Procainamide and lidocaine produce dissimilar changes in ventricular repolarization and arrhythmogenicity in guinea‐pig

Abstract

Procainamide is class Ia Na(+) channel blocker that may prolong ventricular repolarization secondary to inhibition of IK r , the rapid component of the delayed rectifier K(+) current. In contrast to selective IN a blockers such as lidocaine, procainamide was shown to produce arrhythmogenic effects in the clinical setting. This study examined whether pro-arrhythmic responses to procainamide may be accounted for by drug-induced repolarization abnormalities including impaired electrical restitution kinetics, spatial gradients in action potential duration (APD), and activation-to-repolarization coupling. In perfused guinea-pig hearts, procainamide was found to prolong the QT interval on ECG and left ventricular (LV) epicardial monophasic APD, increased the maximum slope of electrical restitution, enhanced transepicardial APD variability, and eliminated the inverse correlation between the local APD and activation time values determined at distinct epicardial recording sites prior to drug infusion. In contrast, lidocaine had no effect on electrical restitution, the degree of transepicardial repolarization heterogeneities, and activation-to-repolarization coupling. Spontaneous episodes of monomorphic ventricular tachycardia were observed in 57% of procainamide-treated heart preparations. No arrhythmia was induced by lidocaine. In summary, this study suggests that abnormal changes in repolarization may contribute to pro-arrhythmic effects of procainamide.

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

“…This change can also contribute to excessive QT lengthening and increased torsadogenic risks during procainamide treatment, as mentioned above. In study VIII (Osadchii 2014a), procainamide‐induced APD lengthening was associated with a steepened electrical restitution slope upon dynamic pacing in perfused guinea‐pig hearts (Fig. , panels a–c), thus indicating a proarrhythmic tendency.…”

“…The impaired activation–repolarization coupling may also contribute to abnormal repolarization gradients during steady‐state beating, an effect that has been invoked to explain proarrhythmic effects produced by adrenergic agonist infusion, hypokalaemia, and class I and III antiarrhythmic drugs (Osadchii 2012e, 2014a, 2014c: studies VI, VIII, and X, respectively) . Collectively, these findings raise the point that the slope of APD‐to‐activation time relationships may serve as a sensitive metric of arrhythmic susceptibility, and the therapies that improve activation–repolarization coupling are likely to prevent arrhythmia.…”

“…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.…”

“…, panels a and b). Notably, lidocaine, a class Ib I Na blocker with a clinically safe profile, had no effect on electrical restitution, spatial APD dispersion, and activation–repolarization coupling (Osadchii 2014a: study VIII) …”

Ibutilide for the control of refractory ventricular tachycardia and ventricular fibrillation in patients with myocardial ischemia and hemodynamic instability

“…Lidocaine is a sodium channel blocker that has no effect on ventricular repolarization. Finally, procainamide prolongs repolarization but also depresses conduction velocity, potentially exacerbating reentrant arrhythmias …”