Circulating trimethyllysine and risk of acute myocardial infarction in patients with suspected stable coronary heart disease.

BACKGROUND: The carnitine precursor trimethyllysine (TML) is associated with progression of atherosclerosis, possibly through a relationship with trimethylamine-N-oxide (TMAO). Riboflavin is a cofactor in TMAO synthesis. We examined prospective relationships of circulating TML and TMAO with acute myocardial infarction (AMI) and potential effect modifications by riboflavin status. METHODS: By Cox modelling, risk associations were examined amongst 4098 patients (71.8% men) with suspected stable angina pectoris. Subgroup analyses were performed according to median plasma riboflavin. RESULTS: During a median follow-up of 4.9 years, 336 (8.2%) patients experienced an AMI. The age- and sex-adjusted hazard ratio (HR) (95% CI) comparing the 4th vs. 1st TML quartile was 2.19 (1.56-3.09). Multivariable adjustment for traditional cardiovascular risk factors and indices of renal function only slightly attenuated the risk estimates [HR (95% CI) 1.79 (1.23-2.59)], which were particularly strong amongst patients with riboflavin levels above the median (Pint  = 0.035). Plasma TML and TMAO were strongly correlated (rs  = 0.41; P < 0.001); however, plasma TMAO was not associated with AMI risk in adjusted analyses [HR (95% CI) 0.81 (0.58-1.14)]. No interaction between TML and TMAO was observed. CONCLUSION: Amongst patients with suspected stable angina pectoris, plasma TML, but not TMAO, independently predicted risk of AMI. Our results motivate further research on metabolic processes determining TML levels and their potential associations with cardiovascular disease. We did not adjust for multiple comparisons, and the subgroup analyses should be interpreted with caution.

B vitamin treatments modify the risk of myocardial infarction associated with a MTHFD1 polymorphism in patients with stable angina pectoris.

BACKGROUND: Methylenetetrahydrofolate dehydrogenase (MTHFD1) catalyzes three sequential reactions that metabolize derivatives of tetrahydrofolate (THF) in folate-dependent one-carbon metabolism. Impaired MTHFD1 flux has been linked to disturbed lipid metabolism and oxidative stress. However, limited information is available on its relation to the development of atherothrombotic cardiovascular disease. METHODS AND RESULTS: We explored the association between a MTHFD1 polymorphism (rs1076991 C > T) and acute myocardial infarction (AMI), and potential effect modifications by folic acid/B12 and/or vitamin B6 treatment in suspected stable angina pectoris patients (n = 2381) participating in the randomized Western Norway B Vitamin Intervention Trial (WENBIT). During the median follow-up of 4.9 years 204 participants (8.6%) suffered an AMI. After adjusting for established CVD risk factors, the MTHFD1 polymorphism was significantly associated with AMI (HR: 1.49; 95% CI, 1.23-1.81). A similar association was observed among patients allocated to treatment with vitamin B6 alone (HR: 1.53; 95% CI, 1.01-2.31), and an even stronger relationship was seen in patients treated with both vitamin B6 and folic acid/B12 (HR: 2.35; 95% CI, 1.55-3.57). However, no risk association between the MTHFD1 polymorphism and AMI was seen in patients treated with placebo (HR: 1.29; 95% CI, 0.86-1.93) or folic acid/B12 (1.17; 95% CI, 0.83-1.65). CONCLUSION: A common and functional MTHFD1 polymorphism is associated with increased risk of AMI, although the risk seems to be dependent on specific B vitamin treatment. Further studies are warranted to elucidate the possible mechanisms, also in order to explore potential effect modifications by nutritional factors.

Vitamin B6 status and interferon-γ-mediated immune activation in primary hyperparathyroidism.

OBJECTIVES: Primary hyperparathyroidism (PHPT) has been associated with low-grade inflammation and elevated risk of cardiovascular disease (CVD). In inflammatory conditions, interferon-γ (IFN-γ) activity is enhanced and a decreased circulating concentration of vitamin B6 is often observed. Such changes in IFN-γ activity or vitamin B6 levels have been associated with increased incidence of CVD. The aim of the study was to investigate systemic markers of IFN-γ-mediated immune activation, such as neopterin, the kynurenine-to-tryptophan ratio (KTR) and kynurenine pathway metabolites, as well as B6 vitamers in patients with PHPT. DESIGN/SUBJECTS: A total of 57 patients with PHPT and a control group of 20 healthy blood donors were included in this study. PHPT patients who responded positively to parathyroidectomy were followed for 6 months. Forty-three patients participated in the longitudinal study in which blood samples were taken at inclusion and 1, 3 and 6 months after surgery. RESULTS: Plasma concentrations of the B6 vitamers pyridoxal 5'-phosphate (PLP) (P = 0.007) and pyridoxal (P = 0.013) were significantly lower in the patient group compared to healthy control subjects. An increase in the KTR indicated that the kynurenine pathway of tryptophan metabolism was altered in PHPT patients (P = 0.015). During the initial 6 months after surgery, levels of PLP (P < 0.001) and anthranilic acid (P < 0.001) increased significantly, whereas neopterin decreased (P = 0.018). CONCLUSIONS: The results of this study demonstrate altered levels of vitamin B6 and the KTR in PHPT patients, both of which may reflect cellular immune activation. These abnormalities should be considered in relation to the increased risk of CVD previously observed in patients with PHPT.