Structuring (right) atrial fibrillation: location matters

This editorial refers to ‘Differences in the structural characteristics and distribution of epicardial adipose tissue between left and right atrial fibrillation’ by H. Hasebe et al., 20(3);435–442. Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. It is a frequent cause of thromboembolic events/stroke and, due to activation of AF-dependent atrial remodelling, facilitates disease progression and recurrence. The prevalence of AF increases with age. Besides, various clinical conditions are associated with an increased incidence of AF, among them hypertension, diabetes, hyperthyroidism, heart failure, valvular disease or replacement, and obesity.1 Re-entry of excitation wavefronts and focal activity (triggered or enhanced automaticity) are considered the main mechanisms of AF. There is considerable regional variation in the atrial action potential morphology. Haissaguerre et al.2 in their pioneering work demonstrated rapid activity with a very short cycle length in the pulmonary vein (PV) area, which represents, therefore, a frequent target in AF ablation therapy. In addition, the left atrial appendage (LAA) is another relevant source of ectopy. In a recent paper, Hasebe et al.3 reported on patients with right atrial fibrillation (RAF) characterized by right atrial (RA) ectopic initiation and right-to-left dominant frequency (DF) gradients. As, in contrast, a LA-to-RA DF gradient prevails in most cases of paroxysmal AF,1 this observation per se is a very interesting finding and might well represent a phenomenon underestimated in current ablation therapy. Hasebe et al.4 provide a structural characterization of RA and right atrial appendage (RAA) and give volume and distribution measures of epicardial adipose tissue (EAT) in RAF patients. The comparison of these structural and EAT data to those derived from ‘typical’ AF patients (ectopic initiation in the PV area and LA-to-RA DF) revealed very interesting findings. Whereas the direct relationship between left atrial diameter (LAD) and electromechanical remodelling has been well established previously5 and could be also confirmed here for LAF patients, the RAA volume index was significantly higher in the RAF group.4 Accordingly, the LAA/RAA volume ratio appears to be much lower in RAF patients when compared to LAF, thus providing a potentially useful diagnostic marker that could help to identify AF patients who were likely non-responders to pulmonary vein isolation (PVI). The EAT volume has been shown previously to be highly associated with paroxysmal and persistent AF and this is fully independent of ‘classical’ risk factors as for instance LAD.5 The distribution of EAT around the LA is uneven with most EAT located within superior vena cava, right pulmonary artery, right-sided roof of the LA, aortic root, pulmonary trunk, LAA, and between the left inferior PV and left atrioventricular groove.6 EAT locations were associated with high-DF sites, providing a reasonable mechanism for EAT contribution to AF maintenance. Recent data suggest that the contribution of EAT to AF substrate may differ between LA and RA.7 In this regard, the current study of Hasebe et al.4 considerably adds to our understanding of AF mechanisms by demonstrating that EAT volumes surrounding RA and LA were significantly smaller in the RAF group than in the LAF group. The data further support the view that RAF is distinguished from the more common LAF type, probably due to rather substantial differences in their (genetic) background. The contribution of genetic factors has not been studied in this report; however, the relative early onset of RAF when compared to typical LAF observed by Hasebe et al.4 make this a promising route forward. It has been previously shown that the RA responds more strongly to proarrhythmic stimuli such as adenosine triphosphate,8 a phenomenon that mechanistically could be very recently attributed to higher RA expression levels of adenosin A1 receptors (A1R) and G protein-coupled inwardly rectifying potassium channels (GIRK4).9 Further support for a genetic background of RAF comes from the finding that genetic variants of PITX2, a transcription factor involved in determination of ‘leftness’, are indeed non-responders to PVI.10 That RA and LA produce quantitatively or qualitatively divergent responses to AF or AF-related stimuli is not a too rare observation. However, if and to what extent the AF-dependent remodelling processes, in particular the structural remodelling that is so typically characterized by fibrosis and fatty infiltration, are different between patients with RAF and those with LAF has not been studied, yet, but remains an interesting open question. Likewise, whether or not the smaller LADs observed in RAF patients by Hasebe et al.4 are of any clinical relevance and may serve as useful indicators, e.g. AF progression or a favourable prognosis with respect to cardiac function or mortality in RAF patients, requires further investigation. In this way, the study of Hasebe and colleagues certainly opens a door and provides motivation for further studies on this topic.