From channel protein to body surface ECG: Investigating electrocardiographic effects of ion channel mutations using computational heart models

在过去的十年里，影响心脏电生理学的突变一直是科学研究的热点。通过改变特定的离子通道特征，这些突变与发生室性心律失常和猝死的高风险相关。虽然DNA分析增强了我们对潜在过程的理解，但个体间的差异阻碍了定量预测突变通道对心电的影响。该项目专注于使用计算方法识别和区分一种名为长QT综合征(LQTS)的心脏通道病的突变基因类型。基于MRI构建了受影响患者的几何数据集。结合详细的心脏电生理数学模型，对个体心脏解剖结构的兴奋传导进行了模拟。正向计算允许确定体表上的电信号和提取标准的心电导联。为了验证和优化计算模型，将计算的体表信号与患者的通道心电记录进行了比较。交感神经系统的影响被包括在LQTS的计算机模型中，因为心率和肾上腺素能调节影响离子通道特性，从而影响心脏活动。特别是，T波形态在不同LQTS基因型之间的差异将被用来确定心电电极位置，从而允许一种新的基于心电的突变基因型的识别。

Mutations that impact on cardiac electrophysiology have been of scientific interest throughout the last decade. By altering specific ion channel characteristics these mutations are associated with a high risk for the development of ventricular arrhythmias and sudden death. Although DNA analysis has enhanced our understanding of the underlying processes, inter-individual differences impede to quantitatively predict the effects of the mutated channels on the ECG. This project is focused on identifying and discriminating genotypes of mutations in a cardiac channelopathy called Long QT syndrome (LQTS) using a computational approach. Geometrical datasets of affected patients are constructed based on MRI. Together with detailed mathematical models of cardiac electrophysiology, the excitation conduction on the individual cardiac anatomy is simulated. A forward calculation allows the determination of electrical signals on the body surface and the extraction of standard ECG leads. For verification and optimization of the computational model, this calculated signals on the body surface is compared to 64 channel ECG recordings from patients. Effects of the sympathetic nervous system are included into the computer model of the LQTS as heart rate and adrenergic regulation influence ion channel characteristics and thereby cardiac activity. Especially the differences of the T wave morphology between the genotypes of LQTS will be used to derive ECG electrode positions that allow a new ECG-based discrimination of the mutation genotype.