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

ABSTRACT: 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.

SUBMITTER: Yamaguchi N

PROVIDER: S-EPMC6245660 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Yamaguchi Naoko N Yamakawa Kentaro K Rajendran Pradeep S PS Takamiya Tatsuo T Vaseghi Marmar M

Heart rhythm 20180309 8

<h4>Background</h4>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.<h4>Objective</h4>The purpose of this study was to evaluate the electrophysiological effects of VNS after CSD in normal and infarcted hearts.<h4>Methods</h4>In 10 normal and 6 infarcted pi ...[more]

PMID: 29530832

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Project description:Background Ventricular arrhythmia after myocardial infarction is the most important risk factor for sudden cardiac death, which poses a serious threat to human health. As the correlation between autonomic nervous systemic dysfunction and heart rhythm abnormality has been gradually revealed, remedies targeting autonomic nervous system dysfunction, especially the sympathetic nerve, have emerged. Among them, renal denervation is noted for its powerful effect on the inhibition of sympathetic nerve activity. We aim to investigate whether renal denervation can reduce ventricular arrhythmia after myocardial infarction and thus decrease the risk of sudden cardiac death. In addition, we explore the potential mechanism with respect to nerve activity and remodeling. Methods and Results Twenty-four beagles were randomized into the control (n=4), renal denervation (n=10), and sham (n=10) groups. Permanent left anterior descending artery ligation was performed to establish myocardial infarction in the latter 2 groups. Animals in the renal denervation group underwent both surgical and chemical renal denervation. Compared with dogs in the sham group, dogs in the renal denervation group demonstrated attenuated effective refractory period shortening and inhomogeneity, flattened restitution curve, increased ventricular threshold, and decreased ventricular arrhythmia. Heart rate variability assessment, catecholamine measurement, and nerve discharge recordings all indicated that renal denervation could reduce whole-body and local tissue sympathetic tone. Tissue analysis revealed a significant decrease in neural remodeling in both the heart and stellate ganglion. Conclusions Surgical and chemical renal denervation decreased whole-body and local tissue sympathetic activity and reversed neural remodeling in the heart and stellate ganglion. Consequently, renal denervation led to beneficial remodeling of the electrophysiological characteristics in the infarction border zone, translating to a decrease in ventricular arrhythmia after myocardial infarction.

Project description:Background: It had been shown that selective cardiac vagal activation holds great potential for heart regeneration. Optogenetics has clinical translation potential as a novel means of modulating targeted neurons. This study aimed to investigate whether cardiac vagal activation via optogenetics could improve heart regenerative repair after myocardial infarction (MI) and to identify the underlying mechanism. Methods: We used an adeno-associated virus (AAV) as the vector to deliver ChR2, a light-sensitive protein, to the left nodose ganglion (LNG). To assess the effects of the cardiac vagus nerve on cardiomyocyte (CM) proliferation and myocardial regeneration in vivo, the light-emitting diode illumination (470 nm) was applied for optogenetic stimulation to perform the gain-of-function experiment and the vagotomy was used as a loss-of-function assay. Finally, sequencing data and molecular biology experiments were analyzed to determine the possible mechanisms by which the cardiac vagus nerve affects myocardial regenerative repair after MI. Results: Absence of cardiac surface vagus nerve after MI was more common in adult hearts with low proliferative capacity, causing a poor prognosis. Gain- and loss-of-function experiments further demonstrated that optogenetic stimulation of the cardiac vagus nerve positively regulated cardiomyocyte (CM) proliferation and myocardial regeneration in vivo. More importantly, optogenetic stimulation attenuated ventricular remodeling and improved cardiac function after MI. Further analysis of sequencing results and flow cytometry revealed that cardiac vagal stimulation activated the IL-10/STAT3 pathway and promoted the polarization of cardiac macrophages to the M2 type, resulting in beneficial cardiac regenerative repair after MI. Conclusions: Targeting the cardiac vagus nerve by optogenetic stimulation induced macrophage M2 polarization by activating the IL-10/STAT3 signaling pathway, which obviously optimized the regenerative microenvironment and then improved cardiac function after MI.

Dataset Information

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

Publications

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

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