Pro-arrhythmic Effects of Low Plasma [K+] in Human Ventricle: An Illustrated Review

[EN] Potassium levels in the plasma, [Kþ]o, are regulated precisely under physiological conditions. However, increases (from approx. 4.5 to 8.0 mM) can occur as a consequence of, e.g., endurance exercise, ischemic insult or kidney failure. This hyperkalemic modulation of ventricular electrophysiology has been studied extensively. Hypokalemia is also common. It can occur in response to diuretic therapy, following renal dialysis, or during recovery from endurance exercise. In the human ventricle, clinical hypokalemia (e.g., [Kþ]o levels of approx. 3.0 mM) can cause marked changes in both the resting potential and the action potential waveform, and these may promote arrhythmias. Here, we provide essential background information concerning the main Kþ-sensitive ion channel mechanisms that act in concert to produce prominent short-term ventricular electrophysiological changes, and illustrate these by implementing recent mathematical models of the human ventricular action potential. Even small changes (~1 mM) in [Kþ]o result in significant alterations in two different Kþ currents, IK1 and HERG. These changes can markedly alter in resting membrane potential and/or action potential waveform in human ventricle. Specifically, a reduction in net outward transmembrane Kþ currents (repolarization reserve) and an increased substrate input resistance contribute to electrophysiological instability during the plateau of the action potential and may promote pro-arrhythmic early after-depolarizations (EADs). Translational settings where these insights apply include: optimal diuretic therapy, and the interpretation of data from Phase II and III trials for anti-arrhythmic drug candidates.In Valencia, this work was supported by: (i) the “Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016” from the Ministerio de Economía, Industria y Competitividad of Spain (DPI2016-75799-R) and AEI/FEDER, UE, and by the “Programa Prometeu (PROMETEU/2016/088) de la Conselleria d'Educació, Formació I Ocupació, Generalitat Valenciana”. and (v) GileadSciences, Ltd. Wayne Giles acknowledges receipt of financial support in the form of a salary award (Medical Scientist) from Alberta Innovates-Health Solutions, and operating funding from the Canadian Institutes for Health Research and the Heart and Stroke Foundation of Alberta.Trénor Gomis, BA.; Cardona-Urrego, KE.; Romero Pérez, L.; Gómez García, JF.; Saiz Rodríguez, FJ.; Rajamani, S.; Belardinelli, L.... (2018). Pro-arrhythmic Effects of Low Plasma [K+] in Human Ventricle: An Illustrated Review. Trends in Cardiovascular Medicine. 28(4):233-242. https://doi.org/10.1016/j.tcm.2017.11.002S23324228

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.This work was supported by (1) Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica, (2) Plan Avanza en el marco de la Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion del Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), (3) Programa de Apoyo a la Investigacion y Desarrollo (PAID-06-11-2002) de la Universidad Politecnica de Valencia, (4) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana and (5) Gilead Sciences, Ltd.Trenor Gomis, BA.; Gomis-Tena Dolz, J.; Cardona Urrego, KE.; Romero Pérez, L.; Rajamani, S.; Belardinelli, L.; Giles, WR.... (2013). In silico assessment of drug safety in human heart applied to late sodium current blockers. Channels. 7(4):1-14. doi:10.4161/chan.24905S11474Maltsev, V. 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Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Carbon monoxide (CO) that is produced in a number of different mammalian tissues is now known to have significant effects on the cardiovascular system. These include: (i) vasodilation, (ii) changes in heart rate and strength of contractions, and (iii) modulation of autonomic nervous system input to both the primary pacemaker and the working myocardium. Excessive CO in the environment is toxic and can initiate or mediate life threatening cardiac rhythm disturbances. Recent reports link these ventricular arrhythmias to an increase in the slowly inactivating, or “late” component of the Na+ current in the mammalian heart. The main goal of this paper is to explore the basis of this pro-arrhythmic capability of CO by incorporating changes in CO-induced ion channel activity with intracellular signaling pathways in the mammalian heart. To do this, a quite well-documented mathematical model of the action potential and intracellular calcium transient in the human ventricular myocyte has been employed. In silico iterations based on this model provide a useful first step in illustrating the cellular electrophysiological consequences of CO that have been reported from mammalian heart experiments. Specifically, when the Grandi et al. model of the human ventricular action potential is utilized, and after the Na+ and Ca2+ currents in a single myocyte are modified based on the experimental literature, early after-depolarization (EAD) rhythm disturbances appear, and important elements of the underlying causes of these EADs are revealed/illustrated. Our modified mathematical model of the human ventricular action potential also provides a convenient digital platform for designing future experimental work and relating these changes in cellular cardiac electrophysiology to emerging clinical and epidemiological data on CO toxicity.In Valencia, this work was supported by: (i) VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica from the Ministerio de Economia y Competitividad of Spain (TIN2012-37546-0O3-01) and the European Commission (European Regional Development Funds-ERDF-FEDER)., (ii) Plan Avanza en el marco de la Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion del Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), (iii) Programa deApoyo a la Investigacion y Desarrollo (PAID-06-11-2002) de la Universitat Politecnica de Valencia, (iv) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana, and (v) GileadSciences, Ltd. Wayne Giles acknowledges receipt of financial support in the form of a salary award (Medical Scientist) from Alberta Innovates-Health Solutions, and operating funding from the Canadian Institutes for Health Research and the Heart and Stroke Foundation of Alberta.Trénor Gomis, BA.; Cardona-Urrego, KE.; Saiz Rodríguez, FJ.; Rajamani, S.; Belardinelli, L.; Giles, WR. (2013). Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations. Frontiers in Physiology. 4:1-11. https://doi.org/10.3389/fphys.2013.00282S111

A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current

[EN] Background: The QT interval is a phase of the cardiac cycle that corresponds to action potential duration (APD) including cellular repolarization (T-wave). In both clinical and experimental settings, prolongation of the QT interval of the electrocardiogram (ECG) and related proarrhythmia have been so strongly associated that a prolonged QT interval is largely accepted as surrogate marker for proarrhythmia. Accordingly, drugs that prolong the QT interval are not considered for further preclinical development resulting in removal of many promising drugs from development. While reduction of drug interactions with hERG is an important goal, there are promising means to mitigate hERG block. Here, we examine one possibility and test the hypothesis that selective inhibition of the cardiac late Na current (I-NaL) by the novel compound GS-458967 can suppress proarrhythmic markers. Methods and results: New experimental data has been used to calibrate INaL in the Soltis-Saucerman computationally based model of the rabbit ventricular action potential to study effects of GS-458967 on INaL during the rabbit ventricular AP. We have also carried out systematic in silico tests to determine if targeted block of INaL would suppress proarrhythmia markers in ventricular myocytes described by TRIaD: Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion. Conclusions: Our computer modeling approach based on experimental data, yields results that suggest that selective inhibition of INaL modifies all TRIaD related parameters arising from acquired Long-QT Syndrome, and thereby reduced arrhythmia risk. This study reveals the potential for adjunctive pharmacotherapy via targeted block of INaL to mitigate proarrhythmia risk for drugs with significant but unintended off-target hERG blocking effects.The National Institutes of Health R01 HL128537-01 (CEC), U01 HL126273-01 (CEC) and R01HL128170-02 (CEC).Yang, P.; El-Bizri, N.; Romero Pérez, L.; Giles, W.; Rajamani, S.; Belardinelli, L.; Clancy, CE. (2016). A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current. Journal of Molecular and Cellular Cardiology. 99:151-161. https://doi.org/10.1016/j.yjmcc.2016.08.011S1511619