Cardiac sympathetic innervation via middle cervical and stellate ganglia and antiarrhythmic mechanism of bilateral stellectomy

Abstract

Cardiac sympathetic denervation (CSD) is reported to reduce the burden of ventricular tachyarrhythmias [ventricular tachycardia (VT)/ventricular fibrillation (VF)] in cardiomyopathy patients, but the mechanisms behind this benefit are unknown. In addition, the relative contribution to cardiac innervation of the middle cervical ganglion (MCG), which may contain cardiac neurons and is not removed during this procedure, is unclear. The purpose of this study was to compare sympathetic innervation of the heart via the MCG vs. stellate ganglia, assess effects of bilateral CSD on cardiac function and VT/VF, and determine changes in cardiac sympathetic innervation after CSD to elucidate mechanisms of benefit in 6 normal and 18 infarcted pigs. Electrophysiological and hemodynamic parameters were evaluated at baseline, during bilateral stellate stimulation, and during bilateral MCG stimulation in 6 normal and 12 infarcted animals. Bilateral CSD (removal of bilateral stellates and T₂ ganglia) was then performed and MCG stimulation repeated. In addition, in 18 infarcted animals VT/VF inducibility was assessed before and after CSD. In infarcted hearts, MCG stimulation resulted in greater chronotropic and inotropic response than stellate ganglion stimulation. Bilateral CSD acutely reduced VT/VF inducibility by 50% in infarcted hearts and prolonged global activation recovery interval. CSD mitigated effects of MCG stimulation on dispersion of repolarization and T-peak to T-end interval in infarcted hearts, without causing hemodynamic compromise. These data demonstrate that the MCG provides significant cardiac sympathetic innervation before CSD and adequate sympathetic innervation after CSD, maintaining hemodynamic stability. Bilateral CSD reduces VT/VF inducibility by improving electrical stability in infarcted hearts in the setting of sympathetic activation.NEW & NOTEWORTHY Sympathetic activation in myocardial infarction leads to arrhythmias and worsens heart failure. Bilateral cardiac sympathetic denervation reduces ventricular tachycardia/ventricular fibrillation inducibility and mitigates effects of sympathetic activation on dispersion of repolarization and T-peak to T-end interval in infarcted hearts. Hemodynamic stability is maintained, as innervation via the middle cervical ganglion is not interrupted.

Keywords: autonomic nervous system; cardiac sympathetic denervation; stellectomy; sympathetic nervous system; ventricular arrhythmias.

Fig. 1.

Isolation of the middle cervical ganglia (MCG) and Tp-Te interval and ARI recordings. A: anatomy of MCG and surrounding tissue is shown. The MCG sits just at the thoracic inlet and provides cardiopulmonary nerves that innervate the heart. B: customized bipolar needle electrodes were placed in the isolated MCG. C: method for the measurement of Tp-Te interval from surface ECG. The peak of the T wave was determined as the highest voltage of the T wave (T-p). T-end (T-e) was determined by the tangent of the T wave. D: the region of scar in infarcted hearts predominantly involved the LV apex, anterior, and anterolateral walls. E: 56-electrode sock is placed over the ventricles to obtain unipolar electrograms that are used for ARI analysis. F: template for the polar maps used to display regional ARIs from the sock electrodes. Ant, anterior; Lat, lateral; Post, posterior; RVOT, right ventricular outflow tract.

Fig. 2.

Experimental protocol in normal hearts and effect of bilateral stellate ganglion stimulation (BSGS) compared with bilateral MCG stimulation (BMCGS). A: timeline of the experimental protocol in 6 normal animals. HEX, hexamethonium. *BMCGS or BSGS was performed in a random order. B: in all normal animals, BMCGS had an effect on ARI similar to that of BSGS. C: polar maps from a normal animal show the effects of MCG and stellate ganglion stimulation on ARI. Blue dashed lines indicate course of left anterior descending coronary artery (LAD). BL, baseline.

Fig. 3.

A: the time course of ARI shortening with bilateral stellate ganglion stimulation (BSGS) was similar to that with bilateral MCG stimulation (BMCGS) (n = 6). B: there were no significant regional differences between BSGS and BMCGS in normal hearts (P values > 0.05 for all regions, n = 6). C: apical ventricular pacing before CSD demonstrated shorter global ARIs than right atrial (RA) pacing in normal animals (n = 6) at the same cycle lengths. However, after CSD there was no significant difference in ARI between ventricular and atrial pacing, suggesting that apical pacing may cause reflex sympathetic activation that is prevented by CSD. Ant, anterior; Lat, lateral; Post, posterior wall; RV, right ventricle; LV, left ventricle.

Fig. 4.

Effects of CSD in normal animals. A: there was no difference in global ARI in normal heart before compared with after CSD. B: bilateral MCG stimulation after CSD had similar effects on global ARI compared with before CSD, with significant ARI shortening observed. C: there were no differences in the regional effects of MCG stimulation after CSD compared with before CSD. *P < 0.05; †P < 0.1. D: before CSD bilateral MCG stimulation increased dispersion of repolarization in normal hearts, and this effect was not modified by CSD. E: bilateral MCG stimulation in normal hearts also increased Tp-Te interval, with no differences observed in this parameter before compared with after CSD in normal hearts.

Fig. 5.

Effects of hexamethonium on MCG stimulation. A: the increase in global ARI during right vagal nerve stimulation (VNS) was no longer observed after infusion of hexamethonium (Hex) in normal animals (n = 6). B: global ARI during bilateral MCG stimulation significantly decreased even after administration of hexamethonium in all normal hearts (n = 6). C: % change in global ARI during right VNS and bilateral MCGS stimulation showed that hexamethonium significantly blocked nicotinic receptors but did not affect the response to bilateral MCG stimulation.

Fig. 6.

Experimental protocol in infarcted hearts and effect of bilateral stellate ganglion stimulation (BSGS) compared with bilateral MCG stimulation (BMCGS). A: timeline of the experimental protocol in 12 infarcted animals. *BMCGS or BSGS was performed in a random order. B: in all infarcted animals BSGS significantly decreased ARI, as did BMCGS. BMCGS, however, caused greater ARI shortening than BSGS. C: polar maps from an infarcted animal show the effects of MCG and stellate ganglion stimulation on ARI. Black dashed circle indicates region of the infarct/scar on polar maps. Blue dashed lines indicate course of left anterior descending coronary artery (LAD). BL, baseline.

Fig. 7.

Effects of CSD and VT inducibility before and after CSD. A: epicardial global ARI from infarcted animals significantly increased with CSD (n = 12). Blue dashed circle indicates region of the infarct on polar maps. B: inducibility of VT/VF was reduced after CSD in infarcted animals (n = 18: 12 were inducible at baseline; of these 12 only 6 were inducible after CSD). C: example of VT induction with ventricular extrastimulus pacing. VT/VF was induced before CSD with double extrastimuli at cycle lengths of 600/320/200 ms. After CSD, ERP was reached at an interval of 600/340 ms with double extrastimuli. Therefore, the S2 stimulus was increased by 20 ms to 600/360 ms (to allow for consistent capture) and S3 was added and the interval reduced by 10 ms. The animal reached ERP at 270 ms with triple extrastimuli (S3). Therefore, the S3 coupling interval was increased to 290 ms (to allow for consistent capture), and S4 was reduced by 10 ms, starting at 600/360/290/400 ms. Despite reduction of S4 extrastimulus (triple extrastimulus testing) to a coupling interval of 200 ms, no ventricular arrhythmias could be induced. RVD, distal poles of right ventricular endocardial catheter; RVP, proximal poles of right ventricular endocardial catheter.

Fig. 8.

MCG stimulation and its effects before and after CSD on infarcted hearts. A: global ARI at baseline (BL) and during bilateral MCG stimulation (BMCGS) after CSD and % change in ARI before vs. after CSD during BMCGS in infarcted hearts (n = 12). MCG stimulation decreased ARI despite CSD. B: examples of polar maps at baseline and during MCG stimulation after CSD in infarcted hearts. Black dashed lines indicate course of left anterior descending coronary artery (LAD). Blue dashed circle indicates region of scar. C: although MCG stimulation significantly increased DOR before CSD, this effect was mitigated after CSD in infarcted hearts (n = 12). D: the prolongation in Tp-Te interval during MCG stimulation was reduced by CSD in infarcted hearts.

Fig. 9.

Modulation of propagation and activation time by CSD. A: polar maps of activation time/sequence obtained during scar/apical pacing in this infarct animal demonstrated a localized region at the septal border zone of the infarct that was activated late as compared with the surrounding area. This area of functional block (localized regions of late activation, delineated as “II”) before CSD was no longer observed after CSD, and the entire area was activated more homogeneously. B: polar maps of activation time/sequence during scar pacing at baseline (BL) and during bilateral MCG stimulation (BMCGS) before and after CSD in a different infarcted animal. During MCG stimulation, 2 localized regions of late activation are seen at the border zone of the infarct, creating a potential isthmus or area of slow conduction that could serve as the substrate for a reentrant circuits. Both of these regions of late myocardial activation are no longer observed during MCG stimulation after CSD. After CSD, the entire region is more uniformly activated. Black dashed circle indicates region of the infarct on polar maps.

Fig. 10.

Efferent and afferent cardiac sympathetic pathways. Afferent fibers from the myocardium that traverse through the MCG pass through the stellate ganglia before reaching the spinal cord, and some of these pathways are interrupted by CSD. In addition, preganglionic efferent fibers that pass from the spinal cord through the stellate ganglia and to the MCG and any postganglionic fibers that arise from the stellate ganglia and innervate the myocardium are also interrupted. However, efferent postganglionic fibers from MCG neurons to the myocardium remain intact despite CSD. Aff, afferent neurons; Eff, efferent neurons; DRG, dorsal root ganglion; IML, intermediolateral nucleus; DH, dorsal horn of the spinal cord.