Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol
Abstract Short QT syndrome (SQTS) is a rare but dangerous genetic disease. In this research, we conducted a comprehensive in silico investigation into the arrhythmogenesis in KCNH2 T618I-associated SQTS using a multi-scale human ventricle model. A Markov chain model of I Kr was developed firstly to...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-11-01
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| Series: | npj Systems Biology and Applications |
| Online Access: | https://doi.org/10.1038/s41540-022-00254-5 |
| _version_ | 1798044542882021376 |
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| author | Shugang Zhang Weigang Lu Fei Yang Zhen Li Shuang Wang Mingjian Jiang Xiaofeng Wang Zhiqiang Wei |
| author_facet | Shugang Zhang Weigang Lu Fei Yang Zhen Li Shuang Wang Mingjian Jiang Xiaofeng Wang Zhiqiang Wei |
| author_sort | Shugang Zhang |
| collection | DOAJ |
| description | Abstract Short QT syndrome (SQTS) is a rare but dangerous genetic disease. In this research, we conducted a comprehensive in silico investigation into the arrhythmogenesis in KCNH2 T618I-associated SQTS using a multi-scale human ventricle model. A Markov chain model of I Kr was developed firstly to reproduce the experimental observations. It was then incorporated into cell, tissue, and organ models to explore how the mutation provided substrates for ventricular arrhythmias. Using this T618I Markov model, we explicitly revealed the subcellular level functional alterations by T618I mutation, particularly the changes of ion channel states that are difficult to demonstrate in wet experiments. The following tissue and organ models also successfully reproduced the changed dynamics of reentrant spiral waves and impaired rate adaptions in hearts of T618I mutation. In terms of pharmacotherapy, we replicated the different effects of a drug under various conditions using identical mathematical descriptions for drugs. This study not only simulated the actions of an effective drug (quinidine) at various physiological levels, but also elucidated why the I Kr inhibitor sotalol failed in SQT1 patients through profoundly analyzing its mutation-dependent actions. |
| first_indexed | 2024-04-11T23:05:51Z |
| format | Article |
| id | doaj.art-f9f920d3b4714e179849e30640670834 |
| institution | Directory Open Access Journal |
| issn | 2056-7189 |
| language | English |
| last_indexed | 2024-04-11T23:05:51Z |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Systems Biology and Applications |
| spelling | doaj.art-f9f920d3b4714e179849e306406708342022-12-22T03:58:02ZengNature Portfolionpj Systems Biology and Applications2056-71892022-11-018111710.1038/s41540-022-00254-5Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalolShugang Zhang0Weigang Lu1Fei Yang2Zhen Li3Shuang Wang4Mingjian Jiang5Xiaofeng Wang6Zhiqiang Wei7College of Computer Science and Technology, Ocean University of ChinaDepartment of Educational Technology, Ocean University of ChinaSchool of Mechanical, Electrical, and Information Engineering, Shandong UniversityCollege of Computer Science and Technology, Qingdao UniversityCollege of Computer Science and Technology, China University of Petroleum (East China)School of Information and Control Engineering, Qingdao University of TechnologyMindRank AI ltd., HangzhouCollege of Computer Science and Technology, Ocean University of ChinaAbstract Short QT syndrome (SQTS) is a rare but dangerous genetic disease. In this research, we conducted a comprehensive in silico investigation into the arrhythmogenesis in KCNH2 T618I-associated SQTS using a multi-scale human ventricle model. A Markov chain model of I Kr was developed firstly to reproduce the experimental observations. It was then incorporated into cell, tissue, and organ models to explore how the mutation provided substrates for ventricular arrhythmias. Using this T618I Markov model, we explicitly revealed the subcellular level functional alterations by T618I mutation, particularly the changes of ion channel states that are difficult to demonstrate in wet experiments. The following tissue and organ models also successfully reproduced the changed dynamics of reentrant spiral waves and impaired rate adaptions in hearts of T618I mutation. In terms of pharmacotherapy, we replicated the different effects of a drug under various conditions using identical mathematical descriptions for drugs. This study not only simulated the actions of an effective drug (quinidine) at various physiological levels, but also elucidated why the I Kr inhibitor sotalol failed in SQT1 patients through profoundly analyzing its mutation-dependent actions.https://doi.org/10.1038/s41540-022-00254-5 |
| spellingShingle | Shugang Zhang Weigang Lu Fei Yang Zhen Li Shuang Wang Mingjian Jiang Xiaofeng Wang Zhiqiang Wei Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol npj Systems Biology and Applications |
| title | Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol |
| title_full | Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol |
| title_fullStr | Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol |
| title_full_unstemmed | Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol |
| title_short | Computational analysis of arrhythmogenesis in KCNH2 T618I mutation-associated short QT syndrome and the pharmacological effects of quinidine and sotalol |
| title_sort | computational analysis of arrhythmogenesis in kcnh2 t618i mutation associated short qt syndrome and the pharmacological effects of quinidine and sotalol |
| url | https://doi.org/10.1038/s41540-022-00254-5 |
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