Inflammation and atrial fibrillation: cause or para-phenomenon?

Atrial fibrillation (AF) is the commonest cardiac arrhythmia clinicians encounter in their daily clinical practice. Atrial fibrillation affects 1–1.5% of the population in the developed world. 1 The prevalence and incidence of AF increase sharply with advancing age. The overall prevalence of AF was 5.5%, rising from 0.7% in the age group 55–59 years to 17.8% in those aged 85 years and above. 2 Treatment of AF represents a significant healthcare burden especially when treating the in-patient. From the 2001 federally funded database in the USA, 3 the total annual costs for treatment of AF were estimated at $6.65 billion, including $2.93 billion (44%) for hospitalizations with a principal discharge diagnosis of AF, $1.95 billion (29%) for the incremental inpatient cost of AF as a co-morbid diagnosis, $1.53 billion (23%) for outpatient treatment of AF, and $235 million (4%) for prescription drugs. In all regressions, AF was a significant contributor to hospital cost. In France, patients with persistent/permanent AF had significantly higher hospitalization rates and costs than patients with paroxysmal AF (€3579 vs. €2586) with the cost of hospital care accounted for roughly half of total costs. 4 The mechanism of AF is still debatable. Several mechanisms have been proposed. Traditional mechanism theory suggested that AF is maintained by multiple migrating wavelets of re-entrant atrial activation. The wavelet collisions cause chaotic re-excitation and ‘multiple propagating wavelets’. 5 Recently, it has been shown that AF could be caused by a rapidly firing focal source (usually in the superior pulmonary veins but can be in other pulmonary veins, inferior vena cava, or right atrium) that has the ‘highest dominant frequency’ and drives the AF wave front which can be eliminated by focal ablation. 6 Moreover, atrial interstitial fibrosis has also been shown to increase AF vulnerability by creating a substrate for intra-atrial re-entry circuit (intracellular scar) that promotes AF. 7 Recently, many studies have also indicated that inflammation might play a significant role in the generation, maintenance, and perpetuation of AF. The association between AF and inflammation can be extracted from the observation that AF is frequently associated with inflammatory conditions of the heart, such as myocarditis, pericarditis, and following coronary artery bypass surgery, a state of intense inflammatory process. 8 , 9 This is further evidenced by the increase in C-reactive protein and IL-6 in both paroxysmal and persistent AF and marked inflammatory infiltrates, myocyte necrosis, and fibrosis found in atrial biopsies of patients with lone AF. 10–12 C-reactive protein was two-fold higher in AF patients when compared with a control group with no history of atrial arrhythmia. Higher C-reactive protein levels were also observed in patients with persistent compared with paroxysmal AF; longer duration of AF and larger left atrial dimensions; suggesting that elevated C-reactive protein may be related to the ‘burden’ or type of AF and structural remodelling. 11 , 13 Nevertheless, it is unclear whether inflammation is a cause or merely a consequence of AF. As significantly higher C-reactive protein levels were seen in the persistent compared with paroxysmal AF subgroups, it is possible that inflammation may play a role in promoting maintenance rather than initiation of AF via atrial structural remodelling. On the other hand, as abnormal atrial histology and occult myocarditis were consistently found in patients with lone AF, compared with normal histology controls, it is also possible that inflammation acts as an initiator rather than as a consequence of AF. 12 Although C-reactive protein is synthesized primarily by the liver in response to IL-6 and IL-1, which have both pro-inflammatory and cyto-protective effects and in themselves produced by T-cells, macrophages, and endothelial cells, 14 the association between IL-6 and AF is less consistent compared with C-reactive protein. 8 The roles of many other inflammatory markers such as TNF-α, fibrinogen, white cell count, P-selectin, thrombin–antithrombin complex in AF are less well studied. In the current issue of Europace, Henningsen et al.15 demonstrated that patients with permanent AF have significantly elevated levels of YKL-40 biomarker than those with persistent AF which in turn higher than that from healthy subjects. YKL-40, however, was not a significant predictor of successful cardioversion to sinus rhythm and its plasma level did not fall after restoration of sinus rhythm. YKL-40 is a new biomarker of inflammation produced by inflammatory cells such as macrophages and neutrophils, but is different and independent of C-reactive protein. Elevated plasma YKL-40 levels are seen in patients with inflammatory diseases such as rheumatoid arthritis, cancer, asthma, and chronic obstructive lung disease, inflammatory bowel disease, liver fibrosis, diabetes and in patients with ST-elevation myocardial infarction, and stable chronic coronary artery disease. Although the study demonstrated that YKL-40 may be a marker of AF burden, it failed to show any superiority over C-reactive protein or IL-6 as a biomarker for the study of inflammation in AF. Indeed, the authors explained that as the plasma level of YKL-40 correlated to the levels of IL-6, it is possible that YKL-40 is linked to IL-6 in the inflammatory cascade, thereby a surrogate marker of IL-6, rather than an independent marker of inflammation. With that, it is hard to see what advantages YKL-40 have over the wide-array of inflammatory biomarkers that are currently available as aforementioned. Furthermore, the authors did not perform a multivariate comparison between YKL-40 and other biomarker including C-reactive protein and IL-6 especially the authors had previously shown that IL-6 before cardioversion was an independent predictor of recurrent AF after cardioversion from the same cohort of patients. Thus, it remains to be seen whether YKL-40 is an independent risk predictor of AF burden or has any incremental predictive value over that of C-reactive protein and IL-6. This represents a missed opportunity. Furthermore, in this study, when compared with persistent AF patients, those with permanent AF had worse left ventricular dysfunction, a process that may be associated with heightened inflammatory process. Although this did not reach statistical significance, it could have influenced the outcome of the study. Moreover, the authors did not adjust their analysis for any confounding factors. Patients with persistent AF who had successful DC cardioversion and remained in sinus rhythm 1 month later had higher proportion of subjects being on statins, a well-recognized anti-inflammatory agent, than persistent AF patients with failed DC cardioversion. However, the beneficial anti-inflammatory effects of statins in this group could be confounded by a larger proportion of their patients with previous myocardial infarction, hypertension, and ischaemic heart disease, conditions that are associated with inflammatory process. Thus, it remains to be seen whether YKL-40 is an independent biomarker playing an active player in the inflammatory processes that lead to AF or simply a para-phenomenon of the inflammation itself. In summary, there appear to be consistent links between inflammatory markers and AF. Although it is possible to modulate inflammatory marker level such as C-reactive protein with pharmacological interventions including statins, anti-inflammatory agents, aspirin, and antioxidants, it is unclear at present whether reductions in inflammatory marker levels, be it C-reactive protein, IL-6, YKL-40, or others, would have a beneficial effect on the clinical incidence or persistence of AF. It is conceivable that the prevention of AF or thromboembolism in patients with elevated inflammatory markers might be improved by the use of anti-inflammatory agents but further data from prospective and interventional studies would be needed to see whether these links are merely associations or causal in the complex pathophysiology of AF.