Spinal cord stimulation reduces ventricular arrhythmias during acute ischemia by attenuation of regional myocardial excitability.

Myocardial ischemia creates autonomic nervous system imbalance and can trigger cardiac arrhythmias. We hypothesized that neuromodulation by spinal cord stimulation (SCS) will attenuate local cardiac sympathoexcitation from ischemia-induced increases in afferent signaling, reduce ventricular arrhythmias, and improve myocardial function during acute ischemia. Yorkshire pigs (n = 20) were randomized to SCS (50 Hz at 200-µs duration, current 90% motor threshold) or sham operation (sham) for 30 min before ischemia. A four-pole SCS lead was placed percutaneously in the epidural space (T1-T4), and a 56-electrode mesh was placed over the heart for high-resolution electrophysiological recordings, including activation recovery intervals (ARIs), activation time, repolarization time, and dispersion of repolarization. Electrophysiological and hemodynamic measures were recorded at baseline, after SCS/sham, during acute ischemia (300-s coronary artery ligation), and throughout reperfusion. SCS 1) reduced sympathoexcitation-induced ARI and repolarization time shortening in the ischemic myocardium; 2) attenuated increases in the dispersion of repolarization; 3) reduced ventricular tachyarrythmias [nonsustained ventricular tachycardias: 24 events (3 sham animals) vs. 1 event (1 SCS animal), P < 0.001]; and 4) improved myocardial function (dP/dt from baseline to ischemia: 1,814 ± 213 to 1,596 ± 282 mmHg/s in sham vs. 1,422 ± 299 to 1,380 ± 299 mmHg/s in SCS, P < 0.01). There was no change in ventricular electrophysiology during baseline conditions without myocardial stress or in the nonischemic myocardium. In conclusion, in a porcine model of acute ventricular ischemia, SCS reduced regional myocardial sympathoexcitation, decreased ventricular arrhythmias, and improved myocardial function. SCS decreased sympathetic nerve activation locally in the ischemic myocardium with no effect observed in the normal myocardium, thus providing mechanistic insights into the antiarrhythmic and myocardial protective effects of SCS.NEW & NOTEWORTHY In a porcine model of ventricular ischemia, spinal cord stimulation decreased sympathetic nerve activation regionally in ischemic myocardium with no effect on normal myocardium, demonstrating that the antiarrhythmic effects of spinal cord stimulation are likely due to attenuation of local sympathoexcitation in the ischemic myocardium and not changes in global myocardial electrophysiology.

Effect of Thoracic Epidural Anesthesia on Ventricular Excitability in a Porcine Model.

BACKGROUND: Imbalances in the autonomic nervous system, namely, excessive sympathoexcitation, contribute to ventricular tachyarrhythmias. While thoracic epidural anesthesia clinically suppresses ventricular tachyarrhythmias, its effects on global and regional ventricular electrophysiology and electrical wave stability have not been fully characterized. The authors hypothesized that thoracic epidural anesthesia attenuates myocardial excitability and the proarrhythmic effects of sympathetic hyperactivity. METHODS: Yorkshire pigs (n = 15) had an epidural catheter inserted (T1 to T4) and a 56-electrode sock placed on the heart. Myocardial excitability was measured by activation recovery interval, dispersion of repolarization, and action potential duration restitution at baseline and during programed ventricular extrastimulation or left stellate ganglion stimulation, before and 30 min after thoracic epidural anesthesia (0.25% bupivacaine). RESULTS: After thoracic epidural anesthesia infusion, there was no change in baseline activation recovery interval or dispersion of repolarization. During programmed ventricular extrastimulation, thoracic epidural anesthesia decreased the maximum slope of ventricular electrical restitution (0.70 ± 0.24 vs. 0.89 ± 0.24; P = 0.021) reflecting improved electrical wave stability. Thoracic epidural anesthesia also reduced myocardial excitability during left stellate ganglion stimulation-induced sympathoexcitation through attenuated shortening of activation recovery interval (-7 ± 4% vs. -4 ± 3%; P = 0.001), suppression of the increase in dispersion of repolarization (313 ± 293% vs. 185 ± 234%; P = 0.029), and reduction in sympathovagal imbalance as measured by heart rate variability. CONCLUSIONS: Our study describes the electrophysiologic mechanisms underlying antiarrhythmic effects of thoracic epidural anesthesia during sympathetic hyperactivity. Thoracic epidural anesthesia attenuates ventricular myocardial excitability and induces electrical wave stability through its effects on activation recovery interval, dispersion of repolarization, and the action potential duration restitution slope.

Vagal nerve stimulation activates vagal afferent fibers that reduce cardiac efferent parasympathetic effects.

Vagal nerve stimulation (VNS) has been shown to have antiarrhythmic effects, but many of these benefits were demonstrated in the setting of vagal nerve decentralization. The purpose of this study was to evaluate the role of afferent fiber activation during VNS on efferent control of cardiac hemodynamic and electrophysiological parameters. In 37 pigs a 56-electrode sock was placed over the ventricles to record local activation recovery intervals (ARIs), a surrogate of action potential duration. In 12 of 37 animals atropine was given systemically. Right and left VNS were performed under six conditions: both vagal trunks intact (n = 25), ipsilateral right (n = 11), ipsilateral left (n = 14), contralateral right (n = 7), contralateral left (n = 10), and bilateral (n = 25) vagal nerve transection (VNTx). Unilateral VNTx significantly affected heart rate, PR interval, Tau, and global ARIs. Right VNS after ipsilateral VNTx had augmented effects on hemodynamic parameters and increase in ARI, while subsequent bilateral VNTx did not significantly modify this effect (%change in ARI in intact condition 2.2 ± 0.9% vs. ipsilateral VNTx 5.3 ± 1.7% and bilateral VNTx 5.3 ± 0.8%, P < 0.05). Left VNS after left VNTx tended to increase its effects on hemodynamics and ARI response (P = 0.07), but only after bilateral VNTx did these changes reach significance (intact 1.1 ± 0.5% vs. ipsilateral VNTx 3.6 ± 0.7% and bilateral VNTx 6.6 ± 1.6%, P < 0.05 vs. intact). Contralateral VNTx did not modify VNS response. The effect of atropine on ventricular ARI was similar to bilateral VNTx. We found that VNS activates afferent fibers in the ipsilateral vagal nerve, which reflexively inhibit cardiac parasympathetic efferent electrophysiological and hemodynamic effects.

Effect of electroacupuncture on porcine cardiac excitability induced by left stellate ganglion stimulation.

Augmentation of cardiac sympathetic tone has been shown to induce ventricular arrhythmias. Acupuncture has been clinically used to treat hypertension, angina pectoris, and atrial arrhythmias. However, the effects of acupuncture on ventricular electrophysiology and autonomic tone remain unknown. We hypothesized that acupuncture attenuates cardiac excitability and corrects the imbalance of autonomic tone during sympathetic hyperactivity. Fourteen Yorkshire pigs were randomized to electroacupuncture (EA, 2 Hz, 0.3-0.5 mA, 0.5 ms duration) or control (without EA) groups. Animals were sedated with terazol. General anesthesia consisted of isoflurane and fentanyl during surgical preparation and was transitioned to α-chloralose during experimental protocols. Through a median sternotomy, the heart was exposed and fitted with an elastic epicardial 56-electrode sock. Cardiac excitability was measured via activation recovery interval (ARI) and dispersion of repolarization (DOR) while autonomic balance was evaluated by heart rate variability (HRV) power spectrum analysis at baseline and during left stellate ganglion stimulation (LSS) with and without EA delivered at P 5-6 acupoints. 30-min of EA did not alter the baseline ARI and DOR, but significantly suppressed cardiac excitability during LSS through attenuation of ARI shortening (EA 2.1 ±â€¯0.3% vs. control 5.2 ±â€¯0.7%, P < 0.05) and DOR (EA 74.3 ±â€¯26.9% vs., control 110.1 ±â€¯22.9%, P < 0.05). EA significantly attenuated the increase in LF/HF (EA 0.6 ±â€¯0.1 vs. control 1.1 ±â€¯0.2, P < 0.05). In conclusion, EA reduces the cardiac excitability induced by LSS through correction of cardiac sympathovagal balance. This study provides mechanistic insights underlying cardiac neuromodulation of EA during sympathoexcitation.

Antiarrhythmic effects of vagal nerve stimulation after cardiac sympathetic denervation in the setting of chronic myocardial infarction.

BACKGROUND: Neuraxial modulation with cardiac sympathetic denervation (CSD) can potentially reduce burden of ventricular tachyarrhythmia (VT). However, despite catheter ablation and CSD, VT can recur in patients with cardiomyopathy and the role of vagal nerve stimulation (VNS) in this setting is unclear. OBJECTIVE: The purpose of this study was to evaluate the electrophysiological effects of VNS after CSD in normal and infarcted hearts. METHODS: In 10 normal and 6 infarcted pigs, electrophysiological and hemodynamic parameters were evaluated before and during intermittent VNS pre-CSD (bilateral stellectomy and T2-T4 thoracic ganglia removal) as well as post-CSD. The effect of VNS during isoproterenol was also assessed pre- and post-CSD. Multielectrode ventricular activation recovery interval (ARI) recordings, a surrogate of action potential duration, were obtained. VT inducibility was tested during isoproterenol infusion after CSD with and without VNS. RESULTS: VNS increased the global ARI by 4% ± 4% pre-CSD and by 5% ± 6% post-CSD, with enhanced effects observed during isoproterenol infusion (10% ± 8% pre-CSD and 12% ± 9% post-CSD) in normal animals. In infarcted animals pre-CSD, VNS increased ARI by 6% ± 7% before and by 13% ± 8% during isoproterenol infusion. Post-CSD, VNS increased ARI by 6% ± 5% before and by 11% ± 7% during isoproterenol infusion. VT was inducible in all infarcted animals post-CSD during isoproterenol infusion; this inducibility was reduced by 67% with VNS (P = .01). In all animals, the hemodynamic effects of VNS remained after CSD. CONCLUSION: After CSD, the beneficial electrophysiological effects of VNS remain. Furthermore, VNS can reduce VT inducibility beyond CSD in the setting of circulating catecholamines, suggesting a role for additional parasympathetic modulation in the treatment of ventricular arrhythmias.

Effect of thoracic epidural anesthesia on heart rate variability in a porcine model.

Heart rate variability (HRV) is increasingly recognized as a means of evaluating autonomic tone. Thoracic epidural anesthesia (TEA) has been previously demonstrated to suppress the electrical storms in patients. However, the effect of TEA on HRV during sympathoexcitation remains unknown. In this study, we aimed to determine the effects of TEA on HRV response to left stellate ganglion stimulation (LSS) in a porcine model. In 12 anesthetized pigs after insertion of an epidural catheter to T1 level, a median sternotomy was performed to expose the heart and the left stellate ganglion. A 56-electrode sock was used for obtaining epicardial activation recovery interval (ARI). Animal received LSS at 4 Hz for 30 sec. After 30 min of bupivacaine epidural injection, LSS was performed in the same way as the baseline condition. LSS significantly increased low-frequency normalized units (LF: 44.9 ± 6.7 vs. 13.6 ± 3.1 msec2 baseline, P < 0.05) and decreased high-frequency normalized units (HF: 11.5 ± 4.6 vs. 41.9 ± 5.1 msec2 baseline, P < 0.05). As a result, LF/HF significantly increased from 0.3 ± 0.2 to 3.9 ± 1.4 during LSS TEA significantly attenuated the LF/HF from 3.9 ± 1.4 to 1.6 ± 0.8 with increased HF components from 11.5 ± 4.6 to 26.5 ± 3.2 msec2 LF component significantly correlates with global ARI (r = -0.81) and dispersion of repolarization (r = 0.85). HRV can precisely reflect the cardiac autonomic tone and TEA modulates the HRV by enhancing the HF components probably through a parasympathetic nerve system.

Inflammatory and apoptotic remodeling in autonomic nervous system following myocardial infarction.

BACKGROUND: Chronic myocardial infarction (MI) triggers pathological remodeling in the heart and cardiac nervous system. Abnormal function of the autonomic nervous system (ANS), including stellate ganglia (SG) and dorsal root ganglia (DRG) contribute to increased sympathoexcitation, cardiac dysfunction and arrythmogenesis. ANS modulation is a therapeutic target for arrhythmia associated with cardiac injury. However, the molecular mechanism involved in the pathological remodeling in ANS following cardiac injury remains to be established. METHODS AND RESULTS: In this study, we performed transcriptome analysis by RNA-sequencing in thoracic SG and (T1-T4) DRG obtained from Yorkshire pigs following either acute (3 to 5 hours) or chronic (8 weeks) myocardial infarction. By differential expression and weighted gene co-expression network analysis (WGCNA), we identified significant transcriptome changes and specific gene modules in the ANS tissues in response to myocardial infarction at either acute or chronic phases. Both differential expressed genes and the member genes of the WGCNA gene module associated with post-infarct condition were significantly enriched for inflammatory signaling and apoptotic cell death. Targeted validation analysis supported a significant induction of inflammatory and apoptotic signal in both SG and DRG following myocardial infarction, along with cellular evidence of apoptosis induction based on TUNEL analysis. Importantly, these molecular changes were observed specifically in the thoracic segments but not in their counterparts obtained from lumbar sections. CONCLUSION: Myocardial injury leads to time-dependent global changes in gene expression in the innervating ANS. Induction of inflammatory gene expression and loss of neuron cell viability in SG and DRG are potential novel mechanisms contributing to abnormal ANS function which can promote cardiac arrhythmia and pathological remodeling in myocardium.

Targeted stellate decentralization: Implications for sympathetic control of ventricular electrophysiology.

BACKGROUND: Selective bilateral cervicothoracic sympathectomy has proven to be effective for managing ventricular arrhythmias in the setting of structural heart disease. In the procedure currently used, the caudal portions of both stellate ganglia along with thoracic chain ganglia down to T4 ganglia are removed. OBJECTIVE: The purpose of this study was to define the relative contributions of the T1-T2 and T3-T4 paravertebral ganglia in modulating ventricular electrical function. METHODS: In anesthetized vagotomized porcine subjects (n = 8), the heart was exposed via sternotomy along with right and left paravertebral sympathetic ganglia to the T4 level. A 56-electrode epicardial sock was placed over both ventricles to assess epicardial activation-recovery intervals (ARIs) in response to individually stimulating right and left stellate vs T3 paravertebral ganglia. Responses to T3 stimuli were repeated after surgical removal of the caudal portions of stellate ganglia and T2 bilaterally. RESULTS: In intact preparations, stellate ganglion vs T3 stimuli (4 Hz, 4-ms duration) were titrated to produce equivalent decreases in global ventricular ARIs (right side: 85 ± 6 ms vs 55 ± 10 ms; left side: 24 ± 3 ms vs 17 ± 7 ms). Threshold of stimulus intensity applied to T3 ganglia to achieve threshold was 3 times that of T1 threshold. ARIs in unstimulated states were unaffected by bilateral stellate-T2 ganglion removal. After acute decentralization, T3 stimulation failed to change ARIs. CONCLUSION: Preganglionic sympathetic efferents arising from the T1-T4 spinal cord that project to the heart transit through stellate ganglia via the paravertebral chain. Thus, T1-T2 surgical excision is sufficient to functionally interrupt central control of peripheral sympathetic efferent activity.