Trimethyllysine predicts all-cause and cardiovascular mortality in community-dwelling adults and patients with coronary heart disease

Espen Ø Bjørnestad; Indu Dhar; Gard F T Svingen; Eva R Pedersen; Mads M Svenningsson; Grethe S Tell; Per M Ueland; Stein Ørn; Gerhard Sulo; Reijo Laaksonen; Ottar Nygård

doi:10.1093/ehjopen/oeab007

Trimethyllysine predicts all-cause and cardiovascular mortality in community-dwelling adults and patients with coronary heart disease

Eur Heart J Open. 2021 Jul 16;1(1):oeab007. doi: 10.1093/ehjopen/oeab007. eCollection 2021 Aug.

Authors

Espen Ø Bjørnestad¹, Indu Dhar², Gard F T Svingen³, Eva R Pedersen^{3

4}, Mads M Svenningsson³, Grethe S Tell⁵, Per M Ueland⁴, Stein Ørn¹, Gerhard Sulo⁶, Reijo Laaksonen⁷, Ottar Nygård^{2

3}

Affiliations

¹ Department of Cardiology, Stavanger University Hospital, Gerd-Ragna Bloch Thorsens gate 8, 4011 Stavanger, Norway.
² Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Postboks 7804, 5020 Bergen, Norway.
³ Department of Cardiology, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway.
⁴ Department of Clinical Science, University of Bergen, Postboks 7804 NO-5020 Bergen, Norway.
⁵ Department of Global Public Health and Primary Care, University of Bergen, Årstadveien 17, 5020 Bergen, Norway.
⁶ Centre for Disease Burden, Division of Mental and Physical Health, Norwegian Institute of Public Health, Zander Kaaesgate 7, 5015 Bergen, Norway.
⁷ Finnish Cardiovascular Research Center, University of Tampere, Tampere University Hospital, Arvo Ylpön Katu 34, 33520 Tampere, Finland.

Abstract

Aims: Trimethyllysine (TML) is involved in carnitine synthesis, serves as a precursor of trimethylamine N-oxide (TMAO) and is associated with cardiovascular events in patients with established coronary heart disease (CHD). We prospectively examined circulating TML as a predictor of all-cause and cardiovascular mortality in community-dwelling adults and patients with CHD.

Methods and results: By Cox regression modelling, risk associations were examined in 6393 subjects in the community-based Hordaland Health Study (HUSK). A replication study was conducted among 4117 patients with suspected stable angina pectoris in the Western Norway Coronary Angiography Cohort (WECAC). During a mean follow-up of 10.5 years in the HUSK-cohort, 884 (13.8%) subjects died, of whom 287 from cardiovascular causes. After multivariable adjustments for traditional cardiovascular risk factors, the hazard ratio (HR) [95% confidence interval (95% CI)] for all-cause mortality comparing the 4th vs. 1st TML-quartile was 1.66 (1.31-2.10, P < 0.001). Particularly strong associations were observed for cardiovascular mortality [HR (95% CI) 2.04 (1.32-3.15, P = 0.001)]. Corresponding risk-estimates in the WECAC (mean follow-up of 9.8 years) were 1.35 [1.10-1.66, P = 0.004] for all-cause and 1.45 [1.06-1.98, P = 0.02] for cardiovascular mortality. Significant correlations between plasma TML and TMAO were observed in both cohorts (r_s ≥ 0.42, P < 0.001); however, additional adjustments for TMAO did not materially influence the risk associations, and no effect modification by TMAO was found.

Conclusions: Elevated TML-levels were associated with increased risk of all-cause and cardiovascular mortality both in subjects with and without established CHD.

Keywords: Cardiovascular outcomes; Epidemiology; Mortality; Risk factor.