Julio Gomis-Tena

A multiscale simulation system for the prediction of drug-induced cardiotoxicity.

The preclinical assessment of drug-induced ventricular arrhythmia, a major concern for regulators, is typically based on experimental or computational models focused on the potassium channel hERG (human ether-a-go-go-related gene, K(v)11.1). Even if the role of this ion channel in the ventricular repolarization is of critical importance, the complexity of the events involved make the cardiac safety assessment based only on hERG has a high risk of producing either false positive or negative results. We introduce a multiscale simulation system aiming to produce a better cardiotoxicity assessment. At the molecular scale, the proposed system uses a combination of docking simulations on two potassium channels, hERG and KCNQ1, plus three-dimensional quantitative structure-activity relationship modeling for predicting how the tested compound will block the potassium currents IK(r) and IK(s). The obtained results have been introduced in electrophysiological models of the cardiomyocytes and the ventricular tissue, allowing the direct prediction of the drug effects on electrocardiogram simulations. The usefulness of the whole method is illustrated by predicting the cardiotoxic effect of several compounds, including some examples in which classic hERG-based models produce false positive or negative results, yielding correct predictions for all of them. These results can be considered a proof of concept, suggesting that multiscale prediction systems can be suitable for being used for preliminary screening in lead discovery, before the compound is physically available, or in early preclinical development when they can be fed with experimentally obtained data.

Effects of the Antiarrhythmic Drug Dofetilide on Transmural Dispersion of Repolarization in Ventriculum. A Computer Modeling Study

Dofetilide is a class-Ill drug that inhibits the rapid component of the delayed potassium current (IKr). Experimental studies have shown that the different layers of ventricular muscle present differences in action potential duration (APD) and different responses to class III agents. It has been suggested that it contributes to APD heterogeneity in the ventricles. However, in vivo studies suggest that the strong cellular coupling reduces APD dispersion in intact heart. The aim of this paper is to study the effect of dofetilide on the action potentials (APs) in isolated ventricular cells and on APD dispersion in a strand of ventricular tissue. A mathematical model of dofetilide effects on IKr has been developed and incorporated into the Luo-Rudy dynamic model of ventricular AP. Our results show that dofetilide induces in midmyocardium cells a faster time-course inhibition of IKr than in endocardial or epicardial cells, and periods of instability with beat-to-beat APs variability. This behavior could favor temporal dispersion of repolarization between the different cells. The results also indicate that although dofetilide increases, the transmural gradient of APD in the ventricular wall, early after depolarizations (EADs) did not appear even under strong uncoupling conditions. However, reduced repolarization reserve favors the induction of EADs, even under normal coupling conditions.

In silico assessment of drug safety in human heart applied to late sodium current blockers

Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (INaL) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K+ current (IKr). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of IKr/INaL ratio of steady-state block of drug candidates on “torsadogenic” biomarkers. The O’Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of INaL and IKr were evaluated. “Safety plots” were developed to illustrate the value of the specific biomarker for selected combinations of IC50s for IKr and INaL of potential drugs. The reference biomarkers at baseline changed depending on the “drug” specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of INaL) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle.

Sex and age related differences in drug induced QT prolongation by dofetilide under reduced repolarization reserve in simulated ventricular cells

The aim of this study was to investigate sex and age related differences in drug induced QT prolongation by dofetilide under reduced repolarization reserve in simulated ventricular cells. Left ventricular endocardial action potentials were simulated using a modified Luo Rudy model. Sex, age and regional differences in currents ICaL, IKr, IKs, and Ito were incorporated into the model by modifying the equations representing them. A model of dofetilide, a class III antiarrhythmic drug, was developed and included into a ventricular cell models. The reduced repolarization reserve was reproduced decreasing the IKs current. Our results shown that the adult female cells had longer action potentials, a steeper APD-BCL relationship and a higher susceptibility to EADs than adult male cells, under control, drug induced and reduced repolarization reserve conditions. On the other hand, young female and young male cells had similar action potentials under control conditions. However, young male cells had longer action potentials and higher susceptibility to EADs than young female cells under drug induced and reduced repolarization reserve conditions. Sex and age dependent differences in ICaL, IKr, IKs, and Ito may explain the age and sex disparities in prolongation of APD by the action of dofetilide.

Role of Ca2+-Dependent Cl− Current on Delayed Afterdepolarizations. A Simulation Study

Calcium-dependent chloride current (ICl,Ca) is the second component (Ito2) of the transient outward current (Ito) that provokes the action potential (AP) phase 1 repolarization. This current contributes to the transient inward current (Iti) that generates delayed afterdepolarizations (DAD) in several pathological conditions. The present work uses a computer AP model of rabbit atrial myocyte and a one-dimensional (1D) tissue model of 400 cells to study the role of ICl,Ca on the generation of DAD and triggered activity under calcium-overload conditions. A mathematical model describing the dependence of ICl,Ca on intracellular Ca2+ is proposed. This model takes into account the experimentally recorded characteristics of ICl,Ca: (1) calcium dependence, (2) voltage-dependent inactivation, and (3) I–V field-diffusion relation. Our results support the hypothesis that ICl,Ca plays an important role in action potential repolarization, mainly at high frequencies. In the calcium-overload conditions tested in this work, ICl,Ca represents between 28% and 44% of the total Iti that provokes DADs. Our simulations also show that the blockage of ICl,Ca reduces the calcium overload range in which DADs provoke triggered activity.

Modulation of the regional dispersion of repolarization by the action of class III antiarrhythmic drug dofetilide

It is well known that short-long (S-L) sequences frequently precede the onset of malignant ventricular arrhythmias. Experimental studies have shown that a single long coupled extra-beat (L) after a previous basic cycle length resulted in a critical increase of the dispersion of repolarization pattern that promoted reentrant excitation. However, in normal intact heart little differences in repolarization among different myocardial layers have been observed after abrupt slowing of heart rate. We used the Luo and Rudy model (LRd00) of AP and the model of IKr blockade by the action of dofetilide previously developed by our group to study the effect of dofetilide (a class III antiarrhythmic drug) on the modulation of APD dispersion in a strand of ventricular tissue. Our results show that dofetilide increases dramatically the APD of the strand and that the effect of dofetilide on the modulation of dispersion is complex, indicating that the highest dispersion could appear before the highest effect of the drug is reached

Effects of the antiarrhythmic drug dofetilide on regional heterogeneity of action potential duration: a computer modelling study

DifSerent experimental studies have shown that ventricular cells present several diflerences between epicardium, endocardium and M-cells. M-cells have longer APDs and higher sensitivity to agents with class III actions and they could contribute to APD heterogeneity in the ventriculum. However, in-vivo studies have observed that the strong cellular coupling reduces the APD dispersion in intact heart. We used the Luo and Rudy model (LRdOO) of AP and the model of IKr blockade by the action of dofetilide developed previously by our group ro study the effect of dofetilide (a class III antiarrhythmic drug) on the APD dispersion in a strand of ventricular tissue. Our results show that dofetilide increases dramatically the APD dispersion and may modify the transmural gradient of APR even in normal coupling condirions such as those in intact heart, Higher dispersion and, a more complex behaviour, such as 2:1 block, could appear when the coupling decreases.

Effects of the antiarrhythmic drug dofetilide on myocardial electrical activity: a computer modelling study

Dofetilide selectively inhibits the rapid component of the delayed potassium current (I/sub Kr/). In this work, a mathematical model of dofetilide effects on I/sub Kr/ has been developed. This model has been incorporated to the Luo and Rudy (II) model of guinea pig ventricular action potential and the effect of different dofetilide concentrations on the action potential characteristics has been studied. Our results show that the steady-state block of I/sub Kr/ is dose-dependent with a block of 10%, 53% and 92% for 1 nM, 10 nM and 100 nM of dofetilide respectively (IC/sub 50/=8.7 nM). This increment of I/sub Kr/ block when the concentration increases induces a prolongation of APD also in a dose-dependent way. We observed prolongations of APD/sub 90/ of 13% and 28% for 10 nM and 100 nM of dofetilide respectively. In agreement with experimental results, the interaction between dofetilide and the receptor in the channel presents slow kinetics and reverse use-dependence in our model.

Inhibition of atrial action potentials alternans by calcium-activated chloride current blockade - simulation study

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Atrial action potential (AP) alternans appearance during atrial flutter play a determinant role as AF precursor. AP alternans involves intracellular calcium concentration alternation that affects calcium dependent currents like I/sub NaCa/ und I/sub ClCa/. In this study, a modified rabbit atrial AP mode, that includes I/sub ClCa/ formulation is used. In order to induce alternans, the pacing cycle length was abruptly shortened from a basic drive of 1000 ms after 7.5 s of stimulation. The role of I/sub ClCa/was investigated by blocking the current. When increasing pace rate, from a cycle length of 1000 ms to 180 ms, beat-to-beat alternans appear. Repeating the procedure in I/sub ClCa/blockade situation, in the range of 60 to 100 %, alternans disappear. Our results suggest that I/sub ClCa/ blockade prevents alternans and for this reason I/sub ClCa/ blockade could be potentially antiarrhythmic, preventing AF.

A computer model of reflection induced by early afterdepolarizations in ventricular tissue

A computer model has been developed in which reflection was observed. Reflection is a type of reentry in a one-dimensional structure of cardiac cells. The model consists of two segments of ventricular tissue partially coupled by a coupling resistance (R) and it was used to study conditions that provoke the development of EADs, and the generation of reflection and ectopic activity. In the present study, EADs were induced in one segment by enhancing ICaL current and decreasing IKr and IKS currents. The other segment was maintained under normal physiological conditions. The results suggest that ectopic activity in a zone of myocardium could appear due to the reflection induced by EADs generated in neighboring tissue zones. The coupling between areas and the blocked factor of the two components of the delayed rectifier K+ current (IKr and IKs ), have a great influence. The results suggest that a partial coupling between segments and severe conditions in the abnormal segment increase the likelihood of both the ectopic activity and the triggered activity