TARGETING THE CARDIAC GANGLIONATED PLEXI FOR ATRIAL FIBRILLATION-MODULATE OR DESTROY?

Atrial fibrillation (AF) has been targeted by various catheter based ablative approaches and has emerged as a mainstay for the treatment of of drug refractory AF. However, high rates of AF recurrence has led to the evaluation of modified ablation strategies such as targeting complex fractionated atrial electrograms or linear ablation that have thus far limited success in improving rates of freedom from recurrence.(1) The critical role of the autonomic nervous system (ANS) in the initiation and maintenance of atrial fibrillation has also been well recognized (2,3) and provided the rationale for neural structures in the heart to be targeted for catheter ablation. The intrinsic cardiac nervous system harbors clusters of neurons, the ganglionated plexi (GP), which are nestled in epicardial fat pads and contain parasympathetic and sympathetic efferent, afferent, and local circuit neurons. Pulmonary vein isolation (PVI) and other catheter ablation procedures could transect fibers connecting these GPs or directly damage them and thereby mediate some of the benefits of catheter ablation. Therefore, adjunctive ablation of GPs has been evaluated over the past decade in atrial fibrillation ablation.(4,5) In the past several years, two divergent approaches have evolved for targeting cardiac GP’s. One approach involves modulating cardiac neurons (e.g. injection of botulinum toxin) and the other approach has been directed toward ablation/destruction of these structures.

In this issue of JACC: Clinical Electrophysiology, Yu et al. (JACC EP to add citation) report a novel approach to perform atrial GP ablation using magnetic nanoparticles to selectively ablate neural tissue while minimizing off-target effects. The authors had previously demonstrated the ability to perform GP ablation using magnetic nanoparticles with neurotoxin and extend this approach in the present study to utilize calcium-mediated neurotoxicity. (6) Three weeks after direct calcium chloride injections into the anterior right GP (ARGP), inferior right GP (IRGP), and superior left GP (SLGP) of 12 dogs, the investigators provide histologic confirmation of the apoptosis of GP neurons and reduced R-R interval prolongation in response to high frequency stimulation (HFS) of GPs. Furthermore, the injections mitigated electrical remodeling after six hours of right atrial pacing through preventing reductions in effective refractory period and decreasing AF inducibility. Subsequently they show that a calcium chloride payload in magnetic nanoparticles could be targeted to the atrial GPs, as injections of magnetic nanoparticles in the left circumflex arteries reduced function of the IRGP and SLGP without any effect on the ARGP, which is perfused by the right coronary artery. By assessing response to HFS of the GPs, the authors were able to demonstrate effective suppression of GP function secondary to calcium-mediated neurotoxicity. The authors conclude that this novel approach of targeting atrial GPs using magnetic nanoparticles with calcium chloride payload may reduce the risk of AF without affecting the atrial myocardium or exhibiting other off-target effects.

The novel approach of using magnetic nanoparticles to perform targeted neural ablation is a technical advance but should be viewed with cautious optimism. Clinical translation of a targeted therapeutic with a potentially favorable safety profile given the biodegradable nature of the magnetic nanoparticles is certainly enticing. However, several scientific questions remain unanswered. Given the interconnectedness of the atrial GPs, further characterization of the hierarchy of GPs and the minimum number of and specific atrial GPs that ought to be targeted in AF is crucial, as studies have ablated either isolated or several GPs in AF. (7,8) Although the authors show persistent effects at three weeks in their pre-clinical model, reinnervation has been identified in surgical GP ablation in dogs at four weeks. (9) Moreover, the role of atrial GP ablation as a stand-alone procedure has not proven successful using more conventional approaches; Katritsis et al. showed that GP ablation alone is not associated with improved outcomes over combined GP ablation and PVI (8), and this has been further supported by a meta-analysis.(10)

While the proposed approach shows a favorable safety profile, adverse effects of GP ablation remain a concern. Potential adverse effects of atrial GP ablation on ventricular electrophysiology and coronary vasculature need to be further characterized, as increases in ventricular arrhythmia post-MI and coronary vasospasm have been described post-GP ablation, respectively (11–13). Ventricular myocardial denervation using nuclear imaging has also been demonstrated post AF ablation in patients when GP’s were targeted.(14) In the largest randomized clinical trial of GP ablation, the AFACT study highlighted some of the pitfalls of GP ablation.(15) In this study, the investigators performed thoracoscopic GP ablation in addition to PVI and linear ablation and demonstrated no reduction in AF recurrence with adjunctive GP ablation, but did have major adverse events including major bleeding, sinus node dysfunction, and need for pacemaker implantation.

Nanoparticle technology has been used previously in pre-clinical models of cardiovascular disease to target cardiomyocytes, coronary vessels, and cardiac macrophages in myocardial infarction.(16) In the present study, the authors discuss the favorable safety profile of this targeted therapeutic approach. However, the low zeta potential raises the issue of efficiency in cellular uptake and risk of aggregation of the nanoparticles, the effects of which were not assessed in this study. Also, for those nanoparticles that do not reach the GPs, assessment of calcium-mediated toxicity in other tissues warrants evaluation. Once a nanoparticle is delivered to the site of interest, the use of neuromodulatory rather than neurotoxic agents is another potential avenue of investigation. Recent data suggest that ‘temporary’ botulinum toxin injection may reduce post-operative AF following coronary artery bypass grafting in the post-operative period (17) and up to 3 years.(18)

The proposed approach heralds the potential of a targeted therapeutic that acts at the cardiac neuraxis for the treatment of AF. However, the significant challenge we face in the field of electrophysiology is to discover actionable mechanisms of atrial fibrillation and to discern the specific role played by the nervous system in the disease. In the interim, targeted ablation of neural structures, using magnetic nanoparticles provides a strategy to destroy neural tissues for mechanistic studies for discerning the role of GP’s in AF. The challenge is now for basic and translational scientists to define the path ahead and provide guidance to the question of whether these structures should be modulated or destroyed.