Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia. Its prevalence is increasing worldwide ^[1][2][1,2]. The lifetime risk of developing AF beyond 40 years of age is 26% and 23% for males and females, respectively. Hypertension, obesity, obstructive sleep apnea, alcohol consumption, and thyroid disorders are some of the modifiable risk factors. Age is the most important non-modifiable risk factor in AF [3]. The research has shown that prevalence roughly doubles with each decade of life [4].

AF is associated with a higher risk of morbidity and mortality from cardiovascular events (heart failure, myocardial infarction, and sudden cardiac death), thromboembolism, ischemic stroke, and renal disease ^[2][4][5][2,4,5].

To date, pulmonary vein isolation (PVI) is predominantly performed through conventional thermal methods that include radiofrequency, cryotherapy, laser, and ultrasound. However, it has been well-studied that these methods are associated with indiscriminate tissue damage leading to esophageal, phrenic nerve, and aortic injuries ^[6][7][8][6,7,8]. The thermal methods work by inducing coagulative necrosis and subsequently reparative fibrosis, which may result in pulmonary vein stenosis and impaired left atrial reservoir function [9]. In contrast, pulsed field ablation (PFA) is a new approach to cardiac ablation of AF. It employs a non-thermal ablative mechanism in which cell death is obtained by applying ultra-short electrical pulses to induce pores in cell membranes ^[6][10][6,10]. It has higher myocardial tissue selectivity compared to conventional methods. PFA ablation is effective for paroxysmal and persistent AF ^[7][11][7,11] and is associated with low AF recurrence at one-year follow-up [12].

2.1. Successful Pulmonary Vein Isolation (PVI)

Pulmonary vein isolation (PVI) is one of the major determining factors for the efficacy of PFA ^[8][11][13][8,11,13]. Among the six studies, 100% successful PVI was reported in four studies. However, in a study by Reddy VY et al. ^[14][17] where PFA was performed by ablation catheter (endocardial cohort, n = 15) and surgical method (epicardial cohort, n = 7), 100% successful PVI was performed only in the endocardial cohort (15 out of 15). The epicardial cohort, where PFA was carried out by surgical means, had 86% (six out of seven) successful PVI. The remaining unsuccessful PVI was attributed to the system’s failure to deliver PFA appropriately due to technical problems. As for that, the patients (six out seven) who received successful delivery of pulsed electric field (PEF) pulses had pulmonary veins isolated in all of the cases. In addition to PVI, Reddy VY et al. ^[14][17] reported successful left atrial posterior wall (LAPW) isolation in all of the cases (six out of seven) who received successful delivery of PEF pulses. Similarly, successful LAPW ablation (24 out of 24 patients) and cavo-tricuspid isthmus block (100% on both studies by Reddy VY et al.) are reported by Reddy VY et al. ^[7][15][7,16]. The durability of LAPW (100%, n = 21 of 21) and PVI (96%, 82 of 85 PVs) lesions was reported by Reddy VY et al. [7]. Likewise, the success rate of PVI in MANIFEST-PF was 99.9%. This points towards the efficacy of PFA in producing successful ablative lesions in AF patients.

2.2. Adverse Events/Outcomes

The common adverse events due to PFA that have been described include esophageal injury, phrenic nerve palsy, aortic injury, vascular access site hemorrhage, cardiac tamponade/perforation, stroke, myocardial infarction, heart block, pericarditis, death, atrioesophageal fistula, and PV stenosis/narrowing ^{[1][7][9][14][15]}[1,7,9,16,17]. Groin hematomas were the complications observed in the study by Nakatani et al. [9] where the comparator was a thermal group. Of the groin hematomas, one of them happened in the PFA group (n = 18) and two in the thermal group (n = 23). They were conservatively managed without requiring any surgical intervention. On cardiac magnetic resonance (CMR) imaging, signs of intramural hemorrhage or microvascular damage were seen in none of the patients after PFA as compared to the thermal group (PFA vs. thermal group, p < 0.001) where such signs (mix of hyper-enhanced and dark areas) were seen in all patients. Similarly, acute tissue edema was slightly less in PFA than in the thermal group (10.0 ± 1.5 mL vs. 12.0 ± 2.1 mL, p = 0.002). In the chronic stage, the acute late gadolinium enhancement (LGE) seen on CMR had disappeared in the majority of the PFA group (mean LGE reversibility 60 (55–65)% of acute values). However, this reversible change was seen much less in the thermal group (18 (12–34)%, p < 0.001 vs. PFA). This finding ensures tissue safety by PFA as compared to a conventional method such as thermal ablation. This is evidenced by the preservation of the extracellular matrix framework and the lack of provoking inflammatory reactions by PFA ^[16][17][18][19,20,21]. The effect on left atrium (LA) structure and function was shown by evidence of LA fibrosis (16.7 ± 3.4% vs. 17.3 ± 3.7%, PFA vs. thermal group) and declined LA ejection fraction (58 (48–66)% vs. 55 (41–65)%, PFA vs. thermal group) in cine images of CMR. The decline in LA ejection fraction was less in the PFA group with a lower percentage of LA fibrosis as compared to the thermal group. Finally, the wall compliance, which declined acutely in both PFA and thermal ablation recovered only with PFA in the chronic stage. This led to the recovery of the left atrium reservoir and booster pump functions which is suggestive of PFA preserving the LA kinetic function. In the study by Verma et al. [1], no serious adverse events occurred in any patient (n = 38) in 30 days post-procedure follow-up. However, one vascular access site hemorrhage was reported as a procedure-related event. Similarly, as described by Verma et al. the duration of energy application in PFA is shorter as compared to sustained energy application in the thermal ablative procedure. This signifies the efficiency of PFA compared to other conventional ablative procedures such as thermal ablation. The study by Reddy VY et al. [7] reported only one adverse event, cardiac tamponade/perforation, out of a total of 25 patients (1/25, 4%). The explanation behind this event was that it occurred during remapping using radiofrequency only. The post-procedure esophagogastroduodenoscopy and repeat cardiac computed tomography revealed no mucosal lesions or PV narrowing, respectively. Likewise, there were no esophageal lesions and phrenic nerve paresis/palsy. However, due to a single occurrence of inadvertent transient acute left atrial appendage (LAA) isolation with subsequent recovery, it warrants careful assessment of ablation catheter and spline positioning when in proximity to such critical structures. In another study by Reddy VY et al. ^[15][16], a total of five vascular complications (one major left groin hematoma and four minor groin hematomas) were reported (n = 76) with a vascular complication rate of 6.6%. Additionally, the primary safety endpoint rate was 1.3% i.e., one out of seventy-six patients requiring surgical revision. There were no instances of pericardial tamponade, phrenic nerve palsy, PV stenosis, stroke, atrioesophageal fistula, or death. Similarly, there were no device-related complications, except minor mucosal thermal injury in two of thirty-six patients where PFA and RFA were performed posteriorly and anteriorly,, respectively. The post-procedure MRI brain in 51 of 76 (67%) patients at 1.2 ± 0.6 days revealed silent cerebral events and cerebral lesions in 5 (9.8%) and 3 (5.9%) patients, respectively. However, all the lesions were asymptomatic. Furthermore, cardiac computed tomography at acute post-ablation and 75 ± 11 days (n = 44 patients) revealed no evidence of PV stenosis. In another study by Reddy VY et al. ^[14][17], no adverse events during the procedure or post- procedure as stated above were reported (n = 22). Likewise, there was no evidence of malignant arrhythmias, significant electrocardiographic repolarization changes, and ventricular repolarization occurrence. Additionally, at the one-month follow-up, no adverse events were reported. The major adverse events such as cardiac tamponade and vascular complications requiring surgery were comparatively lower in the MANIFEST-PF survey ^[19][18]. This could be explained by the very large study population of this survey which seems to be more representative of a larger population. However, some unusual complications were also reported by this survey that included intraprocedural coronary artery spasm, hemoptysis, and dry cough persistent for six weeks. One of the limitations of this study is that it only explained the acute cases but did not report the recurrence of arrhythmia post-ablation.

2.3. Recurrence of AF or Other Atrial Arrhythmias

Out of the five studies, Nakatani et al. [9] described the recurrence of AF or any other atrial arrhythmias over a comparable follow-up duration (9 ± 3 months vs. 9 ± 4 months, PFA vs. thermal group) for the PFA and thermal group. The atrial arrhythmia recurred in 2 (11%) and 9 (39%) cases in PFA and thermal groups over that duration, respectively. This led to the finding that the arrhythmia-free survival rate was higher in the PFA group as compared to the thermal group (log-rank, p = 0.098). Although the remaining four studies mentioned no adverse events in the follow-up, the recurrence of AF or any other atrial arrhythmias was not highlighted.