Resynchronizing the Failing Heart: Insights from a Multiscale Cardiac Model

重新同步衰竭的心脏：来自多尺度心脏模型的见解

• 批准号: 8066173
• 负责人: NATALIA A. TRAYANOVA
• 金额: $ 61.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066173
• 关键词: Address; American; Basic Science; Behavior; Canis familiaris; Cardiac; Cardiomyopathies; Chronic; Cicatrix; Complex; Computer Simulation; Development; Diagnostic; Diffusion Magnetic Resonance Imaging; Disease; Effectiveness; Environment; Exhibits; Health; Health Care Costs; Health Expenditures; Heart; Heart failure; Hospitalization; Image; Individual; Infarction; Lead; Left; Location; Magnetic Resonance Imaging; Measurement; Mechanics; Medical Economics; Modality; Modeling; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial Contraction; Myocardial Infarction; Patients; Play; Research; Resolution; Role; Selection Criteria; Symptoms; Techniques; Therapeutic; Three-Dimensional Image; Treatment Efficacy; Ventricular; base; economic impact; global health; heart function; improved; insight; mortality; predictive modeling; response; simulation; spatiotemporal; time interval

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.

描述（由申请人提供）：该提案是对“健康与疾病中心脏的预测模型” PAR-08-023的回应。 心力衰竭是发病率和死亡率的主要原因，对全球健康支出产生了重大贡献。心力衰竭患者经常表现出收缩的障碍，这会降低心脏收缩功能。心脏重新同步疗法（CRT）采用双腹性步调来重新坐标心脏的收缩。 CRT已被证明可以改善心力衰竭症状并减少住院治疗，但大约30％的患者未能对该疗法做出反应。当前方法识别潜在反应者的预测能力差反映了对机械性不足的复杂病理生理和机电因素的不完全理解。 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.本应用程序解决了这一需求。 这项研究的总体目的是阐明慢性MI在心力衰竭Dyssyn-Chrony及其对CRT有效性的影响。 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.然后，将使用这种强大的预测建模方法1）提供机械洞察梗塞位置的贡献以及透壁疤痕范围对左心室心力衰竭收缩性障碍的贡献，以及2）确定最佳CRT策略。 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 效力。根据本研究获得的DHF+MI心脏机电行为的新基本科学见解，预计最终会导致缺血性心肌病患者的CRT递送的合理优化，并改善了可行CRT候选者的选择标准。 公共卫生相关性：心脏重新同步疗法（CRT）采用双室性起搏来重新配置心脏的收缩，但大约30％的患者未能对治疗做出反应。在当前强调降低医疗保健成本并优化治疗的环境中，可靠的诊断方法来识别将受益于CRT的患者，并区分那些无法从CRT中受益的患者，将会产生巨大的个人，医学和经济影响。拟议的项目提供了对心力衰竭脉冲和CRT的机械洞察力，可以有助于这种方法的发展。