The Association between Progression of Atherosclerosis and the Methylated Amino Acids Asymmetric Dimethylarginine and Trimethyllysine

Abstract

ObjectiveWe 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).Methods183 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.ResultsA 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.ConclusionIn 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 RegistrationControlled-Trials.com NCT00354081

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“…However, Krempl et al [ 14 ] demonstrated that ADMA levels in unstable angina pectoris patients were significantly higher than SAP patients, in which “multivessel disease” was considered to reflect complication of vascular lesions. However, the cases in both studies were relatively limited and did not fully consider the complication and severity of vascular lesions, which proven to be related with ADMA levels, [ 15 ] that was higher ADMA could result from more severe vascular lesion. The CAS in both groups had no significant difference in our study, which indicated that ADMA levels should be similar between SAP and ACS patients after eliminating bias from complicated vascular lesions.…”

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“…ADMA and the L-arginine:ADMA ratio has been shown to predict mortality and adverse outcome in a range of cardiovascular disorders [ 5 , 13 - 16 ]. Both preclinical and clinical studies have shown that ADMA has a pathophysiological role in the induction of vascular dysfunction and human cardiovascular disease [ 11 ].…”

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“…ADMA and TML are both produced by post-translational SAM-dependent methylation of precursor amino acid via proteolytic release. In patients with established CAD, baseline ADMA and TML was associated with angiographic progression of CAD, but treatment with FA/B12 (± B6) did not alter the levels of neither ADMA nor TML [56].…”