Cunjin Luo

The virtual heart as a platform for screening drug cardiotoxicity

To predict the safety of a drug at an early stage in its development is a major challenge as there is a lack of in vitro heart models that correlate data from preclinical toxicity screening assays with clinical results. A biophysically detailed computer model of the heart, the virtual heart, provides a powerful tool for simulating drug–ion channel interactions and cardiac functions during normal and disease conditions and, therefore, provides a powerful platform for drug cardiotoxicity screening. In this article, we first review recent progress in the development of theory on drug–ion channel interactions and mathematical modelling. Then we propose a family of biomarkers that can quantitatively characterize the actions of a drug on the electrical activity of the heart at multi‐physical scales including cellular and tissue levels. We also conducted some simulations to demonstrate the application of the virtual heart to assess the pro‐arrhythmic effects of cisapride and amiodarone. Using the model we investigated the mechanisms responsible for the differences between the two drugs on pro‐arrhythmogenesis, even though both prolong the QT interval of ECGs. Several challenges for further development of a virtual heart as a platform for screening drug cardiotoxicity are discussed.

In silico assessment of the effects of quinidine, disopyramide and E-4031 on short QT syndrome variant 1 in the human ventricles

Aims Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro-arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1. Therefore, this study aimed to assess the potential effects of E-4031, disopyramide and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology. Methods The ten Tusscher et al. biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate IKr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the IKr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channel-blocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values from literatures. Effects of drugs on cell AP duration (APD), effective refractory period (ERP) and pseudo-ECG traces were calculated. Effects of drugs on the ventricular temporal and spatial vulnerability to re-entrant excitation waves were measured. Re-entry was simulated in both 2D regular and realistic ventricular tissue. Results At the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell APD at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90. Quinidine prolonged and decreased the maximal transmural AP heterogeneity (δV); this led to the decreased transmural heterogeneity of APD across the 1D strand. Quinidine caused QT prolongation and a decrease in the T-wave amplitude, and increased ERP and decreased temporal susceptibility of the tissue to the initiation of re-entry and increased the minimum substrate size necessary to prevent re-entry in the 2D regular model, and further terminated re-entrant waves in the 2D realistic model. Quinidine exhibited significantly better therapeutic effects on SQT1 than E-4031 and disopyramide. Conclusions The simulated pharmacological actions of quinidine exhibited antiarrhythmic effects on SQT1. This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients.

EFFECTS OF ACUTE GLOBAL ISCHEMIA ON RE-ENTRANT ARRHYTHMOGENESIS: A SIMULATION STUDY

Sudden cardiac death is mainly caused by arrhythmogenesis. For a functional abnormal heart, such as an ischemic heart, the probability of arrhythmia occurring is greatly increased. During myocardial ischemia, re-entry is prone to degenerate into ventricular fibrillation (VF). Therefore it has important meaning to investigate the intricate mechanisms underlying VF under an ischemic condition in order to better facilitate therapeutic interventions. In this paper, to analyze the functional influence of acute global ischemia on cardiac electrical activity and subsequently on re-entrant arrhythmogenesis, we take into account three main pathophysiological consequences of ischemia: hyperkalaemia, acidosis, and anoxia, and develop a 3D human ventricular ischemic model that combines a detailed biophysical description of the excitation kinetics of human ventricular cells with an integrated geometry of human ventricular tissue which incorporates fiber direction anisotropy and the stimulation activation sequence. The results show that under acute global ischemia, the tissue excitability and the slope of ventricular cellular action potential duration restitution (APDR) are greatly decreased. As a result, the complexity of VF activation patterns is reduced. For the three components of ischemia, hyperkalaemia is the dominant contributor to the stability of re-entry under acute global ischemia. Increasing [K+]o acts to prolong the cell refractory period, reduce the tissue excitability and slow the conduction velocity. Our results also show that VF can be eliminated by decreasing cellular excitability, primarily by elevating the concentration value of extracellular K+.

Modelling the effects of chloroquine on KCNJ2 -linked short QT syndrome

A gain-of-function KCNJ2 D172N mutation in KCNJ2-encoded Kir2.1 channels underlies one form of short QT syndrome (SQT3), which is associated with increased susceptibility to arrhythmias and sudden death. Anti-malarial drug chloroquine was reported as an effective inhibitor of Kir2.1 channels. Using biophysically-detailed human ventricle computer models, this study assessed the effects of chloroquine on SQT3. The ten Tusscher et al. model of human ventricular cell action potential was modified to recapitulate functional changes in the inward rectifier K+ current (IK1) due to heterozygous and homozygous forms of the D172N mutation. Mutant formulations were incorporated into multi-scale models. The blocking effects of chloroquine on ionic currents were modelled using IC50 and Hill coefficient values from literatures. Effects of chloroquine on action potential duration (APD), effective refractory period (ERP) and pseudo-ECGs were quantified. It was shown that chloroquine caused a dose-dependent reduction in IK1, prolonged APD, and decreased the maximum voltage heterogeneity. Chloroquine prolonged QT interval and declined the T-wave amplitude. Although chloroquine reduced tissue’s temporal vulnerability, it increased the minimum substrate size necessary for sustaining re-entry. The actions of chloroquine decreased arrhythmia risk, due to the reduced tissue vulnerability, prolonged ERP and wavelength of re-entrant excitation waves, which in combination prevented and terminated re-entry in the tissue models. In conclusion, the results of this study provide new evidence that the anti-arrhythmic effects of chloroquine on SQT3 and, by extension, to the possibility that chloroquine may be a potential therapeutic agent for SQT3 treatment.

Effects of amiodarone on short QT syndrome variant 3 in human ventricles: a simulation study

BackgroundShort QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mutation to the KCNJ2 gene that causes a gain-of-function to the inward rectifier potassium channel current (IK1), which shortens the ventricular action potential duration (APD) and effective refractory period (ERP). Pro-arrhythmogenic effects of SQTS have been characterized, but less is known about the possible pharmacological treatment of SQTS. Therefore, in this study, we used computational modeling to assess the effects of amiodarone, class III anti-arrhythmic agent, on human ventricular electrophysiology in SQT3.MethodsThe ten Tusscher et al. model for the human ventricular action potentials (APs) was modified to incorporate IK1 formulations based on experimental data of Kir2.1 channels (including WT, WT-D172N and D172N conditions). The modified cell model was then implemented to construct one-dimensional (1D) and 2D tissue models. The blocking effects of amiodarone on ionic currents were modeled using IC50 and Hill coefficient values from literatures. Effects of amiodarone on APD, ERP and pseudo-ECG traces were computed. Effects of the drug on the temporal and spatial vulnerability of ventricular tissue to genesis and maintenance of re-entry were measured, as well as on the dynamic behavior of re-entry.ResultsAmiodarone prolonged the ventricular cell APD and decreased the maximal voltage heterogeneity (δV) among three difference cells types across transmural ventricular wall, leading to a decreased transmural heterogeneity of APD along a 1D model of ventricular transmural strand. Amiodarone increased cellular ERP, prolonged QT interval and decreased the T-wave amplitude. It reduced tissue’s temporal susceptibility to the initiation of re-entry and increased the minimum substrate size necessary to sustain re-entry in the 2D tissue.ConclusionsAt the therapeutic-relevant concentration of amiodarone, the APD and ERP at the single cell level were increased significantly. The QT interval in pseudo-ECG was prolonged and the re-entry in tissue was prevented. This study provides further evidence that amiodarone may be a potential pharmacological agent for preventing arrhythmogenesis for SQT3 patients.

Effects of amiodarone on ventricular excitation associated with the KCNJ2-linked short QT syndrome: Insights from a modelling study

Short QT syndrome (SQTS) is associated with ventricular arrhythmias that may lead to cardiac sudden death. However, effective pharmacological treatment for SQTS remains unclear. Amiodarone has emerged as the leading antiarrhythmic therapy for termination and prevention of ventricular arrhythmia in different clinical settings because of its proven efficacy and safety. The aim of this study was to investigate the effects of amiodarone on cardiac excitation of the KCNJ2-linked short QT syndrome. Effects of Kir2.1 D172N mutation-induced changes in IK1 were incorporated into human ventricular cell and tissue models that considered the intrinsic electrical heterogeneity in the left ventricle. Actions of amiodarone were simulated by implementing a simple block pore theory to simulate the drugs effects on ICaL and IKr block for several doses. In cellular simulations, current traces of IKr and ICaL and action potential duration of ENDO, M, and EPI cells were simulated in control, mutant, and amiodarone-in-action conditions. In tissue simulations, the pharmacological effects of amiodarone on the characteristics of ECG were examined. This study provides new insights into the pharmacokinetics of amiodarone for treatment of SQT3 under WT-D172N and D172N conditions.

Effects of island-distribution of mid-cardiomyocytes on ventricular electrical excitation associated with the KCNQ1-linked short QT syndrome

AIMS Short QT syndrome (SQTS) is a new genetic disorder of the electrical system of the heart. To date, there are six gene mutations in ion channels underlying SQTS. However, functional effects of spatial heterogeneities, such as island-distribution of mid-cardiomyocytes (M island) on ventricular electrical excitation in SQTS condition are poorly understood or even not understood at all. Therefore, this study used computational modelling to investigate such possible effects. METHODS The spatial heterogeneities of ventricular tissue was studied by using ten Tusscher et al. MODEL The model was modified to simulate changes to IKs based on experimental observations of KCNQ1 V307L mutation in SQT2 condition. Cell models were coupled to construct a strand tissue, among which 35% were mid-cardiomyocytes, either distributed in island form or in band form, 25% were endocardial (ENDO), and the rest part were epicardial (EPI) cells. RESULTS In simulations, the QT interval was shortened due to the KCNQ1 V307L mutation. The model with M band form failed to reproduce a markedly increase in the T-wave height. However, the model with M island form was able to produce a markedly increased T-wave height with the V307L mutation, matching the major features of SQT clinical ECGs. CONCLUSIONS This study substantiates a causal link between the M island and T-wave amplitude in the KCNQ1-linked short QT syndrome.Aims: Short QT syndrome (SQTS) is a new genetic disorder of the electrical system of the heart. To date, there are six gene mutations in ion channels underlying SQTS. However, functional effects of spatial heterogeneities, such as island-distribution of mid-cardiomyocytes (M island) on ventricular electrical excitation in SQTS condition are poorly understood or even not understood at all. Therefore, this study used computational modelling to investigate such possible effects.

Modelling the effects of quinidine, disopyramide, and E-4031 on short QT syndrome variant 3 in the human ventricles

OBJECTIVE Short QT syndrome (SQTS) is an inherited cardiac channelopathy, but at present little information is available on its pharmacological treatment. SQT3 variant (linked to the inward rectifier potassium current I K1) of SQTS, results from a gain-of-function mutation (Kir2.1 D172N) in the KCNJ2-encoded channels, which is associated with ventricular fibrillation (VF). Using biophysically-detailed human ventricular computer models, this study investigated the potential effects of quinidine, disopyramide, and E-4031 on SQT3. APPROACH The ten Tusscher et al model of human ventricular myocyte action potential (AP) was modified to recapitulate the changes in I K1 due to heterozygous and homozygous forms of the D172N mutation. Wild-type (WT) and mutant WT-D172N and D172N formulations were incorporated into one-dimensional (1D) and 2D tissue models with transmural heterogeneities. Effects of drugs on channel-blocking activity were modelled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values. Effects of drugs on AP duration (APD), effective refractory period (ERP) and QT interval of pseudo-ECGs were quantified, and both temporal and spatial vulnerability to re-entry was measured. Re-entry was simulated in the 2D ventricular tissue. MAIN RESULTS At the single cell level, the drugs quinidine, disopyramide, and E-4031 prolonged APD at 90% repolarization (APD90), and decreased maximal transmural voltage heterogeneity (δV); this caused the decreased transmural dispersion of APD90. Quinidine prolonged the QT interval and decreased the T-wave amplitude. Furthermore, quinidine increased ERP and reduced temporal vulnerability and increased spatial vulnerability, resulting in a reduced susceptibility to arrhythmogenesis in SQT3. In the 2D tissue, quinidine was effective in terminating and preventing re-entry associated with the heterozygous D172N condition. Quinidine exhibited significantly better therapeutic effects on SQT3 than disopyramide and E-4031. SIGNIFICANCE This study substantiates a causal link between quinidine and QT interval prolongation in SQT3 Kir2.1 mutations and highlights possible pharmacological agent quinidine for treating SQT3 patients.

Effects of propafenone on KCNH2-linked short QT syndrome: A modelling study

The identified genetic short QT syndrome (SQTS) is associated with an increased risk of arrhythmia and sudden death. This study was to investigate the potential effects of propafenone on KCNH2-linked short QT syndrome (SQT1) using a multi-scale biophysically detailed model of the heart developed by ten Tusscher and Panfilov. The ion electrical conductivities were reduced by propafenone in order to simulate the pharmacological effects in healthy and SQT1 cells. Based on the experimental data of McPate et al., the pharmacological effect of propafenone was modelled by dose-dependent IKr blocking. Action potential (AP) profiles and 1D tissue level were analyzed to predict the effects of propafenone on SQT1. Both low- and high- dose of propafenone prolonged APD and QT interval in SQT1 cells. It suggests the superior efficacy of high dose of propafenone on SQT1. However, propafenone did not significantly alter the healthy APD or QT interval at low dose, whereas markedly shortened them at high dose. Our simulation data show that propafenone has a dose-dependently anti-arrhythmic effect on SQT1, and a pro-arrhythmic effect on healthy cells. These computer simulations help to better understand the underlying mechanisms responsible for the initiation or termination of arrhythmias in healthy or SQT1 patients using propafenone.

Calcium leak induced arrhythmias in mouse sino-atrial node and ventricle cells: A simulation study.

Bradycardia is found to be a complication during catecholaminergic polymorphic ventricular tachycardia in which calcium leak plays a pivotal role. In this computational study, we determined the effects of sarcoplasmic reticulum calcium leak on the function of sino-atrial node and ventricular model cells.