Eva Ringdal Pedersen1, Nora Tuseth2, Simone J P M Eussen2, Per Magne Ueland2, Elin Strand2, Gard Frodahl Tveitevåg Svingen2, Øivind Midttun2, Klaus Meyer2, Gunnar Mellgren2, Arve Ulvik2, Jan Erik Nordrehaug2, Dennis W Nilsen2, Ottar Nygård2. 1. 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. 2. 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.).
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. APPROACH AND 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.
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. APPROACH AND 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: Jennifer E Cole; Nagore Astola; Adam P Cribbs; Michael E Goddard; Inhye Park; Patricia Green; Alun H Davies; Richard O Williams; Marc Feldmann; Claudia Monaco Journal: Proc Natl Acad Sci U S A Date: 2015-10-05 Impact factor: 11.205
Authors: Andrea M Brennan; Mark Benson; Jordan Morningstar; Matthew Herzig; Jeremy Robbins; Robert E Gerszten; Robert Ross Journal: Med Sci Sports Exerc Date: 2018-07 Impact factor: 5.411