Multi-Scale Modeling of the Failing Heart for Cardiac Rysynchronization Therapy

描述（由申请人提供）：摘要心力衰竭影响超过500万美国人，是死亡的主要原因。心力衰竭治疗的一个重要进展是心脏起搏治疗（CRT），其中电起搏用于改善机械泵功能。然而，由于缺乏患者选择和电极导线放置的预测性客观标准，约30%的患者对手术没有反应。拟议研究的总体目标是解决使用心脏的多尺度计算模型预测心脏栓塞治疗的患者结局所涉及的挑战。具体目标有三：（1）建立衰竭心脏的三维多尺度计算模型。虽然心室电动力学的详细模型已经被开发出来并在动物身上得到验证，但仍需要类似的人类心脏衰竭模型。使用已发表的人体数据和临床可获得的测量结果，我们将开发和测试衰竭人类心脏中心室电动力学的新模型;（2）开发用于将心脏的三维多尺度模型的参数拟合到患者特定临床测量结果的有效方法。我们将开发和测试方法，使失败的人类心脏的基线模型适应个别心力衰竭患者，利用心室腔几何形状，内分泌活动，血液动力学和泵功能的临床测量。我们将检验这样的假设，即调整模型参数的子集将使得有可能匹配我们在适用于心脏起搏治疗的患者中获得的局部和全局心室机械功能和同步性;（3）验证用于预测对心脏起搏治疗的反应的不同步心力衰竭的患者特异性模型。心脏钙化可增强伴有心室内传导延迟的中重度心力衰竭患者的心功能，并可导致逆转性重构。通过实施心室起搏和计算与患者特定的模型的全局和局部的机械功能，我们建议测试心室机电多尺度模型的能力，以预测急性功能改善与心脏起搏治疗。我们将检验以下假设：局部室壁应力的降低或模型计算的局部张力发展同步性的改善对三个月后的逆转性重塑的预测。我们还将探索使用患者特定模型来优化CRT起搏方案。 公共卫生相关性：心脏病不仅是美国公民死亡的主要原因，而且心力衰竭-当心脏无法供应身体对血液的需求时-影响患者生活的各个方面并减少日常活动。在治疗一种常见类型的心力衰竭（其中心脏激活比正常慢）方面，最近的一个重大进展是心脏硬化疗法。在这种治疗中，起搏器用于改善左心室和右心室的搏动时间。然而，约30%的患者对这种治疗没有反应，原因不明。该提案的具体重点是开发针对患者的人类心脏衰竭的计算机模型。然后，这些模型可以用于预测结果-从而提高响应的患者数量-并为患者优化这种起搏器治疗。

DESCRIPTION (provided by applicant): Abstract Heart failure affects over five million Americans and is a leading cause of death. A significant recent advancement in the treatment of heart failure has been cardiac resynchronization therapy (CRT) in which electrical pacing is used to improve mechanical pump function. However, about 30% of patients indicated for the procedure do not respond owing to a lack of predictive objective criteria for patient selection and lead placement. The overall goal of the proposed research is to address the challenges involved using multi-scale computational models of the heart for predicting patient outcomes of cardiac resynchronization therapy. There are three specific aims: (1) To develop three-dimensional multi-scale computational models of the failing human heart. While detailed models of ventricular electromechanics have already been developed and validated for animals, there is a need for comparable models of the failing human heart. Using published human data and clinically accessible measurements, we will develop and test a new model of ventricular electromechanics in the failing human heart; (2) To develop efficient methods for fitting parameters of three- dimensional multi-scale models of the heart to patient-specific clinical measurements. We will develop and test methods for adapting the baseline model of the failing human heart to individual heart failure patients making use of clinical measurements of ventricular chamber geometry, endocardial activity, hemodynamics, and pump function. We will test the hypothesis that adjusting a subset of model parameters will make it possible to match regional and global ventricular mechanical function and synchrony that we obtain in patients indicated for cardiac resynchronization therapy; (3) To validate patient-specific models of dyssynchronous heart failure for predicting responses to cardiac resynchronization therapy. Cardiac resynchronization augments cardiac function in moderate-to-severe heart failure with an intraventricular conduction delay, and can lead to reverse remodeling. By imposing ventricular pacing and computing global and local mechanical function with the patient-specific models, we propose to test the ability of multi-scale models of ventricular electromechanics to predict acute functional improvements with cardiac resynchronization therapy. We will test the hypothesis that the reduction in regional wall stress or an improvement in the synchrony of regional tension development computed by the model in response to resynchronization therapy predicts reverse remodeling after three months. We will also explore the use of patient-specific models to optimize the CRT pacing protocol. PUBLIC HEALTH RELEVANCE: Not only is cardiac disease the leading cause of death among citizens of the USA, but heart failure - when the heart fails to supply the body's demand of blood - affects all aspects of the lives of patients and curtails everyday activities. A significant recent advancement in the treatment of a common type of heart failure - in which the heart is activated slower than normal - has been cardiac resynchronization therapy. In this therapy, a pacemaker is used to improve the timing of the beating of the left and right ventricles. However, about 30% of patients do not respond to this therapy for unknown reasons. The specific focus of this proposal is the development of computer models of failing human hearts, which are patient-specific. The models can then be used to predict the outcome - and thus to improve the number of patients to respond - and optimize this pacemaker therapy for patients.