Atrial fibrillation (AF) is the most common arrhythmia and is associated with a high risk of stroke and an increased risk of death (1). Although an association between AF and inflammation is now well established, the cause-and-effect relationship remains incompletely understood ((2),3). Previous studies have demonstrated that increased inflammation may precede AF ((4),5), supported by evidence that genetic variants related to inflammatory processes may be more prevalent in AF patients ((6),7). Conversely, we and others have shown that AF itself may contribute to an inflammatory state ((8),(9),(10),11).

AF likely represents a final common pathway stemming from multiple subtypes. Identifying AF patients with an inflammation-based subtype is important in selecting candidates for anti-inflammatory therapies. In some cases, inflammation-based subtypes already are apparent. For example, building on the sterile pericarditis canine model (12) and observational cardiac surgery studies (13), trials aimed at decreasing inflammation after cardiac surgery with either steroids (14) or colchicine (15) have shown reductions in post-operative AF.

Left atrial catheter ablation to electronically isolate the pulmonary veins now is commonplace for treatment of symptomatic AF (16). Despite ongoing improvements in the procedure, early recurrence after AF ablation (ERAF) often occurs (17). The cause of ERAF remains unknown, but may involve an inflammatory response to thermal injury, pericarditis, or both (18). Because ERAF likely portends a higher risk of late recurrence, it is of particular interest ((19),20). Three days of corticosteroid administration after AF ablation reduced immediate recurrence of AF (≤3 days after the procedure) and longer-term AF recurrence (21). However, potentially because of the short course of drug administration, a reduction in AF recurrence between 4 and 30 days was not observed. A longer course of steroids may not be prudent given the risk of adverse effects. We previously showed that the inflammation resulting from AF ablation may persist for more than 1 month (22), suggesting that a longer course of an anti-inflammatory agent may be necessary to combat ERAF.

In this issue of the Journal, Deftereos et al. (23) report their findings after randomizing 170 paroxysmal AF patients undergoing pulmonary vein isolation with radiofrequency catheter ablation to 0.5 mg of twice daily colchicine versus placebo. After 3 months of treatment, ERAF was observed in a statistically significantly smaller 16% of those receiving colchicine versus 34% of those receiving placebo.

The study has several strengths. As a blinded and randomized study, the study addressed both known and unknown confounders in an optimal fashion. All patients had paroxysmal AF and all underwent a similar procedure. Vaughn-Williams class I and III antiarrhythmic drugs were not allowed. The colchicine group exhibited significantly lower levels of both C-reactive protein and interleukin 6 by day 4. After adding these markers into a multivariate model, the hazard ratio for colchicine as a predictor of recurrent AF was substantially attenuated. Statistically, this suggests that the effect of colchicine on ERAF was at least in part explained by decreased inflammation. This study likely provides the strongest evidence to date that inflammation is causal in ERAF after ablation.

There are several details worth considering before extending the regular use of post-ablation colchicine to clinical practice. First, the best dose and duration of colchicine remain unknown. Because the primary rationale for the procedure remains quality-of-life improvement, we should avoid replacing one problem (AF) with another (such as gastrointestinal upset, observed in more of those receiving colchicine). Although no serious adverse events were attributed to colchicine, monitoring for both liver toxicity and myelotoxicity occurred. One case of transaminase elevation requiring cessation of colchicine was required. The duration of drug administration was based on our previous findings regarding post-ablation C-reactive protein elevation, measured a median of 49 days after the procedure (interquartile range: 37 to 93 days) (22). It seems that the trial investigators based the 3-month duration of treatment on the 75th percentile of that range. It is possible that a shorter duration would suffice. Discontinuing colchicine for intolerance or adverse reaction before 1 month of therapy was rare, suggesting that 1 month may be a reasonable duration to maximize tolerance.

The as yet unanswered question is whether reduction in ERAF will translate into long-term success. It is likely that ERAF represents 2 different groups: those in whom the procedure simply failed versus those with inflammation-induced AF who are destined for success. If these processes are entirely separate, prevention of ERAF may have no bearing on late recurrence. However, it remains possible that ERAF contributes to adverse remodeling, promoting AF in the long term. A trial with longer follow-up is necessary to determine if such inflammation-related remodeling is important.

In conclusion, the authors provide a valuable contribution to the literature regarding post-ablation AF and perhaps AF in general. The study provides strong evidence that inflammation is sufficient to induce ERAF after pulmonary vein isolation using radiofrequency catheter ablation and that administration of colchicine may provide a safe and effective strategy to reduce ERAF. Future studies will be important to determine the optimal dose and duration of colchicine as well as to determine if these early effects lead to lasting success.

⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.