Atrial fibrillation beyond the arrhythmia: hypercoagulability, adipose tissue, and fibrotic remodelling

Atrial fibrillation is the most common sustained arrhythmia, and its treatment continues to be a challenge. Its managment has recently been reviewed extensively in the 2016 ESC Guidelines on Atrial Fibrillation.1 Current concepts focus on the atrial substrate and triggers from the pulmonary veins as its primary mechanisms. Remodelling of artrial tissue appears to provide the substrate upon which the atrial arrhythmia can develop. In their review article ‘Magnetic resonance imaging of atrial fibrosis: redefining atrial fibrillation to a syndrome’,2 Pim Gal and Nassir F. Marrouche from the University of Utah School of Medicine in Salt Lake City, USA remind us that delayed enhancement-magnetic resonamce imaging (DE-MRI) has recently been introduced in the diagnosis and treatment of atrial fibrillation for the assessment of atrial fibrosis, which is considered the hallmark of the arrhythmogenic substrate in atrial fibrillation. Atrial fibrosis is an independent predictor of arrhythmia recurrences. Post-ablation DE-MRI allows for the assessment of the total scar burden, the degree of complete encirclement of pulmonary veins, and the assessment of residual fibrosis, all strong predictors of arrhythmia recurrences post-ablation. Current pathophysiological perspectives for atrial fibrillation are heavily based on the adage ‘AF begets AF’. Potentially, atrial fibrosis as such is a disease process that triggers the initiation and maintenance of atrial fibrillation While anticoagulation with vitamin K antagonists and currently mostly with novel oral anticoagulants (NOACs) prevents the most important complication of atrial fibrillation,3,4 the arrhythmia itself is managed either with drugs or with catheter ablation. Indeed, catheter ablation has become an effective treatment of paroxysmal atrial fibrillation;5 however, its use in patients with persistant atrial fibrillation is less well established. In a second clinical review entitled ‘Catheter ablation in patients with persistent atrial fibrillation’, Paulus Kirchhof and colleagues from the University of Birmingham in the UK6 remind us that approximately one-third of ablation procedures are currently performed in patients with persistent or long-standing persistent atrial fibrillation. The authors review the available information to guide catheter ablation in these more chronic forms of atrial fibrillation, and identify the following principles: first, our clinical ability to discriminate paroxysmal and persistent atrial fibrillation is limited. Thus, pulmonary vein isolation is a reasonable and effective first approach in persistent atrial fibrillation. Secondly, other ablation strategies are being developed and need to be evaluated properly in controlled, multicentre trials. Thirdly, treatment of co-morbidities promoting recurrent atrial fibrillation by lifestyle interventions and medical therapy should be a routine adjunct to catheter ablation of persistent atrial fibrillation. Finally, early rhythm control therapy has a biological rationale, and trials evaluating its value are underway. Overall, there is a clear need to generate more evidence for the best approach to ablation of persistent atrial fibrillation beyond pulmonary vein isolation in the form of adequately powered controlled multicentre trials. Atrial fibrillation is the most common arrhythmia and produces a hypercoagulable state. Stimulation of protease-activated receptors by coagulation factors in turn provokes profibrotic, prohypertrophic, and proinflammatory responses in a variety of tissues.7 In their Clinical Review entitled ‘Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation’, Ulrich Schotten and colleagues from Maastricht University in The Netherlands8 discuss the effects of thrombin on atrial fibroblasts and the hypothesis that hypercoagulability contributes to the development of a substrate for atrial fibrillation—another view on the concept that atrial fibrillation begets atrial fibrillation. Thrombin dose-dependently increased expression of (A) interleukin-6 (n = 8–13) and (B) monocyte chemotactic protein-1 (n = 8–12). Dabigatran reduced these effects. IL6, interleukin-6; MCP-1, monocyte chemoattractant protein-1. *P < 0.05 compared with control; #P < 0.05 compared with thrombin only. (from Spronk HM, De Jong AM, Verheule S, De Boer HC, Maass AH, Lau DH, Rienstra M, van Hunnik A, Kuiper M, Lumeij S, Zeemering S, Linz D, Kamphuisen PW, Ten Cate H, Crijns HJ, Van Gelder IC, van Zonneveld AJ, Schotten U. Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation. See pages 38--50.) The roles of fat tissue, obesity,10 or even lean body mass11 as a risk factor of atrial fibrillation are controversially debated. While obesity and also underweight appear to increase the risk of the arrthythmia, obesity is associated with a more favourable outcome of those treated with NOACs.12 However, accumulation of atrial adipose tissue is truly associated with atrial fibrillation. In their Basic Science article ‘Atrialfibrillationis associated with the fibrotic remodelling of adipose tissue in the subepicardium of human and sheep atria’, Peter Haemers and colleagues from the Katholieke Universiteit Leuven in Belgium examined the relationship between fatty infiltrates of the atrial myocardium and a history of atrial fibrillation.13 To that end, atrial samples of 92 patients as well as a sheep model of persistent atrial fibrillation were analysed. In sections of human right atria, subepicardial fatty infiltrations were commonly observed in the majority of patients. Fibro-fatty infiltrates were seen in two-thirds of the patients with permanent atrial fibrillation, half of those with paroxysmal atrial fibrillation, but only in one-third of controls. An inverse correlation between fibrotic remodelling and the amount of subepicardial adipose tissue suggested progressive fibrosis of fatty infiltrates in permanent atrial fibrillation. This was tested in a sheep model of atrial fibrillation where an increased accumulation of peri-atrial fat deposits was noted using cardiac MRI. Dense fibro-fatty infiltrations predominated in the left atria of sheep with atrial fibrillation. Furthermore, cellular inflammation, mainly consisting of functional cytotoxic T lymphocytes, was present near adipocytes which had undergone cell death in human atria. Thus, atrial fibrillation is associated with fibrosis of subepicardial fatty infiltrates, a process in which cytotoxic lymphocytes might be involved. Such a remodelling of the atrial subepicardium could contribute to structural remodelling leading to a substrate for atrial fibrillation. This concept is further discussed in an interesting Editorial by Johann Auer from the General Hospital Braunau in Austria.14 Atrial fibrillation is increasingly recognized as a highly heritable condition.15–17 David O. Arnar and colleagues from the Landspitali University Hospital in Reykjavik, Iceland provide additional evidence in their paper entitled ‘A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation’.18 The authors aimed to determine genetic risk factors for early-onset atrial fibrillation, i.e. diagnosed before 60 years of age, sequenced the whole genomes of 8453 Icelanders, and imputed genotypes of the 25.5 million sequence variants they discovered into 1799 Icelanders with early-onset atrial fibrillation and 337 453 controls. Each sequence variant was tested for association based on multiplicative and recessive inheritance models. They discovered a rare frameshift deletion in the myosin MYL4 gene (c.234delC) that associates with early-onset atrial fibrillation under a recessive mode of inheritance and an allelic frequency of 0.58%. They found eight homozygous carriers of the mutation, all of whom had early-onset atrial fibrillation. Six of the homozygotes were diagnosed by the age of 30 and the remaining two in their 50s. Three of the homozygotes had received pacemaker implantations due to sick sinus syndrome, three had suffered an ischaemic stroke, and one suffered sudden cardiac death. The authors conclude that through a population approach they found a loss-of-function mutation in the myosin gene MYL4 that, in the homozygous state, is completely penetrant for early-onset atrial fibrillation. This finding provides novel insight into the molecular mechanisms of the arrhythmia, a notion that is further discussed in an Editorial by Stanley Nattel from the University of Montreal in Quebec, Canada.19 The editors hope that readers of this issue of the European Heart Journal will find it of interest.