Bigeminal potentials in the pulmonary vein indicate arrhythmogenic trigger of atrial fibrillation

Abstract Background The pulmonary veins (PVs) have unique electrophysiological properties triggering and maintaining atrial fibrillation (AF). Bigeminal PV electrical activity (PV bigeminy) during sinus rhythm has been reported; however, its mechanisms and clinical implication remain unclear. We hypothesized that PV bigeminy indicates arrhythmogenic activities and influences clinical outcome. Methods and Results We retrospectively analyzed electrophysiological studies in 465 patients with AF who underwent first session PV isolation (PVI). PV bigeminy was observed in 30 PVs of 23 patients (4.9% of patients). PV bigeminy was observed in left inferior PV (LIPV) in 15 patients, which was the most prevalent, followed by left superior in seven and right superior in seven and right inferior in one. In response to atrial extra stimulus, the second PV potentials (PV2) showed decremental conduction properties, suggesting reentrant mechanisms involved (n = 5). Interestingly, AF was initiated from the 23 PVs with bigeminy in 21 patients (76.7% of 30 PVs with bigeminy), spontaneously or in response to drugs, which was significantly more prevalent from the AF initiation rate from each PV in the control 442 patients (182 firings in 1290 PVs, 14.1%, P < .0001). PVI‐based ablation was completed in the 23 patients with PV bigeminy and no recurrence was observed during 1‐year follow‐up, whereas four patients needed second sessions. Conclusions PV bigeminy is relatively rare but a unique electrophysiological finding in AF patients, suggesting reentrant substrate within the PV and/or surrounding tissue. PV bigeminy is a strong indicator of arrhythmogenic vein triggering AF, and ensures an excellent clinical outcome after PVI.


| INTRODUC TI ON
Pulmonary veins (PVs) are the major arrhythmogenic trigger sites of atrial fibrillation (AF). 1,2 Ectopic activities and complex conduction properties are the crucial electrical characteristics of PVs, which initiate and maintain AF. 3,4 Variety of unique electrical activities in PV have been reported. 5 Bigeminal PV potentials (PV bigeminy) are rare phenomenon characterized by a second series of PV potential that is separate in time phase from the ordinary PV potentials observed in the PV ostia during sinus rhythm. Pathophysiology and clinical implications of PV bigeminy still remain unclear. [6][7][8][9][10][11] A recent study has suggested that a concealed PV bigeminy may be an indicator of arrhythmogenic activity. 11 In this study, we aimed to characterize PV bigeminy and clarify their roles in AF.

| Study subjects
We retrospectively analyzed 465 patients who underwent first session catheter ablation for symptomatic AF from 2011 to 2018.
Paroxysmal AF (pAF) and non-paroxysmal AF (non-pAF) were defined according to the guideline of the American College of Cardiology/American Heart Association/Heart Rhythm Society. 12 All patients underwent therapeutic protocols based on standard extensive PV isolation (PVI). Antiarrhythmic drugs (AADs) were discontinued for at least five half-lives prior to ablation procedures.
This study was in compliance with the principles outlined in the Declaration of Helsinki and was approved by the institutional review board for ethics at our institution, Kyushu University Hospital (approval no. 29-44). An informed consent was obtained in the form of opt-out on the website: https://www.cardi ol.med.kyush u-u.ac.jp/ resea rch/clini cal-resea rch/.

| AF induction test
Isoproterenol (5 μg) was administered intravenously to induce AF or PV firing. If it remained on sinus rhythm, adenosine triphosphate (ATP, 20 mg) was further administered. If AF or PV firing was induced, earliest activation site was defined as an AF trigger site. Three PVs (left superior, left inferior, and right superior) were monitored simultaneously using two multipolar electrodes and an ablation catheter unless spontaneous arrhythmogenic activity of right inferior PV was observed 2 ( Figure 1A). Linear ablation (LA roof line/mitral isthmus line) or defragmentation ablations were added in some patients at attending operators' decisions.

| Follow-up
No AADs were prescribed after 3 months of a blanking period of index procedures for 23 patients. Patients underwent continuous in-hospital electrocardiographic monitoring for 2 days after the procedure. Patients underwent observation of every month at the outpatient clinic. The outcome of AF ablation was evaluated on the basis of patient's symptoms and periodic 24 hour electrocardiogram at 3, 6, and 12 months after the procedure. AF recurrence was defined as AF lasting for >60 seconds after a blanking period of 3 months.

| Statistical analysis
The data are expressed as mean ± standard deviation (SD) for continuous variables, and counts and percentages for categorical variables. A comparison of categorical variables between pairs of groups was carried out using the Chi-square test or Fisher's exact test. A comparison of continuous variables between pairs of groups was carried out using Student's t-test. All P-values <.05 were considered significant. Analyses were conducted using a software program JMP (SAS, Cary, NC). The power for the log-rank test was calculated using the bootstrap method that repeat simulating analyses for re-extracted datasets (SAS ver.14.0).  Table 1. Female and non-pAF patients were less prevalent in the PV bigeminy group. CHADS 2 score was significantly less in the PV bigeminy group. In respect to the AF type, PV bigeminy was observed in 18 of 275 in pAF (6.5%) and in 5 of 190 in non-pAF (2.6%), which is more prevalent in pAF (P < .05).   Figure 3A). Thus, it was suggested that PV bigeminy (PV2) appeared via a reentrant mechanism rather than triggered activity or automaticity. PV2 was followed by an atrial  to PV2 ( Figure 3C). In one patient with LIPV bigeminy, isolated and organized PV tachycardia with a cycle length of 180 ms in the LIPV was observed after PVI, suggesting an establishment of a reentry circuit in the isolated PV (Figure 4).

| PV bigeminy and related arrhythmogenic activity
Initiation of AF was observed in 23 PVs of the 30 PVs with PV bigeminy (76.7%), spontaneously or in response to isoproterenol and/or ATP ( Figure 5). By contrast, AF initiation was observed in only 182 PVs among the total 1290 PVs (three observed PVs in each) in the control group (14.1%, P < .0001 vs PVs with bigeminy, Figure 6). Likewise, in the 23 patients with PV bigeminy, AF initiation from the other PVs without bigeminy was observed only in three. In patient basis, inducibility of AF from any PV could be observed in 22 of 23 patients with PV bigeminy (95.7%), which is significantly more prevalent than that in patients without PV bigeminy (162 patients of 442, 36.7%, P < .0001).

| Electrophysiologic property of PV bigeminy
Although the studied number is very small, the pacing study showed that the bigeminal PV potentials exhibited decremental conduction properties in response to atrial extra stimuli, suggesting a sort of reentry rather than triggered activities or ectopic automaticity as responsible mechanisms at least in a certain proportion of cases. This is the first report showing decremental conduction properties of PV bigeminy. PV bigeminy was prevalently seen in the LIPV in our study.
In a patient with LIPV bigeminy, an epicardial conduction pathway from PV to epicardial tissue in the CS region was suggested. Taken together, a reentry circuit responsible for PV bigeminy may involve epicardial conduction pathways, such as the ligament of Marshall, as a part of mechanisms. 14

| Limitations
There were several limitations in the present study. First, this is a single-center, observational study and the number of study popu- Third, mechanisms of PV potential could not be fully evaluated in this study. The pacing study could not be carried out in the majority of patients because the PV bigeminy is sporadic and not very consistent. In addition, mechanisms of PV bigeminy may be heterogeneous in terms of both anatomical and electrophysiological aspects.

| CON CLUS IONS
PV bigeminy is a unique electrophysiological finding observed in patients with AF suggesting reentrant substrate within the PVs and/ or surrounding epicardial tissue. PV bigeminy is a strong indicator of arrhythmogenic vein triggering AF and ensures excellent clinical outcome after PVI.

CO N FLI C T O F I NTE R E S T S
The authors declare no conflict of interests for this article.