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. 2025 Oct 1;10(10):1000-1009.
doi: 10.1001/jamacardio.2025.2698.

Circulating Trimethylamine N-Oxide and Growth Rate of Abdominal Aortic Aneurysms and Surgical Risk

Scott J Cameron  1   2 , Xinmin S Li  1   3 , Tyler W Benson  4   5 , Kelsey A Conrad  4   5   6 , Zeneng Wang  1   3 , Salma Fleifil  4   5 , Lars Maegdefessel  7   8   9 , Kevin Mani  10 , Martin Björck  10 , Alliefair Scalise  2 , Michael Pham  2 , Sharon Shim  2 , Anders Wanhainen  10   11 , Betemariam Sharew  1 , Melissa Y Tian  1 , Yuping Wu  12 , Aldons J Lusis  13   14   15 , Sean P Lyden  16 , W H Wilson Tang  1   2   3 , A Phillip Owens 3rd  4   5   6 , Stanley L Hazen  1   2   3
Affiliations

Circulating Trimethylamine N-Oxide and Growth Rate of Abdominal Aortic Aneurysms and Surgical Risk

Scott J Cameron et al. JAMA Cardiol. .

Abstract

Importance: Plasma levels of the gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) are associated with prevalent abdominal aortic aneurysms (AAA) in humans and fostering of AAA progression in animal models; therapeutic targeting of TMAO production blocks AAA progression and rupture in multiple mouse models. A blood biomarker that identifies individuals at risk for incident AAA development, accelerated AAA expansion, or recommendation for surgical AAA repair could be an asset for risk stratification.

Objective: To determine whether TMAO is associated with risk for AAA development, rapid AAA expansion, and risk for recommended surgical intervention.

Design, setting, and participants: This was a prospective cohort study using 2 independent clinical cohorts undergoing aorta imaging surveillance: a European cohort and a US cohort. Included in this study were patients undergoing serial imaging surveillance of the aorta and long-term outcome monitoring. Patients were recruited from single-center studies in Uppsala, Sweden, and Cleveland, Ohio. Study data were analyzed from October 2023 to May 2025.

Exposures: Plasma TMAO concentrations measured by stable isotope dilution liquid chromatography with tandem mass spectrometry.

Main outcomes and measures: The association of TMAO levels with AAA risk, fast-growing AAA (≥4.0 mm per year), and recommended surgical intervention (≥4.0 mm per year or ≥5.5 cm diameter).

Results: The European cohort included 237 individuals (median [IQR] age, 65 [65-73] years; 211 male [89.0%]), and the US cohort included 658 individuals (median [IQR] age, 63 [57-70] years; 523 male [79.5%]). In the European cohort, elevated circulating TMAO was significantly associated with AAA risk independent of traditional risk factors and kidney function. Moreover, elevated TMAO predicted both greater risk for fast-growing AAA (adjusted odds ratio [aOR], 2.75; 95% CI, 1.20-6.79) and recommended surgical intervention (aOR, 2.67; 95% CI, 1.24-6.09). Similar patterns were observed in the US cohort and the combined European and US cohort, with heightened circulating TMAO corresponding with significantly increased adjusted risk for fast-growing AAA (US cohort: aOR, 2.71; 95% CI, 1.53-4.80; combined cohort: aOR, 2.30; 95% CI, 1.47-3.62) and recommended surgical intervention (US cohort: aOR, 2.73; 95% CI, 1.56-4.80; combined cohort: aOR, 2.41; 95% CI, 1.55-3.74). Addition of TMAO to base models containing traditional cardiovascular risk factors resulted in significant improvement in both risk estimation for fast-growing AAA and predicting recommended surgical intervention.

Conclusion and relevance: Results of this cohort study suggest that elevated circulating TMAO levels were associated with increased risk of AAA and identified patients at heightened risk for fast-growing AAA and recommended surgical intervention. TMAO may help identify individuals who may benefit from more frequent surveillance imaging and early surgical intervention to prevent aortic dissection or rupture.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Wang reported receiving royalties from Cleveland Heart Lab and Proctor & Gamble and having a patent for trimethylamine-containing compounds for diagnosis and prediction of disease issued. Dr Sharew reported receiving grants from the American Heart Association Scholarship for Cardiovascular Disease and Stroke during the conduct of the study. Dr Tang reported receiving consulting fees from Zehna Therapeutics, Cardiol Therapeutics, Genomics, Boston Scientific, WhiteSwell Inc, CardiaTec Biosciences, Bristol Myers Squibb, Alleviant Medical, Alexion Pharmaceuticals, Salubris Biotherapeutics, and BioCardia and serving as author/editor for the American Board of Internal Medicine, Springer, and Belvoir Media Group outside the submitted work. Dr Owens reported serving as associate editor for the American Heart Association journal Arteriosclerosis, Thrombosis, and Vascular Biology outside the submitted work. Dr Hazen reported receiving grants from the National Institutes of Health, research funds from Zehna Therapeutics, and royalties for patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics from Cleveland HeartLab, Quest Diagnostics, and Procter & Gamble. No other disclosures were reported.

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