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）引起的左心室重构引起的。重构表现为左室扩张和整体收缩功能丧失；这些患者中至少有35%出现明显的二尖瓣反流（缺血性二尖瓣反流- IMR），并可能加剧这一现象。该项目的目标是使用具有良好特征和临床相关性的绵羊梗死模型来阐明心肌梗死后重构的机制，这在一定程度上是以前不可能的。我们将重点讨论心肌梗死的两种常见的机械性后遗症：梗死扩张和IMR。在具体目标1中，我们验证了梗死扩张（拉伸）通过增加边界区（BZ）心肌的压力来驱动左室重塑的假设。增加的BZ应激产生一种自我延续的现象，通过减少该区域的收缩应变，引起肌细胞和细胞外基质生物学的固有变化，使异常应力场逐渐传播到更远的心肌区域。我们已经开发了创新和强大的技术能力来定量评估这一病理级联的所有组成部分。标记MRI图像的光流映射将用于测量真正的3D心肌应变。心肌应力分布将使用基于MRI应变数据的最先进的有限元分析来计算。梗塞材料的特性将采用双轴力学测试来测量。在Specific Aim 1中，将研究三种限制心肌梗死后早期梗死扩张的治疗方法：Acorn CSD(R)心脏包裹、梗死再灌注和羟基磷灰石钙微球凝胶注射。在Specific Aim 2中，我们使用相同的工具，专注于治疗慢性重构心脏，并验证左室壁体积即使很小（<4.5%）的微小变化（由羟基磷灰石钙微球凝胶注射引起）在最佳定位时也能显著改善心脏力学的假设。在具体目标3中，我们将重点放在慢性重塑心脏的IMR和测试的假设，手术修复技术旨在增加二尖瓣小叶曲率（理论上减少小叶/弦索应力）将优于平环成形术在改善局部和整体左室功能的严重重构心脏已建立的IMR。鞍形环成形术和小叶增大术将用于控制小叶曲率。一种新的基于三维超声心动图的方法来测量小叶几何将被使用。

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.