Effects of Na+ Channel Blockers on Extrasystolic Stimulation-evoked Changes in Ventricular Conduction and Repolarization

Abstract

Antiarrhythmic agents which belong to class Ia (quinidine) and Ic (flecainide) reportedly increase propensity to ventricular tachyarrhythmia, whereas class Ib agents (lidocaine and mexiletine) are recognized as safe antiarrhythmics. Clinically, tachyarrhythmia is often initiated by a premature ectopic beat, which increases spatial nonuniformities in ventricular conduction and repolarization thus facilitating reentry. This study examined if electrical derangements evoked by premature excitation may be accentuated by flecainide and quinidine, but unchanged by lidocaine and mexiletine, which would explain the difference in their safety profile. In perfused guinea pig hearts, a premature excitation evoked over late repolarization phase was associated with prolonged epicardial activation time, reduced monophasic action potential duration (APD), and increased transepicardial dispersion of the activation time and APD. Flecainide and quinidine increased conduction slowing evoked by extrasystolic stimulation, prolonged APD, and accentuated spatial heterogeneities in ventricular conduction and repolarization associated with premature excitation. Spontaneous episodes of nonsustained monomorphic ventricular tachycardia were observed in 50% of heart preparations exposed to drug infusion. In contrast, lidocaine and mexiletine had no effect on extrasystolic stimulation-evoked changes in ventricular conduction and repolarization or arrhythmic susceptibility. These findings suggest that flecainide and quinidine may promote arrhythmia by exaggerating electrophysiological abnormalities evoked by ectopic beats.

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

“…In contrast, class Ib Na + channel blockers such as lidocaine and mexiletine, the agents with a clinically safe antiarrhythmic profile, were found to reduce the endocardial‐to‐epicardial ERP difference. Finally, during extrasystolic stimulation, flecainide and quinidine have been shown to accentuate spatial heterogeneities in ventricular conduction and repolarization associated with premature activation, thus facilitating arrhythmia (Osadchii 2014b: study IX) . In contrast, lidocaine and mexiletine had no effect on electrical derangements produced by extrasystolic stimulation.…”

“…In perfused canine ventricular wedge preparations, drug‐induced increase in transmural dispersion of repolarization, but not QT interval prolongation, was found to discriminate proarrhythmic agents from those with a safe profile . Drug‐induced arrhythmia is also often associated with increased interventricular repolarization gradients, and apico‐basal APD dispersion . Nevertheless, an increase in transmural APD dispersion is likely to be more arrhythmogenic, because in this case, APD changes occur over a shorter distance, determined by the thickness of LV wall, thus leading to considerably steepened repolarization gradient.…”

“…In survivors of acute myocardial infarction, the presence of frequent closely coupled extrasystolic beats on ECG has been shown to independently predict the increased risk of sudden arrhythmic death . Second, the increased propensity to develop VT following ectopic activation is thought to be accounted for by amplified regional non‐uniformities in ventricular conduction and APD . When premature stimulus is applied immediately upon the recurrence of excitability in phase 3, the induced extrasystolic beat propagates with an increased conduction delay owing to the incomplete recovery of Na + channels from inactivation.…”

“…Furthermore, in contrast to class Ib agents, class Ia and Ic drugs exhibit much slower Na + channel unbinding rates, and hence provoke substantial conduction slowing; this would likely exacerbate conduction abnormalities imposed by ectopic activation. In study IX (Osadchii 2014b), these possibilities were addressed by measuring local activation latencies and APDs in six LV and RV epicardial recording sites in perfused guinea‐pig hearts, both during regular pacing and extrasystolic stimulations applied immediately upon the termination of ERP. Both flecainide and quinidine were found to produce non‐uniform conduction slowing throughout the ventricular epicardium in extrasystolic beats, thus further accentuating an increase in dispersion of the conduction time imposed by premature activation.…”

The influence of regional anaesthesia and local anaesthetics on cardiac repolarization

“…The flow of "late" sodium current is not uniform in all cells, so the dispersion of the action potential is observed, along with the increased, pathological excitability of the working cardiomyocytes, triggered activity (EADs) and the substrate for reentry. The presence of the pathological "late" sodium current also contributes to the prolongation of the action potential resulting from the blocking of the I Kr channel, which results in bradycardia-dependent ventricular arrhythmias [15]. Moreover, the arrhythmogenic potential of the LQTS3 is aggravated during bradycardia [16].…”