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

描述(由申请者提供)：心力衰竭影响了500多万美国人，是导致死亡的主要原因。心力衰竭治疗的一个重要进展是心脏再同步治疗(CRT)，其中使用电子起搏来改善机械泵功能。然而，由于缺乏患者选择和导线放置的预测性客观标准，约30%的接受该手术的患者没有反应。拟议研究的总体目标是利用心脏的多尺度计算模型来预测心脏再同步治疗的患者结果，以解决所涉及的挑战。具体目标有三个：(1)建立人体心脏衰竭的三维多尺度计算模型。虽然已经开发了详细的室电模型并在动物身上进行了验证，但仍需要可比的人类心脏衰竭模型。利用已发表的人体数据和临床可获得的测量数据，我们将开发和测试衰竭心脏中的新的室电模型；(2)开发有效的方法，使心脏的三维多尺度模型的参数与患者特定的临床测量相匹配。我们将开发和测试方法，利用临床测量的室腔几何形状、心内膜活动、血流动力学和泵功能来适应个体心力衰竭患者的心力衰竭基线模型。我们将检验这样一种假设，即调整模型参数的子集将使我们能够匹配我们在心脏再同步治疗患者中获得的局部和全局心室机械功能和同步性；(3)验证用于预测心脏再同步治疗反应的不同步心力衰竭患者特定模型。心脏再同步化可增强中到重度心力衰竭伴室内传导延迟的心功能，并可导致逆转重塑。通过实施心脏起搏和使用患者特定的模型计算全局和局部机械功能，我们建议测试多尺度心室机电模型预测心脏再同步治疗急性功能改善的能力。我们将检验这样一种假设，即模型计算的局部壁应力的减少或局部张力发展的同步性的改善预示着三个月后的反向重塑。我们还将探索使用特定于患者的模型来优化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--心脏无法供应身体对血液的需求--影响了患者生活的方方面面，并减少了日常活动。最近在治疗一种常见类型的心力衰竭--心脏激活慢于正常--方面的一个重大进展是心脏再同步治疗。在这种疗法中，起搏器被用来改善左、右室搏动的时机。然而，约30%的患者因不明原因对这种疗法没有反应。这项提案的具体重点是开发人体心脏衰竭的计算机模型，这些模型是针对患者的。然后，这些模型可以用来预测结果--从而改善需要反应的患者数量--并优化患者的起搏器治疗。

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.