Plasma kynurenines and prognosis in patients with heart failure

Fig 1. The kynurenine pathway. The kynurenine pathway (KP) is the major route of Trp degradation. The first step is the formation of formylkynurenine from Trp, catalysed by hepatic tryptophan 2,3-dioxygenase (TDO), predominantly expressed in the liver, or indoleamine-2,3-dioxygenase (IDO), expressed in monocytes. Formylkynurenine is rapidly converted to kynurenine (Kyn). Kyn in turn is converted to a variety of metabolites, many of which have immunomodulatory effects. These include 3-hydroxykynurenine (HK, formed by the flavin adenine dinucleotide (FAD)-dependent kynurenine monooxygenase (KMO)), kynurenic acid (KA) and xanthurenic acid (XA) (products of the pyridoxal 5-phosphate (PLP)-dependent kynurenine aminotransferase (KAT)), anthranilic acid (AA) and 3-hydroxyanthranilic acid (HAA) (products of the pyridoxal 5-phosphate (PLP)-dependent kynureninase (KYNU). HAA is further fully oxidized and in the process produce picolinic acid (not shown in figure) or converted to quinolinic acid (QA) in several steps and further to nicotinic acid mononucleotide and ultimately to NAD+. Abbreviations: KP, kynurenine pathway; AA, anthranilic acid; FAD, flavin adenine dinucleotide; HAA,…

Fig 2. Propensity score matching of cases and controls. 3425 patients were identified as potential controls, who did not meet criteria for heart failure and did not report having a diagnosis of heart failure and did not use loop diuretics. These potential controls were propensity score matched to the heart failure group based on age, gender, number of vessels affected by CAD and prior MI generating controls with similar levels of CAD as the heart failure group (CAD-C). A subgroup of the potential controls without CAD and prior MI were propensity score matched based on age and gender, generating a control group without CAD (NCAD-C). Abbreviations: CAD, coronary artery disease represented by number of vessels affected by significant coronary artery stenosis on coronary angiography; MI, myocardial infarction; WECAC, western norway coronary angiography cohort; CAD-C coronary artery disease controls; NCAD-C, non-coronary artery disease controls.

Fig 3. 3-hydroxykynurenine, xanthurenic acid, quinolinic acid, the kynurenine-to-tryptophan ratio and survival. Predicted estimates from Cox regression with age, gender, current smoking, estimated glomerular filtration rate, diabetes mellitus, C-reactive protein and pyridoxal 5’phosphate as covariates. The analyses were performed in each group (HF, CAD-C and NCAD-C). The predicted estimates are shown at the mean level of each metabolite (black line), and 1 standard deviation above (red line) and below (blue line) the mean. Abbreviations: HF, heart failure; CAD-C, coronary artery disease controls; NCAD-C, non-coronary artery disease controls; HK, 3-hydroxykynurenic acid; XA, xanthurenic acid; KTR, kynurenine to tryptophan ratio; QA, quinolinic acid; SD, standard deviation.