Autonomic conflict exacerbates long QT associated ventricular arrhythmias

Abstract

This study tested the hypothesis that concomitant sympathetic and parasympathetic stimulation ("autonomic conflict") may act as a trigger for arrhythmias in long QT syndrome (LQTS). Studies were performed in isolated innervated rabbit hearts treated with clofilium (100 nmol/L); a potassium channel blocker. The influence of vagus nerve stimulation (VNS) on spontaneous ventricular arrhythmias was assessed in the absence/presence of sustained noradrenaline perfusion (100 nmol/L) and with sudden adrenergic stress (injections of noradrenaline into the perfusion line). Hearts were instrumented for a pseudo-electrocardiogram and monophasic action potential recordings. VNS, which slows heart rate, was associated with a stimulation frequency-dependent incidence of spontaneous early after-depolarisations (EADs) and ventricular tachycardia (VT), best predicted by the duration of the electrocardiographic T-wave and by triangulation of the ventricular action potential. In the presence of sustained (steady-state) noradrenaline perfusion, the incidence of EADs and VT with VNS was decreased from 73/55% to 45/27%, respectively. However, sudden adrenergic stress, imposed during periods of sustained VNS, was associated with a transient increase in the incidence of severity of observed arrhythmias, as indicated by an increase in the average arrhythmias score (1.6 ± 0.4 vs. 2.1 ± 0.7, p = .01). Analysis of electrophysiological parameters suggests that sudden adrenergic stress is associated with a transient prolongation, and increased triangulation, of the ventricular action potential, which may predispose to triggered activity. This study demonstrates that autonomic conflict is a pro-arrhythmic stimulus in LQTS. However, combined adrenergic and parasympathetic stimulation has a complex relationship with arrhythmogenicity, with differences in the effects of steady-state adrenergic activation vs. sudden adrenergic stress.

Keywords: Autonomic conflict; Autonomic nervous system; Long QT syndrome; Parasympathetic; Sympathetic; Torsades de pointes.

Fig. 1

Sustained noradrenaline perfusion suppresses LQTS associated arrhythmias. A) Representative traces demonstrating the slowing of heart rate with increasing intensities of vagus nerve stimulation (VNS) in a clofilium-treated (100 nmol/L) rabbit heart. In this example, early afterdepolarisations (EADs) are triggered at 20 Hz VNS. B&C) Arrhythmias counts for 11-experiments demonstrating a reduction in the incidence of EADs and ventricular tachycardia (VT) with sustained noradrenaline (NA, 100 nmol/L) perfusion. D&E) Individual and average (Tukey's box plot) arrhythmias scores during VNS and with VNS + NA (sustained). Different from VNS alone; *p < .05. Comparisons by Wilcoxon's matched-groups signed rank-sum test (n = 11 hearts).

Fig. 2

Suppression of VNS triggered arrhythmias by rapid pacing. Representative traces showing spontaneous episodes of early afterdepolarisations and ventricular tachycardia following vagus nerve stimulation (VNS), with subsequent rapid ventricular pacing (cycle length = 190 ms) and on the cessation of pacing (following 1-min of sustained pacing).

Fig. 3

Electrophysiological changes during VNS with and without sustained noradrenaline. A) Representative traces demonstrating changes in electrocardiogram (ECG) parameters during VNS in a clofilium-treated (100 nmol/L) rabbit heart, with and without sustained noradrenaline (NA, 100 nmol/L) perfusion. B–E) Average values on the change in heart rate, QT interval, T-wave peak to end interval (TpTe) and monophasic action potential (MAP) triangulation. Data represent mean (SD). Different from clofilium (control); *p < .05. Two-way repeated measures ANOVA, with Sidak's post-hoc tests (n = 7 hearts).

Fig. 4

Bolus noradrenaline facilitates LQTS associated arrhythmias. A) Representative episodes of spontaneous ventricular tachycardia (VT) in a clofilium-treated (100 nmol/L) rabbit heart. The left trace was observed during VNS and the right following bolus noradrenaline (NA) perfusion (0.1 mL of 1 mM stock), in separate experiments. B-D) Arrhythmias counts for 12-experiments, demonstrating an increase in the incidence of early aftedepolarizations (EADs), VT and sustained VT (VT_sus)/ventricular fibrillation (VF) with VNS + NA (bolus). E&F) Individual and average arrhythmias scores during VNS and with VNS + NA (bolus). Different from VNS alone; *p < .05. Comparisons by Wilcoxon's matched-groups signed rank-sum test (n = 12 hearts).

Fig. 5

Electrophysiological effects of bolus noradrenaline in LQTS. A) Experimental trace demonstrating the change in heart rate and monophasic action potential duration (MAPD₉₀) following bolus noradrenaline (NA) perfusion (0.1 mL of 1 mM stock) in a clofilium treated (100 nmol/L) rabbit heart. A transient increase in MAPD₉₀ is seen immediately following NA perfusion. The inset shows representative action potentials recorded at the times indicated on the MAPD₉₀ trace. B–E) Average values for QT interval, T-wave peak to end interval (TpTe), MAPD₉₀ and action potential triangulation at baseline, at peak response and at 30-second post-peak response. Data represent mean (SD). Different from baseline; *p < .05. Comparisons by one-way ANOVA, with Sidak's post-hoc tests (n = 9 hearts).