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We aim to exploit AF simulations in 800 virtual atria to identify key patient characteristics that guide the optimal selection of anti\u2010arrhythmic drugs. The virtual cohort considered variability in electrophysiology and low voltage areas (LVA) and was developed and validated against experimental and clinical data from ionic currents to ECG. AF sustained in 494 (62%) atria, with large inward rectifier K+<\/jats:sup> current (I<\/jats:italic>K1<\/jats:sub>) and Na+<\/jats:sup>\/K+<\/jats:sup> pump (I<\/jats:italic>NaK<\/jats:sub>) densities (I<\/jats:italic>K1<\/jats:sub> 0.11\u00a0\u00b1\u00a00.03 vs<\/jats:italic>. 0.07\u00a0\u00b1\u00a00.03 S\u00a0mF\u20131<\/jats:sup>; I<\/jats:italic>NaK<\/jats:sub> 0.68\u00a0\u00b1\u00a00.15 vs<\/jats:italic>. 0.38\u00a0\u00b1\u00a026 S\u00a0mF\u20131<\/jats:sup>; sustained vs<\/jats:italic>. un\u2010sustained AF). In severely remodelled left atrium, with LVA extensions of more than 40% in the posterior wall, higher I<\/jats:italic>K1<\/jats:sub> (median density 0.12\u00a0\u00b1\u00a00.02 S\u00a0mF\u20131<\/jats:sup>) was required for AF maintenance, and rotors localized in healthy right atrium. For lower LVA extensions, rotors could also anchor to LVA, in atria presenting short refractoriness (median L\u2010type Ca2+<\/jats:sup> current, I<\/jats:italic>CaL<\/jats:sub>, density 0.08\u00a0\u00b1\u00a00.03 S\u00a0mF\u20131<\/jats:sup>). This atrial refractoriness, modulated by I<\/jats:italic>CaL<\/jats:sub> and fast Na+<\/jats:sup> current (I<\/jats:italic>Na<\/jats:sub>), determined pharmacological treatment success for both small and large LVA. Vernakalant was effective in atria presenting long refractoriness (median I<\/jats:italic>CaL<\/jats:sub> density 0.13\u00a0\u00b1\u00a00.05 S\u00a0mF\u20131<\/jats:sup>). For short refractoriness, atria with high I<\/jats:italic>Na<\/jats:sub> (median density 8.92\u00a0\u00b1\u00a02.59 S\u00a0mF\u20131<\/jats:sup>) responded more favourably to amiodarone than flecainide, and the opposite was found in atria with low I<\/jats:italic>Na<\/jats:sub> (median density 5.33\u00a0\u00b1\u00a01.41 S\u00a0mF\u20131<\/jats:sup>). In silico<\/jats:italic> drug trials in 800\u00a0human atria identify inward currents as critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics.\nimage<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>Key points<\/jats:title>\nAtrial fibrillation (AF) maintenance is facilitated by small L\u2010type Ca2+<\/jats:sup> current (I<\/jats:italic>CaL<\/jats:sub>) and large inward rectifier K+<\/jats:sup> current (I<\/jats:italic>K1<\/jats:sub>) and Na+<\/jats:sup>\/K+<\/jats:sup> pump.<\/jats:p><\/jats:list-item>\nIn severely remodelled left atrium, with low voltage areas (LVA) covering more than 40% of the posterior wall, sustained AF requires higher I<\/jats:italic>K1<\/jats:sub> and rotors localize in healthy right atrium. For lower LVA extensions, rotors can also anchor to LVA, if the atria present short refractoriness (low I<\/jats:italic>CaL<\/jats:sub>)<\/jats:p><\/jats:list-item>\nVernakalant is effective in atria presenting long refractoriness (high I<\/jats:italic>CaL<\/jats:sub>). For short refractoriness, atria with fast Na+<\/jats:sup> current (I<\/jats:italic>Na<\/jats:sub>) up\u2010regulation respond more favourably to amiodarone than flecainide, and the opposite is found in atria with low I<\/jats:italic>Na<\/jats:sub>.<\/jats:p><\/jats:list-item>\nThe inward currents (I<\/jats:italic>CaL<\/jats:sub> and I<\/jats:italic>Na<\/jats:sub>) are critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp284730","type":"journal-article","created":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T05:27:28Z","timestamp":1689917248000},"page":"4013-4032","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["What determines the optimal pharmacological treatment of atrial fibrillation? Insights from in silico<\/i> trials in 800 virtual atria"],"prefix":"10.1113","volume":"601","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8649-8203","authenticated-orcid":false,"given":"Albert","family":"Das\u00ed","sequence":"first","affiliation":[{"name":"Department of Computer Science University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.B.","family":"Pope","sequence":"additional","affiliation":[{"name":"Department of Cardiology Oxford University Hospitals NHS Foundation Trust Oxford UK"},{"name":"Department for Human Development and Health University of Southampton Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8261-8343","authenticated-orcid":false,"given":"Rohan S.","family":"Wijesurendra","sequence":"additional","affiliation":[{"name":"Department of Cardiology Oxford University Hospitals NHS Foundation Trust Oxford UK"},{"name":"Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim R.","family":"Betts","sequence":"additional","affiliation":[{"name":"Department of Cardiology Oxford University Hospitals NHS Foundation Trust Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0800-5984","authenticated-orcid":false,"given":"Rafael","family":"Sachetto","sequence":"additional","affiliation":[{"name":"Departamento de Ci\u00eancia da Computa\u00e7\u00e3o Universidade Federal de S\u00e3o Jo\u00e3o del\u2010Rei S\u00e3o Jo\u00e3o del\u2010Rei Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfonso","family":"Bueno\u2010Orovio","sequence":"additional","affiliation":[{"name":"Department of Computer Science University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Computer Science University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,20]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1109\/TBME.2011.2112658"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.633735"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/euac116"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1007678"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-57246-5"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10557-012-6374-4"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12872-016-0289-0"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/euy095"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8159.1998.tb01203.x"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8159.1994.tb03810.x"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-019-0437-9"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2008.03.029"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-013-1293-1"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.07.046"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1080\/14728214.2018.1446941"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.3.5720.429"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/euz159"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1998.275.1.H301"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehac544.572"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.966046"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.09.007"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000016960.61087.86"},{"issue":"1","key":"e_1_2_5_24_1","first-page":"75","article-title":"Amiodarone inhibits the Na+\u2010K+ pump in rabbit cardiac myocytes after acute and chronic treatment","volume":"284","author":"Gray D. 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