Computer Model of the Canine Ventricle

犬心室的计算机模型

• 批准号: 6835191
• 负责人: Robert F Gilmour
• 金额: $ 47.84万
• 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/6835191
• 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）： 心室颤动 (VF) 继发的猝死仍然是美国死亡的主要原因。 VF 的治疗在很大程度上是无效的，主要是因为 VF 的潜在机制尚不清楚，并且由于无法精确改变特定离子电流而阻碍了对潜在机制的探索。为了解决这些问题，我们建议开发一个数据驱动的犬心室电行为计算机模型。具体来说，我们将： 1) 实验表征从心室特定区域获得的肌细胞中的 IKr、ICa、IK1、INaCa 和晚期钠电流 INa。将研究这些特殊电流，因为它们在复极化中发挥重要作用。将使用以快速起搏速率记录的动作电位作为命令波形来测量它们，以复制快速心律失常期间的当前行为。 2) 使用特定目标 1 下获得的时间序列和稳态电流数据，为每个解剖区域的每个离子电流开发确定性 Hodgkin-Huxley 和 Markov 模型。优化例程将用于通过将模型电流与实验数据进行比较来确定模型中的未知参数。 3）将个体电流模型纳入区域特异性单犬心室肌细胞的计算机模型中。将开发基底和心尖起源的左心室和右心室心外膜、心肌中层和心内膜肌细胞以及右心室和左心室浦肯野肌细胞的模型。 4) 使用修改版本的相场方法将单细胞模型纳入犬心室的 3D 计算机模型中。该模型将使用可移植并行版本的代码编写，并在并行计算机和多节点集群上运行。最初，该模型将由左心室、心外膜层、心肌中层和心内膜层组成。随后将构建更详细的解剖模型，包括希氏-浦肯野系统和右心室。 5) 使用 3-D 模型来测试 VF 发展的候选假设。初始测试将确定抑制动态电不均匀性是否可以预防心室颤动。我们提出的心室电功能计算机模型将为药物发现以及抗心动过速和抗纤颤起搏和除颤算法的评估提供宝贵的工具。因此，该模型预计将对致命性心律失常的诊断和治疗产生重大影响。