A Novel Paradigm for a New Class of Anti-Arrhythmic Drugs Based on Targeting Ca Channel Gating Properties

Background: Early after depolarizations (EADs) play a key role in the genesis of arrhythmias in cardiac diseases including congenital and acquired long QT syndrome and heart failure. It is the underlying mechanism of... [ view full abstract ]

Background: Early after depolarizations (EADs) play a key role in the genesis of arrhythmias in cardiac diseases including congenital and acquired long QT syndrome and heart failure. It is the underlying mechanism of polymorphic ventricular arrhythmias such as Torsades de Pointes, and often underlies atrial fibrillation and VF, which are associated with significant morbidity and mortality. Most pharmacological anti-arrhythmic drug strategy is focused on “ion channel blocking” which has been shown to be ineffective and even pro-arrhythmic in some cases as seen in the CAST and SWORD trials. In this study, we propose a new paradigm for anti-arrhythmic drug development based on modulation of ion channel gating, ie. “ion channel gating modulation” rather than “ion channel blocking”, with a focus on targeting Ca channel gating properties without adversely impacting excitation-contraction (E-C) coupling.

Methods and Results: Optical mapping of cultured neonatal rat ventricular myocyte (NRVMs) monolayer tissue exposed to BayK8644 and isoproterenol revealed robust bursts of EADs resembling those seen in neurons, and is thus an ideal in vitro model of EADs to test anti-arrhythmic strategies. Modulation of the gating properties of the Ca channels with Roscovitine, a chemotherapy agent with unique properties of accelerating inactivation of the Ca channel and reducing late Ca current without significantly impacting the peak Ca current, eliminated EAD bursts in 90% of NRVM monolayers (n=10). Roscovitine did not significantly affect APD (surrogate of QT interval), while peak Ca fluorescence was slightly but significantly increased.

Conclusion: Targeting Ca channel kinetics without adversely impacting E-C coupling may serve as a viable therapeutic strategy for the development of this new class of anti-arrhythmic drugs.