Tryptophan metabolites and incident cardiovascular disease: The EPIC-Norfolk prospective population study

被引:14
作者
Teunis, Charlotte J. [1 ]
Stroes, Erik S. G. [1 ]
Boekholdt, S. Matthijs [2 ]
Wareham, Nicholas J. [3 ]
Murphy, Andrew J. [4 ,5 ]
Nieuwdorp, Max [1 ]
Hazen, Stanley L. [6 ,7 ]
Hanssen, Nordin M. J. [1 ]
机构
[1] Univ Amsterdam, Med Ctr, Dept Internal & Vasc Med, NL-1105 AZ Amsterdam, Netherlands
[2] Univ Amsterdam, Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands
[3] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 0QQ, England
[4] Baker IDI Heart & Diabet Inst, Haematopoiesis & Leukocyte Biol, Melbourne 3004, Australia
[5] Monash Univ, Dept Immunol, Melbourne 3004, Australia
[6] Cleveland Clin, Dept Cardiovasc & Metab Sci, Cleveland, OH 44195 USA
[7] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44195 USA
关键词
Tryptophan; Metabolites; Cardiovascular Disease; Inflammation; Epidemiology; ARYL-HYDROCARBON RECEPTOR; PLASMA; KYNURENINE; SEROTONIN; RISK; ACTIVATION; DEGRADATION; RATIO;
D O I
10.1016/j.atherosclerosis.2023.117344
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background and aims: Cardiovascular disease (CVD) remains the largest cause of death globally due to various risk factors. One novel potential contributor to CVD might be the metabolism of the essential amino acid tryptophan (Trp), which through many pathways can produce immunomodulatory metabolites such as kynurenine, indole-3propionate and serotonin. We aim to identify the metabolites with the strongest association with cardiovascular disease, utilizing a substantial and diverse cohort of individuals. In our pursuit of this aim, our primary focus is to validate and reinforce the findings from previous cross-sectional studies.Methods: We used the community-based EPIC-Norfolk cohort (46.3 % men, age 59.8 +/- 9.0) with a median followup of 22.1 (17.6-23.3) years to study associations between the relative levels of Trp metabolites measured with untargeted metabolomics and incident development of CVD. Serum from n = 11,972 apparently healthy subjects was analysed, of which 6982 individuals had developed CVD at the end of follow-up. Cox proportional hazard models were used to study associations, adjusted for sex, age, conventional cardiovascular risk factors and CRP. All metabolites were Ln-normalised prior to analysis.Results: Higher levels of Trp were inversely associated with mortality (HR 0.73; CI 0.64-0.83) and fatal CVD (HR 0.76; CI 0.59-0.99). Higher levels of kynurenine (HR 1.33; CI 1.19-1.49) and the [Kynurenine]/[Tryptophan]ratio (HR 1.24; CI 1.14-1.35) were associated with a higher incident development of CVD. Serotonin was not associated with overall CVD, but we did find associations for myocardial infarction and stroke. Adjustment for CRP did not yield any discernible differences in effect size.Conclusions: Tryptophan levels were inversely correlated with CVD, while several of its major metabolites (especially kynurenine and serotonin) were positively correlated. These findings indicate that mechanistic studies are required to understand the role of Trp metabolism in CVD with the goal to identify new therapeutic targets.
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页数:9
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