Computational Tools to Describe Cardiac Post-MI Structure and Function Remodeling

描述（由申请人提供）：作为对疾病的反应，心肌经历时间依赖性重构，表现为心脏形状和运动在心脏周期中的改变。例如，在冠状动脉疾病和左心室功能障碍患者中，心室重构导致心室舒张末期和收缩末期体积逐渐增加，心室壁变薄，心室几何形状改变，心脏运动改变。在微观结构尺度上，心肌中正常的三维肌纤维组织被打乱，其绕左心室旋转的角度由其跨壁位置决定。虽然已经有人尝试识别指示疾病风险的基因和蛋白质，但很少有人努力量化和评估区域心脏形状、纤维取向和运动变化，以预测疾病和监测各种治疗的反应。我们的工作将集中于开发新的算法，从计算功能解剖学（CFA）的新兴学科，分析心脏形状（几何形状和纤维结构）和运动的变化，并探索这些图像衍生参数可用于描述疾病状态和进展的程度。我们将采用再灌注小鼠梗死模型来测量心室几何形状、纤维取向和心室运动的差异，使用体内三维时间演变结构和标记MRI成像以及体外扩散张量成像在正常小鼠和梗死小鼠中进行。预防心肌梗死（MI）后的不良重构是一项治疗挑战，因为许多患者的心室在MI后继续扩大，尽管治疗，死亡率和发病率仍然很高。一些研究表明，细胞外胶原基质（ECCM）在心肌梗死后重构中起着重要作用，似乎针对ECCM重构的治疗可能是有益的。然而，由于梗死区和非梗死区表现出不同的病理生理反应，整个问题变得更加复杂。因此，详细了解ECCM重构的时间/空间演变是制定针对梗死区和非梗死区治疗策略的必要步骤。本提案中开发的CFA方法将用于未来的研究，以获得有关降解ECCM的基质金属蛋白酶等物质对心室结构重塑和心脏力学的影响的有价值的信息。

DESCRIPTION (provided by applicant): In response to disease, the myocardium undergoes time-dependent remodeling that manifests as alterations of heart shape and motion during the cardiac cycle. For example, in patients with coronary artery disease and left ventricular dysfunction, ventricular remodeling results in a gradual increase of ventricular end-diastolic and end- systolic volumes, wall thinning, changes of chamber geometry, and alterations of heart motion. At the micro-structure scale, the normal 3D organization of muscle fibers in the myocardium that spirals around the left ventricle with a angle that is determined by their transmural location is perturbed. While there have been attempts to identify genes and proteins that are indicative of disease risk, there have been few efforts to quantify and assess regional cardiac shape, fiber orientation, and motion changes to predict disease and to monitor response in various therapies. Our work will focus on developing new algorithms, from the emerging discipline of computational functional anatomy (CFA), for analyzing changes of heart shape (geometry and fiber structure) and motion and exploring the extent to which such image-derived parameters can be used to describe disease state and progression. We will pursue this by employing a reperfused murine model of infarction to measure differences in ventricular geometry, fiber orientation, and motion of the cardiac ventricles using in-vivo 3D time evolving structural and tagged MRI imaging and ex-vivo diffusion tensor imaging in normal vs. infarcted mouse. Prevention of adverse remodeling after myocardial infarction (MI) is a therapeutic challenge as ventricles in many patients continue to enlarge after MI and mortality and morbidity remain significant in spite of therapy. Several studies indicated that extracellular collagen matrix (ECCM) plays an important role in post-MI remodeling and it may appear that treatments that targeting ECCM remodeling might be beneficial. However, the whole matter is further complicated by the fact that infarct and non-infarct zones demonstrate differential pathophysiological responses. Therefore a detailed understanding of temporal/spatial evolution of ECCM remodeling is a necessary step in developing treatment strategies that target both infarcted and non-infarcted zones. CFA methods that are developed in this proposal will be utilized in future studies to acquire valuable information about the effect of substances such as matrix metalloproteinases that degrade ECCM on the ventricular structural remodeling and cardiac mechanics. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop mathematical tools to characterize ventricular shape (geometry and fiber structure) and function in post myocardial infarction (post-MI) remodeling. The process of post-MI remodeling often leads to the deterioration of cardiac pump function and increased susceptibility to arrhythmias. Therefore developing computational tools that can advance our understanding of the remodeling process will allow design of improved diagnostic and therapeutic interventions that might limit adverse cardiac remodeling.