Development of Channel-based Electrophysiology Simulator using CellML

Marcellinus Aroli,Qauli Ali Ikhsanul,Kimoo Lim(임기무) 대한기계학회 2020 대한기계학회 춘추학술대회 Vol.2020 No.8

Prediction of Sensitivity in Cardiac Alternans According to the Combinations of Ion Channel Conductivity using Human Ventricular Electrophysiological Population Model

정다운,Aroli Marcellinus,임기무 대한기계학회 2021 대한기계학회 춘추학술대회 Vol.2021 No.4

심근세포에서 활동전위 간의 교대 현상인 alternans은 일반적으로 심박수가 높을 때 발생하여 심장 부정맥을 유발하는 것으로 알려져 있으나, 임상에서 관찰되는 alternans의 일부는 낮은 심박수 조건에서 발생하여 심장 부정맥의 유발가능성이 증가시킨다. 하지만, 심장의 전기생리학적 조건은 너무 방대하고 다양하여 alternans이 어떠한 조건에서 더 쉽게 발생하는지에 대해서는 밝혀지지 않았다. 따라서, 본 연구에서는 심근세포의 10개의 이온 채널 전도도 변화에 따른 alternans의 발생 여부를 확인하고 각 이온 채널들의 변화 조합을 통해 alternans의 발생에 가장 많은 영향을 미치는 이온 채널을 규명하였다. 이를 위해 Ten Tusscher 인간 심실 세포 모델을 통해 10개의 이온 채널의 전기전도도에 변화가 없을 때와 50% 감소하였을 때, 150% 증가하였을 때에 따른 조합 조건을 구현하였다. 그에 따라 생성된 310개의 이온 채널 전도도 조합 조건에서 alternans 유발 프로토콜을 기반으로 시뮬레이션을 수행하였다. 그후, alternans이 발생하였을 때의 자극 주기(AOCL)와 그 때의 평균 활동 전위기간(AO APD)를 계산하고 다차원 밀도 모델을 통해 alternans의 유발에 가장 많은 영향을 미치는 이온 채널과 전기전도도 조합 조건을 확인하였다. 그 결과, AOCL과 AO APD에 민감하게 변화를 주는 이온 채널은 각각 달랐으나, 공통적으로 inward K+ 채널과 rapid rectifier K+ 채널의 전도도 변화에 가장 민감하게 반응하였다. 본 연구의 결과는 심근 세포에서 alternans 발생의 원인과 메커니즘을 세포의 전기생리학적 가변성을 기반으로 이해하는 데 도움을 줄 수 있을 것으로 예상한다.

Assessment Pro-Arrhythmic Drug with An Explainable XGBoost-Based Approach

유넨다,Aroli Marcellinus,Muhammad Adnan Pramudito,임기무 대한기계학회 2023 대한기계학회 춘추학술대회 Vol.2023 No.4

약물의 염전성 부정맥 유발 예측 지표로서 심장의 전기생리학적 특징 값들의 검증

유예담,정다운,Aroli Marcellinus,임기무 대한의용생체공학회 2022 의공학회지 Vol.43 No.1

The Comprehensive in vitro Proarrhythmic Assay(CiPA) project was launched for solving the hERG assay problem of being classified as high-risk groups even though they are low-risk drugs due to their high sensitivity. CiPA presented a protocol to predict drug toxicity using physiological data calculated based on the in-silico model. in this study, features calculated through the in-silico model are analyzed for correlation of changing action potential in the near future, and features are verified through predictive performance according to drug datasets. Using the O'Hara Rudy model modified by Dutta et al., Pearson correlation analysis was performed between 13 features(dVm/dtmax, APpeak, APresting, APD90, APD50, APDtri, Capeak, Caresting, CaD90, CaD50, CaDtri, qNet, qInward) calculated at 100 pacing, and between dVm/dtmax_repol calculated at 1,000 pacing, and linear regression analysis was performed on each of the 12 training drugs, 16 verification drugs, and 28 drugs. Indicators showing high coefficient of determination(R2) in the training drug dataset were qNet 0.93, AP resting 0.83, APDtri 0.78, Ca resting 0.76, dVm/dtmax 0.63, and APD90 0.61. The indicators showing high determinants in the validated drug dataset were APDtri 0.94, APD90 0.92, APD50 0.85, CaD50 0.84, qNet 0.76, and CaD90 0.64. Indicators with high coefficients of determination for all 28 drugs are qNet 0.78, APD90 0.74, and qInward 0.59. The indicators vary in predictive performance depending on the drug data- set, and qNet showed the same high performance of 0.7 or more on the training drug dataset, the verified drug data- set, and the entire drug dataset.

qNet-T as a new biomarker for assessment of drug cardiac toxicity from the cardiac tissue Model

Ulfa Latifa Hanum,Aroli Marcellinus,임기무 대한기계학회 2023 대한기계학회 춘추학술대회 Vol.2023 No.4

A Computational Study of the Efficacy of Mexiletine Therapy on Patients with A1656D Mutation Using a 3D Cardiac Electrophysiological Model

Ali Ikhsanul Qauli,Yedam Yoo,Aroli Marcellinus,Ki Moo Lim 대한기계학회 2022 대한기계학회 춘추학술대회 Vol.2022 No.4

합성곱 신경망을 사용한 미분된 활동전위 형상에 따른 약물의 부정맥 위험도 분류

정다운(Da Un Jeong),Aroli Marcellinus,임기무(Ki Moo Lim) 대한기계학회 2021 대한기계학회 춘추학술대회 Vol.2021 No.11

CiPA projects for assessing proarrhythmic drugs suggested a logistic regression model using qNet as the Torsade de Pointes risk assessment biomarker, obtained from In-silico simulation. However, In-silico simulation requires high-performance computation resources and a lot of times. Thus, this study proposed a deep CNN model using differential action potential (AP) shapes to classify three proarrhythmic risk levels: high, intermediate, and low. We performed an In-silico simulation and got AP shapes with drug effects using IC50 and Hill coefficients of 28 drugs released by CiPA groups. Then, we trained the deep CNN model with the differential AP shapes of 12 drugs and tested it with those of 16 drugs. Our model had a better performance for classifying the proarrhythmic risk of drugs than the traditional logistic regression model using qNet. The classification accuracy was 98% for high-risk level drugs, 94% for intermediate-risk level drugs, and 89% for low-risk level drugs.

Application of qNet Variability Through the Convolution Neural Network for Assessment of Drug Proarrhythmicity

Rakha Zharfarizqi Danadibrata,Da Un Jeong,Aroli Marcellinus,Ki Moo Lim 대한기계학회 2021 대한기계학회 춘추학술대회 Vol.2021 No.11

As part of the Comprehensive in vitro Proarrhythmia Assay initiative, methodologies for predicting the incidence of Torsade de Pointes (TdP) by drugs were recently developed, leading to the importance of assessment using In-silico simulations. We performed the In-silico simulation using the ventricular cell model suggested by Sara Dutta using IC50 and hill coefficient as the input that we got from the In-vitro experiment of drug-response of ion channels. From the In-silico simulation, we obtained the qNet variability according to pace. To increase drug toxicity evaluation performance, we proposed deep CNN model utilized the qNet variability as an input and classify into high-risk, intermediate-risk, and low-risk. We trained the model with 12 drugs and tested it with the remaining 16 drugs. In the high-risk , the proposed CNN model had an AUC of 0.90, 0.75 in the intermediate-risk, and 0.82 in the low-risk.

다형 심실빈맥의 예측을 위한 dVm/dt_{Max_repol}의 이온채널 전도도에 대한 민감도 분석

정다운,유예담,임기무,Jeong, Da Un,Yoo, Yedam,Marcellinus, Aroli,Lim, Ki Moo 대한의용생체공학회 2022 의공학회지 Vol.43 No.5

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 necessarily 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/dt_{max_repol}). This study aimed to predict the sensitivity of dVm/dt_{max_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 g_NaL, g_Kr, g_Ks, g_to, g_K1, and g_CaL. Additionally, we verified the availability of dVm/dt_{max_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 sixion channel conductances, dVm/dt_{max_repol} and qNet responded most sensitively to the change in g_Kr, followed by g_NaL. Furthermore, dVm/dt_{max_repol} showed a statistically significant high negative correlation with qNet. The dVm/dt_{max_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/dt_{max_repol} as a new biomarker metric for TdP risk assessment.

심근세포의 전기생리학적 불안정성의 지표로서의 APD alternan onset cycle length와 APD90의 비

이현수(Hyeon Su Lee),정다운(Da Un Jeong),Aroli Marcellinus,임기무(Ki Moo Lim) 한국정보기술학회 2021 Proceedings of KIIT Conference Vol.2021 No.6

심장부정맥 중 심실세동 (VF)은 발생 후 수분 내에 심장 급사를 유발할 수 있는 위험한 심장질환이다. 이러한 심장 부정맥의 유발원인은 현재까지 정확하게 밝혀지지 않았다. 따라서 본 연구는 교대맥의 발생 기전을 확인하고자 인간 심실 세포 모델을 사용한 밀도 시뮬레이션을 수행하였다. 그리고 10개의 이온 채널 전기전도도 비율 조합에 따른 Alternans onset cycle length (AOCL)과 평균 APD90의 비를 계산하여 심근세포의 전기생리학적 불안정성을 확인하였다. 이를 위해 임상적인 페이싱 조건에서 이온채널 전도도 변화 조합에 따른 단일 세포의 전기생리학적 시뮬레이션을 수행하였으며, 밀도시뮬레이션 지도를 사용하여 AOCL과 평균 APD90의 비를 효과적으로 표현하였다. 결론적으로 AOCL과 평균 APD<SUP>90 </SUP>비의 값이 클수록 교대맥 발생 위험이 크며, 교대맥의 발생 위험에 가장 큰 영향을 미치는 이온 채널은 gk1인 것을 밝혀냈다. 본 연구에서 사용한 AOCL과 평균 APD90의 비는 심근세포의 전기생리학적 불안정성을 평가하기 위한 지표로 사용될 수 있으며, 이러한 결과는 향후 심장부정맥 메커니즘을 규명하기 위한 연구에 도움이 될 수 있을 것이다. Ventricular fibrillation is a dangerous heart condition that can cause sudden cardiac death within minutes of onset. The cause of these heart arrhythmias has not yet been determined. In this study, we performed density modeling using a human ventricular tissue model to identify the mechanism in the generation of alternans. Then, we calculated the ratio of Alternans onset cycle length (AOCL) and mean APD90 according to the combination of 10-ion channel conductance in variation to confirm the electrophysiological instability of myocardial cells. For this purpose, we performed electrophysiological simulations at the single-cell level using the clinical pacing protocol according to the variation of ion channel conductances and effectively expressed the ratio of AOCL and mean APD90 using a population map. In conclusion, we found that the greater the ratio of AOCL and mean APD90, the greater the risk of alternans generation and that gK1 was the ion channel that most influences the risk of alternans generation. The ratio of AOCL and mean APD90 used in this study can be used as an index for evaluating electrophysiological instability in myocardial cells. These results may be helpful in future studies investigating the cardiac arrhythmia mechanism.