Enhanced Late Na and Ca Currents as Effective Antiarrhythmic Drug Targets

Area of Science:

• Cardiovascular Pharmacology
• Cardiac Electrophysiology
• Molecular Cardiology

Background:

• Current antiarrhythmic drug (AAD) classifications (Classes I-V) are based on blocking peak ionic currents or receptor activity.
• The link between AAD mechanisms and suppression of dynamic arrhythmia mechanisms is not fully understood.
• Cardiac Ca/calmodulin-dependent protein kinase II (CaMKII) enhances late sodium (I_Na-L) and late L-type calcium (I_Ca,L) currents, contributing to ventricular tachycardia/fibrillation (VT/VF) in high-risk patients.

Purpose of the Study:

• To investigate the potential of targeting enhanced late inward currents (I_Na-L and I_Ca,L) as a novel antiarrhythmic strategy.
• To evaluate the efficacy of selective late inward current inhibition in suppressing early afterdepolarization (EAD)-mediated VT/VF.

Main Methods:

• Utilized prototype drugs GS-967 (selective I_Na-L inhibitor) and roscovitine (selective I_Ca,L inhibitor).
• Assessed the impact of these drugs on EADs and VT/VF in models of cardiac remodeling and oxidative stress.
• Focused on drugs that selectively inhibit late currents without affecting peak currents.

Main Results:

• Pathological enhancement of I_Na-L and/or late I_Ca,L promotes EADs and triggered activity, initiating VT/VF.
• Selective inhibition of I_Na-L with GS-967 suppressed EAD-mediated VT/VF.
• Selective inhibition of late I_Ca,L with roscovitine suppressed oxidative EAD-mediated VT/VF.

Conclusions:

• Specific blockers of late inward currents (gating modifiers) represent a new class of AADs, termed "Class VI."
• Development of safe Class VI drugs offers a rational and effective approach to treat VT/VF, especially in conditions with enhanced CaMKII activity like heart failure.