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KMID : 1137820220430050331
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의공학회지
2022 Volume.43 No. 5 p.331 ~ p.340
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Sensitivity Analysis of dVm/dtMax_repol to Ion Channel Conductance for Prediction of Torsades de Pointes Risk
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Jeong Da-Un
Yoo Ye-Dam
Marcellinus Aroli
Lim Ki-Moo
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Abstract
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Early afterdepolarization (EAD), a significant cause of fatal ventricular arrhythmias including Torsade de Pointes (TdP) in long QT syndromes, is a depolarizing afterpotential at the plateau or repolarization phase in action potential (AP) profile early before completing one pace. AP duration prolongation is related to EAD but is not nec- essarily accounted for EAD. Several computational studies suggested EAD can form from an abnormality in the late plateau and/or repolarization phase of AP shape. In this sense, we hypothesized the slope during repolarization has the characteristics to predict TdP risk, mainly focusing on the maximum slope during repolarization (dVm/dtmax_repol). This study aimed to predict the sensitivity of dVm/dtmax_repol to ion channel conductances as a TdP risk metric through a population simulation considering multiple effects of simultaneous reduction in six ion channel conductances of gNaL, gKr, gKs, gto, gK1, and gCaL. Additionally, we verified the availability of dVm/dtmax_repol for TdP risk prediction through the correlation analysis with qNet, the representative TdP metric. We performed the population simulations based on the methodology of Gemmel et al. using the human ventricular myocyte model of Dutta et al. Among the six- ion channel conductances, dVm/dtmax_repol and qNet responded most sensitively to the change in gKr, followed by gNaL. Furthermore, dVm/dtmax_repol showed a statistically significant high negative correlation with qNet. The dVm/dtmax_repol values were significantly different according to three TdP risk levels of high, intermediate, and low by qNet (p<0.001). In conclusion, we suggested dVm/dtmax_repol as a new biomarker metric for TdP risk assessment.
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KEYWORD
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dVm/dtmax_repol, Torsades de Pointes (TdP), Population model, Ion channel conductance, Human ventricular cell model
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