Autonomic modulation of electrical restitution, alternans and ventricular fibrillation initiation in the isolated heart

Objective: Abnormal autonomic nerve activity is a strong prognostic marker for ventricular arrhythmias but the mechanisms underlying the autonomic modulation of ventricular fibrillation (VF) initiation are poorly understood. We examined the effects of direct sympathetic (SS) and vagus (VS) nerve stimulation on electrical restitution, alternans and VF threshold (VFT) in a novel isolated rabbit heart preparation with intact dual autonomic innervation. Methods: Monophasic Action Potentials (MAPs) were recorded from a left ventricular epicardial site on innervated, isolated rabbit hearts (n = 16). Standard restitution, effective refractory period (ERP), electrical alternans and VFT were measured at baseline and during SS and VS separately. Results: The restitution curve was shifted downwards and made steeper with SS whilst VS caused an upward shift and a flattening of the curve. The maximum slope of restitution was increased from 1.30 +/- 0.10 at baseline to 1.86 +/- 0.17 (by 45 +/- 12%, P < 0.01) with SS and decreased to 0.69 +/- 0.10 (by 51 +/- 6%, P < 0.001) with VS. ERP was decreased from 127.3 +/- 2.5 ms to 111.8 +/- 1.8 ms with SS (by 12 +/- 2%, P < 0.001) and increased to 144.0 +/- 2.2 ms with VS (by 13 2%, P0.001). VFT was decreased from 4.7 +/- 0.6 mA to 1.9 +/- 0.5 mA with SS (by 64 +/- 5%, P < 0.001) and increased to 8.7 +/- 1.1 mA with VS (by 89 +/- 14%, P < 0.0005). There was a significant inverse relationship between the maximum slope of restitution and VFT (r = -0.63, P < 0.0001). When compared with baseline, SS caused electrical alternans at longer pacing cycle lengths (139.0 +/- 8.4 vs. 123.0 +/- 7.8 ms, P < 0.01) with greater degree of alternans (32.5 +/- 9.9 vs. 15.4 +/- 3.2%, P < 0.05). It also caused a wider range of cycle lengths where alternans occurred (53.0 +/- 6.2 vs. 41.0 +/- 7.0 ins, P < 0.05) whilst vagus nerve stimulation shortened this range (33.0 +/- 7.3 ms, P < 0.001). Conclusions: Sympathetic stimulation increased maximum slope of restitution and electrical alternans but decreased ERP and VF threshold whilst vagus nerve stimulation had opposite effects. The interaction between action potential duration and beat-to-beat interval may play an important role in the autonomic modulation of VF initiation. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.