Plasma TMAO as a predictor of incident lower extremity arterial disease: a prospective cohort study in Thailand

Abstract

Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has been implicated in atherosclerosis and adverse cardiovascular outcomes, but prospective data on lower extremity arterial disease (LEAD) in Asian populations remain limited. We conducted a single-center prospective cohort study of 155 Thai patients (mean age 63.5 ± 8.8 years; 64.5% male) with angiographically confirmed coronary artery disease and without LEAD at baseline. Plasma TMAO levels were measured by nuclear magnetic resonance spectroscopy and categorized into quartiles. Incident LEAD was assessed after 3 years, and all-cause mortality after 5 years. Multivariable logistic regression was used to evaluate incident LEAD, whereas Cox proportional hazards models were used to assess mortality. Higher TMAO quartiles were associated with progressively greater odds of incident LEAD (P for trend < 0.001). Compared with the lowest quartile, participants in the third and fourth quartiles had adjusted odds ratios of 5.30 (95% CI 1.32–20.48; P = 0.018) and 14.0 (95% CI 3.38–57.64; P < 0.001), respectively. The median follow-up duration, estimated using the reverse Kaplan–Meier method, was 59.1 months (interquartile range 58.3–60.3 months). Higher TMAO levels were also associated with increased 5-year all-cause mortality. In fully adjusted Cox models, the highest TMAO quartile was independently associated with mortality (hazard ratio 4.17, 95% CI 1.11–15.76; P = 0.035), and Kaplan–Meier analysis demonstrated progressively lower survival across increasing quartiles (log-rank P = 0.005). These findings support elevated plasma TMAO as an independent predictor of incident LEAD and long-term mortality in an Asian population. Trial Registration: This was an observational, non-interventional cohort study. The study was registered in the Thai Clinical Trials Registry to enhance transparency of reporting. Thai Clinical Trials Registry (TCTR20250613001).