Circulating trimethyllysine predicts total and cardiovascular mortality in patients with and without coronary heart disease

Abstract

Abstract Background The carnitine precursor trimethyllysine (TML) is associated with the microbiota-derived metabolite trimethylamine N-oxide (TMAO) and predicts future cardiovascular events in patients with established coronary heart disease (CHD). Purpose To examine circulating TML as a predictor of total and cardiovascular mortality in two independent cohorts of subjects with or without CHD. Methods By Cox regression modelling, risk associations were examined in 6393 subjects in the community-based Hordaland Health Study (HUSK). A replication study was performed among 4117 patients undergoing coronary angiography for suspected stable angina pectoris in the Western Norway Coronary Angiography Cohort (WECAC). Results During a median follow-up of 10.9 years in the HUSK-cohort, 884 (13.8%) subjects died, of whom 287 from cardiovascular causes. After adjustments for traditional cardiovascular risk factors, the hazard ratio (HR) (95% CI) for total mortality comparing the 4th vs. 1st TML-quartile was 1.66 (1.31–2.10, p<0.001). Particularly strong associations were observed with cardiovascular mortality (HR [95% CI] 2.04 [1.32–3.15, p=0.001]). Corresponding risk estimates in the WECAC-cohort (median follow-up of 10.3 years) were 1.35 (1.10–1.66, p=0.004) for total and 1.45 (1.06–1.98, p=0.02) for cardiovascular mortality. Additional adjustments for plasma TMAO did not materially influence the risk estimates in either cohort, and no effect modification by TMAO was observed. Conclusions Circulating TML is associated with increased risk of total and cardiovascular mortality in both subjects with and without CHD. Funding Acknowledgement Type of funding sources: None.