Variant Aldehyde Dehydrogenase 2 (ALDH2*2) as a Risk Factor for Mechanical LA Substrate Formation and Atrial Fibrillation with Modest Alcohol Consumption in Ethnic Asians

Hung, Chung‐Lieh; Sung, Kuo‐Tzu; Chang, Shun-Chuan; Liu, Yen-Yu; Kuo, Jen‐Yuan; Huang, Wen‐Hung; Su, Cheng‐Huang; Liu, Chuan-Chuan; Tsai, Shin‐Yi; Liu, Chia‐Yuan; Lee, An‐Sheng; Pan, Szu-Hua; Wang, Shih‐Wei; Hou, Charles Jia‐Yin; Hung, Ta‐Chuan; Yeh, Hung‐I

doi:10.3390/biom11111559

Cited by 6 publications

(8 citation statements)

References 43 publications

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“…A recent study in Asians showed that ALDH2*2 increased the risk of atrial fibrillation in habitual drinkers, suggesting that there may be synergistic effects of ALDH2*2 and chronic alcohol consumption on cardiac arrhythmias ( 10 ). To investigate whether ALDH2*2 was associated with higher risk of CAD in chronic drinkers, we examined genetic information and drinking status of human participants from the UK Biobank ( 23 ).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, alcohol consumption is a well-known risk factor for CAD ( 8 ). Although ethanol is not a primary contributor to CAD in studies of non-Asian individuals, it may have a substantial effect on ALDH2*2 carriers of Asian descent ( 9 , 10 ). Thus, it is important to determine the combined effect of ALDH2*2 and alcohol consumption on CAD to develop preventative strategies to reduce CAD risk among ALDH2*2 carriers.…”

Section: Introductionmentioning

confidence: 99%

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SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant

Guo

Liu

et al. 2023

Sci. Transl. Med.

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The common aldehyde dehydrogenase 2 ( ALDH2 ) alcohol flushing variant known as ALDH2*2 affects ∼8% of the world’s population. Even in heterozygous carriers, this missense variant leads to a severe loss of ALDH2 enzymatic activity and has been linked to an increased risk of coronary artery disease (CAD). Endothelial cell (EC) dysfunction plays a determining role in all stages of CAD pathogenesis, including early-onset CAD. However, the contribution of ALDH2*2 to EC dysfunction and its relation to CAD are not fully understood. In a large genome-wide association study (GWAS) from Biobank Japan, ALDH2*2 was found to be one of the strongest single-nucleotide polymorphisms associated with CAD. Clinical assessment of endothelial function showed that human participants carrying ALDH2*2 exhibited impaired vasodilation after light alcohol drinking. Using human induced pluripotent stem cell–derived ECs (iPSC-ECs) and CRISPR-Cas9–corrected ALDH2*2 iPSC-ECs, we modeled ALDH2*2 -induced EC dysfunction in vitro, demonstrating an increase in oxidative stress and inflammatory markers and a decrease in nitric oxide (NO) production and tube formation capacity, which was further exacerbated by ethanol exposure. We subsequently found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin mitigated ALDH2*2 -associated EC dysfunction. Studies in ALDH2*2 knock-in mice further demonstrated that empagliflozin attenuated ALDH2*2 -mediated vascular dysfunction in vivo. Mechanistically, empagliflozin inhibited Na + /H + -exchanger 1 (NHE-1) and activated AKT kinase and endothelial NO synthase (eNOS) pathways to ameliorate ALDH2*2 -induced EC dysfunction. Together, our results suggest that ALDH2*2 induces EC dysfunction and that SGLT2i may potentially be used as a preventative measure against CAD for ALDH2*2 carriers.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant

Guo

Liu

et al. 2023

Sci. Transl. Med.

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“…ALDH2 plays a vital function in resisting oxidative stress by reducing reactive oxygen species and eliminating reactive aldehydes produced by lipid peroxidation, such as 4-hydroxy-2-non-enal (4-HNE) ( 14 – 16 ). Undoubtedly, oxidative stress plays an important role in the occurrence of AF ( 17 ) and is contained in the pathophysiological process for certain cardiovascular diseases which induce AF ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

Association of acetaldehyde dehydrogenase 2 rs671 polymorphism with the occurrence and progression of atrial fibrillation

Han

et al. 2022

Front. Cardiovasc. Med.

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BackgroundAcetaldehyde dehydrogenase 2 (ALDH2) is an essential enzyme in alcohol metabolism, playing a vital function in resisting oxidative stress. Lots of gene variants have been associated with atrial fibrillation (AF), among which the association between ALDH2 rs671 polymorphism and AF is variable. This study aimed to investigate the relationship between ALDH2 rs671 polymorphism and AF occurrence or progression and AF recurrence after catheter ablation.MethodsA total of 924 subjects were enrolled in the study. The ALDH2 genotypes are composed of wild-type homozygotes (ALDH2*1/*1), heterozygotes (ALDH2*1/*2), and mutant homozygotes (ALDH2*2/*2), in which the genotypes ALDH2*1/*2 and ALDH2*2/*2 are combined into the ALDH2*2. Univariate and multivariate logistic regression analyses were performed to investigate the association between ALDH2*2 and AF occurrence and progression. COX regression analysis was used to explore the association of ALDH2*2 with AF recurrence after catheter ablation.ResultsThe prevalence of AF differed significantly between the ALDH2*2 group (102/251) and ALDH2*1/*1 group (330/673) (P = 0.023). For AF occurrence, in the univariate analysis, alcohol consumption was a risk factors (OR: 1.503, P = 0.003), whereas ALDH2*2 was a protective factor (OR: 0.712, P = 0.023). In the multivariate analysis, alcohol consumption (P = 0.156) and ALDH2*2 (P = 0.096) were no longer independent factors. ALDH2*2 with non-drinking was associated with a decreased AF occurrence (OR: 0.65, P = 0.021), whereas ALDH2*2 with drinking was not (P = 0.365). For AF progression, multivariate analysis revealed ALDH2*2 could promote persistent AF in female AF patients (OR: 2.643, P = 0.008). Cox regression analysis suggested that ALDH2*2 (P = 0.752) was not a risk factor for AF recurrence after catheter ablation during a median 6 months follow-up.ConclusionWhile ALDH2*2 was not directly related to AF, ALDH2*2 with non-drinking was associated with a decreased incidence of AF. ALDH2*2 may accelerate AF progression in female patients, increasing the likelihood of developing persistent AF. Therefore, individuals with ALDH2*2 should refrain from consuming alcohol to decrease the onset and progression of AF.

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“…In a study of 249 Asians, modest alcohol consumption was associated with an accumulation of 4-hydroxy-trans-2-nonenal (4-HNE), an ROS-generated aldehyde adduct, prolonged PR interval in the ECG, and a reduction in echocardiographic peak atrial longitudinal strain (PALS) and phasic strain rates. In individuals with ALDH2 polymorphism, an increased association between the daily alcohol intake and LA ejection fraction, PALS and phasic reservoir, and booster functions was observed [ 155 ].…”

Section: Atrial Myocardium and Alcoholmentioning

confidence: 99%

Harmful Impact of Tobacco Smoking and Alcohol Consumption on the Atrial Myocardium

Ohlrogge

Frost

Schnabel

2022

Cells

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Tobacco smoking and alcohol consumption are widespread exposures that are legal and socially accepted in many societies. Both have been widely recognized as important risk factors for diseases in all vital organ systems including cardiovascular diseases, and with clinical manifestations that are associated with atrial dysfunction, so-called atrial cardiomyopathy, especially atrial fibrillation and stroke. The pathogenesis of atrial cardiomyopathy, atrial fibrillation, and stroke in context with smoking and alcohol consumption is complex and multifactorial, involving pathophysiological mechanisms, environmental, and societal aspects. This narrative review summarizes the current literature regarding alterations in the atrial myocardium that is associated with smoking and alcohol.

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Variant Aldehyde Dehydrogenase 2 (ALDH2*2) as a Risk Factor for Mechanical LA Substrate Formation and Atrial Fibrillation with Modest Alcohol Consumption in Ethnic Asians

Cited by 6 publications

References 43 publications

SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant

SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant

Association of acetaldehyde dehydrogenase 2 rs671 polymorphism with the occurrence and progression of atrial fibrillation

Harmful Impact of Tobacco Smoking and Alcohol Consumption on the Atrial Myocardium

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