Computer Model of the Canine Ventricle

犬心室的计算机模型

• 批准号: 7209930
• 负责人: Robert F Gilmour
• 金额: $ 11.41万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7209930
• 关键词: action potentials; calcium channel; cardiac myocytes; computer simulation; dogs; endocardium; heart Purkinje' s fiber; heart electrical activity; heart ventricle; microelectrodes; model design /development; pericardium; potassium channel; sodium channel; tachycardia; ventricular fibrillation; voltage /patch clamp

DESCRIPTION (provided by applicant): Sudden death secondary to ventricular fibrillation (VF) remains a leading cause of mortality in the US. Therapy for VF has been largely ineffectual, principally because the underlying mechanisms for VF are not well understood and probing for potential mechanisms has been hindered by the inability to precisely modify specific ionic currents. To address these issues, we propose to develop a data-driven computer model of the electrical behavior of the canine ventricle. Specifically, we will: 1) Experimentally characterize IKr, ICa, IK1, INaCa, and the late sodium current INa in myocytes obtained from specific regions of the ventricles. These particular currents will be studied because they play a significant role in repolarization. They will be measured using action potentials recorded at rapid pacing rates as the command waveforms, to replicate current behavior during a tachyarrhythmias. 2) Develop deterministic Hodgkin-Huxley and Markov models for each ionic current for each anatomical region using the time series and steady state current data obtained under Specific Aim 1. Optimization routines will be used to determine unknown parameters in the models by comparing the model current to experimental data. 3) Incorporate the models of the individual currents into computer models of region-specific single canine ventricular myocytes. Models of left and right ventricular epicardial, midmyocardial and endocardial myocytes of basal and apical origin and of right and left ventricular Purkinje myocytes will be developed. 4) Incorporate the single cell models into a 3-D computer model of the canine ventricle using a modified version of the phase field method. The model will be written using a portable parallel version of the code and run on a parallel computer and multi-node clusters. Initially, the model will consist of the left ventricle, with epicardial, midmyocardial and endocardial layers. More detailed anatomical models subsequently will be constructed to include the His-Purkinje system and the right ventricle. 5) Use the 3-D model to test candidate hypotheses for the development of VF. The initial test will determine whether suppressing dynamic electrical heterogeneity prevents VF. The computer model of ventricular electrical function we propose will provide an invaluable tool for drug discovery and the evaluation of algorithms for anti-tachycardia and anti-fibrillatory pacing and defibrillation. As such, the model is expected to have a significant impact on the diagnosis and treatment of lethal heart rhythm disorders.

描述（由申请人提供）： 继发于心室纤颤（VF）的猝死仍然是美国死亡率的主要原因。 VF的治疗基本上是无效的，主要是因为VF的基本机制尚不清楚，并且无法精确修改特定离子电流的探索受到了探测潜在机制。为了解决这些问题，我们建议开发犬心室电气行为的数据驱动计算机模型。具体而言，我们将：1）实验表征IKR，ICA，IK1，INACA和从心室特定区域获得的肌细胞中的晚期钠电流INA。这些特殊的电流将被研究，因为它们在复极化中起着重要作用。它们将使用以快速起搏速率记录为命令波形的动作电位来测量它们，以在心律失常中复制当前行为。 2）使用时间序列和特定目标中获得的稳态电流数据为每个解剖区域的每个离子电流开发确定性的Hodgkin-Huxley和Markov模型。将使用优化例程来通过比较模型电流与实验数据来确定模型中的未知参数。 3）将单个电流的模型纳入区域特异性单犬心室心肌细胞的计算机模型中。将开发左右心室心外膜，中膜和心内膜心肌的模型，以及右室和左心室Purkinje肌细胞的模型。 4）使用相位场方法的修改版本将单细胞模型纳入犬心室的3-D计算机模型。该模型将使用代码的便携式并行版本编写，并在并行计算机和多节点群集上运行。最初，该模型将由左心室组成，并具有心外膜，中膜和心内膜层。随后将构建更详细的解剖模型，包括His-Purkinje系统和右心室。 5）使用3-D模型来测试VF开发的候选假设。初始测试将确定抑制动态电异质性是否阻止VF。我们提出的心室电气功能的计算机模型将为药物发现提供宝贵的工具，并评估抗心痛和抗纤维化起搏和除颤算法。因此，该模型有望对致命心律疾病的诊断和治疗产生重大影响。