Trimethylamine-N-oxide (TMAO) and risk of incident cardiovascular events in the multi ethnic study of Atherosclerosis

Trimethylamine-N-oxide (TMAO) is a gut microbiome-derived metabolite of choline, L-carnitine and lecithin, abundant in animal source foods. In experimental models, higher blood TMAO levels enhance atherosclerotic cardiovascular disease (ASCVD). However in humans, most prior studies have evaluated high risk or secondary prevention populations, and no studies have investigated relationships in a diverse, multi-ethnic population. We evaluated 6,767 US adults free of ASCVD at baseline in the community-based Multi-Ethnic Study of Atherosclerosis (MESA), including 38% identifying as White; 28%, as Black; 22%, as Hispanic; and 12%, as Chinese adults. Plasma TMAO was measured serially at baseline and 5-years, and its time-varying association with incident ASCVD determined using Cox proportional hazards. Multivariate analyses adjusted for time-varying demographics, lifestyle factors, medical history, lipid measures, antibiotic use and dietary habits. During median 11.3 years follow-up, 852 ASCVD events occurred. After multivariate adjustment, TMAO associated with higher risk of ASCVD in a dose-dependent fashion, with hazard ratios across quintiles of 1.02, 1.17, 1.23, and 1.33 (95% CI 1.02, 1.74), respectively, compared to the lowest quintile (P-trend = 0.01). Risk appeared possibly larger among Hispanic and Chinese adults; and among individuals with lower baseline renal function; although these interactions did not achieve statistical significance. Plasma concentrations of TMAO associated with higher risk of incident ASCVD in this multi-ethnic US cohort, supporting a need to test dietary and pharmacologic interventions targeting the diet-microbiome axis for potential cardiovascular risk prevention in diverse populations.