Foundational Concepts and Recent Advances in Neuromodulation for Cardiac Arrhythmias

EP Lab Digest. 2023;23(1):1,8-10.

The relationship between the heart and autonomic nervous system (ANS) has evolved to maintain homeostasis with appropriate responses to external stimuli and cardiovascular stressors. Simultaneously, imbalances in the ANS play an integral role in the development and pathophysiology of cardiac arrhythmias. As neural control of the cardiovascular system depends on its intricate feedback system connecting the brain to the heart, the field of cardiac neuromodulation sets out to maintain homeostasis through the identification and intervention of different anatomic targets across the neurocardiac axis.¹ The purpose of this review is to discuss the foundational concepts of cardiac neuromodulation, recent advances in neuromodulatory techniques, and current gaps in knowledge to guide further discovery.

Foundational Concepts of Cardiac Neuromodulation

The neural control of cardiac functions relies on the interactions between central and intrathoracic aspects of the cardiac nervous system (CNS). The brainstem and spine, in addition to higher centers such as the insular cortex, combine to make up the centrally located neural networks that are involved in cardiac control (Figure 1). The resultant afferent projections stemming from their respective preganglionic soma transmit input to the intrathoracic ganglia.² Further, there are intrinsic cardiac neurons found in the intramural ganglia and epicardial fat pads.³ The intrinsic cardiac ganglionated plexi contain a distributed network of afferent, efferent, and interconnecting neurons. This intrinsic CNS takes input from the intrathoracic sympathetic ganglia, in addition to the brainstem and spinal cord, and then serves as the final coordinator in modulating cardiac reflexes.⁴ This multifaceted network creates an integrated response to normal cardiac stressors, and allows for responsive and appropriate control of cardiac output and blood pressure. However, abnormal or pathological stressors such as myocardial ischemia can lead to aberrant responses, creating potentially disastrous results.^5,6

Cardiac neuronal remodeling in response to cardiomyopathies and ischemic pathology, though necessary to maintain homeostasis, has been shown to lead to the progression of disease.⁷ Pathologically stressed hearts lead to afferent sensory transduction, which creates reflexive adrenergic efferent postganglionic output to the heart. The reflex-driven response from higher neural centers that is secondary to inputs from the stressed heart, develops increased heterogeneity which is inherently proarrhythmic and has been shown to lead to the increased risk of sudden cardiac death and progression into heart failure (HF).^8,9 Further, the resultant neural network adjustments demonstrate free-floating adaptation of the control hierarchy based on network plasticity, as the connectivity among neurons in the various levels change in time.^5,10

Cardiac neuromodulatory interventions have the goal of modifying activity on specific nerves, associated neural networks (proximal and distal to site of stimulation), and aspects critical to end-organ function.¹¹ The characteristics of the stimulation protocol and populations of neurons impacted determine the biological response to bioelectronics interventions. The ideal location for interventions are convergence points where efferent and afferent projections meet, such as sympathetic ganglia and the vagus nerve.¹² However, in response to modulation of endogenous control systems by neuromodulatory interventions, the closed system may create a “new normal” between the control system components with an end point that may be difficult to predict.¹³

Recent Advances in Neuromodulatory Techniques

Recent advances in neuromodulatory techniques, designed to increase the parasympathetic tone and suppress the sympathetic tone, focus on several key nexus points located throughout the interacting feedback loops that make up the cardiac ANS.¹⁴ Successful outcomes for neuromodulation depend on the site of intervention within the neurocardiac axis as well as the patient’s pathological status and parameters of stimulation.¹⁵ Figure 2 summarizes the main clinical approaches to cardiac neuromodulation with the antiarrhythmic purposes that will be described in this report.

Vagus Nerve Stimulation (VNS)

Vagal activity is most effectively increased through direct electrical stimulation of the nerve at the cervical level. Prior studies using animal models demonstrated VNS reduced susceptibility for ventricular arrhythmias (VAs) throughout all phases of myocardial injury.^16-18 Although VNS has already been approved for use in the treatment of epilepsy and depression, it is not yet applicable in the acute clinical setting given its invasive nature.^19,20 However, recent advances involve stimulation of the superficial collaterals of the auricular branch of the vagus nerve. This noninvasive alternative has been shown to be effective in both animals, and more recently in human models, where it was shown to significantly reduce the incidence of VAs when applied to patients with ST-elevation myocardial infarction (MI) undergoing percutaneous reperfusion.^21,22

Thoracic Epidural Anesthesia and Spinal Cord Stimulation (SCS)

Spinal cord influences proximal to the stellate ganglia are reduced with the use of neuromodulatory techniques including SCS and thoracic epidural anesthesia. Thoracic epidural anesthesia allows for the blockade of afferent and efferent sympathetic projections between the heart and CNS through the injection of local anesthetics into the thoracic epidural space.²³ Although limited by the temporary duration of local anesthetics, this treatment modality has been shown to be effective in several small case series wherein significant reduction of VA burden was achieved in the majority of patients with refractory arrhythmias.²⁴

SCS within the levels of T1 to T5 allows for the modulation of autonomic output, likely through inhibition of the stellate ganglia.²⁵ SCS, which is achieved with insertion of leads into the epidural space, has previously been studied in the treatment of angina; however, more recent studies on animal models show reduction in heart rate variability, decreased incidence of VAs, and reduction in left stellate ganglion activity in acute MI.²⁵ At present, there is a dearth of clinical data on SCS and VAs in humans with only few case series and small clinical trials. One such study demonstrated significant reduction in VA burden in 2 patients with cardiomyopathy, up to 75%-100% over a 2-month period.²⁶ However, a prospective, multicenter, randomized clinical study designed to evaluate the effects of SCS in the treatment of HF failed to show reduction in symptoms nor reduction in VAs based on data obtained from implantable cardioverter-defibrillator (ICD) interrogations.²⁷ As it stands, SCS remains a potential antiarrhythmic strategy in the setting of myocardial injury; however, the exact mechanism of SCS on VAs as well as clinical safety and efficacy of SCS for the prevention of VA remains undetermined.

Stellate Ganglion Modulatory Therapies

Experimental studies using stellate ganglion modulatory therapies, which include cardiac sympathetic denervation, radiofrequency ablation, and percutaneous blockade with local anesthetics, have been shown to dampen the cardiac sympathetic afferent reflex, in turn, reducing the risk of life-threatening arrhythmias associated with myocardial injury and in structurally normal hearts. Early successful stellate ganglion-targeted therapies centered on denervation through surgical removal of the left thoracic sympathetic ganglia from T1 to T4.²⁸ These early procedures were performed with an open approach, through either thoracotomy or supraclavicular access. This has since been modified, using video-assisted thoracic surgery to allow for a minimally invasive approach. Studies have since shown this to be an effective antiarrhythmic strategy in the treatment of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (VT).^28-30 More recent advances on this technique have shown that implementation of bilateral cardiac sympathetic denervation has even greater efficacy as an antiarrhythmic strategy in patients with structural heart disease than left-sided denervation.³¹ Further, in patients with structural heart disease, bilateral cardiac sympathetic denervation has demonstrated improved reduction in appropriate ICD shocks, in addition to VA recurrence, mortality, and transplantation.³² In the largest study of cardiac sympathetic denervation to date, a retrospective analysis of 121 patients with advanced cardiomyopathy who underwent cardiac sympathetic denervation demonstrated reduction in the median number of ICD shocks from 10 to 0 in the year following cardiac sympathetic denervation.³² A recent report representing the longest follow-up study on bilateral cardiac sympathetic denervation to date demonstrated VT-free survival in 54.5% of patients at 4 years.³³ Although the connection between VAs and advanced structural disease is complex, what these studies demonstrate is the need for consideration of cardiac sympathetic denervation in patients with refractory arrhythmias.

In addition to denervation, the unique anatomical location of the stellate ganglia has long allowed for the safe use of pharmacological stellate ganglia blockade, as seen in the treatment of sympathetic-related pain syndromes involving the upper extremities. More recent advances include an ultrasound-guided approach as well as physical stellate ganglia blockade using pulsed radiofrequency.^34,35 A systematic review on the efficacy of stellate ganglia using local anesthetic injection was associated with significant acute reduction in VA burden in 92% of patients, with a decline in the average number of VA episodes from 12 to 1 episodes per day.³⁵ This elucidates the superior acute protective effects of left stellate ganglia blockade, as compared to the chronic benefits from bilateral cardiac sympathetic denervation.

Interventions on the Intracardiac Nervous System

Given its anatomical location and known role in the manifestation of atrial arrhythmias, approaches on disruption of the cardiac autonomic ganglionic plexi (AGP) through ablation, done by either catheter-based or surgical approaches, have been promoted for the prevention of atrial arrhythmias. This is due, in part, to reports demonstrating improved success in the treatment of atrial fibrillation (AF) with AGP ablation as an adjunct to standard AF ablation. However, studies evaluating percutaneous anatomically-guided ablative therapies of the AGP as a montherapy have shown limited efficacy.^36,37 More recent advances have focused on nonablative strategies to modulate AGP signaling. At the forefront of these advances is the injection of botulinum toxin into the AGP, which has been shown to reduce vulnerability to AF in animal models.³⁸

In human models, the inherent transient nature of this autonomic modulatory technique has led to studies assessing the potential reduction in postoperative AF through botulinum toxin injections into the AGP. In one randomized trial, 60 patients with paroxysmal AF undergoing coronary artery bypass grafting received either botulinum toxin or placebo injected into the epicardial fat pads. Results at 1 month, 1 year, and 3 years following this procedure demonstrate that patients receiving epicardial botulinum toxin had decreased incidence of postoperative AF.^39,40 Future large-scale clinical trials are required to further assess the utility of this treatment modality.

Renal Denervation

Due to the presence of the reflex loop between afferent input from the kidneys to the central nervous system and efferent sympathetic nerve output back to the heart and the kidney, renal denervation and its potential effects on cardiac arrhythmias has become a growing area of study. Renal artery sympathetic fibers run parallel to the artery and denervation via catheter ablation is believed to inhibit the afferent renal sympathetic pathway, thus reducing efferent sympathetic output to the heart from the CNS. While the effects of modulating renal innervation in the treatment of hypertension has been well documented over many years, more recent studies on the effects of renal denervation on VAs have been encouraging.^41-43 In a 2015 observational study involving 10 patients, renal denervation led to a significant decrease in VA burden and ICD shocks at 6 months.⁴⁴ A second multicenter study involving 13 patients with refractory VT who underwent bilateral renal denervation demonstrated reduction in VA burden by 85% at 3 months.⁴⁵ The viability and future utilization of renal denervation in the treatment of cardiac arrhythmias will be dependent on larger studies to yield definitive evidence of its efficacy and safety.

Conclusion

The cardiac ANS has a direct influence on the regulation of cardiac electrophysiology and arrhythmogenesis. The increasing burden of heart rhythm disorders and their significant morbidity and mortality has encouraged the development of novel potential therapies in autonomic neuromodulation. While cardiac neuromodulation is a developing frontier in the management of heart rhythm disorders, standardization and implementation of these strategies in clinical practice requires continued investigation with clinical studies to establish efficacy and safety. Further, much is yet to be determined on the effect of neural axis remodeling following these interventions, which affects the long-term outcomes. However, the current progress in the field of cardiac neuromodulation will allow for optimization of therapies aimed at treating heart rhythm disorders. 

Disclosures: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. They have no conflicts of interest to report regarding the content herein. Outside the submitted work, Dr Ajijola reports grants or contracts from Biosense Webster; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbott, Biosense Webster, and Medtronic; patents planned, issued or pending, for methods for renal neuromodulation; and stock or stock options from Anumana and nference.

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