Correspondence
Name: Professor Dhiraj Gupta, MD https://orcid.org/0000-0002-3490-090X
Address: Department of Cardiology, Liverpool Heart and Chest Hospital, UK L14 3PE
Phone: +44 151 600 1793; Fax: +44 151 600 1696
Email: Dhiraj.gupta@lhch.nhs.uk
Demonstration that the myocardial sleeves of the pulmonary veins (PVs) are the main triggering and maintaining foci for paroxysmal atrial fibrillation (AF) have stimulated studies investigating electrophysiological properties of PVs and the adjacent left atrial (LA) myocardium. It has been shown that PV myocytes have a shorter action potential duration and are more prone to effects of local autonomic nerve stimulation in terms of shortening of action potential duration, early after depolarization formation and triggered firing compared to LA myocytes (1). The intrinsic cardiac autonomic nervous system (ICANS) forms clusters of neurons, ganglionic plexi (GP), and studies using histologic examination of heart sections have shown that these GPs are localized preferentially at certain epicardial sites adjacent to the left and right atria (2). The precise role of targeting ICANS in AF ablation continues to be an area of intense research (3), and matters are not helped by the uncertainty regarding the best way to identify and target ICANS peri-procedurally. As there can be significant variability of GP sites in individual patients, endocardial high-frequency stimulation (HFS) has been used to aid their localization in the electrophysiology laboratory (4). Although HFS stimulation protocols have varied significantly between studies, these mostly involve delivering electrical pulses with a frequency of 20 Hz, amplitude of 0.1–1.0 mA, and pulse duration of 1–10 msec at each site using specially developed stimulators (3, 4). The first 2-4 seconds HFS mostly causes parasympathetic effects as an immediate response, whilst a longer application of 8-10 seconds stimulates a delayed sympathetic response (4). Demonstration of a ≥50% increase in mean R-R interval during AF, often accompanied by hypotension, is accepted as a significant parasympathetic response and serves as a surrogate marker of GP location.
In this issue of the journal, Sandler et al (5) present the results of a pilot study in patients with paroxysmal AF who were randomized to selective endocardial ablation of GPs or to conventional circumferential PV isolation. The investigators delivered synchronized HFS from multiple evenly distributed LA sites (103±28 sites per patient), and ablated those sites where HFS induced atrial ectopy, atrial tachycardia or AF, or where significant parasympathetic effects were elicited (21±10 sites per patient). 67 patients were randomized to GP ablation (n=39) or PV isolation (n=28), although eight of 39 patients initially randomized to GP were crossed-over to the PV isolation group due to sustained AF precluding completion of GP mapping protocol. At the end of 12 months follow-up, 61% patients with PV isolation and 49% patients with GP ablation were free from AF/atrial tachycardia (p=0.27). The amount of RF energy delivered in the GP group was significantly lower, although this did not translate to a lower procedure time (mean 3.7 hours) or in a lower complication rate. The authors should be congratulated for the bold study design in which they were prepared to leave patients in the GP group without PV isolation to test their hypothesis. The randomised double-blind study design is another strength. On the flip side, readers will note the modest 12-month success rates of around 50% seen in both groups in spite of limited ECG monitoring; these are in all likelihood related to the time period when the procedures were performed (2013-2017), before the advent of composite ablation indices and before the current emphasis on lesion contiguity that has enabled much higher single procedure success rates with PVI for paroxysmal AF. Whether the outcomes of a GP based ablation strategy would have been higher with these modern tools is a moot point. We are also left with several unanswered questions. Were the GP sites preferentially located at certain LA regions, why were right atrial sites not tested, what effect did general anaesthesia have on the reliability of GP identification, and importantly, would a third group, that of PV isolation plusGP ablation, have had higher success rates than either strategy alone? Also, given that the mean heart rates of patients in the GP group on serial Holter monitoring at follow up were no different to those in the PVI group, one also wonders how effective ablation actually was in terms of modifying the ICANS. Hopefully, the planned larger randomised study by the same group, NCT02487654, would answer some of these questions.