{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T20:01:25Z","timestamp":1774468885259,"version":"3.50.1"},"reference-count":107,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:00:00Z","timestamp":1687910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Dutch Heart Foundation","award":["2020-2020B003"],"award-info":[{"award-number":["2020-2020B003"]}]},{"name":"Dutch Heart Foundation","award":["NWA.1389.20.157"],"award-info":[{"award-number":["NWA.1389.20.157"]}]},{"DOI":"10.13039\/501100003246","name":"NWA-ORC project CIRCULAR NWO","doi-asserted-by":"publisher","award":["2020-2020B003"],"award-info":[{"award-number":["2020-2020B003"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"NWA-ORC project CIRCULAR NWO","doi-asserted-by":"publisher","award":["NWA.1389.20.157"],"award-info":[{"award-number":["NWA.1389.20.157"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Atrial Fibrillation Innovation Platform foundation","award":["2020-2020B003"],"award-info":[{"award-number":["2020-2020B003"]}]},{"name":"Atrial Fibrillation Innovation Platform foundation","award":["NWA.1389.20.157"],"award-info":[{"award-number":["NWA.1389.20.157"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Despite the many attempts to treat atrial fibrillation (AF), the most common cardiac tachyarrhythmia in the Western world, the treatment efficacy of AF is still suboptimal. A plausible reason for the suboptimal efficacy is that the current treatments are not directed at the underlying molecular mechanisms that drive AF. Recent discoveries revealed that the derailment of specific molecular proteostasis pathways drive electrical conduction disorders, contractile dysfunction and AF. The degree of this so-called \u2018electropathology\u2019 corresponds to the response to anti-AF treatment. Hence, to develop effective therapies to prevent AF, understanding the molecular mechanisms is of key importance. In this review, we highlight the key modulators of proteostasis derailment and describe the mechanisms that explain how they affect electrical and contractile function in atrial cardiomyocytes and AF. The key modulators of proteostasis derailment include (1) exhaustion of cardioprotective heat shock proteins (HSPs), (2) excessive endoplasmic reticulum (ER) stress and downstream autophagic protein degradation, (3) histone deacetylase 6 (HDAC6)-induced microtubule disruption, (4) activation of DNA damage-PARP1 activation and NAD+ axis and (5) mitochondrial dysfunction. Furthermore, we discuss druggable targets within these pathways that are involved in the prevention of proteostasis derailment, as well as the targets that aid in the recovery from AF. Finally, we will elaborate on the most favorable druggable targets for (future) testing in patients with AF, as well as drugs with potential benefits for AF recovery.<\/jats:p>","DOI":"10.3390\/jcm12134352","type":"journal-article","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T01:15:47Z","timestamp":1688001347000},"page":"4352","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Prevention of Atrial Fibrillation: Putting Proteostasis Derailment Back on Track"],"prefix":"10.3390","volume":"12","author":[{"given":"Preetam","family":"Kishore","sequence":"first","affiliation":[{"name":"Physiology, Amsterdam UMC, Vrije Universiteit, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amelie C. T.","family":"Collinet","sequence":"additional","affiliation":[{"name":"Physiology, Amsterdam UMC, Vrije Universiteit, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4768-234X","authenticated-orcid":false,"given":"Bianca J. J. M.","family":"Brundel","sequence":"additional","affiliation":[{"name":"Physiology, Amsterdam UMC, Vrije Universiteit, Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, 1081 HZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41572-022-00347-9","article-title":"Atrial fibrillation","volume":"8","author":"Brundel","year":"2022","journal-title":"Nat. Rev. Dis. 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