The association between progression of atherosclerosis and the methylated amino acids asymmetric dimethylarginine and trimethyllysine

Abstract

Objective: We previously showed that treatment with folic acid (FA)/B12 was associated with more rapid progression of coronary artery disease (CAD). High doses of FA may induce methylation by increasing the availability of S-adenosyl-methionine (SAM). Asymmetric dimethylarginine (ADMA) and trimethyllysine (TML) are both produced through proteolytic release following post-translational SAM-dependent methylation of precursor amino acid. ADMA has previously been associated with CAD. We investigated if plasma levels of ADMA and TML were associated with progression of CAD as measured by quantitative coronary angiography (QCA).

Methods: 183 patients from the Western Norway B Vitamin Intervention Trial (WENBIT) undergoing percutaneous coronary intervention (PCI) were randomized to daily treatment with 0.8 mg FA/0.4 mg B12 with and without 40 mg B6, B6 alone or placebo. Coronary angiograms and plasma samples of ADMA and TML were obtained at both baseline and follow-up (median 10.5 months). The primary end-point was progression of CAD as measured by diameter stenosis (DS) evaluated by linear quantile mixed models.

Results: A total of 309 coronary lesions not treated with PCI were identified. At follow-up median (95% CI) DS increased by 18.35 (5.22-31.49) percentage points per µmol/L ADMA increase (p-value 0.006) and 2.47 (0.37-4.58) percentage points per µmol/L TML increase (p-value 0.021) in multivariate modeling. Treatment with FA/B12 (±B6) was not associated with ADMA or TML levels.

Conclusion: In patients with established CAD, baseline ADMA and TML was associated with angiographic progression of CAD. However, neither ADMA nor TML levels were altered by treatment with FA/B12 (±B6).

Trial registration: Controlled-Trials.com NCT00354081.

Conflict of interest statement

Competing Interests: The main sponsors were nonprofit organizations with no participating role in the trial. Alpharma Inc provided the study capsules, generated the randomization sequence, and concealed the randomization code free of charge and rendered a limited grant to finance the initial phase of the trial. However, Alpharma Inc had no role in the design or implementation of the trial, had no access to study data, and did not participate in data analysis or interpretation or in the preparation, review, or approval of the manuscript. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Asymmetric dimethylarginine, trimethyllysine and angiographic progression of coronary artery disease.

The graph shows the regression line from a linear quantile mixed model. The two left panels show the relation between the asymmetric dimethylarginine (ADMA) and DS measured at follow-up, whereas the two right panels show the relation between trimethyllysine (TML) and DS at follow-up. The bivariate models (adjusted for baseline DS measurement) are on the top and the multivariate (adjusted for age, sex, folic acid/B12 intervention status, follow-up time, diabetes, smoking, systolic blood pressure, body mass index, estimated glomerular filtration rate (eGFR), apolipoprotein B100, C-reactive protein, ADMA or TML) at the bottom. The plasma level of either ADMA or TML is shown on the x-axis, with DS at follow-up on the y-axis. The solid line represents the regression line for the effect on median DS, while the others are displayed according to the legend.

Figure 2. Asymmetric dimethylarginine and trimethyllysine before and after supplementation with folic acid/vitamin B12.

The graph shows empirical cumulative distribution frequencies for asymmetric dimethylarginine on the left and trimethyllysine on the right. Patients receiving folic acid/B12 are displayed on the top, while patients receiving placebo or B6 on the bottom. Time of measurement is shown as baseline (solid line) and follow-up (dashed line) after a median of 10.5 month.