Abstract 19: Prognostic Value of Plasma Choline and Betaine Depend on the Intestinal Microflora-generated Metabolite Trimethylamine N-oxide

Abstract

Background Recent metabolomics and animal model studies show trimethylamine-N-oxide (TMAO), an intestinal microbiota-dependent metabolite formed from dietary phosphatidylcholine (PC), is linked with coronary artery disease (CAD) pathogenesis. Prognostic determinants of other PC metabolites recently associated with prevalent CAD risk, such as choline and betaine, have not been described. Methods We examined the relationship between fasting plasma choline, betaine, and TMAO and future risk of major adverse cardiac events (MACE=death, myocardial infraction, stroke) over 3-year follow-up in 3,916 subjects undergoing elective coronary angiography. All analytes were quantified by stable isotope dilution LC/MS/MS. Results In our study cohort (mean age 63±11 years, 64% male), median [IQR] TMAO, choline, and betaine levels were 3.7 [2.4-6.2] μM, 9.8 [7.9-12.2] μM, and 41.1 [32.5-52.1] μM, respectively. Modest but statistically significant correlations were noted between TMAO and choline (r=0.33, p<0.001) and between TMAO and betaine (r=0.09, p<0.001). Higher plasma TMAO, choline and betaine levels were associated with a 2.7-fold, 1.9-fold, and 1.4-fold increased risk of MACE, respectively (Quartiles 4 vs 1: p<0.01, each). Following adjustments for traditional risk factors and hsCRP, elevated TMAO (Quartiles 4 vs 1: Hazard ratio, 1.97 [95% CI 1.50-2.60], p<0.01), choline (HR 1.34 [95% CI 1.03-1.74], p<0.05) and betaine levels (HR 1.33 [95% CI 1.03-1.73], p<0.05) each predicted increased MACE risk, but only TMAO predicted MACE risk when all 3 metabolites were included in the model (HR, 1.73 [95% CI 1.3-2.31], p<0.01). Choline and betaine only predicted increased MACE risk in those with elevated TMAO levels. Conclusion Elevated plasma levels of TMAO, and to a lesser extent choline and betaine, are associated with incident MACE risk. However, high choline and betaine levels are only associated with higher risk of future MACE with concomitant increase in TMAO. Collectively, these findings further support the atherogenic associations between intestinal-microflora dependent metabolism of PC and atherosclerosis in humans.