Leducq-funded programme: immune targets for the treatment of atrial fibrillation

Atrial fibrillation (AF) is one of the most important healthcare challenges worldwide.1 As the most common sustained arrhythmia, millions of people are already affected today and even more will be affected in the next decades since the incidence and prevalence of its main risk factors (e.g. age, hypertension, diabetes, obesity, or heart failure) are rising.1,2 Morbidity and mortality among patients with AF are high, especially due to its association with stroke, dementia, or heart failure, demonstrating the clinical need for optimal therapy.1 However, current treatment options are insufficient in many patients since their efficacy is limited and relevant side effects are common, e.g. bleeding complications or proarrhythmia when taking oral anticoagulants or antiarrhythmic drugs, respectively.1 A potential explanation is the lack of causal therapies specifically targeting underlying pathophysiological mechanisms for AF. Thus, a better understanding of specific AF mechanisms may allow for tailored therapeutic concepts. Macrophages are key components of the innate immune system defending the organism against pathogens, but a growing body of evidence also suggests a variety of ‘non-canonical’ functions for tissue-resident macrophages, e.g. regulating organ development or maintaining tissue homeostasis.3 In the heart, macrophages are the most abundant leucocytes involved in multiple physiological and pathophysiological mechanisms, including electrical conduction and arrhythmogenesis.3–8 The first hints that macrophages may be electrically active cells were published in the 1970s.9,10 Gallin and colleagues demonstrated that cultured macrophages from various species can hyperpolarize10 and that membrane potential changes are linked to macrophage activation/chemotaxis.9 Forty years later, it has been shown that cardiac resident macrophages are essential regulators of the physiological electrical conduction in the AV node.6 By functional coupling to cardiomyocytes via connexin-43, these macrophages modulate the electrical properties of AV nodal cardiomyocytes (e.g. elevating the resting membrane potential, shortening of the action potential duration) and thereby allow the normal AV conduction.6 This publication was a starting point of an ongoing wave of studies demonstrating important roles of macrophages in cardiac electrophysiology and arrhythmogenesis. Some of these landmark findings within the emerging new field of ‘electroimmunology’ were, e.g.: cardiac resident macrophages facilitate normal electrical conduction and prevent sudden cardiac death during heart stress by regulation of connexin-43 phosphorylation and translocation in cardiomyocytes,8 cardiac macrophages protect against ventricular tachycardia and fibrillation after myocardial infarction by maintaining mitochondrial integrity and function in cardiomyocytes,5 macrophages recruited to the heart after myocardial infarction cause action potential prolongation and heterogeneity in coupled cardiomyocytes, thereby facilitating ventricular arrhythmias.4 Recently, resident macrophages have also been shown as regulators in AF.7 In a novel mouse model, combining several AF risk factors (hypertension, obesity, mitral valve regurgitation, HOMER model), a strong AF phenotype (AF inducibility ↑, AF burden ↑), and a significant structural remodelling (LA enlargement, atrial fibrosis) was observed accompanied by an enhanced recruitment of bone-marrow-derived macrophages.7 The proarrhythmic effects of macrophages were mediated by SPP1 that acts as a pleiotropic amplifier for atrial inflammation and fibrosis resulting in a proarrhythmic atrial substrate.7 Interestingly, a similar pattern of SPP1+ macrophage expansion was observed in atria of patients with AF,7 suggesting that targeting inflammatory macrophages and/or SPP1 could be a novel therapeutic approach in AF. To allow the further investigation and development of novel macrophage-related therapies for AF, the Leducq Foundation funded the transatlantic network of excellence ‘Immune targets for the treatment of atrial fibrillation’. Members of the interdisciplinary team are Florent Ginhoux (Gustave Roussy, INSERM, Villejuif, France), Ulrich Schotten (Maastricht University, The Netherlands), Sebastian Clauss (Ludwig-Maximilians University Munich, Germany), Kamila Naxerova (Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA), Patrick T. Ellinor (Broad Institute of MIT and Harvard, Boston, MA, USA), Matthias Nahrendorf (Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; American Co-ordinator), and Stefan Kääb (Ludwig-Maximilians University Munich, Germany; European Co-ordinator). The motivation was to bring together world-leading experts in the traditionally separated fields of cardiac electrophysiology and macrophage biology and to establish a collaborative network with the following aims: (i) to discover immune pathways contributing to AF using transcriptomics of human atria, (ii) to test druggable AF immune pathways in preclinical systems, and (iii) to train scientists with expertise in electrophysiology and immunology (Figure 1). Aims and working plan of the network of excellence ‘Immune targets for the treatment of atrial fibrillation' The network established a distinct translational pipeline including the investigation of human tissues to identify macrophage-related pathways in AF and AF-related risk factors, the thorough characterization of mouse models to understand underlying mechanisms and to identify therapeutic targets as well as the development of innovative pig models resembling the human AF phenotypes to validate novel immune-related treatment options and by implementing large animal models to close the translational gap between basic research and clinical application. Since the emerging field of electroimmunology needs researchers with interdisciplinary expertise in both cardiac electrophysiology and immunology, a comprehensive training programme will be established as a further goal of the network (Figure 1). M.N. has received funds or material research support from Alnylam, Biotronik, CSL Behring, GlycoMimetics, GSK, Medtronic, Novartis, and Pfizer, as well as consulting fees from Biogen, Gimv, IFM Therapeutics, Molecular Imaging, Sigilon, Verseau Therapeutics, and Bitterroot. He is an inventor on U.S. Provisional Patent application nos. 63/501,286 and 63/525,135 regarding the role of and modulating stromal and immune cells in atrial disease. The research described in this article is made possible by a Leducq Foundation International Network of Excellence awarded to all members of the ‘Immune targets for the treatment of atrial fibrillation’ consortium.