TY - JOUR

T1 - Antiarrhythmic drug effects on premature beats are partly determined by prior cardiac activation frequency in perfused guinea-pig heart

AU - Osadchii, Oleg E.

PY - 2020

Y1 - 2020

N2 - New FindingsWhat is the central question of this study? Can antiarrhythmic drug effects on repolarization, conduction time and excitation wavelength in premature beats be determined by prior cardiac activation frequency?What is the main finding and its importance? In premature beats induced after a series of cardiac activations at a slow rate, antiarrhythmics prolong repolarization but evoke little or no conduction delay, thus increasing the excitation wavelength, which indicates an antiarrhythmic effect. Fast prior activation rate attenuates prolongation of repolarization, while amplifying the conduction delay induced by drugs, which translates into the reduced excitation wavelength, indicating proarrhythmia. These findings suggest that a sudden increase in heart rate can shape adverse pharmacological profiles in patients with ventricular ectopy.Antiarrhythmic drugs used to treat atrial fibrillation can occasionally induce ventricular tachyarrhythmia, which is typically precipitated by a premature ectopic beat through a mechanism related, in part, to the shortening of the excitation wavelength (EW). The arrhythmia is likely to occur when a drug induces a reduction, rather than an increase, in the EW of ectopic beats. In this study, I examined whether the arrhythmic drug profile is shaped by the increased cardiac activation rate before ectopic excitation. Ventricular monophasic action potential durations, conduction times and EW values were assessed during programmed stimulations applied at long (S-1-S-1 [basic drive cycle length] = 550 ms) and short (S-1-S-1 = 200 ms) cycle lengths in perfused guinea-pig hearts. The premature activations were induced with extrastimulus application immediately upon termination of the refractory period. With dofetilide, a class III antiarrhythmic agent, a prolongation in action potential duration and the resulting increase in the EW obtained at S-1-S-1 = 550 ms were significantly attenuated at S-1-S-1 = 200 ms, in both the regular (S-1) and the premature (S-2) beats. With class I antiarrhythmic agents (quinidine, procainamide and flecainide), fast S-1-S-1 pacing was found to attenuate the drug-induced increase in action potential duration, while amplifying drug-induced conduction slowing, in both S-1 and S-2 beats. As a result, although the EW was increased (quinidine and procainamide) or not changed (flecainide) at the long S-1-S-1 intervals, it was invariably reduced by these agents at the short S-1-S-1 intervals. These findings indicate that the increased heart rate before ectopic activation shapes the arrhythmic profiles by facilitating drug-induced EW reduction.

AB - New FindingsWhat is the central question of this study? Can antiarrhythmic drug effects on repolarization, conduction time and excitation wavelength in premature beats be determined by prior cardiac activation frequency?What is the main finding and its importance? In premature beats induced after a series of cardiac activations at a slow rate, antiarrhythmics prolong repolarization but evoke little or no conduction delay, thus increasing the excitation wavelength, which indicates an antiarrhythmic effect. Fast prior activation rate attenuates prolongation of repolarization, while amplifying the conduction delay induced by drugs, which translates into the reduced excitation wavelength, indicating proarrhythmia. These findings suggest that a sudden increase in heart rate can shape adverse pharmacological profiles in patients with ventricular ectopy.Antiarrhythmic drugs used to treat atrial fibrillation can occasionally induce ventricular tachyarrhythmia, which is typically precipitated by a premature ectopic beat through a mechanism related, in part, to the shortening of the excitation wavelength (EW). The arrhythmia is likely to occur when a drug induces a reduction, rather than an increase, in the EW of ectopic beats. In this study, I examined whether the arrhythmic drug profile is shaped by the increased cardiac activation rate before ectopic excitation. Ventricular monophasic action potential durations, conduction times and EW values were assessed during programmed stimulations applied at long (S-1-S-1 [basic drive cycle length] = 550 ms) and short (S-1-S-1 = 200 ms) cycle lengths in perfused guinea-pig hearts. The premature activations were induced with extrastimulus application immediately upon termination of the refractory period. With dofetilide, a class III antiarrhythmic agent, a prolongation in action potential duration and the resulting increase in the EW obtained at S-1-S-1 = 550 ms were significantly attenuated at S-1-S-1 = 200 ms, in both the regular (S-1) and the premature (S-2) beats. With class I antiarrhythmic agents (quinidine, procainamide and flecainide), fast S-1-S-1 pacing was found to attenuate the drug-induced increase in action potential duration, while amplifying drug-induced conduction slowing, in both S-1 and S-2 beats. As a result, although the EW was increased (quinidine and procainamide) or not changed (flecainide) at the long S-1-S-1 intervals, it was invariably reduced by these agents at the short S-1-S-1 intervals. These findings indicate that the increased heart rate before ectopic activation shapes the arrhythmic profiles by facilitating drug-induced EW reduction.

KW - antiarrhythmic agents

KW - excitation wavelength

KW - premature beats

KW - ACTION-POTENTIAL DURATION

KW - RECTIFIER K+-CURRENT

KW - ATRIAL-FLUTTER

KW - VENTRICULAR REPOLARIZATION

KW - PROLONGATION

KW - FIBRILLATION

KW - MECHANISM

KW - ARRHYTHMIAS

KW - CONDUCTION

KW - COMPLEXES

U2 - 10.1113/EP088165

DO - 10.1113/EP088165

M3 - Journal article

C2 - 32175633

VL - 105

SP - 819

EP - 830

JO - Experimental Physiology

JF - Experimental Physiology

SN - 0958-0670

IS - 5

ER -