Pulmonary Vein Isolation: Cornerstone of Atrial Fibrillation Ablation and Its Evolving Challenges. A Critical Review

Authors: Eleftherios M Kallergis, Emmanuel N Simantirakis

Abstract

AF is the most common cardiac arrhythmia, affecting millions worldwide. Catheter ablation has evolved into a cornerstone treatment for AF, offering better rhythm control and symptom relief than antiarrhythmic medications in selected patients. Over the past few decades, AF ablation has evolved significantly. Initially, right atrial approaches were explored before shifting to the left atrium, with pulmonary vein isolation emerging as the principal strategy. Attempts at substrate modification, including complex fractionated atrial electrograms ablation, linear lesions and rotorbased approaches, have been explored, but yielded inconsistent results. Recent studies reaffirm pulmonary vein isolation as the cornerstone of AF ablation. This review critically evaluates the evolution of AF ablation, the scientific rationale behind different strategies, technological advancements and future directions in the field.

AF is the most common sustained arrhythmia, affecting millions worldwide, and contributing significantly to morbidity and mortality. AF increases the risk of stroke, heart failure and hospitalisation, imposing a substantial burden on healthcare systems.1,2 Traditional treatments included rate and rhythm control medications, but catheter ablation has revolutionised AF management by offering a more durable solution to rhythm control.1–5 AF ablation has its roots in surgical maze procedures developed in the 1980s by Dr James Cox. The Cox maze procedure involved creating multiple surgical incisions in the atria to disrupt abnormal conduction pathways. Although highly effective, it was invasive and limited to patients undergoing concomitant cardiac surgery.6 Since the first reports of AF ablation in the late 20th century, techniques have evolved dramatically, improving success rates and reducing complications.1,3 Catheter ablation has become an established treatment modality, particularly for symptomatic and drugrefractory AF.1,3 However, the strategy for effective ablation has evolved significantly, with initial approaches targeting the right atrium before transitioning to the left atrium and pulmonary veins (Figure 1). Despite numerous adjunctive techniques, pulmonary vein isolation (PVI) remains the most effective and widely accepted approach, with a growing body of evidence supporting its long-term efficacy (Table 1).3

Early Approaches: Right Atrial Ablation

Historically, initial ablation attempts for AF focused on the right atrium due to limited access to the left atrium and a lack of understanding of AF mechanisms.7 These procedures targeted fractionated potentials and potential triggers in the right atrium, but demonstrated poor efficacy, leading to a shift in focus to the left atrium.7

A key limitation of right atrial ablation was its failure to address the primary drivers of AF. At the time, there was limited knowledge regarding the role of pulmonary veins in triggering AF episodes.8 As a result, ablation efforts were primarily empirical, often based on targeting areas of presumed conduction abnormalities rather than precise mechanistic understanding. Several studies from the 1990s showed high recurrence rates following right atrial ablation, emphasising the need for more effective strategies.9 Furthermore, the reliance on empirical ablation led to unnecessary procedural risks, including complications from extensive lesion creation and increased procedural times, without significant clinical benefit.9

Additionally, the inability to consistently eliminate AF with right atrial ablation led to concerns regarding its long-term efficacy and the practicality of this approach. The high failure rates prompted electrophysiologists to explore alternative strategies, ultimately leading to a greater focus on the left atrium and pulmonary vein triggers.10 The shift was further supported by emerging data demonstrating that most AF triggers originate in the pulmonary veins, making right atrial approaches inherently inadequate in addressing the arrhythmogenic sources.11

The Pulmonary Vein Paradigm

Discovery of Pulmonary Vein Triggers

The breakthrough discovery that AF was frequently triggered by ectopic beats from the pulmonary veins revolutionised ablation strategies. The landmark study by Haïssaguerre et al. demonstrated that radio frequency (RF) ablation of ectopic foci in the pulmonary veins could suppress AF recurrence.11

This discovery provided a specific, mechanistically driven target for ablation rather than the more empirical approaches previously employed. The study also underscored the need for a left atrial approach to effectively treat AF, marking a departure from earlier right atrial strategies.

The Evolution of Pulmonary Vein Isolation

Following the identification of pulmonary vein (PV) triggers, the initial ablation strategy focused on focal ablation – directly targeting the ectopic sites within the PVs. While effective in some cases, focal ablation had several

• Multiple ectopic ectopic foci were often scattered within a PV or even present in multiple PVs, necessitating repeated procedures.11
• High recurrence due to electrical reconduction and incomplete ablation, arrhythmia recurrence remained a significant issue.12
• Difficult procedural mapping ectopic triggers required AF induction, which was not always reproducible, leading to procedural inefficiencies.13

Pappone et al. introduced a more comprehensive technique called circumferential PV ablation to overcome the limitations of targeting individual ectopic sites.14 Instead of ablating isolated triggers, circumferential PV ablation involved creating continuous encircling lesions around the PV ostia to achieve electrical isolation of the PVs. This approach significantly improved procedural outcomes by preventing ectopic impulses from reaching the left atrium and became the gold standard for AF ablation, offering higher success rates and more durable results.14

Mechanisms Underlying Pulmonary Vein Triggers

The ability of PVs to generate ectopic electrical activity is attributed to several unique anatomical and physiological properties. First, the PVs contain specialised myocardial tissue extending from the left atrium. These muscle fibres possess electrophysiological properties that predispose them to abnormal automaticity, triggered activity and microreentry, leading to AF initiation.15 Additionally, the PV region is rich in autonomic nerve endings, including ganglionated plexi, which can modulate electrical activity and contribute to AF susceptibility. Studies suggest that vagal stimulation can enhance PV ectopy, reinforcing the role of autonomic modulation in AF triggers.16 Moreover, PV anatomy exhibits significant interindividual variation, with differences in vein number, size and branching patterns. Some patients have common ostia (e.g. a shared left PV trunk), which may impact ablation strategies.17

Substrate Modification: Beyond Pulmonary Vein Isolation

While PVI improved outcomes in paroxysmal AF, persistent and longstanding AF presented greater challenges, prompting the exploration of additional

• Linear additional linear lesions (e.g. mitral isthmus, roofline) aimed to prevent re-entrant circuits, but had high rates of reconnection and proarrhythmia.18
• Complex fractionated atrial electrogram (CFAE) CFAEs were thought to represent sites of AF maintenance. However, trials such as STAR AF II showed no additional benefit over PVI alone.19
• Rotors and focal computational models suggested the existence of stable rotors sustaining AF, but trials such as FIRMAP AF study failed to demonstrate consistent superiority over PVI alone.20

The Return to Pulmonary Vein Isolation as the Cornerstone

Despite enthusiasm for substrate modification, accumulating evidence reaffirmed PVI as the primary target for AF ablation. Advances in technology, including contact force-sensing catheters, cryoballoon ablation and pulsed-field ablation (PFA), have improved PVI durability and safety.21

Since its introduction, PVI has been rigorously validated in numerous high-quality clinical trials and is recognised as the cornerstone of AF ablation.

The MANTRA-PAF and SARA trials were early studies comparing catheter ablation – centred on PVI – with antiarrhythmic drugs for AF.22,23 While both showed trends favouring ablation in reducing AF burden and recurrence, neither met statistical significance for their primary endpoints, leading to neutral initial interpretations. MANTRA-PAF reported 85% freedom from AF at 2 years with ablation versus 71% with antiarrhythmic drugs; SARA showed no significant difference in persistent AF at 1 year. Despite limitations, such as small sample sizes and short follow-up, these trials were pivotal in shaping the role of PVI.

Later, larger trials, such as CABANA, EARLY-AF and STOP-AF First, confirmed ablation’s superiority – especially when used earlier – highlighting the evolution of both technique and clinical

• CABANA demonstrated that catheter ablation significantly reduces AF recurrence and improves quality of life. However, high crossover rates and low event rates limit conclusions about major outcomes. In clinical practice, ablation may reduce all-cause mortality, stroke, major bleeding or cardiac arrest in eligible patients, but not in those at lower risk.5
• EAST-AFNET showed that early rhythm control, including PVI, lowers the risk of cardiovascular mortality and stroke.4
• STOP-AF First: demonstrated that first-line cryoballoon PVI is superior to antiarrhythmic drugs in maintaining sinus rhythm.24
• EARLY-AF showed that cryoablation as first-line therapy significantly reduces recurrence risk compared with antiarrhythmic drugs.25

At 1 year post-ablation, arrhythmia-free survival rates range from 50 to 75%, compared with only 10–30% with antiarrhythmic drugs.26 Moreover, early intervention with PVI significantly reduces AF recurrence and progression.26

Limitations and Ongoing Challenges of Pulmonary Vein Isolation

Despite its central role in AF ablation, PVI is not without limitations. Longterm efficacy remains a significant concern, particularly in patients with persistent or long-standing AF. Recurrence rates after a single procedure can range from 25 to 50% at 1 year, often necessitating repeat interventions to maintain sinus rhythm.26 Anatomical variability – including differences in PVs number, ostial size and branching patterns – can hinder the achievement of durable lesion sets and contribute to incomplete isolation.17 Furthermore, electrical reconnection due to lesion gaps or suboptimal energy delivery remains a leading cause of AF recurrence.12

A key point of ongoing debate is the mechanistic sufficiency of PVI in non-paroxysmal AF. While PVI effectively eliminates PV-based triggers in paroxysmal AF, persistent and long-standing AF are often maintained by a more complex and heterogeneous atrial substrate, including atrial fibrosis, non-PV ectopic foci and localised re-entrant circuits. Adjunctive strategies, such as CFAEs ablation, linear lesions and rotor ablation, were developed to address these non-PV mechanisms. However, randomised trials, such as STAR AF II and FIRMAP AF study, failed to demonstrate clear incremental benefit over PVI alone, leading to a reassessment of their clinical utility.19,20 These findings underscore the limitations of a ‘one-size-fits-all’ approach and highlight the need for more individualised ablation strategies in advanced AF.

Future Directions and Technological Advances

Emerging technologies, such as PFA, electrogram-based mapping and artificial intelligence-guided ablation, offer potential to further refine AF ablation outcomes. Additionally, patient-specific strategies incorporating genetic, electrophysiological and imaging data may enhance individualised treatment approaches.1

The introduction of PFA represents an exciting advancement. Unlike RF and cryoablation, which use thermal energy, PFA applies non-thermal electrical fields to selectively ablate myocardial tissue while preserving surrounding structures, such as the oesophagus and phrenic nerve.27

Recent studies on PFA

• ADVENT trial (2023): demonstrated that PFA is non-inferior to RF and cryoablation in achieving durable PVI, with potentially fewer complications.28
• ADVANTAGE AF trial (2025): showed that PFA maintains high procedural success rates with reduced collateral damage compared with traditional thermal ablation.29

Building on this growing body of evidence, the ADVANTAGE trial further highlights the evolving role of PFA beyond pulmonary vein targets.30 The trial demonstrated that extending PFA application to additional sites, such as the posterior wall and broader left atrial substrate, significantly enhances arrhythmia outcomes in patients with persistent AF. Importantly, PFA enables safer and more durable ablation in these extra-PV regions compared with RF, owing to its tissue selectivity and minimised risk of injury to adjacent structures. These findings suggest that PFA may redefine substrate modification strategies in a way that traditional thermal techniques cannot.

However, it is crucial to note that PFA does not replace PVI; rather, it represents a more efficient and safer modality for achieving this foundational goal. PVI remains the cornerstone of AF ablation, and PFA’s primary contribution lies in improving how this principle is executed.27

Future Directions

Beyond PVI?

Despite the reaffirmation of PVI as the foundational strategy in AF ablation, there is growing interest in exploring complementary and alternative approaches to enhance outcomes, especially in persistent AF. These

Hybrid AF combining catheter-based and surgical techniques, hybrid procedures aim to achieve more comprehensive lesion sets, particularly in challenging cases of long-standing persistent AF. Studies such as the CONVERGE trial have shown improved arrhythmia-free survival by integrating epicardial posterior wall isolation with endocardial catheter ablation.31

Autonomic ablation of ganglionated plexi has shown promise in modifying the autonomic triggers of AF. Although clinical outcomes remain mixed, ongoing trials are refining patient selection and procedural endpoints to enhance efficacy.32

Artificial intelligence (AI)-guided and personalised ablation AI is increasingly leveraged to guide real-time decision-making during ablation. AI-enhanced electroanatomical mapping platforms now enable the identification of patient-specific arrhythmogenic substrates by analysing electrogram complexity, low-voltage areas and fibrosis distribution. For example, early trials using AI-assisted mapping systems, such as the TAILORED-AF study, demonstrated improved procedural efficiency and tailored lesion delivery.33 Moreover, the integration of advanced imaging modalities (e.g. late gadolinium-enhanced MRI) and genetic profiling is paving the way for precision ablation, where lesion sets are customised to each patient’s unique atrial remodelling and fibrotic burden.

Genetic and molecular emerging research has identified specific genetic polymorphisms and molecular markers associated with AF susceptibility and recurrence risk. Ongoing work in translational genomics suggests that targeted therapies – ranging from pharmacogenomics to substrate-targeted ablation – may soon become feasible for select patient populations.34

The Future of Substrate Modification

While PFA is already reshaping the landscape of PVI by offering faster procedures with a superior safety profile, its full transformative potential lies in substrate modification strategies for persistent AF. Beyond the pulmonary veins, PFA has demonstrated efficacy in targeting non-PV lesion sets, including posterior wall isolation, fibrosis-guided ablation and even autonomic modulation through ganglionated plexi ablation.35,36 Preclinical models and early-phase human studies have shown that PFA delivers lesions with consistent depth control, electrical homogeneity and reduced collateral injury – capabilities that make it ideally suited for anatomically complex or delicate regions.

The ADVANTAGE trial and other ongoing investigations underscore that PFA’s tissue selectivity and rapid energy delivery may allow for a more individualised and safer approach to substrate modification – achievements that RF and cryoablation have struggled to accomplish reliably.37 As these techniques are refined, PFA could become central to a precision-guided, multitarget ablation strategy tailored to the unique substrate characteristics of each AF patient.

In addition, recent studies have provided valuable insights into evolving ablation strategies for AF, particularly in persistent and long-standing cases. Wollner et al. conducted a decade-long follow-up study assessing the outcomes of combining PVI with CFAEs ablation in patients with persistent AF.38 Their findings revealed modest long-term success rates, with only 24.7% of patients remaining arrhythmia-free after a single procedure, and 45.2% following multiple interventions. Furthermore, the study highlighted a significant incidence of atrial flutter post-ablation, raising concerns about potential proarrhythmic effects associated with extensive substrate modification.

In contrast, Pranata et al. performed a meta-analysis comparing very high-power short-duration ablation with conventional techniques for PVI.39 This approach demonstrated comparable or improved efficacy, significantly reduced procedure times and maintained a similar safety profile, suggesting very high-power short-duration as a promising alternative for enhancing the efficiency and consistency of PVI procedures. Collectively, these studies underscore the importance of refining ablation techniques, balancing procedural complexity with long-term outcomes, and tailoring strategies to AF type and patient characteristics.

Conclusion

The journey of AF ablation has come full circle, from right atrial approaches to left atrial PVI, exploring substrate modification, and ultimately reaffirming PVI as the cornerstone. Despite decades of research and evolving technology, PVI is strongly supported by clinical evidence as the cornerstone of catheter ablation for AF, particularly paroxysmal AF. Whether performed with RF, cryoablation or PFA, the goal remains complete electrical isolation of the PVs. Ongoing innovations in substrate modification and the use of novel energy sources, such as PFA, may significantly reshape the landscape of AF treatment, particularly for persistent and long-standing forms of the disease.

PVI remains a foundational approach in AF ablation, with ongoing innovations reinforcing its role in current and future practice. Until an entirely new mechanism ofAF pathophysiology is uncovered, PVI remains a cornerstone of therapy, with enduring relevance. Nearly three decades after its discovery, it has stood the test of time, proving to be enduring and foundational. Ongoing research and technological advancements will continue to shape the future of AF ablation.