Discussion
The major findings of this study are that low dose colchicine was associated with a significant reduction in AF recurrence after AF ablation. There was a 22% reduction in AF recurrence in the entire cohort and a 29% reduction in the PSM subgroup. Our results suggest that low dose colchicine may be useful to reduce long-term AF recurrence after AF ablation.
Catheter ablation has been validated as the most effective therapy for atrial fibrillation. The 12-month and 62-month success rate for pulmonary vein isolation for paroxysmal AF has been demonstrated to be as high as 78% and 59%, respectively 5. Adjunctive approaches to achieve more durable AF ablation efficacy continue to be explored. Deftereos et al reported that 0.5mg colchicine twice daily for 3 months was associated with a significant reduction in AF recurrence at 12 months after de novo ablation in paroxysmal AF patients (31.1% vs. 49.5%).9 However, there were frequent reported side effects with a treatment discontinuation rate of 10.8%. Agarwal et al reported that 0.6mg colchicine twice daily was associated with reduction of AF recurrence at 12 months19. In the Post Ablation Pericarditis Reduction Study (PAPERS ) trial 20, patients were randomized on the day of the procedure to receive 0.6 mg of colchicine twice daily for 7 days. Significant side effects were reported in the treatment group (47%) with no difference in pericarditis rates. All of these studies used higher doses of colchicine than we employed in the present study. To our knowledge, our study is the first to report the effect of short term (1 month), low dose (0.6 mg daily) colchicine use on long-term AF recurrence after AF ablation. We hypothesize that the efficacy of the low dose, short-term colchicine regimen that we used is attributable to less treatment discontinuation, although this could not be tested due to inconsistent reporting in the medical record. Short term colchicine administration may improve compliance without compromising efficacy, as AF incidence was reduced to a similar extent after cardiac surgery with 1 month and 3 month treatment durations.22 It is notable that colchicine was associated with a long-term reduction in AF recurrence despite a higher incidence of persistent AF and more extensive substrate ablation in the colchicine group, which would be expected to increase AF recurrence.
Colchicine has historically been used to treat gout and other inflammatory conditions including pericarditis 1. Colchicine inhibits the assembly and activation of the NLRP3 inflammasome as well as the release of neutrophil enzymes that activate inflammatory interleukins 1ß and 18 5, 18. The NLRP3 inflammasome has cardiac specific effects, and plays a role in the secretion of cytokines while also promoting ectopic firing and adverse atrial remodeling 5. In the immediate-term, reducing neutrophil activation by microtubule inhibition may attenuate inflammatory responses that could precipitate arrhythmogenesis5. The NLRP3 inflammasome has been found to promote upregulation of RYR2 receptors and subsequent Ca2+ release from the sarcoplasmic reticulum21, which promotes ectopic firing through delayed afterdepolarizations. Additionally, through Caspase1-mediated pyroptosis, an inflammatory cascade ultimately leads to recruitment of inflammatory mediators that promote formation of fibrosis and the atrial substrate that ultimately facilitates AF5. Furthermore, colchicine reduces serum inflammatory biomarkers after ablation, including C-reactive protein (CRP) and interleukin-6 (IL-6)9, 10.
It is unclear how short-term colchicine use prevents long-term AF recurrence. Colchicine reduces early AF recurrence and pericarditis, which could decrease the risk of long-term AF recurrence.13 However, amiodarone reduced early, but not long-term AF recurrence.23 Colchicine has been associated with reduced myocardial fibrosis in animal studies, which could influence long-term AF recurrence.24