Resynchronizing the Failing Heart: Insights from a Multiscale Cardiac Model

描述（由申请人提供）：本提案是对PAR-08-023“健康和疾病中心脏的预测模型”的回应。 心力衰竭是发病率和死亡率的主要原因，对全球卫生支出有重大贡献。心力衰竭患者经常表现出收缩不同步，这降低了心脏收缩功能。心脏起搏治疗（CRT）采用双心室起搏来重新协调心脏的收缩。CRT已被证明可以改善心力衰竭症状并减少住院治疗，但约30%的患者对治疗无效。目前确定CRT潜在应答者的方法预测能力较差，反映了对机械不同步基础的复杂病理生理和机电因素的不完全理解。具体而言，鉴于大部分CRT无应答者是慢性心肌梗死（MI）心力衰竭患者，确定慢性MI对不同步心力衰竭（DHF）的贡献以及彻底探索其限制CRT获益的机制对CRT有效性的改善至关重要。本申请解决了这一需求。 本研究的总体目标是阐明慢性MI在心力衰竭不同步中的作用及其对CRT有效性的影响。为了实现所提出的研究目标，我们将从磁共振成像（MRI）和扩散张量MRI扫描中，从分子水平到完整心脏水平，对犬心脏心室电力学进行个体化的基于3D图像的多尺度计算模型，该模型将与DHF和慢性MI相关的有害结构、机械和电生理重塑纳入其中。然后将使用这种强大的预测建模方法1）提供对梗死位置和透壁瘢痕程度对左心室心力衰竭收缩不同步的贡献的机制见解，以及2）确定最佳CRT策略。DHF和慢性MI患者心室电力学预测模型的建立（DHF+MI心脏模型）克服了当前实验技术不能以高时空分辨率同时记录心脏的3D电和机械活动，从而了解慢性心肌梗死对心力衰竭不同步和CRT有效性的影响。在本研究中获得的DHF+MI心脏机电行为的新基础科学见解有望最终导致缺血性心肌病患者CRT输送的合理优化，并改善可行CRT候选人的选择标准。 公共卫生相关性：心脏起搏治疗（CRT）采用双心室起搏来重新协调心脏的收缩，但约30%的患者对治疗无效。在当前强调降低医疗保健成本和优化治疗的环境下，确定将从CRT中受益的患者并区分那些不能受益的患者的稳健诊断方法将具有显著的个人、医疗和经济影响。拟议的项目提供了心力衰竭不同步和CRT，可以有助于这种方法的发展机制的见解。

DESCRIPTION (provided by applicant): This proposal is in response to PAR-08-023 "Predictive Models of the Heart in Health and Disease". Heart failure is a major cause of morbidity and mortality, contributing significantly to global health expenditure. Heart failure patients often exhibit contractile dyssynchrony, which diminishes cardiac systolic function. Cardiac resynchronization therapy (CRT) employs bi-ventricular pacing to re-coordinate the contraction of the heart. CRT has been shown to improve heart failure symptoms and reduce hospitalization, yet approximately 30% of patients fail to respond to the therapy. The poor predictive ability of current approaches to identify potential responders to CRT reflects the incomplete understanding of the complex pathophysiologic and electromechanical factors that underlie mechanical dyssynchrony. Specifically, given that a large portion of CRT non-responders are heart failure patients with chronic myocardial infarction (MI), it is of paramount importance to the improvement in CRT effectiveness that the contribution of chronic MI to dyssynchronous heart failure (DHF) is identified, and the mechanisms by which it limits CRT benefit thoroughly explored. The present application addresses this need. The overall objective of this research is to elucidate the role of chronic MI in heart failure dyssyn- chrony and its effect on CRT effectiveness. To achieve the objective of the proposed research, we will de- flop, from magnetic resonance imaging (MRI) and diffusion tensor MRI scans, individualized 3D image-based multiscale computational models of ventricular electromechanics in canine hearts that incorporate the deleterious- ous structural, mechanical, and electrophysiological remodeling associated with DHF and chronic MI, from the level of the molecule to that of the intact heart. This powerful predictive modeling approach will then be used 1) to provide mechanistic insight into the contribution of the infarct location and of the degree of transmural scar extent to left ventricular heart failure contractile dyssynchrony, and 2) to determine the optimal CRT strategy. The development of a validated predictive model of ventricular electromechanics in the setting of DHF and chronic MI (DHF+MI heart model), as proposed in this application, overcomes the inability of current experimental techniques to simultaneously record the 3D electrical and mechanical activity of the heart with high spatiotemporal resolution, and thus to provide an understanding of the contribution of chronic MI to heart failure dyssynchrony and CRT effectiveness. The new basic-science insights into the electromechanical behavior in the DHF+MI heart to be acquired under this study are expected to ultimately lead to rational optimization of CRT delivery in patients with ischemic cardiomyopathy and to improvements in the selection criteria for viable CRT candidates. PUBLIC HEALTH RELEVANCE: Cardiac resynchronization therapy (CRT) employs bi-ventricular pacing to re-coordinate the contraction of the heart, yet approximately 30% of patients fail to respond to the therapy. In the current environment which emphasizes reducing health care costs and optimizing therapy, robust diagnostic approaches to identify patients that would benefit from CRT and distinguish those who could not, would have a dramatic personal, medical and economic impact. The proposed project offers mechanistic insight into heart failure dissynchrony and CRT that can contribute to the development of such approaches.