Plasma kynurenines and prognosis in patients with heart failure

Autoři: Anders Lund aff001;  Jan Erik Nordrehaug aff001;  Grete Slettom aff001;  Stein-Erik Hafstad Solvang aff001;  Eva Kristine Ringdal Pedersen aff001;  Øivind Midttun aff005;  Arve Ulvik aff005;  Per Magne Ueland aff001;  Ottar Nygård aff001;  Lasse Melvaer Giil aff001
Působiště autorů: Department of Clinical Science, University of Bergen, Bergen, Norway aff001;  Department of Cardiology, Stavanger University Hospital, Stavanger, Norway aff002;  Department of Heart Disease, Haukeland University Hospital, Bergen, Norway aff003;  Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway aff004;  Bevital AS, Bergen, Norway aff005;  Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway aff006
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0227365



Metabolites of the kynurenine pathway (mKP) relate to important aspects of heart failure pathophysiology, such as inflammation, energy-homeostasis, apoptosis, and oxidative stress. We aimed to investigate whether mKP predict mortality in patients with heart failure.


The study included 202 patients with heart failure (73.8% with coronary artery disease (CAD)), propensity score matched to 384 controls without heart disease, and 807 controls with CAD (71%). All underwent coronary angiography and ventriculography at baseline. Plasma mKP, pyridoxal 5’phosphate (PLP) and CRP were measured at baseline. Case-control differences were assessed by logistic regression and survival by Cox regression, adjusted for age, gender, smoking, diabetes, ejection fraction, PLP, eGFR and CRP. Effect measures are reported per standard deviation increments.


Higher plasma levels of kynurenine, 3- hydroxykynurenine (HK), quinolinic acid (QA), the kynurenine-tryptophan-ratio (KTR) and the ratio of HK to xanthurenic acid (HK/XA) were detected in heart failure compared to both control groups. The mortality rate per 1000 person-years was 55.5 in patients with heart failure, 14.6 in controls without heart disease and 22.2 in CAD controls. QA [HR 1.80, p = 0.013], HK [HR 1.77, p = 0.005], HK/XA [HR 1.67, p < 0.001] and KTR [HR 1.55, p = 0.009] were associated with increased mortality in patients with heart failure, while XA [HR 0.68–0.80, p = 0.013–0.037] were associated with lower mortality in all groups. HK and HK/XA had weak associations with increased mortality in CAD-controls.


Elevated plasma levels of mKP and metabolite ratios are associated with increased mortality, independent of CAD, in patients with heart failure.

Klíčová slova:

Angiography – Coronary heart disease – Death rates – Diabetes mellitus – Heart failure – Metabolites – Myocardial infarction – Tryptophan


1. Gullestad L, Ueland T, Vinge LE, Finsen A, Yndestad A, Aukrust P. Inflammatory cytokines in heart failure: mediators and markers. Cardiology. 2012;122(1):23–35. doi: 10.1159/000338166 22699305.

2. Sawyer DB. Oxidative stress in heart failure: what are we missing? Am J Med Sci. 2011;342(2):120–4. doi: 10.1097/MAJ.0b013e3182249fcd 21747279.

3. Zhang Y, Bauersachs J, Langer HF. Immune mechanisms in heart failure. Eur J Heart Fail. 2017;19(11):1379–89. doi: 10.1002/ejhf.942 28891154.

4. Sager HB, Hulsmans M, Lavine KJ, Moreira MB, Heidt T, Courties G, et al. Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure. Circ Res. 2016;119(7):853–64. doi: 10.1161/CIRCRESAHA.116.309001 27444755.

5. Ueland PM, McCann A, Midttun O, Ulvik A. Inflammation, vitamin B6 and related pathways. Mol Aspects Med. 2017;53:10–27. doi: 10.1016/j.mam.2016.08.001 27593095.

6. Badawy AAB. Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects. International journal of tryptophan research: IJTR. 2017;10:1178646917691938. doi: 10.1177/1178646917691938 28469468

7. Levick SP, Goldspink PH. Could interferon-gamma be a therapeutic target for treating heart failure? Heart Fail Rev. 2014;19(2):227–36. doi: 10.1007/s10741-013-9393-8 23589353.

8. Zuo H, Ueland PM, Ulvik A, Eussen SJ, Vollset SE, Nygard O, et al. Plasma Biomarkers of Inflammation, the Kynurenine Pathway, and Risks of All-Cause, Cancer, and Cardiovascular Disease Mortality: The Hordaland Health Study. American journal of epidemiology. 2016;183(4):249–58. doi: 10.1093/aje/kwv242 26823439.

9. Pedersen ER, Tuseth N, Eussen SJ, Ueland PM, Strand E, Svingen GF, et al. Associations of plasma kynurenines with risk of acute myocardial infarction in patients with stable angina pectoris. Arterioscler Thromb Vasc Biol. 2015;35(2):455–62. doi: 10.1161/ATVBAHA.114.304674 25524770.

10. Konishi M, Ebner N, Springer J, Schefold JC, Doehner W, Dschietzig TB, et al. Impact of Plasma Kynurenine Level on Functional Capacity and Outcome in Heart Failure- Results From Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF). Circ J. 2016;81(1):52–61. doi: 10.1253/circj.CJ-16-0791 27904018.

11. Seccareccia F, Zuccaro P, Pacifici R, Meli P, Pannozzo F, Freeman KM, et al. Serum cotinine as a marker of environmental tobacco smoke exposure in epidemiological studies: the experience of the MATISS project. European journal of epidemiology. 2003;18(6):487–92. Epub 2003/08/12. doi: 10.1023/a:1024672522802 12908713.

12. Pedersen AG, Ellingsen CL. Data quality in the Causes of Death Registry. Tidsskr Nor Laegeforen. 2015;135(8):768–70. 25947599.

13. Austin PC. A comparison of 12 algorithms for matching on the propensity score. Stat Med. 2014;33(6):1057–69. doi: 10.1002/sim.6004 24123228.

14. Midttun O, Hustad S, Ueland PM. Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry. Rapid communications in mass spectrometry: RCM. 2009;23(9):1371–9. Epub 2009/04/02. doi: 10.1002/rcm.4013 19337982.

15. Schafer JL. Analysis of incomplete multivariate data: Chapman and Hall/CRC; 1997.

16. Lee PH. Should we adjust for a confounder if empirical and theoretical criteria yield contradictory results? A simulation study. Sci Rep. 2014;4:6085. doi: 10.1038/srep06085 25124526.

17. Ezekowitz J, McAlister FA, Humphries KH, Norris CM, Tonelli M, Ghali WA, et al. The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J Am Coll Cardiol. 2004;44(8):1587–92. Epub 2004/10/19. doi: 10.1016/j.jacc.2004.06.072 15489090.

18. Aquilani R, Opasich C, Verri M, Boschi F, Febo O, Pasini E, et al. Is nutritional intake adequate in chronic heart failure patients? J Am Coll Cardiol. 2003;42(7):1218–23. Epub 2003/10/03. doi: 10.1016/s0735-1097(03)00946-x 14522484.

19. Pawlak K, Domaniewski T, Mysliwiec M, Pawlak D. The kynurenines are associated with oxidative stress, inflammation and the prevalence of cardiovascular disease in patients with end-stage renal disease. Atherosclerosis. 2009;204(1):309–14. doi: 10.1016/j.atherosclerosis.2008.08.014 18823890.

20. Theofylaktopoulou D, Midttun O, Ulvik A, Ueland PM, Tell GS, Vollset SE, et al. A community-based study on determinants of circulating markers of cellular immune activation and kynurenines: the Hordaland Health Study. Clinical and experimental immunology. 2013;173(1):121–30. Epub 2013/04/24. doi: 10.1111/cei.12092 23607723.

21. Young SN. Acute tryptophan depletion in humans: a review of theoretical, practical and ethical aspects. J Psychiatry Neurosci. 2013;38(5):294–305. doi: 10.1503/jpn.120209 23428157.

22. Stone TW, Darlington LG. Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov. 2002;1(8):609–20. Epub 2002/10/31. doi: 10.1038/nrd870 12402501.

23. Parry HM, Deshmukh H, Levin D, Van Zuydam N, Elder DH, Morris AD, et al. Both high and low HbA1c predict incident heart failure in type 2 diabetes mellitus. Circ Heart Fail. 2015;8(2):236–42. Epub 2015/01/07. doi: 10.1161/CIRCHEARTFAILURE.113.000920 25561089.

24. Theofylaktopoulou D, Ulvik A, Midttun O, Ueland PM, Vollset SE, Nygard O, et al. Vitamins B2 and B6 as determinants of kynurenines and related markers of interferon-gamma-mediated immune activation in the community-based Hordaland Health Study. Br J Nutr. 2014;112(7):1065–72. doi: 10.1017/S0007114514001858 25105221.

25. Anand IS, Latini R, Florea VG, Kuskowski MA, Rector T, Masson S, et al. C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation. 2005;112(10):1428–34. doi: 10.1161/CIRCULATIONAHA.104.508465 16129801.

26. Wang Q, Liu D, Song P, Zou MH. Tryptophan-kynurenine pathway is dysregulated in inflammation, and immune activation. Front Biosci (Landmark Ed). 2015;20:1116–43. Epub 2015/05/12. doi: 10.2741/4363 25961549.

27. Zuo H, Tell GS, Vollset SE, Ueland PM, Nygard O, Midttun O, et al. Interferon-gamma-induced inflammatory markers and the risk of cancer: the Hordaland Health Study. Cancer. 2014;120(21):3370–7. Epub 2014/06/21. doi: 10.1002/cncr.28869 24948355.

28. Midttun O, Townsend MK, Nygard O, Tworoger SS, Brennan P, Johansson M, et al. Most blood biomarkers related to vitamin status, one-carbon metabolism, and the kynurenine pathway show adequate preanalytical stability and within-person reproducibility to allow assessment of exposure or nutritional status in healthy women and cardiovascular patients. J Nutr. 2014;144(5):784–90. doi: 10.3945/jn.113.189738 24647388.

29. Jones SP, Franco NF, Varney B, Sundaram G, Brown DA, de Bie J, et al. Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease. PLoS One. 2015;10(6):e0131389. doi: 10.1371/journal.pone.0131389 26114426.

30. Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science. 2017;357(6349). doi: 10.1126/science.aaf9794 28751584.

31. Hulsmans M, Sam F, Nahrendorf M. Monocyte and macrophage contributions to cardiac remodeling. J Mol Cell Cardiol. 2016;93:149–55. doi: 10.1016/j.yjmcc.2015.11.015 26593722.

32. Gulati A, Jabbour A, Ismail TF, Guha K, Khwaja J, Raza S, et al. Association of fibrosis with mortality and sudden cardiac death in patients with nonischemic dilated cardiomyopathy. JAMA. 2013;309(9):896–908. doi: 10.1001/jama.2013.1363 23462786.

33. Ho JE, Liu C, Lyass A, Courchesne P, Pencina MJ, Vasan RS, et al. Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community. J Am Coll Cardiol. 2012;60(14):1249–56. doi: 10.1016/j.jacc.2012.04.053 22939561.

34. Aziz N, Detels R, Quint JJ, Li Q, Gjertson D, Butch AW. Stability of cytokines, chemokines and soluble activation markers in unprocessed blood stored under different conditions. Cytokine. 2016;84:17–24. Epub 2016/05/22. doi: 10.1016/j.cyto.2016.05.010 27208752.

35. Mandi Y, Vecsei L. The kynurenine system and immunoregulation. J Neural Transm (Vienna). 2012;119(2):197–209. doi: 10.1007/s00702-011-0681-y 21744051.

36. Minovic I, van der Veen A, van Faassen M, Riphagen IJ, van den Berg E, van der Ley C, et al. Functional vitamin B-6 status and long-term mortality in renal transplant recipients. Am J Clin Nutr. 2017;106(6):1366–74. doi: 10.3945/ajcn.117.164012 28978540.

37. Wang Q, Zhang M, Ding Y, Wang Q, Zhang W, Song P, et al. Activation of NAD(P)H oxidase by tryptophan-derived 3-hydroxykynurenine accelerates endothelial apoptosis and dysfunction in vivo. Circ Res. 2014;114(3):480–92. doi: 10.1161/CIRCRESAHA.114.302113 24281189.

38. Mailankot M, Nagaraj RH. Induction of indoleamine 2,3-dioxygenase by interferon-gamma in human lens epithelial cells: apoptosis through the formation of 3-hydroxykynurenine. Int J Biochem Cell Biol. 2010;42(9):1446–54. doi: 10.1016/j.biocel.2010.04.014 20435158.

39. Wei H, Leeds P, Chen RW, Wei W, Leng Y, Bredesen DE, et al. Neuronal apoptosis induced by pharmacological concentrations of 3-hydroxykynurenine: characterization and protection by dantrolene and Bcl-2 overexpression. J Neurochem. 2000;75(1):81–90. doi: 10.1046/j.1471-4159.2000.0750081.x 10854250.

40. Reyes Ocampo J, Lugo Huitron R, Gonzalez-Esquivel D, Ugalde-Muniz P, Jimenez-Anguiano A, Pineda B, et al. Kynurenines with neuroactive and redox properties: relevance to aging and brain diseases. Oxid Med Cell Longev. 2014;2014:646909. doi: 10.1155/2014/646909 24693337.

41. Ulvik A, Theofylaktopoulou D, Midttun O, Nygard O, Eussen SJ, Ueland PM. Substrate product ratios of enzymes in the kynurenine pathway measured in plasma as indicators of functional vitamin B-6 status. Am J Clin Nutr. 2013;98(4):934–40. doi: 10.3945/ajcn.113.064998 24004893.

42. Han Q, Cai T, Tagle DA, Li J. Structure, expression, and function of kynurenine aminotransferases in human and rodent brains. Cell Mol Life Sci. 2010;67(3):353–68. Epub 2009/10/15. doi: 10.1007/s00018-009-0166-4 19826765.

43. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119–31. doi: 10.1056/NEJMoa1707914 28845751.

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