Proarrhythmic Effects of Sympathetic Activation Are Mitigated by Vagal Nerve Stimulation in Infarcted Hearts

Abstract

Objectives: The goal of this study was to evaluate whether intermittent VNS reduces electrical heterogeneities and arrhythmia inducibility during sympathoexcitation.

Background: Sympathoexcitation increases the risk of ventricular tachyarrhythmias (VT). Vagal nerve stimulation (VNS) has been antiarrhythmic in the setting of ischemia-driven arrhythmias, but it is unclear if it can overcome the electrophysiological effects of sympathoexcitation in the setting of chronic myocardial infarction (MI).

Methods: In Yorkshire pigs after chronic MI, a sternotomy was performed, a 56-electrode sock was placed over the ventricles (n = 17), and a basket catheter was positioned in the left ventricle (n = 6). Continuous unipolar electrograms from sock and basket arrays were obtained to analyze activation recovery interval (ARI), a surrogate of action potential duration. Bipolar voltage mapping was performed to define scar, border zone, or viable myocardium. Hemodynamic and electrical parameters and VT inducibility were evaluated during sympathoexcitation with bilateral stellate ganglia stimulation (BSS) and during combined BSS with intermittent VNS.

Results: During BSS, global epicardial ARIs shortened from 384 ± 59 milliseconds to 297 ± 63 milliseconds and endocardial ARIs from 359 ± 36 milliseconds to 318 ± 40 milliseconds. Dispersion in ARIs increased in all regions, with the greatest increase observed in scar and border zone regions. VNS mitigated the effects of BSS on border zone ARIs (from -18.3% ± 6.3% to -2.1% ± 14.7%) and ARI dispersion (from 104 ms² [1 to 1,108 ms²] to -108 ms² [IQR: -588 to 30 ms²]). VNS reduced VT inducibility during sympathoexcitation (from 75%-40%; P < 0.05).

Conclusions: After chronic MI, VNS overcomes the detrimental effects of sympathoexcitation by reducing electrophysiological heterogeneities exacerbated by sympathetic stimulation, decreasing VT inducibility.

Keywords: dispersion; myocardial infarction; neuromodulation; sympathetic; vagal nerve stimulation; ventricular arrhythmias.

Figure 1.. Ventricular epicardial effects of sympathetic stimulation and its attenuation by VNS following MI.

(a-b) Percutaneous creation of MI in region of the LAD coronary artery via injection of microspheres through a transluminal angioplasty catheter (red arrowhead indicates tip of catheter). (c-d) Following injection of microspheres, lack of flow was observed in the distal portion of the LAD (red circle), accompanied by ST-segment elevation. (e) Six to eight weeks after MI, prominent scarring of the anterior RV and LV was observed along with regions of patchy scar (black arrowheads) and a 56-electrode sock is placed around the ventricles to record unipolar electrograms. (f) Electrograms were then mapped onto a 2-D polar map for the assessment of regional electrophysiological differences. The difference in time between activation and recovery time (AT and RT, respectively) was defined as ARI and used a surrogate of local action potential duration at each electrode/site. (g-h) The stellate ganglia and cervical vagus nerves were isolated for bipolar stimulation. Stimulation of the bilateral stellate ganglia are performed at 4 Hz for 3–5 minutes with and without concomitant 10 Hz VNS (50% duty cycle). (i) ERP from the RV endocardium was significantly shortened by BSS. Concomitant bilateral VNS reduced effects on ERP. (j-k) Representative polar maps at baseline (BL) and during BSS indicate a shortening of ARIs in infarct and remote regions of the RV and LV. Accordingly, a significant shortening of global epicardial ARIs across animals was observed. (l-m) Representative polar map at BL and during BSS+VNS suggests attenuation of BSS-induced ARI shortening. (n) Changes in epicardial ARIs from baseline (pre-stimulation) with BSS were significantly attenuated by concomitant VNS. BSS=bilateral stellate stimulation, VNS=bilateral vagus nerve stimulation, ERP=effective refractory period. Data are shown as mean ± SEM (n = 17). *p<0.05, ****p<0.0001, ns=not significant.

Figure 2.. Ventricular endocardial effects of sympathetic stimulation and attenuation by VNS.

(a-c) A 64-electrode Constellation catheter was advanced into the LV for assessment of local endocardial unipolar electrograms. Sufficient contact of the basket catheter with the endocardium was confirmed by echocardiography. (d) Local unipolar electrograms from the endocardium were mapped onto a 2-D polar map. (e) A representative polar map of ARIs at baseline and during BSS indicates significant shortening of endocardial ARIs. (f) There was no significant ARI change during BSS+VNS relative to baseline. (g-h) BSS-induced shortening in endocardial ARI was significantly blunted by concomitant bilateral VNS. BSS=bilateral stellate stimulation, VNS=bilateral vagus nerve stimulation. Data are shown as mean ± SEM (n = 6). *p<0.05.

Figure 3.. VNS mitigates ventricular ARI shortening and heterogeneities induced by sympathetic activation.

(a) Representative electroanatomic map confirms the presence of a dense antero-apical scar encircled by broad regions of heterogenous electrical border zone and remote, healthy myocardium. Based on the bipolar voltage at each site, electrodes were designated as viable (> 1.5 mV), border zone (0.5 – 1.5 mV) or scar (< 0.5 mV) with sample electrograms shown. (b) BSS induced significant shortening of ARIs in all regions (c-d) and these effects were significantly attenuated by concomitant VNS. (e) Importantly, BSS led to significant increases in regional dispersion, a measure of local heterogeneity in ARIs. (f-g) Increases in regional dispersion with BSS were attenuated by concomitant bilateral VNS. BSS=bilateral stellate stimulation, VNS=bilateral vagus nerve stimulation. Regional ARI data are shown as mean ± SEM and regional dispersion as median and interquartile range (n = 12). *p<0.05, **p<0.01, ****p<0.0001, ns=not significant.

Figure 4.. VNS reduces ventricular arrhythmias despite sympathoexcitation.

(a) Representative examples of programmed electrical stimulation during BSS alone or with concomitant VNS. (b) Pacing protocols used to induce VT/VF in each animal are shown. (c-d) During BSS alone, 13 of 17 animals were inducible. Concomitant VNS caused a significant reduction in VT inducibility with only 7 animals remaining inducible for VT. One animal had spontaneous VT during BSS without any extra-stimulus pacing. BSS=bilateral stellate stimulation, VNS=bilateral vagus nerve stimulation, NSVT=non-sustained VT.

Figure 5. Central Illustration. Summary Figure:

Sympathoexcitation exacerbates baseline electrophysiological heterogeneities in chronically infarcted hearts, predisposing to VT/VF. These heterogeneities are reduced back to baseline, and even further mitigated below baseline in border zone regions, by intermittent vagal nerve stimulation. Vagal nerves stimulation reduces VT inducibility during states of elevated sympathetic tone.