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)重构引起的。重塑表现为左室扩张和整体收缩功能丧失；至少35%的患者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。这个项目的目标是使用具有良好特征和临床相关性的绵羊梗塞模型来阐明心肌梗死后重构的机制，这是以前所不可能的。我们将关注两种常见的心肌梗塞的机械后遗症：梗塞扩大和IMR。在特定的目标1中，我们测试了梗塞扩大(拉伸)通过增加交界区(BZ)心肌的应力来驱动左室重构的假说。增加的BZ应力通过减少该区域的收缩应变而产生一种自我延续的现象，并导致心肌细胞和细胞外基质生物学的内在变化，从而允许异常应力场传播到逐渐更偏远的心肌区域。我们开发了创新和强大的技术能力，以定量评估这一病理级联的所有组件。标记的MRI图像的光流映射将被用于真实地测量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。将使用双轴机械测试来测量脑梗塞材料的特性。具体目标1将研究三种限制心肌梗死后早期梗塞扩大的治疗方法：用橡子CSD(R)包裹心脏、梗塞再灌注和注射羟基磷灰石微球凝胶。在具体目标2中，使用相同的工具，我们专注于治疗慢性重塑的心脏，并测试假设，即使是微小的(&lt；4.5%)室壁体积的部分变化(由注射羟基磷灰石微球凝胶引起)，当位置最佳时，可以显着改善心脏力学。在具体目标3中，我们将重点放在有IMR的慢性重塑心脏上，并检验这样一种假设，即旨在增加二尖瓣叶曲率(理论上减少二尖瓣/弦向应力)的外科修复技术在改善已建立的IMR严重重塑心脏的局部和整体左心功能方面优于平环成形术。将采用鞍形瓣环成形术和瓣叶扩大术来操纵瓣叶曲率。将使用一种新的基于三维超声心动图的方法来测量瓣叶几何形状。公共卫生相关性：该项目试图确定梗死后左室重构的机制。我们将研究梗塞扩大和缺血性二尖瓣返流的作用。强大的新的成像和分析工具将被用来阐明梗死物质特性和二尖瓣-心室相互作用随时间的变化如何影响局部心肌应力分布、局部收缩功能和局部心肌细胞和细胞外基质生物学。新的早期和晚期治疗对重塑过程的影响也将被评估。

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.