Gut microbe-generated metabolite trimethylamine N-oxide and risk of abdominal aortic aneurysm: a cohort study

BACKGROUND AND AIMS: Abdominal aortic aneurysms (AAAs) are associated with increased mortality in older adults. The gut microbe-generated metabolite trimethylamine N-oxide (TMAO) has been linked to AAA risk and promotes AAA progression in animal models. Whether circulating TMAO levels in apparently healthy older adults predict AAA development and adverse AAA outcomes remains unknown. METHODS: Plasma TMAO levels were quantified using stable isotope dilution liquid chromatography-tandem mass spectrometry in 4442 community-dwelling adults (aged ≥65 years) in the Cardiovascular Health Study. Participants underwent ultrasound screening and prospective follow-up. Multivariable models assessed associations of serial TMAO levels with AAA development and incident risk for adverse AAA events, adjusting for traditional risk factors, renal function, socioeconomic status, and cardiometabolic lifestyle factors. RESULTS: Higher baseline TMAO levels were associated with larger infrarenal aortic diameter and increased AAA risk. Over a median 12.2-year follow-up (54 402 person-years), 79 participants experienced incident adverse AAA events (repair, rupture, or AAA-related death). Elevated TMAO levels were independently associated with higher risk of adverse AAA events, whether modelled continuously [adjusted hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.07-1.54 per doubling], by quantiles (HR for tertile 3 vs tertile 1: 2.46, 95% CI 1.32-4.59), or using a clinical threshold (≥6.2 µM; HR 1.93, 95% CI 1.25-2.99). CONCLUSIONS: In community-based older adults, higher TMAO levels were independently associated with increased risk of AAA development and adverse AAA events. Findings support TMAO as a novel risk factor for AAA and a potential therapeutic target for AAA prevention.