A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice

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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article number610
JournalCommunications Biology
Volume6
Issue number1
DOIs
Publication statusPublished - Dec 2023

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Biochemistry,Genetics and Molecular Biology
  • General Agricultural and Biological Sciences

Fingerprint

Dive into the research topics of 'A Common East Asian aldehyde dehydrogenase 2*2 variant promotes ventricular arrhythmia with chronic light-to-moderate alcohol use in mice'. Together they form a unique fingerprint.

Cite this