Does inflammation influence atrial fibrillation recurrence following catheter ablation?

Recent clinical and experimental data suggest the pivotal role of inflammation in the pathogenesis of atrial fibrillation (AF). Large epidemiological studies have linked an amplified baseline inflammatory state with the development of cardiovascular events, including future AF, 1 whereas certain inflammatory cytokines have been used to predict AF recurrence following successful electrical or chemical cardioversion. 2 , 3 The increased incidence of AF following cardiac surgery, which is known to induce a potent inflammatory response through ischaemia, cardiopulmonary bypass, and cardiotomy, has further implicated inflammation in the pathogenesis of AF. 4 In addition, patients with documented AF have demonstrated features of chronic inflammation that is proportional to the type and chronicity of AF. 5 Finally, medications with an established anti-inflammatory effect, such as statins and corticosteroids, have been successfully used for primary and secondary prevention of AF. 6 , 7 Despite occasional methodological limitations or heterogeneity between clinical and experimental studies, the association between inflammation and AF is apparent. However, the exact mechanisms by which inflammation causes the initiation or perpetuation of the arrhythmia can only be speculated. Conditions that predispose to oxidative stress, ischaemia, and ultimately tissue injury lead to the release of acute phase proteins and disarray of cellular membranes. Spatial derangement of the phospholipid bilayer under enzymatic interaction with secretory phospholipase A 2 generates lysophosphatidylcholine, which is a ligand for C-reactive protein. 8 The binding of C-reactive protein to lysophospholipids activates the complement cascade, neutrophil influx, and phagocytosis. This process may not accurately distinguish between irreversibly and reversibly (apoptotic) injured cells in the myocardium, leading to disproportionate tissue damage and fibrosis. 9 One of the dominant theories associating atrial structural remodelling with AF proposes that fibrosis in the atrial myocardium creates areas of conduction block that delay electrical impulse propagation; therefore, wavefronts may impinge on myocytes that have recovered excitability and lead to wavelet re-entry. 10 In addition, there is evidence to suggest that the abundance of lysophosphatidylcholine in ischaemic myocardium is independently arrhythmogenic, leading eventually to delayed afterdepolarizations and triggered automaticity, which might act as a driver for AF. 11 Experimental data also suggest that the inflammatory mediator arachidonic acid is responsible for tissue anisotropy and shortening of conduction velocity, which are also known to favour AF. 12 The hypothesis that inflammation is involved in the development and maintenance of AF has recently been used to predict the efficacy of certain therapeutic modalities. A recent meta-analysis of observational studies examining the association of baseline C-reactive protein levels on AF recurrence following successful electrical cardioversion has demonstrated higher C-reactive protein levels in those who failed to maintain sinus rhythm. 13 Despite the significant heterogeneity among studies, largely attributed to differences in assays used for C-reactive protein quantification, it is apparent that the inflammatory burden is a risk factor for AF maintenance. Similar associations have been demonstrated in patients with paroxysmal AF undergoing pharmacological cardioversion. 3 , 14 The advent of catheter ablation techniques for the treatment of AF has proved to be a useful modality in symptomatic AF patients refractory or intolerant to conventional pharmacological treatment. However, the long-term efficacy of catheter ablation and its impact on mortality and morbidity are still being investigated, and various factors, including differences in technique or use of anti-arrhythmic medications, may influence the variability of outcomes between studies. In line with the inflammatory hypothesis in the pathogenesis of AF, the question is inevitably raised: does inflammation influence outcomes following catheter ablation? Letsas et al.15 examine the effect of an augmented baseline inflammatory state on the success of pulmonary vein isolation. In a cohort of patients with paroxysmal and persistent AF, failure to maintain sinus rhythm was associated with components of metabolic syndrome, such as hypertension and obesity, and structural abnormalities, such as reduced ejection fraction and left atrial enlargement. Baseline white cell count and high-sensitivity C-reactive protein were also associated with AF recurrence. However, following multivariate regression analysis, only hypertension, left atrial diameter, and white blood cell count were independent predictors of recurrence. This study is suggestive of the potential effect of a proinflammatory state on the intermediate success rates of catheter ablation; nevertheless, its results need to be interpreted with caution. The retrospective nature of the study and the mixture of patients with both paroxysmal and persistent AF, who were subjected to different medical management and possibly ablation techniques, may have influenced the outcomes. It is recommended that a blanking period of 3 months post-ablation should be endorsed, as early AF recurrences are frequent but not necessarily predictive of intermediate or long-term results. 16 The elected period of 1-month post-ablation for the assessment of endpoint in this study may have led to the overestimation of AF recurrences. Despite these limitations, the authors have recognized a possible association between inflammatory burden and AF recurrence after ablation, and although not designed to provide a mechanistic link, their study further supports the inflammatory hypothesis in the pathogenesis of AF. In a previous study by Marcus et al. , 17 patients with a history of atrial flutter (AFL) or AF undergoing catheter ablation had significantly higher baseline C-reactive protein levels compared with those with paroxysmal supraventricular tachycardia (SVT). This effect was mainly attributed to those who were in flutter or AF at the time of the procedure. Interestingly, C-reactive protein levels were significantly decreased at first follow-up visit after successful ablation and found in lower concentrations in blood from the coronary sinus than from the femoral vein. These findings are suggestive that the arrhythmia precedes and gradually causes inflammation and that the production of inflammatory cytokines may be extracardiac in origin. This second hypothesis has been supported by a study in which patients with permanent AF had significantly higher interleukin-8 levels in their peripheral circulation than in the pulmonary veins. 18 However, a more recent study aiming at inflammation as a predictor of early AF recurrence following ablation demonstrated that C-reactive protein levels were significantly elevated at first follow-up visit (median 49 days) compared with baseline. 19 Moreover, patients with early recurrence were found to have increased C-reactive protein levels, following appropriate adjustments for confounders. It is worth mentioning that older patients were more likely to have a pronounced inflammatory response and that patients with AF required additional radiofrequency applications for longer periods of time and increased power, hence more tissue damage and inflammation compared with their AFL and SVT counterparts. Myocardial necrosis and systemic inflammation after catheter ablation have also been identified in another study of patients with paroxysmal AF, in which the increase in troponin T and creatine kinase was followed by interleukin-6 release and rise of C-reactive protein and circulating leukocytes. 20 The authors speculate that early AF recurrences may be related to the transient inflammatory response due to myocardial injury. In conclusion, there is increasing evidence to associate inflammation with AF. Although the cause–effect relationship is not always apparent, inflammation interferes with the structural and electrical properties of the atrial myocardium, creating a susceptible substrate for the domestication of AF. The value of studies linking inflammation with clinical endpoints following different treatment modalities for AF is not limited to the validation of such pathogenetic association. Prediction of outcomes and risk stratification according to inflammatory status, efficacy of pharmacological management, and development of novel therapies aiming at the amelioration of inflammatory response are some of the new concepts that such studies invoke.