Localising re‐entry in atrial fibrillation: Anatomical clues to the substrate of rotors

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans. Although AF prevalence is lower in Asian populations (~1%) than in Caucasians, the absolute numbers of patients in Asia suggest that the overall disease burden attributable to AF may eclipse that found in Western countries [1]. To combat this surging regional AF epidemic, new strategies resting on a more detailed understanding of the AF pathophysiology will be needed. A fundamental challenge in the field is that arrhythmia dynamics during AF remain unclear, despite over a century of research [2]. AF has been hypothesised to involve a combination of local drivers, including re-entrant circuits known as rotors and focal sources, or due to multiple simultaneous re-entrant wavelets, with a related postulated role for endo-epicardial wavefront dissociation [3]. It is clear that AF arises in the context of electrophysiological and structural remodelling occurring in the context of clinical risk factors including aging, heart failure, valvular heart disease, sinus node disease, hypertension, obesity and obstructive sleep apnoea. These factors are known to modulate local conduction velocity, refractoriness and heterogeneity to create the critical substrate for AF arrhythmogenesis. Recently, increasing attention has been paid to the role of detailed muscular architecture of the atrium in providing the substrate for AF re-entrant circuits. The complex interlacing myoarchitecture of the atrium, whose detailed structure was first outlined by Papez [4], may provide a functional substrate for AF, even in the absence of disease. Specific attention has been focused on the histoanatomy of the pulmonary vein (PV)–posterior left atrium (LA) junction. Klos et al. identified source–sink mismatch at the PV–LA junction as a possible mechanism for wavebreak at the onset of AF in the sheep heart [5]. Simulation studies have further delineated the 3-dimensional nature of myofiber orientation as a critical player. In humans, the PV–LA junction and posterior LA have similarly been determined as locations for conduction delay and block, providing an intrinsic histologically pre-determined substrate for re-entry [6]. It is in this context, that the recent study of Matsuyama et al. sheds further light on the relationships between histoanatomy and atrial arrhythmogenesis [7]. This investigation used high-density optical mapping to study atrial flutter/atrial fibrillation in isolated rat hearts [7]. Atrial arrhythmia was induced in 15 of 19 hearts tested by programmed stimulation from the right atrium [7]. Atrial arrhythmia in this model was predominantly initiated by a common re-entrant mechanism, with conduction slowing and block at the left atrial roof, with rapid antegrade conduction along the coronary sinus, providing the basis for a re-entry on the posterior wall of the LA. For the first time, these findings were correlated with the intrinsic histology of the regions [7]. Myocyte density was reduced and fibrosis increased on the roof and posterior LA compared to the CS [7]. Myocytes in the LA roof had a broader distribution of cut lengths than in the CS, with more lateralised expression on Cx 43, providing a mechanism for this slower activation propagation [7]. The data together provide crucial new information that links the basic histologic anatomy of with conduction abnormalities and arrhythmogenesis, even in the absence of conventional clinical disease markers. In interpretation of these data, some potential limitations must also be kept in mind. Firstly, the data were obtained in the rat atria, a model whose small size means that AFL/AF dynamics tends to be more organised and regular compared to larger animals and humans. The authors acknowledge this point by naming the induced arrhythmias in the model as AFL/AF. Second, the experiments were performed in excised hearts, thereby lacking autonomic regulation which may play an important role in arrhythmia modulation. Thirdly, mapping was limited to the epicardial surface, and therefore 3-dimensional characterisation of the arrhythmia circuit could not be performed. The arrhythmia duration was not stated in the manuscript, but typically in small animals with normal underlying substrate would be expected to be of short duration. The results nevertheless have significant implications for clinical AF mapping in humans. By demonstration that the locations of atrial re-entry relate to intrinsic myoarchitecture, it would suggest that the locations of driving rotors in human AF are unlikely to be randomly or functionally distributed, but may be preferentially located within specific regions of the atria. Knowing in advance the likely anatomic locations for re-entry would assist current efforts to map rotors in humans [8]-[10]. The study of Matsuyama et al. provides a strong foundation for future human investigations. Dr Anand Ganesan is supported by an Australian Early Career Health Practitioner Fellowship from the National Health and Medical Research Council of Australia. Dr. Sanders is supported by the National Heart Foundation of Australia and New Zealand and a Practitioner Fellowship from the National Health and Medical Research Council of Australia. Dr. Sanders reports having served on the advisory board of Biosense-Webster, Medtronic, St. Jude Medical, Sanofi-Aventis and Merck, Sharpe and Dohme. Dr. Sanders reports having received lecture and/or consulting fees from Biosense-Webster, Medtronic, St. Jude Medical, Boston Scientific, Merck, Sharpe and Dohme, Biotronik and Sanofi-Aventis. Dr. Sanders reports having received research funding from Medtronic, St. Jude Medical, Boston Scientific, Biotronik and Sorin.