Role of Late Sodium Channel Current Block in the Management of Atrial Fibrillation

Abstract

The anti-arrhythmic efficacy of the late sodium channel current (late INa) inhibition has been convincingly demonstrated in the ventricles, particularly under conditions of prolonged ventricular repolarization. The value of late INa block in the setting of atrial fibrillation (AF) remains poorly investigated. All sodium channel blockers inhibit both peak and late INa and are generally more potent in inhibiting late vs. early INa. Selective late INa block does not prolong the effective refractory period (ERP), a feature common to practically all anti-AF agents. Although the late INa blocker ranolazine has been shown to be effective in suppression of AF, it is noteworthy that at concentrations at which it blocks late INa in the ventricles, it also potently blocks peak INa in the atria, thus causing rate-dependent prolongation of ERP due to development of post-repolarization refractoriness. Late INa inhibition in atria is thought to suppress intracellular calcium (Cai)-mediated triggered activity, secondary to a reduction in intracellular sodium (Nai). However, agents that block late INa (ranolazine, amiodarone, vernakalant, etc) are also potent atrial-selective peak INa blockers, so that the reduction of Nai loading in atrial cells by these agents can be in large part due to the block of peak INa. The impact of late INa inhibition is reduced by the abbreviation of the action potential that occurs in AF patients secondary to electrical remodeling. It stands to reason that selective late INa block may contribute more to inhibition of Cai-mediated triggered activity responsible for initiation of AF in clinical pathologies associated with a prolonged atrial APD (such as long QT syndrome). Additional studies are clearly needed to test this hypothesis.

Late sodium current dysregulation as a causal factor in arrhythmia

“…A wealth of pre-clinical data support the utility of I Na,L blockers in preventing a wide range of arrhythmias [2,4,8,[14][15][16]. Moreover, recent clinical trials demonstrate efficacy of the I Na,L blocker ranolazine for reducing incidence of supraventricular arrhythmias and new onset AF in myocardial infarction patients, as well as termination of paroxysmal AF and prevention of post-operative AF [6,7]. These studies all point to the anti-arrhythmia efficacy of I Na,L blocking drugs.…”

“…Much focus has been given to ion channels as targets for anti-arrhythmia agents, but unintended pro-arrhythmia and off-target effects associated with ion channel blocking drugs motivate the continued pursuit of new and improved anti-arrhythmia agents [3]. Exciting recent work in the field suggests that a novel anti-arrhythmia approach with great potential involves targeting a pathogenic component of voltage-gated Na + current ('late' Na + current, I Na,L ) [4][5][6][7][8]. Na v generate the cardiac action potential (AP) upstroke through a tightly controlled gating process involving rapid channel activation followed immediately by inactivation, which sets the stage for smaller conductance/slower ion channels (mostly voltage-gated Ca 2+ and K + channels) to repolarize the membrane in preparation for the next heartbeat.…”

“…heart failure, atrial fibrillation (AF)) [9][10][11][12][13]. I Na,L likely promotes arrhythmogenesis by (1) increasing a depolarizing current that prolongs the AP and increases susceptibility to secondary depolarizations (afterdepolarizations) that serve as potential arrhythmia triggers and (2) increasing intracellular Na + that promotes intracellular Ca 2+ accumulation via altered activity of Na + /Ca 2+ exchanger [2,6]. Consistent with pro-arrhythmia of I Na,L , drugs that block I Na,L have been shown in pre-clinical and clinical trials to reduce arrhythmia incidence, although the precise mode of action is not resolved [4,7,8,[14][15][16].…”

The Significance of the Late Na+ Current for Arrhythmia Induction and the Therapeutic Antiarrhythmic Potential of Ranolazine

“…However, owing to the fact that this sodium channel has a more negative steady state inactivation voltage in the atria 8 and the atrial resting membrane potential (RMP) is less negative compared to ventricle, the actual amount of available current is similar in atria versus ventricle. 9 A small fraction of these cardiac Na þ channels has alternative gating 10,11 and carries the late Na þ current (I Na,late ). Sodium channels producing this additional current are thought to remain active over a longer period (inactivating more slowly) or even to reopen 12 and can be found in the atria and ventricles.…”

“…The consequence of this is at higher pacing rates, ranolazine loses its selectivity for blocking I Na,late and block of I Na,peak becomes more prominent, that is, reduction in V max and excitability. 9 The protection offered by ranolazine against ventricular arrhythmias occurs despite its I Kr blocking properties and QT interval prolonging effects. This is thought to be due to the accompanying block of I Na,late .…”