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. 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 ...

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