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Get a Red Face After Drinking? You May Have a Higher Risk of Heart Disease

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A new study has found that a gene variant that causes a flush reaction after alcohol consumption also increases inflammation and impacts circulation. This finding could explain why individuals carrying this gene variant also have an increased risk of developing a common type of heart disease. The study also identified a common drug that may be able to mitigate this impact.

The research, published in Science Translational Medicine, pairs studies conducted in cells and mice with analysis of genomic data taken from Biobank resources in Japan and the UK.

Flushing out alcohol’s link to heart disease

Excessive drinking has an infamously large list of implications for human health, from short-term impacts such as headache, nausea and a desire to consume large amounts of fast food, to longer term impacts on cancer risk and liver function.

But these health impacts, for much of the human population, are significantly mitigated by the activity of an enzyme called mitochondrial aldehyde dehydrogenase (ALDH2). This breaks down alcohol into less harmful components in a multi-step process. First, ethanol (the chemical name for alcohol) is transformed into a compound called acetaldehyde by an enzyme called alcohol dehydrogenase. Acetaldehyde is then rapidly broken down into acetate by ALDH2. This is just as well, because acetaldehyde is a highly toxic molecule that is responsible for many of the damaging effects of alcohol. But for individuals with an ALDH2*2 gene variant, the process isn’t so straightforward. Their ALDH2 enzyme has significantly reduced function. As a result, toxic acetaldehyde hangs around for far longer in their bodies, imparting worse health effects from excessive drinking (and more severe hangovers). This variant is almost absent in most parts of the world except East Asia, where the variant is present in roughly a third of people. The “flush” reaction is a visible sign of impaired ALDH2 activity.

People who drink despite having this genotype are at an increased risk of cancer and also have up to a 48% increased risk of heart disease. How this latter disease links to ALDH2 activity has remained unclear. To tease out this link, the team, led by senior author Joseph C. Wu, also director of the Stanford Cardiovascular Institute, performed a genome-wide analysis on 29,319 cases of coronary artery disease and 183,134 controls from Biobank Japan. After confirming the strong link between the ALDH2*2 variant and heart disease in their cohort and in a second group recorded by the UK Biobank, they looked at a small sample of nine affected individuals. After one standard drink, the researchers noted that these people had reduced function in their endothelial cells, which play a key role in determining the risk of a common type of heart disease, coronary artery disease.

The researchers deciphered the mechanisms underlying this link in subsequent studies in mice and cells. They created stem cells from people with the ALDH2*2 variant. When directed to become endothelial cells, these cells showed increased signs of stress and inflammation, which became worse after alcohol exposure.

But these effects could be rescued with the addition of a commonly available drug, empagliflozin. Usually used to treat type 2 diabetes, empagliflozin also improved circulation in mice with the ALDH2*2 variant. These promising findings, say the authors, are just the first step and must be replicated in future studies. The team only used male mice and say that further studies using female mice are also required.

Reference: Guo H, Yu X, Liu Y et al. SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant. Sci. Trans. Med. 2023; 15. doi: 10.1126/scitranslmed.abp9952 .