Neural ablation to treat ventricular arrhythmias

This editorial refers to ‘Targeted ablation of cardiac sympathetic neurons improves ventricular electrical remodelling in a canine model of chronic myocardial infarction’ by L. Xiong et al., on pages 2036–2044.

The autonomic nervous system plays a critical role in cardiac physiology (e.g. modulation of chronotropy, dromotropy, inotropy, and lusitropy). In recent years, increasing attention has been paid to the role of autonomic dysfunction in cardiac pathophysiology in general and arrhythmogenesis in particular.¹ Much of the pharmacologic therapy for heart failure and arrhythmia exerts its action through neurohormonal blockade. Many post-myocardial infarction (MI) patients are at risk of developing sudden cardiac death (SCD) due to ventricular arrhythmias, which pharmacologic therapy may not successfully prevent. Such patients may ultimately require invasive procedures including implantable cardioverter-defibrillator implantation and/or catheter ablation to treat ventricular arrhythmias. The development of therapeutics that targets the cardiac autonomic nervous system could provide an effective strategy for treating ventricular arrhythmias.

To devise such neuromodulatory therapies, knowledge of the normal anatomic connections in the cardiac neural hierarchy is crucial. Mechano- and/or chemo-sensory information from the heart is relayed to the central nervous system via visceral afferent neurons, a subset of whose cell bodies reside in the dorsal root ganglia (DRG).² The cardiomotor pre-ganglionic sympathetic neurons originate in the interomediolateral cell column of the spinal cord and project via the C7-T6 rami to cardiac post-ganglionic neurons in the superior cervical, middle cervical, mediastinal, and stellate ganglia. Nerves that span from the spinal cord to the stellate and finally to the heart thus contain both sensory afferent and sympathetic efferent fibres. Sensory information transduced from the heart may be processed with the spinal cord with a cardiac sympathetic reflex response relayed via the sympathetic efferent. Complex interplay and/or disruption of these afferent and efferent pathways as well as those in the brainstem and higher centres may affect sympathovagal balance to cause cardiac autonomic neuropathy post-MI.

The combination of myocardial and neural remodelling creates the substrate for ventricular arrhythmias. After an MI, the myocardial scar region is devoid of nerve fibres and subsequently nerve sprouts have been shown to develop at the scar border. In a human autopsy study, cardiac hyperinnervation around diseased myocardium correlated with a history of ventricular arrhythmia.³ While unresponsive to stellate ganglia stimulation, the denervated areas at and distal to infarcted myocardium are more sensitive to circulating catecholamines in a phenomenon known as denervation supersensitivity.⁴ The changes to the cardiac neurons at the site of MI manifest as alterations to afferent neural signals and neural network connectivity to generate a ‘neural signature’ post-MI.⁵ However, neural remodelling is not restricted to the myocardium, as it also occurs in multiple areas within the cardiac neuraxis post-MI including the stellate ganglia. Indeed, Nguyen et al.⁶ demonstrated increased post-ganglionic sympathetic and pre-ganglionic cholinergic densities in the stellate ganglia following MI in rabbits. Collectively, this neural remodelling results in heterogeneity of myocardial innervation that manifests as aberrances in electric propagation in the myocardium and creates the substrate for ventricular arrhythmia.¹

In this issue of EP Europace, Xiong et al.⁷ report on a neuromodulatory approach to reduce the risk of ventricular arrhythmias post-MI. In their study, the investigators evaluate the suppression of sympathetic remodelling through the targeted ablation of cardiac sympathetic neurons (TACSN) in a canine model of chronic MI. The authors evaluated 38 dogs that underwent either a sham procedure or left anterior descending artery embolization with and without TACSN. Neural ablation was performed by injecting the left stellate ganglion with a cholera toxin B (CTB) subunit-saporin (SAP; CTB-SAP) compound. The CTB subunit is retrogradely transported in neurons while the adjoining SAP component inactivates ribosomes to inhibit protein synthesis and cause apoptosis. The premise of the study was to determine whether ablation of pre-ganglionic sympathetic neurons would mitigate post-ganglionic sympathetic neural remodelling to reduce ventricular arrhythmias post-MI. Two dogs experienced sudden death in the post-MI without TACSN group, while those that did undergo TACSN did not sustain SCD post-MI. However, two dogs that underwent CTB-SAP injections did develop serious chest infections, which raise safety concerns regarding the use of CTB-SAP. The investigators were able to show improvement in structural remodelling, as evidenced by echocardiographic parameters, and electrical remodelling, as measured by electrocardiographic features. They also confirmed reduced stellate ganglia neural activity and plasma norepinephrine levels along with improvement in heart rate variability.

The investigators ought to be commended for their work on this targeted neuromodulatory therapy post-MI. The authors show that this approach, previously described by Lujan et al.,⁸ results in improvement in electrophysiologic parameters associated with arrhythmogenesis including prolonging the corrected QT interval and ventricular effective refractory period and decreasing the T_peak–T_end interval. However, because sensory afferents pass through and cardiomotor efferent neurons are located within the stellate ganglia, it remains unclear targeting which limb of the cardiac sympathetic reflex loop yields the optimal benefit—afferent or sympathetic efferent. Lujan et al.⁸ describe that neurons within the DRG were not affected after TACSN via CTB-SAP injection at the stellate ganglia. As sympathetic sensory afferents travel through the stellate ganglia, one would expect DRG neural involvement after stellate ganglia injection, and re-evaluation of this finding is warranted.⁹ Similarly, at the cardiomotor limb, confirmation of ablation pre-ganglionic sympathetic neurons in the interomediolateral cell columns of the spinal cord would be informative. As surgical stellectomy may be beneficial in its effect on afferents, efferents, or both, more precisely defining the subpopulation of neurons to target would be helpful for future therapy development to limit off-target effects of lesions at the stellate ganglia.

In addition to identifying the neural subpopulation to target, ablating the left vs. bilateral stellate ganglia has been a matter of debate. Xiong et al. focused their therapy on the left stellate ganglion, based on the notion that ablation of the left stellate ganglion increases ventricular fibrillation threshold while ablation of the right stellate ganglion decreases the threshold.¹⁰ However, better scientific evidence on the lateralization of stellate ganglia function has been provided in recent years. The functional innervation of the left stellate ganglion has been shown to be predominantly at the posterior wall while the right stellate ganglion exerts its cardiac electrophysiologic effects at the anterior wall.¹¹ However, it is important to note that both stellate ganglia undergo remodelling due to afferent inputs from the heart following MI regardless of coronary distribution affected.¹² Furthermore, bilateral stellate ganglia stimulation causes inhomogeneous effects on conduction velocity, activation, and repolarization in infarcted myocardium.¹¹ In a recent study of 121 patients who underwent either left or bilateral cardiac sympathetic denervation, the bilateral sympathetic denervation group had improved survival.¹³ Hence, while targeting the left stellate ganglion has been shown to improve clinical outcomes, interventions at the bilateral stellate ganglia may yet yield additional rewards. Finally, while the authors do demonstrate improvement in echocardiographic and electrocardiographic parameters, these data do not directly show whether the risk of ventricular arrhythmia is reduced. Ventricular arrhythmia inducibility with an electrophysiologic study would have helped show whether this approach may curb the risk of SCD post-MI.

Neuromodulation of sympathetic nervous system is an effective strategy to treat ventricular arrhythmias post-MI, as demonstrated by clinical experience of bilateral stellate ganglionectomy. The study in this issue highlights a more refined, molecular approach to ablating cardiac sympathetic neurons. Further definition of the structural and functional changes that occur within the cardiac autonomic nervous system following MI will inform the development of tailored therapy for ventricular arrhythmia.