A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice
Abstract Chronic heavy alcohol use is associated with lethal arrhythmias. Whether common East Asian-specific aldehyde dehydrogenase deficiency (ALDH2*2) contributes to arrhythmogenesis caused by low level alcohol use remains unclear. Here we show 59 habitual alcohol users carrying ALDH2 rs671 have l...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-06-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-04985-x |
| _version_ | 1797806605723500544 |
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| author | An-Sheng Lee Yen-Ling Sung Szu-Hua Pan Kuo-Tzu Sung Cheng-Huang Su Shiao-Li Ding Ying-Jui Lu Chin-Ling Hsieh Yun-Fang Chen Chuan-Chuan Liu Wei-Yu Chen Xuan-Ren Chen Fa-Po Chung Shih-Wei Wang Che-Hong Chen Daria Mochly-Rosen Chung-Lieh Hung Hung-I Yeh Shien-Fong Lin |
| author_facet | An-Sheng Lee Yen-Ling Sung Szu-Hua Pan Kuo-Tzu Sung Cheng-Huang Su Shiao-Li Ding Ying-Jui Lu Chin-Ling Hsieh Yun-Fang Chen Chuan-Chuan Liu Wei-Yu Chen Xuan-Ren Chen Fa-Po Chung Shih-Wei Wang Che-Hong Chen Daria Mochly-Rosen Chung-Lieh Hung Hung-I Yeh Shien-Fong Lin |
| author_sort | An-Sheng Lee |
| collection | DOAJ |
| description | Abstract Chronic heavy alcohol use is associated with lethal arrhythmias. Whether common East Asian-specific aldehyde dehydrogenase deficiency (ALDH2*2) contributes to arrhythmogenesis caused by low level alcohol use remains unclear. Here we show 59 habitual alcohol users carrying ALDH2 rs671 have longer QT interval (corrected) and higher ventricular tachyarrhythmia events compared with 137 ALDH2 wild-type (Wt) habitual alcohol users and 57 alcohol non-users. Notably, we observe QT prolongation and a higher risk of premature ventricular contractions among human ALDH2 variants showing habitual light-to-moderate alcohol consumption. We recapitulate a human electrophysiological QT prolongation phenotype using a mouse ALDH2*2 knock-in (KI) model treated with 4% ethanol, which shows markedly reduced total amount of connexin43 albeit increased lateralization accompanied by markedly downregulated sarcolemmal Nav1.5, Kv1.4 and Kv4.2 expressions compared to EtOH-treated Wt mice. Whole-cell patch-clamps reveal a more pronounced action potential prolongation in EtOH-treated ALDH2*2 KI mice. By programmed electrical stimulation, rotors are only provokable in EtOH-treated ALDH2*2 KI mice along with higher number and duration of ventricular arrhythmia episodes. The present research helps formulate safe alcohol drinking guideline for ALDH2 deficient population and develop novel protective agents for these subjects. |
| first_indexed | 2024-03-13T06:09:48Z |
| format | Article |
| id | doaj.art-d4292105e62146ef9184cd38ab39ac07 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-13T06:09:48Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-d4292105e62146ef9184cd38ab39ac072023-06-11T11:22:37ZengNature PortfolioCommunications Biology2399-36422023-06-016111510.1038/s42003-023-04985-xA Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in miceAn-Sheng Lee0Yen-Ling Sung1Szu-Hua Pan2Kuo-Tzu Sung3Cheng-Huang Su4Shiao-Li Ding5Ying-Jui Lu6Chin-Ling Hsieh7Yun-Fang Chen8Chuan-Chuan Liu9Wei-Yu Chen10Xuan-Ren Chen11Fa-Po Chung12Shih-Wei Wang13Che-Hong Chen14Daria Mochly-Rosen15Chung-Lieh Hung16Hung-I Yeh17Shien-Fong Lin18Department of Medicine, MacKay Medical CollegeInstitute of Biomedical Engineering, College of Electrical and Computer Engineering, National Yang Ming Chiao Tung UniversityGraduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan UniversityDepartment of Medicine, MacKay Medical CollegeDepartment of Medicine, MacKay Medical CollegeDepartment of Medical Research, MacKay Memorial HospitalDepartment of Medical Research, MacKay Memorial HospitalDepartment of Medical Research, MacKay Memorial HospitalDepartment of Medicine, MacKay Medical CollegeDepartment of Physiology Examination, MacKay Memorial HospitalDepartment of Medicine, MacKay Medical CollegeGraduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan UniversityHeart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General HospitalDepartment of Medicine, MacKay Medical CollegeDepartment of Chemical and Systems Biology, Stanford University, School of MedicineDepartment of Chemical and Systems Biology, Stanford University, School of MedicineDepartment of Medicine, MacKay Medical CollegeDepartment of Medicine, MacKay Medical CollegeInstitute of Biomedical Engineering, College of Electrical and Computer Engineering, National Yang Ming Chiao Tung UniversityAbstract Chronic heavy alcohol use is associated with lethal arrhythmias. Whether common East Asian-specific aldehyde dehydrogenase deficiency (ALDH2*2) contributes to arrhythmogenesis caused by low level alcohol use remains unclear. Here we show 59 habitual alcohol users carrying ALDH2 rs671 have longer QT interval (corrected) and higher ventricular tachyarrhythmia events compared with 137 ALDH2 wild-type (Wt) habitual alcohol users and 57 alcohol non-users. Notably, we observe QT prolongation and a higher risk of premature ventricular contractions among human ALDH2 variants showing habitual light-to-moderate alcohol consumption. We recapitulate a human electrophysiological QT prolongation phenotype using a mouse ALDH2*2 knock-in (KI) model treated with 4% ethanol, which shows markedly reduced total amount of connexin43 albeit increased lateralization accompanied by markedly downregulated sarcolemmal Nav1.5, Kv1.4 and Kv4.2 expressions compared to EtOH-treated Wt mice. Whole-cell patch-clamps reveal a more pronounced action potential prolongation in EtOH-treated ALDH2*2 KI mice. By programmed electrical stimulation, rotors are only provokable in EtOH-treated ALDH2*2 KI mice along with higher number and duration of ventricular arrhythmia episodes. The present research helps formulate safe alcohol drinking guideline for ALDH2 deficient population and develop novel protective agents for these subjects.https://doi.org/10.1038/s42003-023-04985-x |
| spellingShingle | An-Sheng Lee Yen-Ling Sung Szu-Hua Pan Kuo-Tzu Sung Cheng-Huang Su Shiao-Li Ding Ying-Jui Lu Chin-Ling Hsieh Yun-Fang Chen Chuan-Chuan Liu Wei-Yu Chen Xuan-Ren Chen Fa-Po Chung Shih-Wei Wang Che-Hong Chen Daria Mochly-Rosen Chung-Lieh Hung Hung-I Yeh Shien-Fong Lin A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice Communications Biology |
| title | A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice |
| title_full | A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice |
| title_fullStr | A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice |
| title_full_unstemmed | A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice |
| title_short | A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice |
| title_sort | common east asian aldehyde dehydrogenase 2 2 variant promotes ventricular arrhythmia with chronic light to moderate alcohol use in mice |
| url | https://doi.org/10.1038/s42003-023-04985-x |
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