PFA is distinguished by its targeted specificity to cardiac myocytes [22], offering a focused therapeutic approach within a concise procedural timeframe. This selectivity is underpinned by empirical studies demonstrating the method’s precision and efficiency [23]. PEF has tissue specificity in inducing IRE; the parameters of PEF can be adjusted to induce IRE in different types of tissue cells, which greatly reduces the incidence of collateral tissue damage in PFA. Table 3 (Ref. [55, 56, 57, 58, 59, 60]) shows the electric field threshold of IRE for different types of tissues under certain pulses. The following is a comprehensive analysis of the effects of PEF on ablation sites and adjacent tissue cells in a series of PFA experiments for AF [55, 56, 57, 58, 59]; when the electric field environment of a certain tissue reaches its corresponding threshold, it undergoes IRE and initiates apoptosis or necrosis.

PFA has obvious advantages in PVI compared to a series of traditional thermal ablation techniques, including RFA and cryoballoon ablation [87]. This advantage is reflected not only in the improved safety and reduced complications of ablation but also in the upfront success rate and durability of PVI, which can have important long-term prognostic implications for AF.

Compared with thermal ablation, PFA showed obvious advantages in single-shot PVI. In a 2022 experimental report [88], the success rate of single-shot PVI induced using PFA in 191 patients with AF was 99.5% (779/783). Comparatively, the isolation rates of single emission and single mapping of cryoballoon ablation and laser balloon ablation were 86% and 91.6%, respectively [89, 90]. Moreover, a different, less supportive guidewire was used in all four instances. Using a modified catheter, all the remaining PVs were isolated after a second series of PFA. Subsequent electrophysiological assessments have elucidated the effects of PFA, demonstrating substantial lesion formation around the pulmonary veins and achieving consistent isolation of the left atrial posterior wall. Notably, this is accomplished with a minimal reduction in tissue voltage, attesting to the precision of PFA [91]. While the incidence is reduced, the phenomenon of early pulmonary vein reconnections post-PFA does manifest. These reconnections tend to localize to specific anatomical regions: the right carina, the anterior segment of the right superior pulmonary vein (RSPV), the posteroinferior quadrant of the right inferior pulmonary vein (RIPV), the posterior sector of the left superior pulmonary vein (LSPV), and the posteroinferior area of the left inferior pulmonary vein (LIPV). Such a distribution mirrors the patterns often observed following thermal ablation procedures. A possible explanation for this similarity may lie in the variable myocardial wall thickness across these regions, coupled with the inherent challenges associated with catheter maneuverability [50, 92].

Over time, owing to incomplete tissue ablation, recovery of the PV electrical connection and recurrence of AF are challenges faced by all types of ablation techniques. Therefore, long-term maintenance of sinus rhythm after PVI is also an important metric for evaluating the relative efficacy of different ablation techniques. In individuals with PAF unresponsive to antiarrhythmic drug therapy, PFA has been administered to achieve sustained PVI [93]. Follow-up investigations, conducted at a median interval of 84 days, revealed cardiac voltage maps consistent with those observed immediately postprocedure in a cohort of 20 patients. This continuity suggests that the ablation-induced isolation of pulmonary vein antral regions may be enduring, hinting at PFA’s capability for establishing long-lasting PVI in PAF patients. In contrast, current data do not demonstrate a comparable advantage for PFA in achieving enduring PVI among patients with PsAF [49, 50, 51].

Although some unresolved issues remain, the feasibility, safety, and durability of PFA for PVI have been demonstrated, and PFA has improved tissue safety compared with conventional thermal ablation. Researchers have made strides in multiple domains to further improve the efficacy and safety of PFA PVI. Currently, a more effective method is the use of a multipolar catheter instead of a traditional single catheter combined with biphasic PEF for ablation [94, 95].

The PFA has obvious advantages in terms of ablation speed. In recent clinical trials [24, 44, 46], the operation time of PFA has generally been controlled at approximately 95–25 min. According to a recently published multinational survey [78] of clinical PFA applications, the average procedure time was 65 min (range, 38–215 min), including pre- and/or postablation electroanatomical mapping in some patients. The fluoroscopy time was 13.7 min (range 4.5–33).

PFA has a protective effect on atrial structure. In experimental studies, in addition to mild inflammation in the early postprocedural stage, the atrial site only showed loss of cardiomyocytes and smooth muscle cells, without destruction of the original cardiac tissue structure, replacement with fibrocytes, formation of new blood vessels, or deposition of collagen [37]. This finding indicates that PFA can maintain normal atrial morphology. Studies have shown that during the atrial recovery period after PFA, the physiological process of chronic fibrosis is less involved [96], which can maintain the tissue compliance of the LA and preserve the cardiac structure and contractile and diastolic functions as much as possible.

The main limitations of the clinical application of AF ablation using PEF are that the selection of an appropriate catheter, optimal parameters of PEF, and ablation positions with high safety have not yet been standardized [64], and these factors can affect the reliability of AF ablation to different degrees. However, with the increasing application of PFA in animal models of AF, these problems will gradually be resolved. In this case, we should analyze the limitations of the current PFA technology in terms of therapeutic effects, which can be used as a reference and research direction for future technical optimization to ensure the efficacy and safety of PFA.

The application of PEF in CA for AF produces unique ablation characteristics in the circumferential venous sinus isolation zone. In 2022, a study [97] described the extent of the PVI zone formed by a single PEF. In this study, 40 patients with PAF or PsAF who had not undergone ablation therapy were treated with PFA (flower/basket-shaped catheter) for the first time. During the 190-day postoperative follow-up, AF recurred in only four patients (15%). High-density three-dimensional electrical mapping was used to compare measurements before and after ablation. Finally, researchers found that an inadequate isolation area was most common in the anterior vena cava segment of the left PV; the greatest area of inadequate isolation in the PV sinus segment was also located anteriorly in the left PV and anteriorly and inferiorly in the right inferior PV. At the same time, an enlarged left atrial isolation zone was most common and widespread in the posterior wall and apical areas on both sides of the LA. In theory, the expanded electrical isolation zone can block the generation and conduction of ectopic triggers more thoroughly but introduces other potential risks. According to prior clinical experience with RFA, an expanded ablation area can result in the following three risks: (1) injury to adjacent tissues, such as the esophagus and phrenic nerve; (2) excessive atrial scarring resulting in loss of systolic function; and (3) separation of normal atrial electrical conduction and formation of a reentrant pathway leading to malignant tachycardia. The first risk can be avoided by adjusting the PEF parameters and improving tissue specificity. However, the second and third are significant risks of additional regional injuries, and special attention should be given to the protection of LAPW myocardium and the roof of the left atrium during PFA PVI.

Gaseous microemboli during cardiac ablation have long been reported. In previous thermal ablation studies, the generation of microbubbles was associated with rapid carbonization, and gas production was associated with tissue injury and necrosis [64]. Although PEF does not use thermal energy to cause necrosis of tissues and cells, microbubbles still occur. Microbubbles generated by PFA can disappear in a short period without obvious physiological effects [98]. Research delineating the safety profile of PFA has produced mixed outcomes regarding cerebrovascular risks. Initial experimental models have suggested that the microbubbles produced during PFA do not precipitate cerebral embolic events [99, 100]. In contrast, data emerging from recent clinical trials indicate the occurrence of asymptomatic cerebral embolisms in a subset of patients following PFA [53, 54, 101]. The potential for such embolisms to occlude critical cerebral vasculature—and thereby precipitate severe neurological sequelae—underscores the imperative for rigorous investigation into prophylactic strategies that might mitigate this risk.

Monophasic PEF ablation causes skeletal muscle contractions and subtle changes in systemic hemodynamics. Some patients with AF have coronary microvascular dysfunction in the absence of obstructive coronary artery disease, which further leads to reduced myocardial perfusion flow and cardiac dysfunction. Perceived AF symptoms cannot often be relieved after undergoing successful ablation [102]. Coronary dysfunction is likely to induce heart failure, which can lead to recurrent arrhythmias, including AF. Therefore, numerous studies have recently adopted biphasic wave PFA to avoid the risk of coronary artery dysfunction [41]. Recent studies have also shown that preoperative nitroglycerin intervention can prevent the occurrence of coronary artery vasospasm [81], which may become a means to reduce the risk of periprocedural myocardial injury during future AF ablations.

Thus far, most trials on PFA only had a few samples and were not randomized controlled trials. The durability of PFA PVI and the rate of recurrent AF must be confirmed through long-term event surveillance. Currently, these two data types are relatively scarce and require further research.

Moreover, it is still unclear how PEF affects other cardiac intervention devices, such as artificial valves, cardiac pacemakers, and coronary stents. The acquisition of long-term outcomes from multicenter randomized trials conducted on targeted clinical groups is imperative to validate the efficacy and safety of PFA. An earlier study [103] indicated that metal intracoronary stents in proximity to the ablation device simply “amplify” the vessel-induced distortion of the E-field with tissue between the artery and ablation electrode, probably being moderately heated during this distortion but not damaged thermally. Initial research into PFA for individuals with cardiac implantable electronic devices (CIEDs) indicates a favorable safety profile. Small-scale clinical investigations have reported that PFA does not compromise the functionality or structural integrity of pacemakers and defibrillators. Specifically, in a cohort of six patients, device performance remained stable post-PFA [104]. Similarly, PFA yielded positive arrhythmia control in a patient with an ICD (implantable cardioverter-defibrillator) [105]. Further studies, including a trial with 20 CIED recipients, suggest that avoiding direct contact between the PFA catheter and the implanted device is essential. Adhering to this precaution, PFA appears to be a viable option for diverse CIED types, using catheters sized 31 mm or 35 mm and energy outputs ranging from 1.9 kV to 2.0 V [106].

The current landscape of PFA for the management of AF shows promise; however, it is imperative to acknowledge that the long-term efficacy and safety profile of this modality remain to be comprehensively characterized. The paucity of extended follow-up data from large-scale, randomized controlled trials poses a notable limitation to the robust evaluation of PFA. This gap in evidence may have consequential implications for clinical decision-making, potentially hindering the development of standardized protocols and the optimization of patient outcomes. This underscores the exigent need for multicenter studies with longitudinal monitoring to substantiate the long-term therapeutic value of PFA and to affirm its role in the evolving paradigm of AF treatment. Such investigations are crucial not only for validating the preliminary positive outcomes but also for ensuring that the benefits of PFA outweigh any delayed adverse effects, thereby enabling informed clinical judgments and enhancing patient care.

In the study of PFA applied for PVI, there are many indications that multipolar CA is superior to single CA, even if the parameters of PFA need to be adjusted. Various types of novel multipolar catheters are available. Currently, flower-shaped and basket-shaped catheters are the most common [44, 46]. Special lattice electrodes [26, 38, 109], circular multipolar catheters [36], and flexible linear epicardial catheters [46] have also been used in some experiments. Table 4 (Ref. [24, 44, 45, 46, 109]) illustrates several novel forms of multipole catheters and their performance in the respective experiments. However, an experiment [110] showed that different discharge modes of multipolar catheters would affect the distribution of the myocardial electric field, resulting in different widths and depths of myocardial lesions, which can influence the ultimate efficacy of PVI. Therefore, an important consideration for further optimization of PFA technology is to achieve the needed depth of the lesion while controlling the area of the myocardial lesion by adjusting the discharge mode of the electrodes as part of the multipolar electric field. In addition to improving the catheter form, optimization of the catheter mapping system is also crucial [111]. PEF has the capability to form cardiac lesions without necessitating direct electrode-tissue contact. However, the proximity of the electrode to myocardial tissue significantly influences lesion size, with closer contact resulting in larger lesions. Notably, the variance in lesion dimensions relative to electrode distance is less pronounced with biphasic PEF compared to monophasic PEF [112]. A robust linear relationship exists between lesion depth and electrode-tissue proximity, achieving maximal lesion depth at zero distance [113]. Incorporating a precise mapping system can streamline the ablation process, enabling accurate localization of arrhythmogenic foci and facilitating control over lesion extent through careful management of electrode proximity.

Table 4.Novel catheters in PFA and related respective trials.

	Flower/Basket-shaped multielectrode catheter	Circular multielectrode catheter	Lattice electrode catheter	Flexible linear epicardial catheter
Catheter conceptual image
Catheter description	The 12-F over-the-wire PFA ablation catheter has 5 splines that each contain 4 electrodes, and it can be deployed in either a flower petal or basket configuration. When fully deployed into a flower pose, the diameter of the distal portion is 31 mm	An over-the-wire, circular array catheter with 9 gold electrodes (electrode length, 3 mm; 20° forward tilted array with a diameter of 25 mm; 9F shaft)	The lattice catheter is a 7.5Fr bidirectional deflectable catheter with an expandable conductive lattice electrode, containing 9 mini-electrodes/temperature sensors (0.7 mm diameter) that are uniformly distributed on its surface (The catheter is inserted into the sheath in a collapsed form, but once in the heart, the lattice expands to a 9 mm diameter spherical configuration)	This is a flexible linear epicardial catheter and incorporates a guidewire lumen. 30 Electrodes for PEF ablation energy delivery are distributed in the midportion of the catheter—the portion that wraps around the PVs and posterior LA
Experimental subject	Patients with symptomatic paroxysmal AF resistant to class I to IV antiarrhythmic medications	Patients 18–80 years of age undergoing first-time CA of paroxysmal or persistent AF that failed at least one antiarrhythmic drug (class I or III)	Yorkshire swine (65–90 kg)	Patients with symptomatic paroxysmal AF refractory to or intolerant of at least one antiarrhythmic drug
Ablation position	Endocardial: the ostium of the right inferior PV	Endocardial: near the level of the PV carina	Endocardial: from SVC to IVC	Epicardial: encircling the posterior LA and the four PVs
Preablation mapping technique	Preprocedure CT or intracardiac echocardiography (ICE) (Acunav, Siemens, Munich, Germany)	Fluoroscopy or intracardiac echocardiography imaging	Fluoroscopy imaging by lattice electrode catheter	Compatible electroanatomical mapping system (Orion and Rhythmia, Boston Scientific, St. Paul, MN, USA)
PEF type	Biphasic	Biphasic	Biphasic	Biphasic
Electric field intensity or voltage	1800–2000 V	500–1500 V	400 V/cm	2100–2400 V
Results	There were no postoperative adverse events. The acute PVI rate was 100%, and the durable PVI rate under optimized waveforms was 96%	The acute PVI rate was 100%. No adverse events occurred 30 days after the operation. The ablation time was significantly shorter than that of RFA	There was little damage to phrenic nerve and esophagus while durable PVI was formed	There was no PV stenosis, arrhythmia, or pericardial effusion after ablation. The acute PVI rate was 100%
Ref.	[24, 44]	[45]	[109]	[46]

Summary of novel PFA catheters and representative experiments. LA, left atrium; PFA, pulsed field ablation; PEF, pulsed electric field; AF, atrial fibrillation; CA, catheter ablation; PV, pulmonary vein; PVI, pulmonary vein isolation; SVC, superior vena cava; IVC, inferior vena cava; CT, computed tomography; RFA, radiofrequency ablation.

Meanwhile, although the current research on PFA does not involve the study of electrode-tissue orientation, previous ablation operations in various fields seem to default to placing the electrode parallel to the tissue, which may be difficult to achieve accurately in some complex organ locations. However, in the study of parameters affecting IRE, electrode-tissue orientation was found to affect the scope and depth of tissue necrosis and the voltage threshold of IRE [114]. This finding is very important for the optimization of parameters in the ablation process.

The meticulous calibration of PEF parameters is integral to achieving ablation specificity, emphasizing the importance of establishing thresholds for the myocardium and surrounding tissues to propel PFA advancements for AF. Optimal thresholds—those precipitating over 80% reduction in cell viability—have been identified, with cardiomyocytes and myocardial fibroblasts exhibiting susceptibility to cell death at an electric field intensity of 1000 V/cm and a pulse quantity of 50 [57].

Moreover, the literature indicates a preference for biphasic short pulses in PFA PVI due to their enhanced efficacy and reduced propensity for muscle contraction, thus preserving atrial architecture post-ablation. Notably, achieving a comparable PVI effect with biphasic short pulses necessitates voltages surpassing 1000 V/cm, unlike monophasic long PEF, which bears implications for potential thermal damage [115]. This necessitates precise PEF parameterization to balance the therapeutic benefits with safety concerns.

Meanwhile, Howard et al. [113] showed that the proximity between the electrode and tissue could affect the depth and offset width of the tissue lesion when using a biphasic electric field for ablation. The depth and offset width of the tissue lesion were linearly related to the electrode-tissue proximity; that is, the greater the distance between the electrode and tissue, the smaller the depth and offset width of the necrosis. When the distance was zero, the depth and offset width of necrosis was the maximum. Therefore, while adjusting the PEF parameters, it is possible to control the degree of myocardial necrosis by adjusting the proximity between the electrode and the tissue. The closer the electrode and the tissue, the higher the possibility of achieving myocardial transmural necrosis, while at the same time, the offset width of the necrotic area will increase.

Moreover, in the treatment of AF, the anisotropic electrical conductivity caused by fiber orientation cannot be ignored. According to one study [116], there is a significant difference in the size of the surface ablation area, ablation isosurface, and ablation volume between anisotropic and isotropic electrical conductivity. Consequently, to develop a more targeted restricted ablation zone, it is necessary to establish an electrically refined cardiac model with anisotropic and isotropic electrical conductivities.

The effect of PFA on PVI in the treatment of PAF is widely recognized. PVs play a crucial role in the initiation and maintenance of AF, particularly PAF [117]. However, because of the complexity of the mechanism of PsAF, simple PVI often cannot achieve a sustained therapeutic effect; therefore, it is still necessary to find new ablation targets to improve the prognostic effect of PsAF ablation. PFA exhibits more limited tissue penetration than conventional thermal ablation, necessitating the identification of supplemental ablation targets. While thermal ablation for AF is effective due in part to its impact on the autonomic nervous system by targeting ganglionated plexi (GP), PFA may not achieve the same extent of intramyocardial autonomic nerve ablation, calling into question its thoroughness and persistence [118, 119].

Many studies have shown that LAPW can be used as a reliable new target for the ablation of PsAF [120, 121]. In an earlier study that included LAPW as a target for PFA, 21 patients undergoing ablation did not have serious complications; the durable isolation rate of LAPW was 100%, the durable PVI rate was 96%, and no recurrence of AF was reported during the 76- to 90-day follow-up [47]. Reliable clinical experiments have also shown that the application of LAPW ablation in the treatment of PsAF does not damage the systolic function of LA [122] and has high feasibility and safety. Concerning PFA’s efficacy, achieving comprehensive electrical isolation of LAPW can be challenging. Although recent small-scale trials have shown promising control of arrhythmias post-LAPW PFA [123], the long-term effectiveness and durability of these outcomes warrant confirmation through larger, randomized studies.

In addition to LAPW, another investigator focused on the Marshall bundle and developed the Marshall–Plan ablation protocol [124]. In this protocol, the left atrial sites were targeted sequentially as follows: the coronary sinus and vein of the Marshall musculature, PVI, and anatomical isthmus (mitral, roof, and cavotricuspid isthmus). The patients recruited in this study had a history of long-term PsAF, and the results showed that the maintenance rate of sinus rhythm 12 months after a single ablation was $>$70% without the use of antiarrhythmic drugs, indicating the high feasibility of this new ablation protocol for the treatment of PsAF. Mitral isthmus PFA has emerged as a viable approach for managing PsAF [80] and is particularly beneficial in cases involving left atrial reentrant tachycardia. However, the applicability of multipolar PFA catheters for mitral isthmus and anterior line ablation may be limited. Focal PFA catheters have been shown to be potentially more suited for these specific ablation targets [125].

The key to finding new ablation targets lies in an in-depth understanding of the electrophysiological mechanism of PsAF. It is now believed that the occurrence and perpetuation of PsAF result from the existence of multiple focal triggers and reentrant pathways in the atrium. Studies have suggested the presence of persistent abnormal activation lesions in the LAPW and three intermittent activation lesions located in the right posterior wall of the atrium. The abnormal conduction pathway had five breaches, two in the PVs, one in the top region of the right atrium, and two in the free wall of the LA [126]. All of these positions may be potential novel ablation targets for AF. Furthermore, it has been found that the formation of an epithelial adipose tissue inflammatory microenvironment, fibrosis, infiltration of atrial tissue, autonomic dysfunction, and oxidative stress are crucial mechanisms that trigger and maintain AF [127]; thus, epithelial adipose tissue may be a novel target for the clinical treatment of AF.