title: The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis.
abstract: Atrial fibrillation (AF) is an extremely common clinical problem associated with increased morbidity and mortality. Current antiarrhythmic options include pharmacological, ablation, and surgical therapies, and have significantly improved clinical outcomes. However, their efficacy remains suboptimal, and their use is limited by a variety of potentially serious adverse effects. There is a clear need for improved therapeutic options. Several decades of research have substantially expanded our understanding of the basic mechanisms of AF. Ectopic firing and re-entrant activity have been identified as the predominant mechanisms for arrhythmia initiation and maintenance. However, it has become clear that the clinical factors predisposing to AF and the cellular and molecular mechanisms involved are extremely complex. Moreover, all AF-promoting and maintaining mechanisms are dynamically regulated and subject to remodelling caused by both AF and cardiovascular disease. Accordingly, the initial presentation and clinical progression of AF patients are enormously heterogeneous. An understanding of arrhythmia mechanisms is widely assumed to be the basis of therapeutic innovation, but while this assumption seems self-evident, we are not aware of any papers that have critically examined the practical contributions of basic research into AF mechanisms to arrhythmia management. Here, we review recent insights into the basic mechanisms of AF, critically analyse the role of basic research insights in the development of presently used anti-AF therapeutic options and assess the potential value of contemporary experimental discoveries for future therapeutic innovation. Finally, we highlight some of the important challenges to the translation of basic science findings to clinical application.
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, The Netherlands.
authors.forename: Jordi
authors.initials: J
authors.lastname: Heijman
authors.affiliation: Department of Medicine, Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Canada H1T 1C8 Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Algalarrondo
authors.affiliation: Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Hufelandstr. 55, D-45122 Essen, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.affiliation: Department of Medicine, Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Canada H1T 1C8 Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Melka
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX, USA Pediatrics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.affiliation: Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Hufelandstr. 55, D-45122 Essen, Germany dobromir.dobrev@uk-essen.de stanley.nattel@icm-mhi.org.
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.affiliation: Department of Medicine, Montreal Heart Institute and Université de Montréal, 5000 Belanger St. E., Montreal, Canada H1T 1C8 Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Hufelandstr. 55, D-45122 Essen, Germany dobromir.dobrev@uk-essen.de stanley.nattel@icm-mhi.org.
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D018450:Disease Progression; D004594:Electrophysiology / Q000379:methods; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D012106:Research
chemical_list: D000889:Anti-Arrhythmia Agents
keywords: Ablation; Antiarrhythmic drugs; Atrial fibrillation; Cellular electrophysiology; Ectopic activity; Imaging; Re-entry