Multiscale Models of Cardiac Growth, Remodeling, and Myocardial Infarction

描述（由申请人提供）：本提案的主要目的是通过多尺度建模来预测心肌梗死后疤痕和未损伤心肌对心脏再同步化治疗的长期生长和重塑。仅在美国，每年就有超过一百万人患有心肌梗塞（心脏病发作）。大多数患者在最初的事件中存活下来，因此梗死后的治疗成为当务之急。在心肌梗死（MI）后的几周、几个月和几年里，受损心脏的生长和重塑（G&R）决定了患者的临床病程和大多数可用治疗的影响。在梗死中，受损的肌肉被疤痕取代，疤痕形成的细节决定了灾难性梗死破裂、梗死扩张和其他严重潜在并发症的风险；在心脏的非梗死区域，改变的机械负荷触发心肌细胞生长和重塑，往往导致心力衰竭。临床医生可用的少数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-包括心脏再同步化治疗(CRT) -通过改变疤痕形成，远程重塑或两者兼而有之。然而，这些治疗方法目前还不能预测它们对梗死后重塑的影响。因此，迫切需要能够准确预测梗死后和未受损心肌重构的计算模型，以及对改变这些过程的治疗的反应。在过去的十年中，心脏电力学的多尺度计算模型变得越来越机械和生物物理详细。他们现在可以预测许多对化学和物理刺激或遗传缺陷的急性反应。此外，超声心动图应变率成像和标记MRI等成像方式的可用性提供了详细的3D应变场，可以严格验证局部心室力学的计算模型。然而，心脏的多尺度模型还不能预测慢性疾病下的长期适应。项目组成员最近发表了一种新的心肌生长规律，并将其整合到心脏和心血管系统的多尺度模型中，准确预测了压力过载（PO）和容量过载（VO）时心脏的长期G&R。我们团队的其他成员开发了一种创新的基于agent的模型，可以准确预测愈合梗死中的疤痕形成和重塑。在这里，我们提出整合我们的机电、G&R和基于主体的模型，并通过发表的和新的实验数据验证它们，通过以下具体目的：目的1：验证基于压力释放和体积过载响应的应变依赖生长规律预测CRT过程中反向重塑的假设；目的2：验证由于梗死伸展和血流动力学代偿的相互作用，较大梗死促进存活心肌偏心肥厚的假设；目的3：验证模型预测的梗死后CRT的G&R。

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.