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 (P int ≤0.05). Evaluated in the total population, hydroxykynurenine and anthranilic acid provided statistically significant net reclassification improvements ( Experimental studies suggest that dysregulation of the Kyn pathway may be involved in the pathogenesis of both CAD 11 and DM. 12 However, Trp catabolites other than Kyn have been related only to a limited extent to clinical outcomes in humans, and there is a paucity of data from large-scale epidemiological studies. Thus, we evaluated plasma levels of kynurenic acid (KA) hydroxykynurenine (HK), anthranilic acid (AA), xanthurenic acid, and hydroxyanthranilic acid (HAA) as predictors of AMI in a prospective cohort of patients with suspected stable angina pectoris. In particular, we were interested in whether any associations with adverse prognosis were modified by evidence of impaired glucose homeostasis. Materials and MethodsMaterials and methods are available in the online-only Data Supplement. ResultsFor the 4122 patients in the current study, median (25th-75th percentile) age at inclusion was 62 (55-70) years and 2967 (72.0%) were men. According to the most recent diagnostic criteria, 1603 (38.9%) had DM, of which the vast majority (97.4%) was classified with type 2 (n=1566). However, only a subset was prescribed antidiabetic medications (Table 1). All together, 1078 (25.9%) of patients were current smokers, 1935 (46.9%) had hypertension, and 1644 (40.4%) reported a prior AMI. Compared with the total population, median age and body mass index were higher in patients with DM, as were the prevalence of hypertension at inclusion and the incidence of AMI during follow-up (Table 1). Kynurenines and Baseline CharacteristicsMedian values of all kynurenines were lower in women than in men (P<0.001). KA, HK, and AA were associated positively with age (ρ≥0.19; P<0.001), and except ...

Annexin A2 is a multifunctional Ca(2+)- and lipid-binding protein. We previously showed that a distinct pool of cellular Annexin A2 associates with mRNP complexes or polysomes associated with the cytoskeleton. Here we report in vitro and in vivo experiments showing that Annexin A2 present in this subset of mRNP complexes interacts with its cognate mRNA and c-myc mRNA, but not with beta(2)-microglobulin mRNA translated on membrane-bound polysomes. The protein recognises sequence elements within the untranslated regions, but not within the coding region, of its cognate mRNA. Alignment of the Annexin A2-binding 3'-untranslated regions of annexin A2 mRNA from several species reveals a five nucleotide consensus sequence 5'-AA(C/G)(A/U)G. The Annexin A2-interacting region of the 3'-untranslated region can be mapped to a sequence of about 100 nucleotides containing two repeats of the consensus sequence. The binding elements appear to involve both single and double stranded regions, indicating that a specific higher order mRNA structure is required for binding to Annexin A2. We suggest that this type of interaction is representative for a group of mRNAs translated on cytoskeleton-bound polysomes.

BACKGROUND: Several compounds in the choline oxidation pathway are associated with insulin resistance and prevalent diabetes; however, prospective data are scarce.

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BackgroundExcess levels of serum acylcarnitines, which are intermediate products in metabolism, have been observed in metabolic diseases such as type 2 diabetes mellitus. However, it is not known whether acylcarnitines may prospectively predict risk of cardiovascular death or acute myocardial infarction in patients with stable angina pectoris.Methods and ResultsThis study included 4164 patients (median age, 62 years; 72% men). Baseline serum acetyl‐, octanoyl‐, palmitoyl‐, propionyl‐, and (iso)valerylcarnitine were measured using liquid chromatography/tandem mass spectrometry. Hazard ratios (HRs) and 95% CIs for quartile 4 versus quartile 1 are reported. The multivariable model included age, sex, body mass index, fasting status, current smoking, diabetes mellitus, apolipoprotein A1, apolipoprotein B, creatinine, left ventricular ejection fraction, extent of coronary artery disease, study center, and intervention with folic acid or vitamin B6. During median 10.2 years of follow‐up, 10.0% of the patients died of cardiovascular disease and 12.8% suffered a fatal or nonfatal acute myocardial infarction. Higher levels of the even‐chained acetyl‐, octanoyl‐, and palmitoyl‐carnitines were significantly associated with elevated risk of cardiovascular death, also after multivariable adjustments (HR [95% CI]: 1.52 [1.12, 2.06]; P=0.007; 1.73 [1.23, 2.44]; P=0.002; and 1.61 [1.18, 2.21]; P=0.003, respectively), whereas their associations with acute myocardial infarction were less consistent.ConclusionsAmong patients with suspected stable angina pectoris, elevated serum even‐chained acylcarnitines were associated with increased risk of cardiovascular death and, to a lesser degree with acute myocardial infarction, independent of traditional risk factors.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00354081.

Aims/hypothesisThe tryptophan metabolite kynurenine has potent immune modulatory and vasoactive properties. Experimental data implicate kynurenine in obesity-related morbidities. Epidemiological studies are, however, sparse. We evaluated associations of the plasma and urine kynurenine:tryptophan ratio (KTR) to incident type 2 diabetes.MethodsWe followed 2519 individuals with coronary artery disease (CAD; 73.1% men) without diabetes at baseline for a median of 7.6 years, during which 173 (6.9%) new incidences of type 2 diabetes were identified. Multivariate Cox regression analyses were applied to investigate the prospective relationships of plasma and urine KTR with new onset type 2 diabetes.ResultsAt inclusion, mean (SD) age was 61.3 (10.4) years, BMI was 25.9 (3.71) kg/m2 and median (interquartile range) HbA1c was 5.6% (5.0%–6.0%) (38 [31–42] mmol/mol). Plasma KTR was not significantly related to type 2 diabetes risk. By contrast, urine KTR showed a strong positive association. Comparing quartile 4 with quartile 1, the HRs (95% CIs) were 2.59 (1.56, 4.30) and 2.35 (1.39, 3.96) in the age- and sex-adjusted and multivariate models, respectively.Conclusions/interpretationUrine KTR is a strong predictor of incident type 2 diabetes in individuals with CAD. Potential clinical implications and possible pathogenic roles of renal kynurenine excretion in type 2 diabetes development should be further elucidated.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-017-4329-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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