Loop diuretics decrease the renal elimination rate and increase the plasma levels of trimethylamine-N-oxide.

AIMS: Trimethylamine-N-oxide (TMAO) is a novel cardiovascular risk marker. We explored the association of commonly used cardiovascular medications with TMAO levels in patients and validated the identified associations in mice. METHODS: Detailed history of drug treatment was recorded in 300 patients with cardiovascular disease without diabetes in an observational, cross-sectional study. Animal study was performed in CD1 mice. RESULTS: Median plasma TMAO (interquartile range) level was 2.144 (1.570-3.104) µmol l-1 . Among nine cardiovascular drug groups, the use of loop diuretics (0.510 ± 0.296 in users vs. 0.336 ± 0.272 in nonusers, P = 0.008) and mineralocorticoid receptor antagonists (0.482 ± 0.293 in users vs. 0.334 ± 0.272 in nonusers, P = 0.007) was associated with increased log-TMAO. Acute concomitant administration of furosemide or torasemide with TMAO in mice significantly influenced TMAO pharmacokinetic profile and almost doubled the plasma TMAO area under the curve. Furosemide decreased the TMAO excretion rate by 1.9-fold during the first 30 min after administration and increased TMAO concentrations in kidney, heart and liver, suggesting the interaction of furosemide and TMAO with efflux transporters. The concentrations of TMAO in blood plasma after the administration of the organic anion transporter inhibitor probenecid were not different from those of the control group, suggesting an effect not mediated by organic anion transporters. CONCLUSIONS: Loop diuretics increased plasma TMAO concentration by decreasing its urinary excretion rate. Loop diuretic use should be considered a potential confounder in TMAO studies.

Diabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels.

Recent studies have revealed strong associations between systemic trimethylamine N-oxide (TMAO) levels, atherosclerosis and cardiovascular risk. In addition, plasma L-carnitine levels in patients with high TMAO concentrations predicted an increased risk for cardiovascular disease and incident major adverse cardiac events. The aim of the present study was to investigate the relation between TMAO and L-carnitine plasma levels and diabetes. Blood plasma samples were collected from 12 and 20 weeks old db/db mice and patients undergoing percutaneous coronary intervention. Diabetic compared to non-diabetic db/L mice presented 10-fold higher TMAO, but lower L-carnitine plasma concentrations at 12 weeks of age. After 8 weeks of observation, diabetic db/db mice had significantly increased body weight, insulin resistance and TMAO concentration in comparison to non-diabetic control. In 191 patients undergoing percutaneous coronary intervention the median (interquartile range) plasma concentration of TMAO was 1.8 (1.2-2.6) µmol/L. Analysis of the samples showed a bivariate association of TMAO level with age, total cholesterol and L-carnitine. The multivariate linear regression analysis revealed that, in addition to L-carnitine as the strongest predictor of log transformed TMAO (p<0.001), the parameters of age, diabetes status and body mass index (BMI) were independently associated with increased log transformed TMAO levels (p<0.01).Our data provide evidence that age, diabetes and BMI are associated with higher TMAO levels independently of L-carnitine. These data support the hypothesis of TMAO as a cardiovascular risk marker and warrant further investigation of TMAO for diabetes research applications.