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Important components of AF management include control of cardiac rhythm, rate, and thromboembolic risk. In this narrative review article, we focus on rhythm-control therapy. The available therapies for cardiac rhythm control include antiarrhythmic drugs and catheter-based ablation procedures; both of these are presently neither optimally effective nor safe. In order to develop improved treatment options, it is necessary to use preclinical models, both to identify novel mechanism-based therapeutic targets and to test the effects of putative therapies before initiating clinical trials. Extensive research over the past 30\u2009years has provided many insights into AF mechanisms that can be used to design new rhythm-maintenance approaches. However, it has proven very difficult to translate these mechanistic discoveries into clinically applicable safe and effective new therapies. The aim of this article is to explore the challenges that underlie this phenomenon. We begin by considering the basic problem of AF, including its clinical importance, the current therapeutic landscape, the drug development pipeline, and the notion of upstream therapy. We then discuss the currently available preclinical models of AF and their limitations, and move on to regulatory hurdles and considerations and then review industry concerns and strategies. Finally, we evaluate potential paths forward, attempting to derive insights from the developmental history of currently used approaches and suggesting possible paths for the future. While the introduction of successful conceptually innovative new treatments for AF control is proving extremely difficult, one significant breakthrough is likely to revolutionize both AF management and the therapeutic development landscape.<\/jats:p>","DOI":"10.1093\/cvr\/cvab093","type":"journal-article","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T20:11:37Z","timestamp":1616616697000},"page":"1616-1631","source":"Crossref","is-referenced-by-count":63,"title":["Why translation from basic discoveries to clinical applications is so difficult for atrial fibrillation and possible approaches to improving it"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5565-3311","authenticated-orcid":false,"given":"Stanley","family":"Nattel","sequence":"first","affiliation":[{"name":"Department of Medicine, Montreal Heart Institute and Universit\u00e9 de Montr\u00e9al, Montreal, Canada"},{"name":"Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada"},{"name":"IHU LIYRC Institute, Bordeaux, France"},{"name":"Faculty of Medicine, Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip T","family":"Sager","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cardiovascuar Research Institute, Stanford University, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7261-7171","authenticated-orcid":false,"given":"J\u00f6rg","family":"H\u00fcser","sequence":"additional","affiliation":[{"name":"Research and Development, Preclinical Research, Cardiovascular Diseases, Bayer AG, Wuppertal, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1418-108X","authenticated-orcid":false,"given":"Jordi","family":"Heijman","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany"},{"name":"Department of Cardiology, Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dobromir","family":"Dobrev","sequence":"additional","affiliation":[{"name":"Department of Medicine, Montreal Heart Institute and Universit\u00e9 de Montr\u00e9al, Montreal, Canada"},{"name":"Faculty of Medicine, Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany"},{"name":"Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"key":"2021122415324072400_cvab093-B1","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1016\/j.jacc.2017.02.020","article-title":"Is atrial fibrillation a preventable disease?","volume":"69","author":"Du","year":"2017","journal-title":"J Am Coll Cardiol"},{"key":"2021122415324072400_cvab093-B2","doi-asserted-by":"crossref","first-page":"2N","DOI":"10.1016\/S0002-9149(98)00583-9","article-title":"Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates","volume":"82","author":"Kannel","year":"1998","journal-title":"Am J 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