Recurrent focal electrical activation (or ectopy) superseding sinus activation is the only mechanism proven to drive paroxysmal atrial fibrillation (AF). However, it has not been possible to show similar focal drivers during AF, owing to the limitations of mapping in persistent AF. RETRO-Mapping has been developed as a method to generate activation maps during AF to test the hypothesis that persistent AF is also maintained by focal drivers.

RETRO-Mapping is able to locate sites of focal activation that were isolated, intermittent, or recurrent during persistent AF. However, a 30-second segment of AF can have approximately 150 wavefronts in a small area of myocardium. Screening for focal activation and manually validating these prior to ablation was not feasible using current commercial systems.

RETRO-Mapping can automatically detect focal activation and a recording system that enables the intracardiac signals to be directly analysed by the RETRO-Mapping software. This will allow RETRO-Mapping to build a detailed classification of focal activation types and study the impact of ablation of these sites on the AF cycle length, to address the hypothesis that persistent AF is maintained by focal drivers.

Multiple large, prospective randomised controlled trials have shown that pulmonary vein isolation (PVI) terminates AF in 50-70% of cases. The continued presence of atrial fibrillation (AF) in those without demonstrable reconnection on a mapping catheter suggests other mechanisms at play. However, outside PV ectopy, drivers of AF initiation or maintenance remain unclear.

Detailed mapping studies have confirmed the presence of both focal activation and spatiotemporally stable planar wavefronts during AF, with limited data suggesting focal activation may drive AF. This study is based on the hypothesis that focal activation may lead to planar wavefronts at its origin, which subsequently disintegrate on exposure to refractory myocardium in different locations, and assumes that randomised studies of adjunctive ablation have shown poor results to date because excessive ablation has been performed at non-driver sites and this ablation scar is pro-arrhythmic.

RETRO-Mapping is a novel algorithmic solution to AF mapping with published validation confirming accuracy of analysis of activation wavefronts, when benchmarked against laborious manual annotation. RETRO-Mapping found that nearly 30% of mapped sites contained focal activation, and these ranged from single events to repetitive events that could either be consecutive or interspersed with other activation patterns. This study now aims to characterise multiple different activation patterns that exist within the milieu of AF, and interrogate their role in the initiation and maintenance of AF by randomising patients to adjunctive ablation of sites of focal activation, versus usual care alone (i.e., PVI).

The effect of this adjunctive ablation on AF cycle length will be the primary outcome measure, and freedom from AF will be a secondary outcome measure. AF termination is usually considered a positive endpoint for adjunctive ablation, but, as a single event, cannot help identify which part of the adjunctive ablation approach led to this useful outcome. By contrast, left atrial appendage and coronary sinus cycle length prolongation can be used as continuous measures of progress towards AF termination, and may allow determination of whether focal activation sites are drivers of persistent AF, and whether the characteristics of focal activation alter the likelihood of it being a driver.

Inclusion Criteria:

• Persistent atrial fibrillation with clinical indication for catheter ablation
• Clinically suitable candidate for catheter ablation
• Signed informed consent

Exclusion Criteria:

• Previous atrial fibrillation or other catheter ablation procedure
• Clinical contraindication to catheter ablation or general anaesthetic, including history of adverse reaction to contrast media, or presence of intracardiac thrombus, or inadequate anticoagulation in the preceding 6 weeks
• Valvular disease graded moderate or greater, or presence of a prosthetic valve
• Moderate-to-severe heart failure, defined as left ventricular ejection fraction <35% and/or New York Heart Association class III-IV
• Any form of cardiomyopathy
• Active infection or fever
• Severe cerebrovascular disease
• Active gastrointestinal bleeding
• Bleeding or clotting disorders, clinically high bleeding risk, or clinical contraindication to receiving heparin
• Baseline serum creatinine >200umol/L
• Currently receiving or at risk of requiring renal replacement therapy
• Uncontrolled diabetes (HbA1c ≥73mmol/mol or HbA1c ≤64mmol/mol and fasting blood glucose ≥9.2mmol/L)
• Malignancy necessitating therapy
• Life expectancy shorter than the duration of the trial
• Pregnancy, or childbearing potential and not using a highly effective method of contraception
• Inability to provide informed consent to participate in the trial

Participants will be blinded to their treatment group, and outcomes will be studied prospectively on both an intention-to-treat and a per-protocol basis.