Cameron Scott J, Li Xinmin S, Benson Tyler W, Conrad Kelsey A, Wang Zeneng, Fleifil Salma, Maegdefessel Lars, Mani Kevin, Björck Martin, Scalise Alliefair, Pham Michael, Shim Sharon, Wanhainen Anders, Sharew Betemariam, Tian Melissa Y, Wu Yuping, Lusis Aldons J, Lyden Sean P, Tang W H Wilson, Owens A Phillip, Hazen Stanley L
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio.
JAMA Cardiol. 2025 Aug 20. doi: 10.1001/jamacardio.2025.2698.
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.
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.
Plasma TMAO concentrations measured by stable isotope dilution liquid chromatography with tandem mass spectrometry.
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).
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.
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.
肠道微生物群依赖的代谢产物氧化三甲胺（TMAO）的血浆水平与人类腹主动脉瘤（AAA）的患病率以及动物模型中AAA进展的促进有关；在多个小鼠模型中，针对TMAO产生的治疗靶点可阻止AAA进展和破裂。一种能够识别发生AAA、AAA加速扩张或建议进行AAA手术修复风险个体的血液生物标志物，可能有助于风险分层。
确定TMAO是否与AAA发生风险、AAA快速扩张以及建议进行手术干预的风险相关。
设计、地点和参与者：这是一项前瞻性队列研究，使用了2个独立的接受主动脉成像监测的临床队列：一个欧洲队列和一个美国队列。本研究纳入了接受主动脉系列成像监测和长期结局监测的患者。患者从瑞典乌普萨拉和俄亥俄州克利夫兰的单中心研究中招募。研究数据于2023年10月至2025年5月进行分析。
通过稳定同位素稀释液相色谱-串联质谱法测量血浆TMAO浓度。
TMAO水平与AAA风险、快速生长的AAA（每年≥4.0 mm）以及建议的手术干预（每年≥4.0 mm或直径≥5.5 cm）之间的关联。
欧洲队列包括237名个体（年龄中位数[四分位间距]，65[65 - 73]岁；男性211名[89.0%]），美国队列包括658名个体（年龄中位数[四分位间距]，63[57 - 70]岁；男性523名[79.5%]）。在欧洲队列中，循环TMAO升高与AAA风险显著相关，且独立于传统风险因素和肾功能。此外，TMAO升高预示着快速生长的AAA风险更高（调整后的优势比[aOR]，2.75；95%置信区间，1.20 - 6.79）以及建议进行手术干预（aOR，2.67；95%置信区间，1.24 - 6.09）。在美国队列以及欧洲和美国联合队列中观察到类似模式，循环TMAO升高与快速生长的AAA调整后风险显著增加（美国队列：aOR，2.71；95%置信区间，1.53 - 4.80；联合队列：aOR，2.
