Sensitivity Analysis of Ion Channel Conductance on Myocardial Electromechanical Delay: Computational Study

Qauli, Ali Ikhsanul; Marcellinus, Aroli; Lim, Ki Moo

doi:10.3389/fphys.2021.697693

Cited by 3 publications

(2 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since the drug combination’s effect is applied to multiple ion channels, the overall effect can be very nonlinear and may result in various responses for each biomarker. For example, qNet, as a well-known TdP metric score, can be affected strongly by the change of channel 6 , and likewise, the variation of CaD90 is strongly influenced by the alteration of channel 40 . Therefore, one may interpret that from panel (B) in Fig.…”

Section: Discussionmentioning

confidence: 99%

In silico assessment on TdP risks of drug combinations under CiPA paradigm

Qauli

Marcellinus

Setiawan

et al. 2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

Researchers have recently proposed the Comprehensive In-vitro Proarrhythmia Assay (CiPA) to analyze medicines’ TdP risks. Using the TdP metric known as qNet, numerous single-drug effects have been studied to classify the medications as low, intermediate, and high-risk. Furthermore, multiple medication therapies are recognized as a potential method for curing patients, mainly when limited drugs are available. This work expands the TdP risk assessment of drugs by introducing a CiPA-based in silico analysis of the TdP risk of combined drugs. The cardiac cell model was simulated using the population of models approach incorporating drug-drug interactions (DDIs) models on several ion channels for various drug pairs. Action potential duration (APD90), qNet, and calcium duration (CaD90) were computed and analyzed as biomarker features. The drug combination maps were also used to illustrate combined medicines' TdP risk. We found that the combined drugs alter cell responses in terms of biomarkers such as APD90, qNet, and CaD90 in a highly nonlinear manner. The results also revealed that combinations of high-risk with low-risk and intermediate-risk with low-risk drugs could result in compounds with varying TdP risks depending on the drug concentrations.

show abstract

Section: Discussionmentioning

confidence: 99%

In silico assessment on TdP risks of drug combinations under CiPA paradigm

Qauli

Marcellinus

Setiawan

et al. 2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Since the DDIs (BI model) is applied to multiple ion channels, the overall effect can be very nonlinear and may result in various responses for each biomarker. For example, qNet, as a well-known TdP metric score, can be affected strongly by the change of K r channel 6 and likewise, the variation of CaD90 is strongly in uenced by the alteration of CaL channel 33 . Therefore, we may interpret that from panel (B) in Fig.…”

Section: Discussionmentioning

confidence: 99%

In Silico Deterministic Assessment on TdP Risks of Drug-drug Interactions under CiPA Paradigm

Qauli

Marcellinus

Setiawan

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Researchers have recently proposed the Comprehensive In-vitro Proarrhythmia Assay (CiPA) to analyze medicines’ TdP risks. Using the TdP metric known as qNet, numerous single-drug effects have been studied to classify the medications as low, intermediate, and high-risk. Furthermore, multiple medication therapies are recognized as a potential method for curing patients, mainly when a limited number of drugs are available. This work expands the TdP risk assessment of drugs by introducing a CiPA-based in silico analysis of the TdP risk of combined drugs. The cardiac cell model was simulated using the population of models approach incorporating drug-drug interactions (DDIs) models for various two-drug combinations. Action potential duration (APD90), qNet, and calcium duration (CaD90) were computed and analyzed as features. The drug combination maps were also utilized to illustrate the impact of DDIs on the TdP risk of combined medicines. We found that the DDIs of the combined drugs alter cell responses in terms of biomarkers such as APD90, qNet, and CaD90 in a highly nonlinear manner. The results also revealed that combinations of high-risk with low-risk and intermediate-risk with low-risk drugs could result in compounds with varying TdP risks depending on the drug concentrations.

show abstract

Modeling incomplete penetrance in long QT syndrome type 3 through ion channel heterogeneity: an in silico population study

Miller

Moise

Weinberg

2023

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Many cardiac diseases are characterized by an increased late sodium current, including heart failure, hypertrophic cardiomyopathy, and inherited long QT syndrome type 3 (LQT3). The late sodium current in LQT3 is caused by a gain-of-function mutation in the voltage-gated sodium channel Nav1.5. Despite a well-defined genetic cause of LQT3, treatment remains inconsistent due to incomplete penetrance of the mutation and variability of anti-arrhythmic efficacy. Here, we investigate the relationship between LQT3-associated mutation incomplete penetrance and variability in ion channel expression, simulating a population of 1,000 "individuals" using the O'Hara-Rudy model of the human ventricular myocyte. We first simulate healthy electrical activity (i.e., in the absence of a mutation), then incorporate heterozygous expression for three LQT3-associated mutations (Y1795C, I1768V, and ΔKPQ), to directly compare the effects of each mutation on individuals across a diverse population. For all mutations, we find that susceptibility, defined either by the presence of an early afterdepolarization (EAD) or prolonged action potential duration (APD), primarily depends on the balance between the conductance of IKr and INa, for which individuals with a higher IKr-INa ratio are less susceptible. Further, we find distinct differences across the population, observing individuals susceptible to zero, one, two, or all three mutations. Individuals tend to be less susceptible with an appropriate balance of repolarizing currents, typically via increased IKs or IK1. Interestingly, the more critical repolarizing current is mutation-specific. We conclude that balance between key currents plays a significant role in mutant-specific presentation of the disease phenotype in LQT3.

show abstract

Sensitivity Analysis of Ion Channel Conductance on Myocardial Electromechanical Delay: Computational Study

Cited by 3 publications

References 61 publications

In silico assessment on TdP risks of drug combinations under CiPA paradigm

In silico assessment on TdP risks of drug combinations under CiPA paradigm

In Silico Deterministic Assessment on TdP Risks of Drug-drug Interactions under CiPA Paradigm

Modeling incomplete penetrance in long QT syndrome type 3 through ion channel heterogeneity: an in silico population study

Contact Info

Product

Resources

About