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

描述（由申请人提供）：在对疾病的反应中，心肌经历时间依赖性重塑，表现为心动周期期间心脏形状和运动的改变。例如，在患有冠状动脉疾病和左心室功能障碍的患者中，心室重构导致心室舒张末期和收缩末期容积的逐渐增加、室壁变薄、腔室几何形状的变化以及心脏运动的改变。在微观结构尺度上，心肌中以由其透壁位置确定的角度围绕左心室螺旋的肌纤维的正常3D组织受到干扰。虽然已经尝试鉴定指示疾病风险的基因和蛋白质，但很少有努力量化和评估局部心脏形状、纤维取向和运动变化以预测疾病并监测各种治疗的反应。我们的工作将集中在开发新的算法，从计算功能解剖学（CFA）的新兴学科，用于分析心脏形状（几何形状和纤维结构）和运动的变化，并探索在何种程度上这些图像衍生的参数可以用来描述疾病状态和进展。我们将通过采用再灌注的小鼠梗死模型来追求这一点，以测量正常与梗死小鼠中心室几何形状，纤维取向和心室运动的差异，使用体内3D时间演变结构和标记的MRI成像和离体扩散张量成像。预防心肌梗死（MI）后的不良重塑是一个治疗挑战，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）在心肌梗死后重塑中起着重要作用，靶向ECCM重塑的治疗可能是有益的。然而，整个问题进一步复杂化的事实，即梗死和非梗死区表现出不同的病理生理反应。因此，详细了解ECCM重塑的时间/空间演变是开发针对梗死和非梗死区的治疗策略的必要步骤。CFA的方法，在这一建议中开发的将被用于在未来的研究中，以获得有价值的信息的物质，如基质金属蛋白酶，降解ECCM对心室结构重塑和心脏力学的影响。 公共卫生相关性：该项目的目标是开发数学工具来表征心肌梗死后（MI后）重构中的心室形状（几何形状和纤维结构）和功能。心肌梗死后重构的过程往往导致心脏泵功能的恶化和心律失常的易感性增加。因此，开发可以促进我们对重塑过程的理解的计算工具将允许设计可能限制不良心脏重塑的改进的诊断和治疗干预。

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.