Abstract
Bradycardia is a risk factor for arrhythmia in several disorders, including acquired long QT syndrome, whereby slowing of heart rate facilitates ectopic activity and torsade de pointes. Slowing of rate is associated with an increase in the spatiotemporal dispersion of ventricular repolarisation (DOR) in electrically paced hearts. However, there have been conflicting reports on the effect of the vagus nerve, which mediates the physiological slowing of heart rate, on DOR. The aim of this study was to investigate the effect of vagus nerve stimulation (VNS) on the heterogeneity of ventricular repolarisation, as assessed using the T-wave peak-to-end interval (TpTe) and monophasic action potentials (MAPs), in normal hearts and in hearts with acquired long QT syndrome. Experiments were conducted in an isolated innervated rabbit heart preparation. The effect of VNS on cardiac electrograms, MAPs and ventricular function was investigated in control and following perfusion of E4031 (50nmol/L); an inhibitor of the rapid delayed rectifying potassium current. VNS was associated with a stimulation frequency-dependent bradycardia (−74±6 [10Hz] vs. −25±4bpm [2Hz], P<0.05). VNS prolonged the TpTe interval (29±1 vs. 20±2ms, P<0.05) and increased T-wave amplitude (1.7±0.3 vs. 0.7±0.2mV, P<0.05) in association with increased apicobasal DOR. The effects of VNS were exacerbated by E4031, with a greater prolongation of TpTe (ΔTpTe 42±6 vs. 8±1ms, P<0.05) and max–min apicobasal time of repolarisation (TRepol; 45±11 vs. 5±2ms, P<0.05). ΔTpTe was strongly correlated with the Δmax–minTRepol (r2=0.87, P<0.05) and TpTe was prolonged to a greater degree in hearts exhibiting spontaneous ventricular tachyarrhythmia. Rate dependent differences in regional action potential prolongation were replicated using computational models. These data demonstrate that VNS increases ventricular DOR and that the effects of the vagus nerve on ventricular electrophysiology are exacerbated in pharmacologically acquired long QT syndrome.
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