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A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice
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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10244406/ https://www.ncbi.nlm.nih.gov/pubmed/37280327 http://dx.doi.org/10.1038/s42003-023-04985-x |
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author | Lee, An-Sheng Sung, Yen-Ling Pan, Szu-Hua Sung, Kuo-Tzu Su, Cheng-Huang Ding, Shiao-Li Lu, Ying-Jui Hsieh, Chin-Ling Chen, Yun-Fang Liu, Chuan-Chuan Chen, Wei-Yu Chen, Xuan-Ren Chung, Fa-Po Wang, Shih-Wei Chen, Che-Hong Mochly-Rosen, Daria Hung, Chung-Lieh Yeh, Hung-I Lin, Shien-Fong |
author_facet | Lee, An-Sheng Sung, Yen-Ling Pan, Szu-Hua Sung, Kuo-Tzu Su, Cheng-Huang Ding, Shiao-Li Lu, Ying-Jui Hsieh, Chin-Ling Chen, Yun-Fang Liu, Chuan-Chuan Chen, Wei-Yu Chen, Xuan-Ren Chung, Fa-Po Wang, Shih-Wei Chen, Che-Hong Mochly-Rosen, Daria Hung, Chung-Lieh Yeh, Hung-I Lin, Shien-Fong |
author_sort | Lee, An-Sheng |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10244406 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-102444062023-06-08 A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice Lee, An-Sheng Sung, Yen-Ling Pan, Szu-Hua Sung, Kuo-Tzu Su, Cheng-Huang Ding, Shiao-Li Lu, Ying-Jui Hsieh, Chin-Ling Chen, Yun-Fang Liu, Chuan-Chuan Chen, Wei-Yu Chen, Xuan-Ren Chung, Fa-Po Wang, Shih-Wei Chen, Che-Hong Mochly-Rosen, Daria Hung, Chung-Lieh Yeh, Hung-I Lin, Shien-Fong Commun Biol Article 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. Nature Publishing Group UK 2023-06-06 /pmc/articles/PMC10244406/ /pubmed/37280327 http://dx.doi.org/10.1038/s42003-023-04985-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lee, An-Sheng Sung, Yen-Ling Pan, Szu-Hua Sung, Kuo-Tzu Su, Cheng-Huang Ding, Shiao-Li Lu, Ying-Jui Hsieh, Chin-Ling Chen, Yun-Fang Liu, Chuan-Chuan Chen, Wei-Yu Chen, Xuan-Ren Chung, Fa-Po Wang, Shih-Wei Chen, Che-Hong Mochly-Rosen, Daria Hung, Chung-Lieh Yeh, Hung-I Lin, Shien-Fong A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice |
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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10244406/ https://www.ncbi.nlm.nih.gov/pubmed/37280327 http://dx.doi.org/10.1038/s42003-023-04985-x |
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