Multiple targets for flecainide action: implications for cardiac arrhythmogenesis

Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca²⁺-mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro-arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Na_v channel or intracellular ryanodine receptor (RyR2)-Ca²⁺ channel function. Flecainide accesses its transmembrane Na_v1.5 channel binding site during activated, open, states producing a use-dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak I_Na related to activation of Na_v channels followed by rapid de-activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro-arrhythmic conditions reflecting loss of function of Na_v1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro-arrhythmic effects attributed to prolonged AP recovery by abnormal late I_NaL following gain-of-function modifications of Na_v1.5 channels in LQTS3 are reduced by flecainide. Anti-arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca²⁺ release could arise from its primary actions on Na_v channels indirectly decreasing [Ca²⁺]_i through a reduced [Na⁺]_i and/or direct open-state RyR2-Ca²⁺ channel antagonism. The consequent [Ca²⁺]_i alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Na_v1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na⁺ currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function. Linked Articles: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.