title: Associations of plasma kynurenines with risk of acute myocardial infarction in patients with stable angina pectoris.
abstract: OBJECTIVE
  Enhanced tryptophan degradation, induced by the proinflammatory cytokine interferon-γ, has been related to cardiovascular disease progression and insulin resistance. We assessed downstream tryptophan metabolites of the kynurenine pathway as predictors of acute myocardial infarction in patients with suspected stable angina pectoris. Furthermore, we evaluated potential effect modifications according to diagnoses of pre-diabetes mellitus or diabetes mellitus.
  
  
  RESULTS
  Blood samples were obtained from 4122 patients (median age, 62 years; 72% men) who underwent elective coronary angiography. During median follow-up of 56 months, 8.3% had acute myocardial infarction. Comparing the highest quartile to the lowest, for the total cohort, multivariable adjusted hazard ratios (95% confidence intervals) were 1.68 (1.21-2.34), 1.81 (1.33-2.48), 1.68 (1.21-2.32), and 1.48 (1.10-1.99) for kynurenic acid, hydroxykynurenine, anthranilic acid, and hydroxyanthranilic acid, respectively. The kynurenines correlated with phenotypes of the metabolic syndrome, and risk associations were generally stronger in subgroups classified with pre-diabetes mellitus or diabetes mellitus at inclusion (Pint≤0.05). Evaluated in the total population, hydroxykynurenine and anthranilic acid provided statistically significant net reclassification improvements (0.21 [0.08-0.35] and 0.21 [0.07-0.35], respectively).
  
  
  CONCLUSIONS
  In patients with suspected stable angina pectoris, elevated levels of plasma kynurenines predicted increased risk of acute myocardial infarction, and risk estimates were generally stronger in subgroups with evidence of impaired glucose homeostasis. Future studies should aim to clarify roles of the kynurenine pathway in atherosclerosis and glucose metabolism.
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.). eva.pedersen@k2.uib.no.
authors.forename: Eva Ringdal
authors.initials: ER
authors.lastname: Pedersen
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.).
authors.forename: Nora
authors.initials: N
authors.lastname: Tuseth
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.).
authors.forename: Simone J P M
authors.initials: SJ
authors.lastname: Eussen
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.).
authors.forename: Per Magne
authors.initials: PM
authors.lastname: Ueland
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.).
authors.forename: Elin
authors.initials: E
authors.lastname: Strand
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.).
authors.forename: Gard Frodahl Tveitevåg
authors.initials: GF
authors.lastname: Svingen
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.).
authors.forename: Øivind
authors.initials: Ø
authors.lastname: Midttun
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.).
authors.forename: Klaus
authors.initials: K
authors.lastname: Meyer
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.).
authors.forename: Gunnar
authors.initials: G
authors.lastname: Mellgren
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.).
authors.forename: Arve
authors.initials: A
authors.lastname: Ulvik
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.).
authors.forename: Jan Erik
authors.initials: JE
authors.lastname: Nordrehaug
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.).
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Nilsen
authors.affiliation: From the Department of Clinical Science (E.R.P., N.T., P.M.U., E.S., G.F.T.S., G.M., J.E.N., D.W.N., O.N.) and Department of Global Public Health and Primary Health Care (S.J.P.M.E.), University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (N.T., O.N.); Department of Epidemiology, School for Public Health and Primary Care-CAPHRI, Maastricht University, Maastricht, The Netherlands (S.J.P.M.E.); Laboratory of Clinical Biochemistry (P.M.U.) and Hormone Laboratory (G.M.), Haukeland University Hospital, Bergen, Norway; Bevital AS, Bergen, Norway (P.M.U., Ø.M., K.M., A.U.); Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (J.E.N., D.W.N.); and KG Jebsen Center for Diabetes Research, Bergen, Norway (G.M., O.N.).
authors.forename: Ottar
authors.initials: O
authors.lastname: Nygård
mesh_terms: D000368:Aged; D060050:Angina, Stable / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D015415:Biomarkers / Q000097:blood; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000453:epidemiology; D005260:Female; D006801:Humans; D015994:Incidence; D007737:Kynurenine / Q000097:blood*; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000453:epidemiology; D008875:Middle Aged; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D009664:Norway / Q000453:epidemiology; D011236:Prediabetic State / Q000097:blood / Q000453:epidemiology; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015854:Up-Regulation; D014977:Xanthurenates / Q000097:blood; D062367:ortho-Aminobenzoates / Q000097:blood
chemical_list: D015415:Biomarkers; D014977:Xanthurenates; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D007737:Kynurenine; C028330:xanthurenic acid
keywords: acute myocardial infarction; atherosclerosis; diabetes mellitus; epidemiology; inflammation; insulin resistance; tryptophan