title: 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,Lin patients at high risk of VT/VF provided a new and a rational AAD target. Pathological rise of either or both of INa-Land late ICa,Lare 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-Lwithout 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,Lwithout 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.
authors.affiliation: Translational Arrhythmia Section, David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, USA; Cardiovascular Research Laboratory, Departments of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, USA.
authors.forename: Hrayr S
authors.initials: HS
authors.lastname: Karagueuzian
authors.affiliation: Translational Arrhythmia Section, David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, USA; Cardiovascular Research Laboratory, Departments of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, USA.
authors.forename: Arash
authors.initials: A
authors.lastname: Pezhouman
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles Los Angeles, CA, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Angelini
authors.affiliation: Cardiovascular Research Laboratory, Departments of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, USA; Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, USA; Department of Physiology, David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Olcese
keywords: GS-458-967; antiarrhythmic drugs; early afterdepolarization; late Ca current; late Na current; roscovitine; triggered activity; ventricular fibrillation