Durability of Pulsed Field Ablation Lesions: Current Understanding and Future Directions

Catheter ablation has become a cornerstone of rhythm control in AF management. Traditional thermal methods, including radiofrequency (RF) and cryoablation, are limited by collateral tissue injury, lesion variability and thromboembolic risk. Pulsed field ablation (PFA) circumvents many thermal limitations through electroporation, preferentially affecting myocardial tissue while sparing adjacent structures such as the oesophagus and phrenic nerve.^1,2 However, unlike thermal ablation, in which lesion maturation follows predictable fibrotic pathways, the biological and structural evolution of PFA lesions and their long-term durability require detailed characterisation to fully validate the technique.

Fundamental Principles of Pulsed Field Ablation Lesion Formation

PFA leverages the biophysical principle of electroporation, wherein high-intensity, short-duration electric fields disrupt cellular membrane integrity by creating nanopores. When the applied electric field exceeds a critical threshold, irreversible electroporation (IRE) occurs, leading to loss of cellular homeostasis and subsequent cell death.^3,4 Importantly, the threshold for IRE varies among tissue types, enabling selective myocardial ablation. The lesion architecture resulting from PFA is sharply demarcated, often with minimal collateral damage to non-cardiac structures.⁵ Durability of these lesions fundamentally depends on the achievement of a uniform and complete transition to IRE across the target tissue.

Several key factors influence lesion formation: field strength (typically 500–2,000 V/cm), pulse duration (typically microseconds), pulse number, electrode configuration and tissue conductivity. Tissue anisotropy, heterogeneity in fibre orientation, and impedance variability influence local electric field distributions, potentially causing uneven lesion formation if not adequately accounted for during catheter design and energy dosing.^6–8

Recent publications have highlighted the importance of catheter–tissue contact, pulse sequencing and waveform optimisation to achieve durable pulmonary vein isolation (PVI) while minimising the risk of collateral damage.^9–11

Role of Reversible Electroporation in the Durability of Pulsed Field Ablation Lesions

A critical consideration in lesion durability is the phenomenon of reversible electroporation. At subthreshold field strengths or insufficient pulse dosing, cells may undergo transient membrane permeabilisation without progressing to irreversible damage. These ‘stunned’ myocardial cells may initially appear electrically silent, contributing to acute procedural success, but later recover function, leading to lesion reconnection and arrhythmia recurrence.^12,13

Reversible electroporation underscores the necessity for optimised energy dosing to ensure that the entire target tissue exceeds the threshold for irreversible cell damage. Pulse parameters such as waveform type (biphasic versus monophasic), pulse repetition frequency and cardiac cycle timing play pivotal roles in minimising the risk of reversible effects.^14,15

Experimental studies have demonstrated that higher field strengths and appropriate pulse train designs significantly reduce the occurrence of reversible electroporation, thereby enhancing chronic lesion durability.^16,17 Koruth et al. reported that reversible electroporation can be advantageous for reversible tissue effects such as arrhythmia mapping but is undesirable in ablation intended to create permanent myocardial lesions.¹²

Furthermore, emerging evidence suggests that intrinsic tissue properties, such as fibrosis and anisotropy, may influence the susceptibility to reversible versus IRE. Fibrotic atrial substrates, commonly encountered in persistent AF, may necessitate tailored energy delivery protocols to ensure complete ablation.^18,19

Unfortunately, at present no method to predict (the extent of) reversible electroporation exists.

Mechanisms of Pulsed Field Ablation and Implications for Lesion Durability

PFA induces cell death by disrupting cellular membranes through high-voltage, short-duration electric fields. The extent and durability of cell death depends on multiple factors, including pulse waveform characteristics, field strength, pulse number and tissue heterogeneity.^20,21 Unlike thermal necrosis, electroporated cells may undergo apoptotic or necrotic pathways depending on the energy delivery, complicating predictions of lesion healing and stability over time.^3,4

Preclinical Insights into Pulsed Field Ablation Lesion Durability

Multiple animal studies have assessed PFA durability, demonstrating persistent, transmural lesions in porcine atria at 30 and 90 days following monophasic and biphasic PFA delivery.^22–24 Other studies confirmed that PFA lesions show sharply demarcated borders with minimal adjacent tissue injury.^1,2,23,25 In contrast to thermal lesions, histological analysis often indicates preserved extracellular matrix scaffolding, suggesting different remodelling dynamics.^5,26

Factors Influencing Pulsed Field Ablation Lesion Durability

Biphasic waveforms appear to yield more durable lesions compared with monophasic pulses, reducing muscle capture and promoting more uniform cell death.^27,28 Pulse repetition, pulse train spacing and synchronisation with the cardiac cycle influence lesion homogeneity and size.^29,30 Multispline designs create circumferential PVI with overlapping fields, promoting durability.³¹ Single-shot versus point-by-point catheter strategies may impact lesion contiguity and inter-lesion gap formation.³² Atrial myocardium requires lower electroporation thresholds than thicker ventricular myocardium or non-cardiac tissues. Variability in atrial thickness could lead to heterogeneous lesion formation, affecting durability.³³ While PFA theoretically requires less contact force than RF ablation, inadequate electrode–tissue contact may lead to subthreshold electroporation and lesion gaps.³⁴ In an animal study in which the influence of electroporation ablation on the phrenic nerve function was investigated, the smallest lesion width was always found at the lateral side of the superior caval vein, in the same region where the phrenic nerve was found during pace-mapping. Also, the widths at the posterior side of the superior caval vein were smaller than the widths at the medial and anterior sides of the superior caval vein. This consistent finding was explained by the fact that the lateral and posterior sides of the superior caval vein are surrounded by air-containing pulmonary tissue with a higher-than-average tissue impedance. In contrast, the medial and anterior sides of the superior caval vein are surrounded by compact tissue that contains no air. As a consequence, the unipolar electroporation current may have favoured the medial and anterior sides of the superior caval vein over the lateral and posterior sides, thus creating larger (wider) electroporation ablation lesions medially and anteriorly. Omnidirectional variations in tissue impedance might thus affect lesion durability.¹

Clinical Outcomes Related to Lesion Durability

Initial PFA trials report high acute PVI success rates (over 95%) and promising short-term durability. The PULSED AF trial using a circular PFA catheter demonstrated 100% acute PVI success with a 1-year freedom from paroxysmal and persistent AF/atrial tachycardia of 66.2% and 55.1%, respectively, without major safety concerns.³⁵ The ADVENT trial is a randomised pivotal study comparing PFA using a pentaspline ablation catheter with traditional thermal ablation: PFA was non-inferior for efficacy and safety at 1 year.³⁶ The inspIRE trial reported high rates of durable PVI (97% reconnection free at remapping) and low adverse event rates with a loop circular PFA catheter for PVI.³⁷ The IMPULSE and PEFCAT trials were early feasibility trials investigating a pentaspline PFA catheter with promising long-term success.^11,38

Most recently, the randomised SINGLE SHOT CHAMPION trial demonstrated that PFA was non-inferior (and even marginally superior) to cryoballoon ablation with respect to the incidence of a first recurrence of atrial tachyarrhythmia, as assessed by continuous rhythm monitoring in patients with paroxysmal AF. In that trial, the operators were required to have a minimum of 6 months of experience using the pentaspline PFA catheter, in contrast to the ADVENT trial, in which almost all of the operators were new to the use of the pentaspline PFA catheter.³⁹

However, remapping studies highlight different degrees of pulmonary vein reconnections, often correlating with anatomical challenges or inadequate energy delivery due to suboptimal electrode–tissue contact.^40–42

Histopathological Evolution of Pulsed Field Ablation Lesions

Histological studies at chronic time points (30–90 days) in animals show complete myocardial cell death, minimal inflammatory response compared with RF lesions, and fibrotic tissue replacement with preserved extracellular matrix architecture.^5,43–45 These findings suggest reduced inflammation, less scar burden, and potentially lower arrhythmogenic potential. However, matrix preservation could theoretically allow for micro-recovery of conduction in some regions if incomplete electroporation occurs.²⁴

There are no reports of adverse events regarding the oesophagus after endocardial PFA in the preclinical and/or clinical arena thus far. Based on the preservation of tissue scaffolding with PFA and the consistent pattern of healing seen in preclinical testing, it appears that the risk of severe oesophageal complications such as fistula is likely to be very low to none with current-generation PFA catheters.⁴⁶

Challenges and Controversies

Despite all of the recent developments and successes, some challenges remain. Some tissues exhibit reversible electroporation, leading to stunned but viable myocardium after ablation.⁴⁷ At present there is no solution to this so-called transient electrophysiological silence. Irregular geometry, complex atrial substrates, epicardial fat and fibrosis may create inhomogeneous fields.^6,8,48 No consensus currently exists on ideal pulse number, voltage or inter-pulse interval for maximising chronic lesion durability. Ultra-selective energy delivery may limit atrial wall penetration, risking non-transmural lesions in thicker regions.^49,50 With increasing field strength, the risk of non-selective tissue damage will also increase: the depth versus selectivity paradox.

Future Directions

Multicentre trials are needed to establish optimal dosing strategies and possibly the standardisation of PFA protocols. More advanced imaging techniques are needed. Possibly, MRI-based scar assessment after PFA could non-invasively track lesion maturation.^51–53 Long-term durability studies extending beyond 2–3 years are necessary to gain a better understanding of clinical endpoints. Combining electroporation with thermal ablation modalities could enhance lesion permanence.^54,55 Next-generation catheters and/or generators capable of dynamic energy modulation based on real-time feedback could possibly address field inhomogeneity.

Conclusion

PFA holds immense promise for safer, more selective myocardial ablation. While early preclinical and clinical results suggest durable lesions with favourable safety profiles, rigorous long-term studies are essential to fully understand the lesion biology and optimise procedural parameters, solidifying PFA’s role relative to traditional thermal approaches.