Abstract 19250: Urinary Homocysteine Thiolactone Predicts Acute Myocardial Infarction in a Randomized Controlled Homocysteine-lowering B-vitamin Trial
Introduction: Elevated plasma total homocysteine (tHcy) is associated with increased risk of coronary artery disease (CAD) and stroke. However, tHcy-lowering by B-vitamin therapy has no effect on cardiovascular disease (CVD), suggesting that tHcy is not causally related to CVD. One Hcy metabolite, Hcy-thiolactone (HTL), not accounted for in clinical tHcy assays, has been independently implicated in CVD. HTL is generated in the human body by methionyl-tRNA synthetase during protein biosynthesis and is cleared by the kidney.
Hypothesis: Our objective was to test the predictive value of urinary HTL as risk marker of incident acute myocardial infarction (AMI) and to evaluate potential effect modification by B vitamin treatment and status.
Methods and Results: We analyzed urinary HTL in samples from 2048 patients (20.5% female, mean age 61.7 years) who underwent coronary angiography for stable angina pectoris and were recruited to the Western Norway B Vitamin Intervention Trial. Linear regression was used to study determinants of baseline urinary HTL/creatinine and no association was observed with established risk factors such as age, gender, hypertension, body mass index, diabetes, apolipoprotein B and A1. Cox regression was used to study its association with subsequent risk of AMI. During median 4.7-years follow-up, 183 patients (8.9%) suffered from AMI. After adjustment for age, gender, diabetes, smoking, extent of CAD at angiography and left ventricular ejection fraction, per tertile increment in HTL/creatinine was significantly associated with AMI (RR 1.23; 95% CI 1.025-1.474; P=0.026). No significant effect-modification by folate/B12 or B6 treatment was observed. The association was entirely confined to patients with low (below median) levels of the inactive B6 metabolite pyridoxic acid (P-interaction 0.020), and identified patients with low risk. The risk association of plasma tHcy was confined to patients with elevated pyridoxic acid (P-interaction 0.001), and identified patients with high risk.
Conclusions: Urinary HTL is a risk predictor of AMI in patients with CAD independent from established risk factors and plasma tHcy, but related to vitamin B6 metabolism. These surprising results should encourage further research into HTL and CVD.
Author Disclosures: H. Jakubowski: None. K. Borowczyk: None. R. Glowacki: None. O. Nygård: None.
- © 2015 by American Heart Association, Inc.