Continuous Low-Level Vagus Nerve Stimulation Reduces Stellate Ganglion Nerve Activity and Paroxysmal Atrial Tachyarrhythmias in Ambulatory Canines

Shen, Mark J.; Shinohara, Tetsuji; Park, Hyung Wook; Frick, Kyle; Ice, Daniel S.; Choi, Eue Keun; Han, Seongwook; Maruyama, Mitsunori; Sharma, Rahul; Shen, Changyu; Fishbein, Michael C.; Chen, Lan S.; Lopshire, John C.; Zipes, Douglas P.; Lin, Shien Fong; Chen, Peng Sheng

doi:10.1161/circulationaha.111.018028

Cited by 207 publications

(177 citation statements)

References 41 publications

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“…One in three patients with paroxysmal AF, and up to 70% of younger patients, present with well-defined adrenergic or vagal triggers 72,73 . Low-level vagal stimulation prevents AF by decreasing sympathetic and parasympathetic cardiac responsiveness in animal models susceptible to AF 74 . High-intensity endurance training is an evolving risk factor underlying AF in middle-aged Europeans without overt structural heart disease 75,76 , which can be mediated by an elevated parasympathetic tone, structural changes, or by changes in ion-channel expression 14,73,77 .…”

Section: Autonomic Dysfunctionmentioning

confidence: 99%

Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

et al. 2015

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Despite the important advances that have enabled better stroke prevention in atrial fibrillation (AF) and more effective maintenance of sinus rhythm over the past decades, a large unmet need to improve the prevention and treatment of AF remains. Mortality for AF remains at 3.5% per year, and death is often experienced as sudden death or as a result of heart failure 1,2 . Each year, approximately 20% of patients with AF need to be hospitalized 3,4 , and stroke occurs in 1.5% of patients with AF who are receiving anticoagulant drugs 5 . Furthermore, more than half of the patients with AF are symptomatic despite adequate anticoagulation and rate control 4,6 . In view of the projected increase in the incidence and prevalence of AF 7-9 , as well as the substantial burden of death and dis ability that is still associated with this condition 10 , the status quo is unacceptable.Current management of patients with AF comprises treatment of the accompanying cardiovascular conditions, oral anticoagulation, rate control -with medications that slow atrioventricular nodal recovery or, rarely, with atrioventricular nodal ablation -and rhythm-control therapy with antiarrhythmic drugs, electrical cardioversion, catheter ablation or, at times, AF surgery 11,12 . Unfortunately, most of these current approaches are disconnected from our understanding of the major mechanisms that cause AF 1,13,14 1,2,7,19,20 Abstract | Despite remarkable advances in antiarrhythmic drugs, ablation procedures, and stroke-prevention strategies, atrial fibrillation (AF) remains an important cause of death and disability in middle-aged and elderly individuals. Unstructured management of patients with AF sharply contrasts with our detailed, although incomplete, knowledge of the mechanisms that cause AF and its complications. Altered calcium homeostasis, atrial fibrosis and ageing, ion-channel dysfunction, autonomic imbalance, fat-cell infiltration, and oxidative stress, in addition to a susceptible genetic background, contribute to the promotion, maintenance, and progression of AF. However, clinical management of patients with AF is currently guided by stroke risk parameters, AF pattern, and symptoms. In response to this apparent disconnect between the known pathophysiology of AF and clinical management, we propose a roadmap to develop a set of clinical markers that reflect the major causes of AF in patients. Thereby, the insights into the mechanisms causing AF will be transformed into a format that can underpin future personalized strategies to prevent and treat AF, ultimately informing better patient care.230 | APRIL 2016 | VOLUME 13 www.nature.com/nrcardio CONSENSUS STATEMENT © 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d . A l l r i g h t s r e s e r v e d .

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Section: Autonomic Dysfunctionmentioning

confidence: 99%

Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

et al. 2015

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“…A number of animal studies using rats and dogs have shown that chronic VNS improved LV hemodynamics 24,25 and, more importantly, improved survival in HF. 26 With an implanted device to continuously record autonomic nerve activity in ambulatory canines, Shen et al 27 observed that chronic VNS led to a significant reduction in sympathetic activity from the left stellate ganglion, which may underlie the cardioprotective property of VNS. Besides, VNS has additional beneficial effects:…”

Section: Preclinical Researchmentioning

confidence: 99%

Interventional and Device-Based Autonomic Modulation in Heart Failure

Shen¹,

Zipes²

2015

Heart Failure Clinics

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Abstract/SummaryHeart failure is an increasingly prevalent disease with high mortality and public health burden. It is associated with autonomic imbalance characterized by sympathetic hyperactivity and parasympathetic hypoactivity. Evolving novel interventional and device-based therapy has sought to restore autonomic balance by neuromodulation.Results of preclinical animal studies and early clinical trials have demonstrated its safety and efficacy in heart failure. In this review article, we will discuss specific neuromodulatory treatment modalities individually-spinal cord stimulation, vagus nerve stimulation, baroreceptor activation therapy and renal sympathetic nerve denervation. Key Points (3-5)• Heart failure (HF) is a disease categorized by sympathetic hyperactivity, parasympathetic withdrawal and impaired baroreflex control of sympathetic activation.• Several measures of autonomic modulation either by implanted devices or interventions seek to restore the autonomic balance in HF and improve outcomes. These measures include spinal cord stimulation, vagus nerve 3 stimulation, baroreceptor activation therapy and renal sympathetic nerve denervation.• Preclinical work and the majority of early clinical trials demonstrate the benefits of these modalities in HF. Additional larger, well-designed, outcome-based clinical trials are warranted to verify the results and determine whether these evolving, innovative neuromodulation approaches can be recommended to the growing population of HF patients.4

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“…Despite the fact that vagal stimulation has been used for years as a method to induce AF, recent experimental studies in dogs have demonstrated that low level VNS (below the threshold needed to reduce heart rate) may be antiarrhythmic in the atrium. Shen et al 80 demonstrated that left-sided low-level vagal stimulation decreased left-sided stellate ganglion activity, decreased the incidence of AF and atrial tachycardia, and decreased sympathetic innervation within the stellate ganglion. 80 Similarly, Sha et al, 81 in a study of acute, right-sided, low-level vagal stimulation, found that the threshold to induce AF was higher in the VNS group, and the response of heart rate to direct sympathetic and parasympathetic stimulation was blunted in the setting of low level vagal stimulation.…”

Section: Vagal Stimulation Vagal Stimulation and Atrial Electrophysiomentioning

confidence: 99%

“…Shen et al 80 demonstrated that left-sided low-level vagal stimulation decreased left-sided stellate ganglion activity, decreased the incidence of AF and atrial tachycardia, and decreased sympathetic innervation within the stellate ganglion. 80 Similarly, Sha et al, 81 in a study of acute, right-sided, low-level vagal stimulation, found that the threshold to induce AF was higher in the VNS group, and the response of heart rate to direct sympathetic and parasympathetic stimulation was blunted in the setting of low level vagal stimulation. In addition, neural activity in a ganglion of the intrinsic cardiac nervous system was reduced with low level VNS, which may be the basis for its antiarrhythmic effect.…”

Section: Vagal Stimulation Vagal Stimulation and Atrial Electrophysiomentioning

confidence: 99%

“…In addition, neural activity in a ganglion of the intrinsic cardiac nervous system was reduced with low level VNS, which may be the basis for its antiarrhythmic effect. 80 Clearly more studies are needed to further explore the possibilities of low level VNS for arrhythmia management; however, these experimental results are intriguing. 12 …”

Section: Vagal Stimulation Vagal Stimulation and Atrial Electrophysiomentioning

confidence: 99%

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Device-Based Approaches to Modulate the Autonomic Nervous System and Cardiac Electrophysiology

Hucker

Singh

Parks

et al. 2014

Arrhythm Electrophysiol Rev

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The interplay between the central nervous system and cardiac electrophysiology is fundamental, and becomes obvious each time one's pulse quickens in response to stress. Normally, cardiac neurohormonal regulation is accomplished through the balanced effects of sympathetic and parasympathetic autonomic stimulation, along with the hormonal regulation of the renin-angiotensinaldosterone system (RAAS). Autonomic and hormonal input modulate multiple facets of cellular electrophysiology -action potential duration, ion channel kinetics and intracellular calcium dynamics (just to name a few) -which translate into macroscopic manifestations of autonomic modulation such as heart rate variability, atrioventricular (AV) conduction time and QT interval variability.1 Therefore, it is no surprise that neurohormonal regulation of cardiac electrophysiology is an area of active investigation for its potential antiarrhythmic effects. Recent reviews have focused on the efficacy of neurohormonal modulation, via non-pharmacological methods, to enhance heart failure treatment. 2,3 This review will attempt to provide a state-of-the-art on the potential antiarrhythmic efficacy of renal artery denervation, spinal cord stimulation and direct vagal stimulation. Neurohormonal Control in the Normal and Failing HeartAutonomic control of cardiac physiology is often conceptualised as parasympathetic (cholinergic) and sympathetic (adrenergic) innervation existing in a 'yin and yang' balance under normal circumstances; however, this concept may be over-simplified. 4 In reality, the intrinsic cardiac nervous system, composed of several ganglia located primarily posterior to the atria, likely acts as a 'little brain' of the heart -it provides efferent input to the myocardium, collects afferent signals on a beat-to-beat basis and performs some integrative functions on its own, all under the tonic modulation of extrinsic sympathetic and parasympathetic input (see Figure 1). 4-8The ganglia are predominantly composed of cholinergic neurons; however, sympathetic efferent neurons are also present. Due to the complex interconnectivity between the ganglia, afferent mechanosensory, nociceptive and chemosensory signals from all four chambers of the heart may be processed within a single ganglion. 4 Such interconnectivity implies that predicting the effect of stimulation or ablation of a particular ganglion may be difficult, because each ganglion performs multiple functions. 7,9Abstract Alterations in resting autonomic tone can be pathogenic in many cardiovascular disease states, such as heart failure and hypertension.Indeed, autonomic modulation by way of beta-blockade is a standard treatment of these conditions. There is a significant interest in developing non-pharmacological methods of autonomic modulation as well. For instance, clinical trials of vagal stimulation and spinal cord stimulation in the treatment of heart failure are currently underway, and renal denervation has been studied recently in the treatment of resistant hypertension. Notably, autonom...

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Continuous Low-Level Vagus Nerve Stimulation Reduces Stellate Ganglion Nerve Activity and Paroxysmal Atrial Tachyarrhythmias in Ambulatory Canines

Cited by 207 publications

References 41 publications

Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

Interventional and Device-Based Autonomic Modulation in Heart Failure

Device-Based Approaches to Modulate the Autonomic Nervous System and Cardiac Electrophysiology

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