Multiscale Models of Cardiac Growth, Remodeling, and Myocardial Infarction

描述(由申请人提供)：这项建议的主要目标是通过多尺度模型预测心肌梗死后疤痕和未受损心肌的长期生长和重构，以响应心脏再同步治疗。仅在美国，每年就有100多万人患有心肌梗塞(心脏病发作)。大多数人在最初的事件中幸存下来，使脑梗塞后的治疗成为高度优先的事项。在心肌梗死(MI)后的几周、几个月、几年内，受损心脏的生长和重构(G&R)决定了患者的临床病程和大多数可用的治疗方法的影响。在梗死区，受损的肌肉被疤痕取代，疤痕形成的细节控制着灾难性的梗死灶破裂、梗死灶扩大和其他严重的潜在并发症的风险；在心脏的非梗死区，机械负荷的改变会触发心肌细胞的生长和重塑，这往往会导致心力衰竭。临床医生可用的为数不多的成功的心肌梗死后治疗方法和目前正在开发的许多治疗方法-包括心脏再同步治疗(CRT)-通过改变疤痕形成、远程重塑或两者兼而有之发挥作用。然而，这些治疗方法目前尚无能力预测其对梗死后重塑的影响。因此，迫切需要计算模型来准确预测梗死后心肌和未受损心肌的重构，以及对改变这些过程的治疗的反应。在过去的十年里，心脏电力学的多尺度计算模型已经变得越来越机械化和生物物理学的详细。他们现在可以预测对化学和物理刺激或遗传缺陷的许多急性反应。此外，超声心动图应变率成像和标记磁共振成像等成像手段的出现提供了详细的三维应变场，可以用来严格验证局部室壁力学的计算模型。然而，心脏的多尺度模型还不能预测慢性条件下的长期适应。项目团队成员最近发表了一种新的心肌生长规律，将其集成到心脏和心血管系统的多尺度模型中，并准确预测了压力超负荷(PO)和容量超负荷(VO)期间的长期心脏G&R。我们团队的其他成员开发了一种创新的基于试剂的模型，该模型可以准确预测愈合梗塞过程中疤痕的形成和重塑。在这里，我们建议整合我们的电力学、G&R和基于试剂的模型，并通过以下具体目的验证它们：目的1：验证基于对压力和容量超载的反应的应变依赖生长规律预测CRT期间反向重构的假设；目标2：验证更大的梗塞延伸和血流动力学补偿相互作用而促进存活心肌偏心性肥厚的假说；目标3：验证模型预测的G&R对梗塞后CRT的反应。

DESCRIPTION (provided by applicant): The major objective of this proposal is to predict through multi-scale modeling long-term growth and remodeling of both post-infarction scar and undamaged myocardium in response to cardiac resynchronization therapy. Over a million people suffer a myocardial infarction (heart attack) each year in the U.S alone. Most survive the initial event, making post-infarction treatment a high priority. In the weeks, months, and years following myocardial infarction (MI), growth and remodeling (G&R) of the damaged heart determine the clinical course of the patient and the impact of most available therapies. In the infarct, damaged muscle is replaced by scar, and the details of scar formation govern the risk of catastrophic infarct rupture, infarct expansion, and other serious potential complications; in noninfarcted regions of the heart, altered mechanical loading triggers myocyte growth and remodeling that often leads to heart failure. The few successful post-MI therapies available to clinicians and many therapies currently under development - including cardiac resynchronization therapy (CRT) - work by altering scar formation, remote remodeling, or both. Yet these therapies are currently developed with no ability to predict their effects on post-infarction remodeling. Therefore, there is a critical need for computational models that can accurately predict post-infarction remodeling in both the infarct and the undamaged myocardium, as well as the response to therapies that alter those processes. Multi-scale computational models of cardiac electromechanics have become increasingly mechanistic and biophysically detailed over the past decade. They can now predict many acute responses to chemical and physical stimuli or genetic defects. Moreover the availability of imaging modalities such as echocardiographic strain rate imaging and tagged MRI have provided detailed 3D strain fields with which computational models of regional ventricular mechanics can be stringently validated. However, multi-scale models of the heart are not yet capable of predicting long-term adaptation under chronic conditions. Members of the project team recently published a novel myocardial growth law, integrated it into a multi-scale model of the heart and cardiovascular system, and accurately predicted long-term cardiac G&R during pressure overload (PO) and volume overload (VO). Other members of our team developed an innovative agent-based model that accurately predicts scar formation and remodeling in healing infarcts. Here, we propose to integrate our electromechanics, G&R and agent-based models and validate them against published and new experimental data, through the following specific aims: Aim 1: To test the hypothesis that strain-dependent growth laws based on the response to relief of pressure and volume overload predict reverse remodeling during CRT; Aim 2: To test the hypothesis that larger infarcts promote eccentric hypertrophy in surviving myocardium due to the interaction of infarct stretching and hemodynamic compensations; Aim 3: To validate model-predicted G&R in response to post-infarction CRT.