Effects of antiarrhythmics on the electrical restitution in perfused guinea-pig heart are critically determined by the applied cardiac pacing protocol

Abstract

New findings: What is the central question of this study? Are modifications in the restitution of ventricular action potential duration induced by antiarrhythmic drugs the same when assessed with premature extrastimulus application at variable coupling intervals (the standard stimulation protocol) and with steady state pacing at variable rates (the dynamic stimulation protocol)? What is the main finding and its importance? With class I and class III antiarrhythmics, the effects on electrical restitution determined with the standard stimulation protocol dissociate from those obtained during dynamic pacing. These findings indicate a limited value of the electrical restitution assessments based on extrasystolic stimulations alone, as performed in the clinical studies, in estimating the outcomes of antiarrhythmic drug therapies.

Abstract: A steep slope of the ventricular action potential duration (APD) to diastolic interval (DI) relationships (the electrical restitution) can precipitate tachyarrhythmia, whereas a flattened slope is antiarrhythmic. The derangements in APD restitution responsible for transition of tachycardia to ventricular fibrillation can be assessed with cardiac pacing at progressively increasing rates (the dynamic stimulation protocol). Nevertheless, this method is not used clinically owing to the risk of inducing myocardial ischaemia. Instead, the restitution kinetics is determined with a premature extrastimulus application at variable coupling intervals (the standard stimulation protocol). Whether the two protocols are equivalent in estimating antiarrhythmic drug effects is uncertain. In this study, dofetilide and quinidine, the agents blocking repolarizing K⁺ currents, increased epicardial APD in perfused guinea-pig hearts, with effects being greater at long vs. short DIs. These changes were more pronounced during dynamic pacing compared to premature extrastimulations. Accordingly, although both agents markedly steepened the dynamic restitution, there was only a marginal increase in the standard restitution slope with dofetilide, and no effect with quinidine. Lidocaine and mexiletine, selective Na⁺ channel blockers, prolonged the effective refractory period without changing APD, and increased the minimum DI that enabled ventricular capture during extrastimulations. No change in the minimum DI was noted during dynamic pacing. Consequently, although lidocaine and mexiletine reduced the standard restitution slope, they failed to flatten the dynamic restitution. Overall, these findings imply a limited value of the electrical restitution assessments with premature extrastimulations alone in discriminating arrhythmic vs. antiarrhythmic changes during drug therapies.

Keywords: action potential duration; antiarrhythmic agents; cardiac pacing; electrical restitution.