Enhanced Late Na and Ca Currents as Effective Antiarrhythmic Drug Targets

Abstract

While recent advances clarified the molecular and cellular modes of action of antiarrhythmic drugs (AADs), their link to suppression of dynamical arrhythmia mechanisms remains only partially understood. The current classifications of AADs (Classes I, III, and IV) rely on blocking peak Na, K and L-type calcium currents (ICa,L), with Class II with dominant beta receptor blocking activity and Class V including drugs with diverse classes of actions. The discovery that the calcium and redox sensor, cardiac Ca/calmodulin-dependent protein kinase II (CaMKII) enhances both the late Na (INa-L) and the late ICa,L in patients at high risk of VT/VF provided a new and a rational AAD target. Pathological rise of either or both of INa-L and late ICa,L are demonstrated to promote cellular early afterdepolarizations (EADs) and EAD-mediated triggered activity that can initiate VT/VF in remodeled hearts. Selective inhibition of the INa-L without affecting their peak transients with the highly specific prototype drug, GS-967 suppresses these EAD-mediated VT/VFs. As in the case of INa-L, selective inhibition of the late ICa,L without affecting its peak with the prototype drug, roscovitine suppressed oxidative EAD-mediated VT/VF. These findings indicate that specific blockers of the late inward currents without affecting their peaks (gating modifiers), offer a new and effective AAD class action i.e., “Class VI.” The development of safe drugs with selective Class VI actions provides a rational and effective approach to treat VT/VF particularly in cardiac conditions associated with enhanced CaMKII activity such as heart failure.

Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade

“…The potent suppressive effect of GS-967 against oxidative AF provides a novel class of antiarrhythmic drug action not considered in previous drug action classification [11]. Interestingly, recent studies demonstrated, consistent with the results of the present study, that increased I Na-L plays a key role in the induction of rapid pacing-induced AF in mice and its suppression by GS-967 [31].…”

“…Interestingly, recent studies demonstrated, consistent with the results of the present study, that increased I Na-L plays a key role in the induction of rapid pacing-induced AF in mice and its suppression by GS-967 [31]. The importance of I Na-L blockade in the suppression of AF with the novel specific I Na-L blocker, eleclazine was also demonstrated in larger animals (pigs) [32] indicating the potential antiarrhythmic efficacy of this new class of drug action in humans [11]. …”

“…While the causative and signaling factors of oxidative AF are reasonably well identified, the mechanism of spontaneous initiation (i.e., not induced by electrical stimulation) of acute oxidative AF in experimental and human studies, remains undefined [10]. The lack of mechanistic cellular insight into the genesis of oxidative AF hampered the development of effective pharmacological therapy to suppress and/or prevent the oxidative AF [11]. For example, beta-blockers [12] and Amiodarone, [13] considered first line preventive drugs against POAF, are only partially effective.…”

Calcium Signaling and Cardiac Arrhythmias

“…EADs are usually, but not exclusively, associated with excessive AP prolongation (e.g. by increased inward I Ca,L 37 and late Na + -current I Na,L or I NCX , 38, 39 or by reduced K + -currents (I K ), allowing I Ca,L to recover from inactivation and depolarize the cardiomyocyte by allowing Ca 2+ to enter. 40 CaMKII-dependent I Ca,L phosphorylation slows inactivation and accelerates recovery from inactivation, further enhancing the likelihood of EADs.…”

Site and Mechanism of Action of Resin Acids on Voltage-Gated Ion Channels

“…Drugs that act on voltage-gated ion channels have for long been used as a treatment for many diseases, even before we knew such channels existed, in particular to control diseases of excitability (Brodie, 2010;Karagueuzian et al, 2017). Historically, natural compounds found in plants and toxins from animals have also been used to gain a better understanding of the structure and function of voltage-gated ion channels (Agnew et al, 1978;Cestèle and Catterall, 2000;MacKinnon, 1991;Stevens et al, 2011).…”