Computer Model of the Canine Ventricle

描述(由申请人提供)： 继发于室颤(VF)的猝死仍然是美国人死亡的主要原因。VF的治疗在很大程度上是无效的，主要是因为VF的潜在机制还没有被很好地理解，并且由于无法精确地改变特定的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脑室电行为的计算机模型。具体地说，我们将：1)对从脑室特定区域获得的心肌细胞的IKR、ICA、IK1、INaCa和晚期钠电流Ina进行实验表征。这些特殊的电流将被研究，因为它们在复极过程中起着重要作用。他们将使用以快速起搏频率记录的动作电位作为命令波形进行测量，以复制快速性心律失常期间的电流行为。2)利用在特定目标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流建立确定性的Hodgkin-Huxley模型和马尔可夫模型1。优化程序将通过比较模型电流和实验数据来确定模型中的未知参数。3)将单个电流的模型合并到特定区域的单个犬心室肌细胞的计算机模型中。将建立基础和心尖来源的左、右室心外膜、中层和心内膜肌细胞模型，以及右和左室浦肯野肌细胞模型。4)使用改进的相场法将单细胞模型合并到犬脑室的三维计算机模型中。该模型将使用可移植的并行代码版本编写，并在并行计算机和多节点集群上运行。最初，该模型将由左心室组成，包括心外膜、心肌中层和心内膜层。随后将构建更详细的解剖模型，以包括希氏-浦肯野系统和右室。5)使用三维模型对VF发展的候选假设进行检验。初步测试将确定抑制动态电性异质性是否能防止VF。我们提出的心室电功能的计算机模型将为药物开发和抗心动过速、抗纤颤起搏和除颤算法的评估提供宝贵的工具。因此，该模型有望对致命性心律失常的诊断和治疗产生重大影响。

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.