these patients and may exacerbate the phenomenon. The goal of this project is use well characterized and clinically relevant ovine infarction models to elucidate the mechanism of post MI remodeling to an extent that has not been previously possible. We will focus on two common mechanical sequelae of MI: infarct expansion and IMR. In Specific Aim 1, we test the hypothesis that infarct expansion (stretching) drives LV remodeling by increasing stress in the borderzone (BZ) myocardium. Increased BZ stress produces a self-perpetuating phenomenon by decreasing contractile strain in the region and causing inherent changes in myocyte and extracellular matrix biology that allows for propagation of the abnormal stress fields to progressively more remote myocardial regions. We have developed innovative and powerful technical capabilities to quantitatively assess all components of this pathologic cascade. Optical flow mapping of tagged MRI images will be used to measure truly 3D myocardial strains. Myocardial stress distribution will be calculated using state-of-the-art finite element analysis based on the MRI strain data. Infarct material properties will be measured using biaxial mechanical testing. In Specific Aim 1 three therapeutic approaches to limit infarct expansion early after MI will be studied: heart wrapping with the Acorn CSD(R), infarct reperfusion and calcium hydroxyapatite microsphere gel injection. In Specific Aim 2 using the same tools we focus on treating the chronically remodeled heart and test the hypothesis that even small (<4.5%) fractional changes in LV wall volume (caused by calcium hydroxyapatite microsphere gel injection) can significantly improve cardiac mechanics when optimally located. In Specific Aim 3 we focus on the chronically remodeled heart with IMR and test the hypothesis that surgical repair techniques that are designed to increase mitral leaflet curvature (and theoretically reduce leaflet/chordal stress) will be superior to flat ring annuloplasty in improving regional and global LV function in severely remodeled hearts with established IMR. Saddle-shaped annuloplasty and leaflet augmentation will be used to manipulate leaflet curvature. A novel 3D echocardiography based approach to measuring leaflet geometry will be used. PUBLIC HEALTH RELEVANCE: This project seeks to determine the mechanism of post infarction left ventricular remodeling. The contribution of infarct expansion and ischemic mitral regurgitation will be studied. Powerful new imaging and analytic tools will be used to elucidate how time- dependent changes in infarct material properties and mitral-ventricular interactions influence regional myocardial stress distribution, regional contractile function and regional myocyte and extracellular matrix biology. The affect of novel early and late therapies on the remodeling process will also be assessed.