{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T02:38:22Z","timestamp":1777516702383,"version":"3.51.4"},"reference-count":84,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,1,15]],"date-time":"2020-01-15T00:00:00Z","timestamp":1579046400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,1,15]],"date-time":"2020-01-15T00:00:00Z","timestamp":1579046400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Sinus node dysfunction (SND) is often associated with atrial fibrillation (AF). Amiodarone is the most frequently used agent for maintaining sinus rhythm in patients with AF, but it impairs the sinoatrial node (SAN) function in one-third of AF patients. This study aims to gain mechanistic insights into the effects of the antiarrhythmic agents in the setting of AF-induced SND. We have adapted a human SAN model to characterize the SND conditions by incorporating experimental data on AF-induced electrical remodelling, and then integrated actions of drugs into the modified model to assess their efficacy. Reductions in pacing rate upon the implementation of AF-induced electrical remodelling associated with SND agreed with the clinical observations. And the simulated results showed the reduced funny current (<jats:italic>I<\/jats:italic><jats:sub><jats:italic>f<\/jats:italic><\/jats:sub>) in these remodelled targets mainly contributed to the heart rate reduction. Computational drug treatment simulations predicted a further reduction in heart rate during amiodarone administration, indicating that the reduction was the result of actions of amiodarone on <jats:italic>I<\/jats:italic><jats:sub><jats:italic>Na<\/jats:italic><\/jats:sub><jats:italic>, I<\/jats:italic><jats:sub><jats:italic>Kur<\/jats:italic><\/jats:sub><jats:italic>, I<\/jats:italic><jats:sub><jats:italic>CaL<\/jats:italic><\/jats:sub><jats:italic>, I<\/jats:italic><jats:sub><jats:italic>CaT<\/jats:italic><\/jats:sub><jats:italic>, I<\/jats:italic><jats:sub><jats:italic>f<\/jats:italic><\/jats:sub> and beta-adrenergic receptors. However, the heart rate was increased in the presence of disopyramide. We concluded that disopyramide may be a desirable choice in reversing the AF-induced SND phenotype.<\/jats:p>","DOI":"10.1038\/s41598-019-57246-5","type":"journal-article","created":{"date-parts":[[2020,1,15]],"date-time":"2020-01-15T11:03:00Z","timestamp":1579086180000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["In silico study of the effects of anti-arrhythmic drug treatment on sinoatrial node function for patients with atrial fibrillation"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2847-350X","authenticated-orcid":false,"given":"Jieyun","family":"Bai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaosheng","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henggui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,1,15]]},"reference":[{"key":"57246_CR1","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1067\/mhj.2000.109652","volume":"140","author":"GA Lamas","year":"2000","unstructured":"Lamas, G. A. et al. The mode selection trial (MOST) in sinus node dysfunction: design, rationale, and baseline characteristics of the first 1000 patients. American heart journal 140, 541\u2013551 (2000).","journal-title":"American heart journal"},{"key":"57246_CR2","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.yjmcc.2015.02.003","volume":"83","author":"O Monfredi","year":"2015","unstructured":"Monfredi, O. & Boyett, M. Sick sinus syndrome and atrial fibrillation in older persons\u2014a view from the sinoatrial nodal myocyte. Journal of molecular and cellular cardiology 83, 88\u2013100 (2015).","journal-title":"Journal of molecular and cellular cardiology"},{"key":"57246_CR3","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/j.arcmed.2014.04.005","volume":"45","author":"J Zhao","year":"2014","unstructured":"Zhao, J., Liu, T. & Li, G. Relationship Between Two Arrhythmias: Sinus Node Dysfunction and Atrial Fibrillation. Archives of Medical Research 45, 351\u2013355 (2014).","journal-title":"Archives of Medical Research"},{"key":"57246_CR4","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1046\/j.1540-8167.2002.00584.x","volume":"13","author":"D Hadian","year":"2002","unstructured":"Hadian, D., Zipes, D. P., Olgin, J. E. & Miller, J. M. Short\u2010term rapid atrial pacing produces electrical remodeling of sinus node function in Humans. Journal of cardiovascular electrophysiology 13, 584\u2013586 (2002).","journal-title":"Journal of cardiovascular electrophysiology"},{"key":"57246_CR5","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1161\/CIRCULATIONAHA.109.935288","volume":"122","author":"VV Fedorov","year":"2010","unstructured":"Fedorov, V. V. et al. Complex interactions between the sinoatrial node and atrium during reentrant arrhythmias in the canine heart. Circulation 122, 782\u2013789 (2010).","journal-title":"Circulation"},{"key":"57246_CR6","doi-asserted-by":"publisher","first-page":"1576","DOI":"10.1161\/CIRCULATIONAHA.108.789677","volume":"119","author":"Y-H Yeh","year":"2009","unstructured":"Yeh, Y.-H. et al. Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardia-bradycardia syndrome. Circulation 119, 1576\u20131585 (2009).","journal-title":"Circulation"},{"key":"57246_CR7","doi-asserted-by":"publisher","first-page":"1892","DOI":"10.1161\/CIRCULATIONAHA.116.018011","volume":"133","author":"RM John","year":"2016","unstructured":"John, R. M. & Kumar, S. Sinus node and atrial arrhythmias. Circulation 133, 1892\u20131900 (2016).","journal-title":"Circulation"},{"key":"57246_CR8","doi-asserted-by":"publisher","first-page":"211","DOI":"10.3349\/ymj.2011.52.2.211","volume":"52","author":"B Joung","year":"2011","unstructured":"Joung, B., Chen, P.-S. & Lin, S.-F. The role of the calcium and the voltage clocks in sinoatrial node dysfunction. Yonsei medical journal 52, 211\u2013219 (2011).","journal-title":"Yonsei medical journal"},{"key":"57246_CR9","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.hrthm.2009.09.018","volume":"7","author":"B Joung","year":"2010","unstructured":"Joung, B. et al. Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation. Heart Rhythm 7, 88\u201395 (2010).","journal-title":"Heart Rhythm"},{"key":"57246_CR10","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.1161\/01.CIR.0000055316.35552.74","volume":"107","author":"K Shinagawa","year":"2003","unstructured":"Shinagawa, K., Shiroshita-Takeshita, A., Schram, G. & Nattel, S. Effects of antiarrhythmic drugs on fibrillation in the remodeled atrium: insights into the mechanism of the superior efficacy of amiodarone. Circulation 107, 1440\u20131446 (2003).","journal-title":"Circulation"},{"key":"57246_CR11","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1056\/NEJM200003303421302","volume":"342","author":"D Roy","year":"2000","unstructured":"Roy, D. et al. Amiodarone to prevent recurrence of atrial fibrillation. New England Journal of Medicine 342, 913\u2013920 (2000).","journal-title":"New England Journal of Medicine"},{"key":"57246_CR12","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/S0002-9149(99)00698-0","volume":"84","author":"I Kodama","year":"1999","unstructured":"Kodama, I., Kamiya, K. & Toyama, J. Amiodarone: ionic and cellular mechanisms of action of the most promising class III agent. American Journal of Cardiology 84, 20\u201328 (1999).","journal-title":"American Journal of Cardiology"},{"key":"57246_CR13","doi-asserted-by":"publisher","first-page":"307","DOI":"10.4236\/pp.2012.33041","volume":"3","author":"D Kondratyeva","year":"2012","unstructured":"Kondratyeva, D., Afanasiev, S., Popov, S. & Batalov, R. Amiodarone Modulation of Intracellular Transport of Calcium Ions in Cardiomyocites. Pharmacology & Pharmacy 3, 307\u2013315 (2012).","journal-title":"Pharmacology & Pharmacy"},{"key":"57246_CR14","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1111\/j.1540-8159.2004.00670.x","volume":"27","author":"V Essebag","year":"2004","unstructured":"Essebag, V., Hadjis, T., Platt, R. W., Abrahamowicz, M. & Pilote, L. Effect of amiodarone dose on the risk of permanent pacemaker insertion. Pacing and clinical electrophysiology 27, 1519\u20131525 (2004).","journal-title":"Pacing and clinical electrophysiology"},{"key":"57246_CR15","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1136\/hrt.42.5.573","volume":"42","author":"P Touboul","year":"1979","unstructured":"Touboul, P., Atallah, G., Gressard, A. & Kirkorian, G. Effects of amiodarone on sinus node in man. Heart 42, 573\u2013578 (1979).","journal-title":"Heart"},{"key":"57246_CR16","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1002\/clc.4960100808","volume":"10","author":"A Hoffmann","year":"1987","unstructured":"Hoffmann, A., Jost, M., Burckhardt, D. & Kappenberger, L. Effect of amiodarone on sinus node function in patients with sick sinus syndrome. Clinical cardiology 10, 451\u2013452 (1987).","journal-title":"Clinical cardiology"},{"key":"57246_CR17","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1253\/circj.CJ-12-1615","volume":"77","author":"H-S Mun","year":"2013","unstructured":"Mun, H.-S. et al. Chronic amiodarone therapy impairs the function of the superior sinoatrial node in patients with atrial fibrillation. Circulation Journal 77, 2255\u20132263 (2013).","journal-title":"Circulation Journal"},{"key":"57246_CR18","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1002\/cpt.1184","volume":"105","author":"Z Li","year":"2018","unstructured":"Li, Z. et al. Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the Ci PA Initiative. Clinical Pharmacology & Therapeutics 105, 466\u2013475 (2018).","journal-title":"Clinical Pharmacology & Therapeutics"},{"key":"57246_CR19","first-page":"128","volume":"43","author":"B Jie-Yun","year":"2016","unstructured":"Jie-Yun, B., Kuan-Quan, W. & Heng-Gui, Z. Potential pathogenesis discovery of arrhythmia based on cardiac electrophysiological models: research progress. Progress in Biochemistry and Biophysics 43, 128\u2013140 (2016).","journal-title":"Progress in Biochemistry and Biophysics"},{"key":"57246_CR20","doi-asserted-by":"crossref","unstructured":"Bai, J. et al. In silico investigation mechanisms underlying atrial fibrillation due to impaired Pitx2. PLoS computational biology In Press (2019).","DOI":"10.1371\/journal.pcbi.1007678"},{"key":"57246_CR21","doi-asserted-by":"publisher","first-page":"668","DOI":"10.3389\/fphys.2017.00668","volume":"8","author":"E Passini","year":"2017","unstructured":"Passini, E. et al. Human in silico drug trials demonstrate higher accuracy than animal models in predicting clinical pro-arrhythmic cardiotoxicity. Frontiers in physiology 8, 668 (2017).","journal-title":"Frontiers in physiology"},{"key":"57246_CR22","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/j.pbiomolbio.2005.06.006","volume":"90","author":"D Bottino","year":"2006","unstructured":"Bottino, D. et al. Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems-based computer model of the heart. Progress in biophysics and molecular biology 90, 414\u2013443 (2006).","journal-title":"Progress in biophysics and molecular biology"},{"key":"57246_CR23","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.vascn.2013.04.004","volume":"68","author":"KA Beattie","year":"2013","unstructured":"Beattie, K. A. et al. Evaluation of an in silico cardiac safety assay: using ion channel screening data to predict QT interval changes in the rabbit ventricular wedge. Journal of pharmacological and toxicological methods 68, 88\u201396 (2013).","journal-title":"Journal of pharmacological and toxicological methods"},{"key":"57246_CR24","doi-asserted-by":"publisher","first-page":"H1466","DOI":"10.1152\/ajpheart.00808.2011","volume":"302","author":"M Davies","year":"2012","unstructured":"Davies, M. et al. An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment. American Journal of Physiology-Heart and Circulatory Physiology 302, H1466\u20131480 (2012).","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"key":"57246_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/1087057115594589","volume":"21","author":"B Fermini","year":"2016","unstructured":"Fermini, B. et al. A new perspective in the field of cardiac safety testing through the comprehensive in vitro proarrhythmia assay paradigm. Journal of biomolecular screening 21, 1\u201311 (2016).","journal-title":"Journal of biomolecular screening"},{"key":"57246_CR26","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1021\/acs.jcim.7b00440","volume":"58","author":"L Romero","year":"2018","unstructured":"Romero, L. et al. In Silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk. Journal of chemical information and modeling 58, 867\u2013878 (2018).","journal-title":"Journal of chemical information and modeling"},{"key":"57246_CR27","doi-asserted-by":"publisher","first-page":"2365","DOI":"10.1113\/JP273259","volume":"595","author":"A Fabbri","year":"2017","unstructured":"Fabbri, A., Fantini, M., Wilders, R. & Severi, S. Computational analysis of the human sinus node action potential: model development and effects of mutations. The Journal of physiology 595, 2365\u20132396 (2017).","journal-title":"The Journal of physiology"},{"key":"57246_CR28","doi-asserted-by":"crossref","unstructured":"Heijman, J., Heusch, G. & Dobrev, D. Pleiotropic effects of antiarrhythmic agents: dronedarone in the treatment of atrial fibrillation. Clinical Medicine Insights: Cardiology, 7, CMC. S8445 (2013).","DOI":"10.4137\/CMC.S8445"},{"key":"57246_CR29","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.ejphar.2011.07.039","volume":"669","author":"X Fan","year":"2011","unstructured":"Fan, X. et al. Novel electropharmacological activity of amiodarone on human HCN channels heterologously expressed in the Xenopus oocytes. European journal of pharmacology 669, 15\u201323 (2011).","journal-title":"European journal of pharmacology"},{"key":"57246_CR30","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1046\/j.1540-8167.2003.03064.x","volume":"14","author":"N Lalev\u00e9e","year":"2003","unstructured":"Lalev\u00e9e, N., Barr\u00e8re\u2010lemaire, S., Gautier, P., Nargeot, J. & Richard, S. Effects of Amiodarone and Dronedarone on Voltage\u2010Dependent Sodium Current in Human Cardiomyocytes. Journal of cardiovascular electrophysiology 14, 885\u2013890 (2003).","journal-title":"Journal of cardiovascular electrophysiology"},{"key":"57246_CR31","doi-asserted-by":"publisher","first-page":"1684","DOI":"10.1124\/mol.105.021253","volume":"69","author":"N Yamashita","year":"2006","unstructured":"Yamashita, N. et al. Short-and long-term amiodarone treatments regulate Cav3. 2 low-voltage-activated T-type Ca2+ channel through distinct mechanisms. Molecular pharmacology 69, 1684\u20131691 (2006).","journal-title":"Molecular pharmacology"},{"key":"57246_CR32","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1111\/j.1476-5381.1996.tb16713.x","volume":"117","author":"A Varr\u00f3","year":"1996","unstructured":"Varr\u00f3, A., Vir\u00e1g, L. & Papp, J. G. Comparison of the chronic and acute effects of amiodarone on the calcium and potassium currents in rabbit isolated cardiac myocytes. British journal of pharmacology 117, 1181\u20131186 (1996).","journal-title":"British journal of pharmacology"},{"key":"57246_CR33","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1161\/01.CIR.103.9.1317","volume":"103","author":"K Kamiya","year":"2001","unstructured":"Kamiya, K. et al. Short-and long-term effects of amiodarone on the two components of cardiac delayed rectifier K+ current. Circulation 103, 1317\u20131324 (2001).","journal-title":"Circulation"},{"key":"57246_CR34","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S0014-2999(01)01381-4","volume":"430","author":"S Kobayashi","year":"2001","unstructured":"Kobayashi, S. et al. Inhibitory effect of bepridil on hKv1. 5 channel current: comparison with amiodarone and E-4031. European journal of pharmacology 430, 149\u2013157 (2001).","journal-title":"European journal of pharmacology"},{"key":"57246_CR35","first-page":"617","volume":"279","author":"Y Watanabe","year":"1996","unstructured":"Watanabe, Y., Hara, Y., Tamagawa, M. & Nakaya, H. Inhibitory effect of amiodarone on the muscarinic acetylcholine receptor-operated potassium current in guinea pig atrial cells. Journal of Pharmacology and Experimental Therapeutics 279, 617\u2013624 (1996).","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"key":"57246_CR36","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1038\/sj.bjp.0703527","volume":"131","author":"Y Watanabe","year":"2000","unstructured":"Watanabe, Y. & Kimura, J. Inhibitory effect of amiodarone on Na+\/Ca2+ exchange current in guinea\u2010pig cardiac myocytes. British journal of pharmacology 131, 80\u201384 (2000).","journal-title":"British journal of pharmacology"},{"key":"57246_CR37","first-page":"75","volume":"284","author":"DF Gray","year":"1998","unstructured":"Gray, D. F. et al. Amiodarone inhibits the Na+-K+ pump in rabbit cardiac myocytes after acute and chronic treatment. Journal of Pharmacology and Experimental Therapeutics 284, 75\u201382 (1998).","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"key":"57246_CR38","doi-asserted-by":"publisher","first-page":"689","DOI":"10.7326\/0003-4819-122-9-199505010-00008","volume":"122","author":"PJ Podrid","year":"1995","unstructured":"Podrid, P. J. Amiodarone: reevaluation of an old drug. Annals of internal medicine 122, 689\u2013700 (1995).","journal-title":"Annals of internal medicine"},{"key":"57246_CR39","doi-asserted-by":"publisher","first-page":"1682","DOI":"10.1345\/aph.1A403","volume":"36","author":"SC Sauro","year":"2002","unstructured":"Sauro, S. C., DeCarolis, D. D., Pierpont, G. L. & Gornick, C. C. Comparison of plasma concentrations for two amiodarone products. Annals of Pharmacotherapy 36, 1682\u20131685 (2002).","journal-title":"Annals of Pharmacotherapy"},{"key":"57246_CR40","doi-asserted-by":"publisher","first-page":"iv30","DOI":"10.1093\/europace\/euu230","volume":"16","author":"A Loewe","year":"2014","unstructured":"Loewe, A. et al. In-silico assessment of the dynamic effects of amiodarone and dronedarone on human atrial patho-electrophysiology. Europace 16, iv30\u2013iv38 (2014).","journal-title":"Europace"},{"key":"57246_CR41","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1111\/j.1540-8159.1998.tb00218.x","volume":"21","author":"EL PRITCHETT","year":"1998","unstructured":"PRITCHETT, E. L. Evolution and revolution in drug labeling: regulation of antiarrhythmic drugs by the Food and Drug Administration 1962\u20131996. Pacing and clinical electrophysiology 21, 1457\u20131469 (1998).","journal-title":"Pacing and clinical electrophysiology"},{"key":"57246_CR42","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1001\/jama.298.11.1312","volume":"298","author":"P Vassallo","year":"2007","unstructured":"Vassallo, P. & Trohman, R. G. Prescribing amiodarone: an evidence-based review of clinical indications. Jama 298, 1312\u20131322 (2007).","journal-title":"Jama"},{"key":"57246_CR43","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/S0008-6363(02)00846-5","volume":"58","author":"W Redfern","year":"2003","unstructured":"Redfern, W. et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovascular research 58, 32\u201345 (2003).","journal-title":"Cardiovascular research"},{"key":"57246_CR44","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1056\/NEJM197904263001705","volume":"300","author":"J Koch-Weser","year":"1979","unstructured":"Koch-Weser, J. Disopyramide. New England Journal of Medicine 300, 957\u2013962 (1979).","journal-title":"New England Journal of Medicine"},{"key":"57246_CR45","doi-asserted-by":"publisher","first-page":"1648","DOI":"10.3390\/ijms17101648","volume":"17","author":"M Yan","year":"2016","unstructured":"Yan, M. et al. Stereoselective blockage of quinidine and quinine in the hERG channel and the effect of their rescue potency on drug-induced hERG trafficking defect. International journal of molecular sciences 17, 1648 (2016).","journal-title":"International journal of molecular sciences"},{"key":"57246_CR46","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1016\/j.amjcard.2012.02.028","volume":"109","author":"ZD Goldberger","year":"2012","unstructured":"Goldberger, Z. D. & Goldberger, A. L. Therapeutic ranges of serum digoxin concentrations in patients with heart failure. American Journal of Cardiology 109, 1818\u20131821 (2012).","journal-title":"American Journal of Cardiology"},{"key":"57246_CR47","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-33958-y","volume":"8","author":"J Bai","year":"2018","unstructured":"Bai, J., Gladding, P. A., Stiles, M. K., Fedorov, V. V. & Zhao, J. Ionic and cellular mechanisms underlying TBX5\/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells. Scientific reports 8, 15642 (2018).","journal-title":"Scientific reports"},{"key":"57246_CR48","doi-asserted-by":"publisher","DOI":"10.1038\/srep31262","volume":"6","author":"J Bai","year":"2016","unstructured":"Bai, J., Wang, K., Li, Q., Yuan, Y. & Zhang, H. Pro-arrhythmogenic effects of CACNA1C G1911R mutation in human ventricular tachycardia: insights from cardiac multi-scale models. Scientific reports 6, 31262 (2016).","journal-title":"Scientific reports"},{"key":"57246_CR49","doi-asserted-by":"publisher","first-page":"771","DOI":"10.3389\/fphys.2017.00771","volume":"8","author":"J Bai","year":"2017","unstructured":"Bai, J. et al. Computational cardiac modeling reveals mechanisms of ventricular arrhythmogenesis in long QT syndrome type 8: CACNA1C R858H mutation linked to ventricular fibrillation. Frontiers in physiology 8, 771 (2017).","journal-title":"Frontiers in physiology"},{"key":"57246_CR50","first-page":"195","volume":"8","author":"J Bai","year":"2017","unstructured":"Bai, J., Yin, R., Wang, K. & Zhang, H. Mechanisms underlying the emergence of post-acidosis arrhythmia at the tissue level: A theoretical study. Frontiers in physiology 8, 195 (2017).","journal-title":"Frontiers in physiology"},{"key":"57246_CR51","first-page":"716","volume":"43","author":"H Liu","year":"2016","unstructured":"Liu, H., Bai, J., Wang, K., Li, Q. & Yuan, Y. Simulation study of ventricular arrhythmia in post acidosis. Prog. Biochem. Biophys 43, 716\u2013724 (2016).","journal-title":"Prog. Biochem. Biophys"},{"key":"57246_CR52","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.3389\/fphys.2019.01314","volume":"10","author":"J Bai","year":"2019","unstructured":"Bai, J., Lu, Y., Lo, A. C., Zhao, J. & Zhang, H. Proarrhythmia in the p. Met207Val PITX2c-linked familial atrial fibrillation-insights from modelling. Frontiers in Physiology 10, 1314 (2019).","journal-title":"Frontiers in Physiology"},{"key":"57246_CR53","doi-asserted-by":"publisher","first-page":"2330","DOI":"10.1016\/j.jacc.2009.12.055","volume":"55","author":"S Sossalla","year":"2010","unstructured":"Sossalla, S. et al. Altered Na+ currents in atrial fibrillation: effects of ranolazine on arrhythmias and contractility in human atrial myocardium. Journal of the American College of Cardiology 55, 2330\u20132342 (2010).","journal-title":"Journal of the American College of Cardiology"},{"key":"57246_CR54","doi-asserted-by":"publisher","first-page":"2346","DOI":"10.1016\/j.jacc.2010.02.028","volume":"55","author":"R Caballero","year":"2010","unstructured":"Caballero, R. et al. In humans, chronic atrial fibrillation decreases the transient outward current and ultrarapid component of the delayed rectifier current differentially on each atria and increases the slow component of the delayed rectifier current in both. Journal of the American College of Cardiology 55, 2346\u20132354 (2010).","journal-title":"Journal of the American College of Cardiology"},{"key":"57246_CR55","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1007\/s00395-003-0409-8","volume":"98","author":"D Dobrev","year":"2003","unstructured":"Dobrev, D. & Ravens, U. Remodeling of cardiomyocyte ion channels in human atrial fibrillation. Basic research in cardiology 98, 137\u2013148 (2003).","journal-title":"Basic research in cardiology"},{"key":"57246_CR56","doi-asserted-by":"publisher","first-page":"H227","DOI":"10.1152\/ajpheart.1997.272.1.H227","volume":"272","author":"G Li","year":"1997","unstructured":"Li, G. & Nattel, S. Properties of human atrial ICa at physiological temperatures and relevance to action potential. American Journal of Physiology-Heart and Circulatory Physiology 272, H227\u2013H235 (1997).","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"key":"57246_CR57","doi-asserted-by":"publisher","first-page":"2651","DOI":"10.1161\/01.CIR.0000145659.80212.6A","volume":"110","author":"T Christ","year":"2004","unstructured":"Christ, T. et al. L-type Ca2+ current downregulation in chronic human atrial fibrillation is associated with increased activity of protein phosphatases. Circulation 110, 2651\u20132657 (2004).","journal-title":"Circulation"},{"key":"57246_CR58","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1161\/01.RES.85.5.428","volume":"85","author":"DR Van Wagoner","year":"1999","unstructured":"Van Wagoner, D. R. et al. Atrial L-type Ca2+ currents and human atrial fibrillation. Circulation research 85, 428\u2013436 (1999).","journal-title":"Circulation research"},{"key":"57246_CR59","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/S0008-6363(01)00453-9","volume":"53","author":"U Schotten","year":"2002","unstructured":"Schotten, U. et al. Atrial fibrillation-induced atrial contractile dysfunction: a tachycardiomyopathy of a different sort. Cardiovascular research 53, 192\u2013201 (2002).","journal-title":"Cardiovascular research"},{"key":"57246_CR60","doi-asserted-by":"publisher","first-page":"1650","DOI":"10.1172\/JCI118960","volume":"98","author":"J Wang","year":"1996","unstructured":"Wang, J. et al. Regional expression of sodium pump subunits isoforms and Na+-Ca++ exchanger in the human heart. The Journal of clinical investigation 98, 1650\u20131658 (1996).","journal-title":"The Journal of clinical investigation"},{"key":"57246_CR61","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1161\/CIRCULATIONAHA.113.006641","volume":"129","author":"N Voigt","year":"2014","unstructured":"Voigt, N. et al. Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation. Circulation 129, 145\u2013156 (2014).","journal-title":"Circulation"},{"key":"57246_CR62","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/S0008-6363(99)00053-X","volume":"43","author":"P Bokn\u00edk","year":"1999","unstructured":"Bokn\u00edk, P. et al. Regional expression of phospholamban in the human heart. Cardiovascular research 43, 67\u201376 (1999).","journal-title":"Cardiovascular research"},{"key":"57246_CR63","doi-asserted-by":"publisher","first-page":"H397","DOI":"10.1152\/ajpheart.2000.279.1.H397","volume":"279","author":"H Zhang","year":"2000","unstructured":"Zhang, H. et al. Mathematical models of action potentials in the periphery and center of the rabbit sinoatrial node. American Journal of Physiology-Heart and Circulatory Physiology 279, H397\u2013H421 (2000).","journal-title":"American Journal of Physiology-Heart and Circulatory Physiology"},{"key":"57246_CR64","doi-asserted-by":"crossref","unstructured":"Barra, S. et al. Acute and sub-acute sinus node dysfunction following pulmonary vein isolation: a case series. European Heart Journal-Case Reports (2018).","DOI":"10.1093\/ehjcr\/ytx020"},{"key":"57246_CR65","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1093\/europace\/eus219","volume":"15","author":"H-Y Chang","year":"2012","unstructured":"Chang, H.-Y. et al. Sinus node dysfunction in atrial fibrillation patients: the evidence of regional atrial substrate remodelling. Europace 15, 205\u2013211 (2012).","journal-title":"Europace"},{"key":"57246_CR66","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1161\/01.CIR.0000090685.13169.07","volume":"108","author":"M Hocini","year":"2003","unstructured":"Hocini, M. et al. Reverse remodeling of sinus node function after catheter ablation of atrial fibrillation in patients with prolonged sinus pauses. Circulation 108, 1172\u20131175 (2003).","journal-title":"Circulation"},{"key":"57246_CR67","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1111\/pace.12340","volume":"37","author":"YW CHEN","year":"2014","unstructured":"CHEN, Y. W. et al. Pacing or Ablation: Which Is Better for Paroxysmal Atrial Fibrillation\u2010Related Tachycardia\u2010Bradycardia Syndrome? Pacing and Clinical Electrophysiology 37, 403\u2013411 (2014).","journal-title":"Pacing and Clinical Electrophysiology"},{"key":"57246_CR68","doi-asserted-by":"publisher","first-page":"1116","DOI":"10.1111\/pace.12934","volume":"39","author":"AM Killu","year":"2016","unstructured":"Killu, A. M. et al. Acute sinus node dysfunction after atrial ablation: incidence, risk factors, and management. Pacing and Clinical Electrophysiology 39, 1116\u20131125 (2016).","journal-title":"Pacing and Clinical Electrophysiology"},{"key":"57246_CR69","first-page":"515","volume":"290","author":"JA Sanchez-Chapula","year":"1999","unstructured":"Sanchez-Chapula, J. A. Mechanism of transient outward K+ channel block by disopyramide. Journal of Pharmacology and Experimental Therapeutics 290, 515\u2013523 (1999).","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"key":"57246_CR70","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1161\/CIRCRESAHA.111.253955","volume":"109","author":"E Grandi","year":"2011","unstructured":"Grandi, E. et al. Human atrial action potential and Ca2+ model: sinus rhythm and chronic atrial fibrillation. Circulation research 109, 1055\u20131066 (2011).","journal-title":"Circulation research"},{"key":"57246_CR71","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1111\/j.1540-8159.2004.00597.x","volume":"27","author":"IE Ovsyshcher","year":"2004","unstructured":"Ovsyshcher, I. E. & Barold, S. S. Drug induced bradycardia: To pace or not to pace? Pacing and clinical electrophysiology 27, 1144\u20131147 (2004).","journal-title":"Pacing and clinical electrophysiology"},{"key":"57246_CR72","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1161\/01.CIR.76.2.442","volume":"76","author":"S Nattel","year":"1987","unstructured":"Nattel, S., Talajic, M., Quantz, M. & DeRoode, M. Frequency-dependent effects of amiodarone on atrioventricular nodal function and slow-channel action potentials: evidence for calcium channel-blocking activity. Circulation 76, 442\u2013449 (1987).","journal-title":"Circulation"},{"key":"57246_CR73","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1177\/1074248407303225","volume":"12","author":"D Celestino","year":"2007","unstructured":"Celestino, D., Medei, E., Moro, S., Elizari, M. V. & Sicouri, S. Acute in vitro effects of dronedarone, an iodine-free derivative, and amiodarone, on the rabbit sinoatrial node automaticity: a comparative study. Journal of cardiovascular pharmacology and therapeutics 12, 248\u2013257 (2007).","journal-title":"Journal of cardiovascular pharmacology and therapeutics"},{"key":"57246_CR74","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.jvc.2018.10.004","volume":"22","author":"A Kalyanasundaram","year":"2019","unstructured":"Kalyanasundaram, A., Li, N., Hansen, B., Zhao, J. & Fedorov, V. Canine and human sinoatrial node: differences and similarities in the structure, function, molecular profiles, and arrhythmia. Journal of veterinary cardiology 22, 2\u201319 (2019).","journal-title":"Journal of veterinary cardiology"},{"key":"57246_CR75","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1128\/CMR.00092-12","volume":"26","author":"D Gonzalez","year":"2013","unstructured":"Gonzalez, D., Schmidt, S. & Derendorf, H. Importance of relating efficacy measures to unbound drug concentrations for anti-infective agents. Clinical microbiology reviews 26, 274\u2013288 (2013).","journal-title":"Clinical microbiology reviews"},{"key":"57246_CR76","doi-asserted-by":"publisher","DOI":"10.1038\/srep02100","volume":"3","author":"J Kramer","year":"2013","unstructured":"Kramer, J. et al. MICE models: superior to the HERG model in predicting Torsade de Pointes. Scientific reports 3, 2100 (2013).","journal-title":"Scientific reports"},{"key":"57246_CR77","doi-asserted-by":"publisher","first-page":"e13172","DOI":"10.14814\/phy2.13172","volume":"5","author":"H Cheng","year":"2017","unstructured":"Cheng, H., Cannell, M. B. & Hancox, J. C. Differential responses of rabbit ventricular and atrial transient outward current (Ito) to the Ito modulator NS5806. Physiological reports 5, e13172 (2017).","journal-title":"Physiological reports"},{"key":"57246_CR78","doi-asserted-by":"crossref","unstructured":"Ni, H., Morotti, S. & Grandi, E. A heart for diversity: simulating variability in cardiac arrhythmia research. Frontiers in physiology, 9 (2018).","DOI":"10.3389\/fphys.2018.00958"},{"key":"57246_CR79","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.yjmcc.2012.09.009","volume":"58","author":"Y-S Lee","year":"2013","unstructured":"Lee, Y.-S., Liu, O. Z. & Sobie, E. A. Decoding myocardial Ca2+ signals across multiple spatial scales: a role for sensitivity analysis. Journal of molecular and cellular cardiology 58, 92\u201399 (2013).","journal-title":"Journal of molecular and cellular cardiology"},{"key":"57246_CR80","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1016\/j.bpj.2012.12.055","volume":"104","author":"Y-S Lee","year":"2013","unstructured":"Lee, Y.-S., Liu, O. Z., Hwang, H. S., Knollmann, B. C. & Sobie, E. A. Parameter sensitivity analysis of stochastic models provides insights into cardiac calcium sparks. Biophysical journal 104, 1142\u20131150 (2013).","journal-title":"Biophysical journal"},{"key":"57246_CR81","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1113\/expphysiol.1996.sp003972","volume":"81","author":"M Lei","year":"1996","unstructured":"Lei, M. & Brown, H. F. Two components of the delayed rectifier potassium current, IK, in rabbit sino\u2010atrial node cells. Experimental physiology 81, 725\u2013741 (1996).","journal-title":"Experimental physiology"},{"key":"57246_CR82","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1254\/jjp.69.303","volume":"69","author":"N Tohse","year":"1995","unstructured":"Tohse, N. & Kanno, M. Effects of dofetilide on membrane currents in sinoatrial node cells of rabbit. The Japanese Journal of Pharmacology 69, 303\u2013309 (1995).","journal-title":"The Japanese Journal of Pharmacology"},{"key":"57246_CR83","doi-asserted-by":"publisher","first-page":"H945","DOI":"10.1152\/ajpheart.00143.2010","volume":"301","author":"S Kharche","year":"2011","unstructured":"Kharche, S., Yu, J., Lei, M. & Zhang, H. A mathematical model of action potentials of mouse sinoatrial node cells with molecular bases. American Journal of Physiology-Heart and circulatory physiology 301, H945\u2013963 (2011).","journal-title":"American Journal of Physiology-Heart and circulatory physiology"},{"key":"57246_CR84","doi-asserted-by":"publisher","first-page":"H561","DOI":"10.1152\/ajpheart.01118.2008","volume":"296","author":"VA Maltsev","year":"2009","unstructured":"Maltsev, V. A. & Lakatta, E. G. Synergism of coupled subsarcolemmal Ca2 clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model. Am J Physiol Heart Circ Physiol 296, H561\u2013H562 (2009).","journal-title":"Am J Physiol Heart Circ Physiol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-57246-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-57246-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-57246-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T05:28:35Z","timestamp":1670304515000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-57246-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,15]]},"references-count":84,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["57246"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-57246-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,15]]},"assertion":[{"value":"19 June 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 December 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 January 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"305"}}