Spinal cord stimulation suppresses atrial fibrillation by inhibiting autonomic remodeling

doi:10.1016/j.hrthm.2015.08.018

Heart Rhythm

Volume 13, Issue 1, January 2016, Pages 274-281

https://doi.org/10.1016/j.hrthm.2015.08.018 Get rights and content

Background

Previous study has shown that spinal cord stimulation (SCS) may suppress atrial fibrillation (AF) inducibility, but the mechanism for this is elusive.

Objective

The purpose of this study was to determine whether SCS could inhibit AF inducibility by suppressing autonomic remodeling in a canine model of rapid atrial pacing (RAP)–induced AF.

Methods

Eighteen canines were randomly divided into an RAP group (n = 9) and an RAP+SCS group (n = 9). Effective refractory period (ERP), window of vulnerability (WOV), AF inducibility, autonomic neural function, and activity from the anterior right ganglionated plexus (ARGP) and left stellate ganglion (LSG) were measured at baseline, at 3 hours of RAP, and at 6 hours of RAP. Then, ARGP and LSG were excised for Western blot and messenger RNA analysis. In another 4 dogs (control group, which received sham RAP and sham SCS), tissues were also excised for analysis.

Results

In the RAP group, RAP resulted in (1) a significant decrease in ERP and an increase in ERP dispersion, ΣWOV, and AF inducibility and (2) activation of ARGP and LSG versus baseline. In the RAP+SCS group, however, these changes were significantly attenuated by SCS. Compared with the control group, c-fos and nerve growth factor (NGF) were significantly up-regulated and small conductance calcium-activated potassium channel type 2 (SK2) was significantly down-regulated in the RAP group. In the RAP+SCS group, however, c-fos, NGF, and SK2 remained at a normal level compared with the control group.

Conclusion

SCS may suppress RAP-induced AF by inhibiting autonomic remodeling, and the underlying mechanism of the salutary effect of SCS might contribute to modulation of the expression of c-fos, NGF, and SK2.

Graphical abstract

Introduction

Atrial fibrillation (AF), the most common cardiac arrhythmia, is known to result from and result in changes in atrial electrophysiology, atrial tissue architecture, and the autonomic nervous system (ANS).1, 2 Bernstein et al³ showed that spinal cord stimulation (SCS) may prolong atrial effective refractory periods (ERPs) and protect against AF induced by rapid atrial pacing (RAP), but the underlying mechanism remains unknown. Previous studies have established that RAP may induce atrial electrical remodeling and autonomic remodeling.4, 5, 6 Furthermore, direct neural activity recording showed that more than 70% episodes of paroxysmal atrial tachycardia and paroxysmal AF were preceded by sympathovagal coactivation, and 100% of the paroxysmal atrial tachycardia and paroxysmal AF were facilitated by activation of ganglionated plexus (GP) neural activity,⁷ which further corroborated the fact that autonomic remodeling plays a key role in the process of AF. Recently, our studies showed that SCS may exert an antiarrhythmic effect by suppressing GP neural activity in a focal rapid firing–induced AF model and by inhibiting left stellate ganglion (LSG) neural activity in a model of acute myocardial infarction.8, 9 Therefore, we hypothesized that SCS may also inhibit RAP-induced AF by suppressing the neural activity of LSGs and GPs.

Section snippets

Animal preparation

Twenty-two canines weighing between 20 and 25 kg were included in this study. The experiments performed in the present study were approved by the Animal Ethics Committee of Wuhan University under approval number 2014-0678 and followed the guidelines outlined by the “Guide for the Care and Use of Laboratory Animals” of the US National Institutes of Health. All surgeries were performed under anesthesia with 3% sodium pentobarbital with an initial dose of 1 ml/kg and a maintenance dose of 2 mL/h.

Effect of SCS on AF inducibility

At baseline, no AF was induced by RAP in the RAP group or the RAP+SCS group. After 3-hour RAP, AF occurred in 5 of 9 dogs in the RAP group and 2 of 9 dogs in the RAP+SCS group (55.56% vs 22.22%, P > .05) (Figure 2A). After 6-hour RAP, however, the spontaneous occurrence of AF was significantly reduced in the RAP+SCS group (33.33% vs 88.89%, P < .05 vs RAP group) (Figure 2B). Furthermore, AF duration was significantly shortened (3-hour RAP: 10.2 ± 6.2 s vs 55.0 ± 10.9 s, P < .01 vs RAP group;

Autonomic remodeling and RAP-induced AF

Previous studies have established that the intrinsic and extrinsic cardiac ANS, such as GP and LSG, plays a key role in the initiation and maintenance of AF.4, 5, 6 Direct autonomic neural recording showed that simultaneous cardiac sympathovagal discharges were the most common triggers of paroxysmal atrial tachycardia and AF.7, 13, 14 Modulation of the ANS by stimulation or ablation, however, may eliminate episodes of paroxysmal AF and atrial tachycardias,7, 15 which indicates that

Conclusion

SCS might suppress RAP-induced AF by attenuating the neural activity of the LSG and ARGP. The underlying mechanism of the salutary effect of SCS might contribute in part to the modulation of c-Fos, NGF, and SK2 expression.

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View full text

Spinal cord stimulation suppresses atrial fibrillation by inhibiting autonomic remodeling

Background

Objective

Methods

Results

Conclusion

Graphical abstract

Introduction

Section snippets

Animal preparation

Effect of SCS on AF inducibility

Autonomic remodeling and RAP-induced AF

Conclusion

J Am Coll Cardiol

Heart Rhythm

Heart Rhythm

Heart Rhythm

J Am Coll Cardiol

Heart Rhythm

J Am Coll Cardiol

Heart Rhythm

Heart Rhythm

Neural mechanisms of atrial arrhythmias

Nat Rev Cardiol

Neural mechanisms of atrial fibrillation

Curr Opin Cardiol

Spinal cord stimulation protects against atrial fibrillation induced by tachypacing

Heart Rhythm

Atrial fibrillation begets atrial fibrillation: autonomic mechanism for atrial electrical remodeling induced by short-term rapid atrial pacing

Circ Arrhythm Electrophysiol

Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines

Circulation

Spinal cord stimulation suppresses focal rapid firing-induced atrial fibrillation by inhibiting atrial ganglionated plexus activity

J Cardiovasc Pharm

Left renal nerves stimulation facilitates ischemia-induced ventricular arrhythmia by increasing nerve activity of left stellate ganglion

J Cardiovasc Elec

Autonomic involvement in idiopathic premature ventricular contractions

Clin Res Cardiol

Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs

Circulation