Late Sodium Current Inhibitors as Potential Antiarrhythmic Agents.
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ABSTRACT:
SUBMITTER: Horvath B
PROVIDER: S-EPMC7184885 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Late Sodium Current Inhibitors as Potential Antiarrhythmic Agents.
Horváth Balázs B Hézső Tamás T Kiss Dénes D Kistamás Kornél K Magyar János J Nánási Péter P PP Bányász Tamás T
Frontiers in pharmacology 20200420
Based on recent findings, an increased late sodium current (I<sub>Na,late</sub>) plays an important pathophysiological role in cardiac diseases, including rhythm disorders. The article first describes what is I<sub>Na,late</sub> and how it functions under physiological circumstances. Next, it shows the wide range of cellular mechanisms that can contribute to an increased I<sub>Na,late</sub> in heart diseases, and also discusses how the upregulated I<sub>Na,late</sub> can play a role in the gener ...[more]
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Project description:Late sodium current (late INa) inhibition has been proposed to suppress the incidence of arrhythmias generated by pathological states or induced by drugs. However, the role of late INa in the human heart is still poorly understood. We therefore investigated the role of this conductance in arrhythmias using adult primary cardiomyocytes and tissues from donor hearts. Potentiation of late INa with ATX-II (anemonia sulcata toxin II) and E-4031 (selective blocker of the hERG channel) slowed the kinetics of action potential repolarization, impaired Ca2+ homeostasis, increased contractility, and increased the manifestation of arrhythmia markers. These effects could be reversed by late INa inhibitors, ranolazine and GS-967. We also report that atrial tissues from donor hearts affected by atrial fibrillation exhibit arrhythmia markers in the absence of drug treatment and inhibition of late INa with GS-967 leads to a significant reduction in arrhythmic behaviour. These findings reveal a critical role for the late INa in cardiac arrhythmias and suggest that inhibition of this conductance could provide an effective therapeutic strategy. Finally, this study highlights the utility of human ex-vivo heart models for advancing cardiac translational sciences.
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Project description:BackgroundDrugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans.Methods and resultsIn this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected J-Tpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001).ConclusionsAnalysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block.Trial registrationNCT02308748 and NCT01873950.
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