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

描述(申请人提供)：作为对疾病的反应，心肌经历了时间相关的重塑，表现为心脏形状和运动在心脏周期中的变化。例如，在冠心病和左心功能不全的患者中，心室重构导致心室舒张末和收缩末期容量逐渐增加，室壁变薄，室腔几何形状改变，心脏运动改变。在微观结构尺度上，心肌中正常的3D肌纤维组织被扰乱，该组织以由其跨壁位置确定的角度绕着左心室旋转。虽然已经尝试确定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局部心脏形状、纤维方向和运动变化来预测疾病和监测各种治疗的反应。我们的工作将集中于从计算功能解剖学(CFA)这一新兴学科开发新的算法，用于分析心脏形状(几何和纤维结构)和运动的变化，并探索此类图像派生参数可用于描述疾病状态和进展的程度。为了实现这一点，我们将采用再灌流的小鼠脑梗塞模型，利用体内3D时间演变的结构和标记磁共振成像以及体外扩散张量成像，测量正常和脑梗塞小鼠在心室几何形状、纤维取向和室壁运动方面的差异。预防心肌梗死(MI)后的不良重构是一项治疗挑战，因为许多患者在MI后脑室继续扩大，尽管进行了治疗，但死亡率和发病率仍然很高。多项研究表明，细胞外胶原基质(ECCM)在心肌梗死后重塑中起重要作用，针对ECCM重塑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的治疗策略的必要步骤。CFA方法将被用于未来的研究，以获得有价值的信息，如基质金属蛋白酶等降解ECCM的物质在心室结构重构和心脏力学中的作用。 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)重塑中的心室形状(几何和纤维结构)和功能。心肌梗死后重构的过程往往会导致心泵功能恶化，增加心律失常的易感性。因此，开发能够促进我们对心脏重塑过程的理解的计算工具将有助于设计改进的诊断和治疗干预措施，从而可能限制不利的心脏重塑。

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.