Urinary excretion of homocysteine thiolactone and the risk of acute myocardial infarction in coronary artery disease patients: the WENBIT trial

K Borowczyk, J Piechocka, R Głowacki, I Dhar, Ø Midtun, G S Tell, P M Ueland, O Nygård, H Jakubowski, K Borowczyk, J Piechocka, R Głowacki, I Dhar, Ø Midtun, G S Tell, P M Ueland, O Nygård, H Jakubowski

Abstract

Objectives: No individual homocysteine (Hcy) metabolite has been studied as a risk marker for coronary artery disease (CAD). Our objective was to examine Hcy-thiolactone, a chemically reactive metabolite generated by methionyl-tRNA synthetase and cleared by the kidney, as a risk predictor of incident acute myocardial infarction (AMI) in the Western Norway B-Vitamin Intervention Trial.

Design: Single centre, prospective double-blind clinical intervention study, randomized in a 2 × 2 factorial design.

Subjects and methods: Patients with suspected CAD (n = 2049, 69.8% men; 61.2-year-old) were randomized to groups receiving daily (i) folic acid (0.8 mg)/vitamin B12 (0.4 mg)/vitamin B6 (40 mg); (ii) folic acid/vitamin B12 ; (iii) vitamin B6 or (iv) placebo. Urinary Hcy-thiolactone was quantified at baseline, 12 and 38 months.

Results: Baseline urinary Hcy-thiolactone/creatinine was significantly associated with plasma tHcy, ApoA1, glomerular filtration rate, potassium and pyridoxal 5'-phosphate (positively) and with age, hypertension, smoking, urinary creatinine, plasma bilirubin and kynurenine (negatively). During median 4.7-years, 183 patients (8.9%) suffered an AMI. In Cox regression analysis, Hcy-thiolactone/creatinine was associated with AMI risk (hazard ratio = 1.58, 95% confidence interval = 1.10-2.26, P = 0.012 for trend; adjusted for age, gender, tHcy). This association was confined to patients with pyridoxic acid below median (adjusted HR = 2.72, 95% CI = 1.47-5.03, P = 0.0001; Pinteraction = 0.020). B-vitamin/folate treatments did not affect Hcy-thiolactone/creatinine and its AMI risk association.

Conclusions: Hcy-thiolactone/creatinine ratio is a novel AMI risk predictor in patients with suspected CAD, independent of traditional risk factors and tHcy, but modified by vitamin B6 catabolism. These findings lend a support to the hypothesis that Hcy-thiolactone is mechanistically involved in cardiovascular disease.

Trial registration: ClinicalTrials.gov NCT00354081.

Keywords: B-vitamins; acute myocardial infarction; atherosclerosis; homocysteine thiolactone; paraoxonase.

© 2018 The Authors Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

Figures

Figure 1
Figure 1
The Hcy‐thiolactone hypothesis of CVD.
Figure 2
Figure 2
Diseases associated with Hcy‐thiolactone, N‐Hcy‐protein and Hcy deduced from effects of these metabolites on gene expression in human vascular endothelial cells. Modified from Ref. 16.

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