Multiscale Models of Cardiac Growth, Remodeling, and Myocardial Infarction

心脏生长、重塑和心肌梗死的多尺度模型

• 批准号: 9144435
• 负责人: JEFFREY W HOLMES
• 金额: $ 53.53万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144435
• 关键词: Acute; Blood Circulation; Bundle-Branch Block; Canis familiaris; Cardiac; Cardiovascular system; Cell model; Chemicals; Chronic; Cicatrix; Clinical; Computer Simulation; Data; Development; Event; Financial compensation; Geometry; Goals; Growth; Healed; Health; Heart; Heart failure; Histologic; Hypertrophy; Image; Individual; Infarction; Laws; Lead; Left; Left ventricular structure; Location; Magnetic Resonance Imaging; Measures; Mechanics; Modeling; Muscle; Muscle Cells; Mutation; Myocardial; Myocardial Infarction; Myocardium; Pacemakers; Patients; Physiological; Process; Property; Publishing; Risk; Rupture; Stimulus; Stretching; Structure; Testing; Tissues; Validation; Ventricular; Work; base; body system; cardiac resynchronization therapy; design; healing; heart dimension/size; hemodynamics; imaging modality; innovation; member; multi-scale modeling; novel; partial recovery; predicting response; pressure; response; treatment response

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.

描述（由申请人提供）：该提案的主要目的是通过多尺度建模，对后孔后疤痕和未损坏的心肌进行多个尺度建模，以响应心脏重新同步治疗。仅在美国，每年，超过一百万的人就会遭受心肌梗塞（心脏病发作）。大多数在初始事件中幸存下来，使进攻后的治疗成为很高的优先级。在心肌梗塞（MI）之后的几周，几个月和几年中，受损心脏的生长和重塑（G＆R）决定了患者的临床过程以及大多数可用疗法的影响。在梗塞中，受损的肌肉被疤痕所取代，疤痕形成的细节控制着灾难性梗塞破裂，梗塞扩张和其他严重潜在并发症的风险；在心脏的非敏感区域中，机械载荷改变会触发心肌细胞的生长和重塑，这通常会导致心力衰竭。临床医生和目前正在开发的许多疗法（包括心脏重新同步疗法（CRT））可用的少数成功的MI疗法（CRT） - 通过改变疤痕形成，远程重塑或两者兼而有之。然而，这些疗法目前是开发的，无法预测其对界面后重塑的影响。因此，对于可以准确预测梗塞和未损坏的心肌的进攻后重塑的计算模型的迫切需要，以及对改变这些过程的疗法的反应。在过去的十年中，心电机的多规模计算模型已变得越来越机械化和生物物理详细介绍。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的MRI等成像方式的可用性提供了详细的3D应变场，可以严格验证区域心室力学的计算模型。但是，心脏的多尺度模型尚未能够预测慢性条件下的长期适应。项目团队的成员最近发布了一项新型的心肌生长法，将其纳入了心脏和心血管系统的多尺度模型，并在压力超负荷（PO）和体积超负荷（VO）期间准确地预测了长期心脏G＆R。我们团队的其他成员开发了一种基于创新的代理模型，该模型可以准确预测疤痕形成和改造中的愈合梗塞。在这里，我们建议通过以下特定目的整合我们的机电机械学，G＆R和基于代理的模型，并通过以下特定目的对其进行验证：目标1：测试假说，即基于压力和体积过载的响应响应压力依赖性生长法律，预测CRT期间的反向重塑；目的2：检验以下假设：由于梗塞拉伸和血液动力学补偿的相互作用，较大的梗塞促进了存活心肌的偏心肥大； AIM 3：以验证模型预测的G＆R，以响应后界CRT。