June 19, 2009Arteriosclerosis Thrombosis and Vascular Biology121 citationsOpen Access
View Full PaperTargeted Metabolomic Evaluation of Arginine Methylation and Cardiovascular Risks
Key Result
An integrated index of arginine methylation (ArgMI) was a significant independent predictor of incident major adverse cardiac events at 3 years (adjusted HR 2.4; 95% CI 1.3-4.5; P=0.006).
Study Design
Type
Cohort (n=1,011)
Structured PICO
Do plasma levels of arginine methylation products predict incident MACE and obstructive CAD in patients undergoing elective diagnostic cardiac catheterization?
P
Population
1011 consecutive consenting subjects undergoing elective diagnostic cardiac catheterization
I
Intervention
Plasma levels of arginine methylation products (ADMA, SDMA, MMA) and integrated index of arginine methylation [ArgMI=(ADMA+SDMA)/MMA]
O
Outcome
Major adverse cardiac events (MACE, including myocardial infarction, stroke, and death) at 3 yearscomposite
Plasma levels of ADMA, SDMA, and an integrated arginine methylation index independently predict incident MACE in stable patients undergoing cardiac evaluation, suggesting mechanisms beyond direct NOS inhibition.
Main Result
Effect estimate: HR 2.4 (95% CI 1.3 to 4.5)
p-value: p=0.006
Abstract
BACKGROUND: We examine the relationship of related posttranslational modification products of arginine methylation and coronary artery disease (CAD) phenotypes. METHODS AND RESULTS: Plasma was isolated from 1011 consecutive consenting subjects undergoing elective diagnostic cardiac catheterization, and future major adverse cardiac events (MACE, including myocardial infarction, stroke, and death) at 3 years were investigated. Plasma levels of asymmetrical dimethylarginine (ADMA, endogenous nitric oxide synthase NOS inhibitor), symmetrical dimethylarginine (SDMA, which lacks NOS inhibitory activity), N-mono-methylarginine (MMA, a potent NOS inhibitor), methyl-lysine (Methyl-Lys, an unrelated methylated amino acid), arginine, and its major catabolites (citrulline and ornithine) were quantified simultaneously by stable isotope dilution HPLC with online electrospray ionization tandem mass spectrometry and adjusted for traditional risk factors, C-reactive protein, and estimated creatinine clearance. High SDMA levels (adjusted odds ratio OR 1.6, 95%CI, 1.1 to 2.6, P<0.001), low MMA (adjusted OR 0.5, 95%CI 0.4 to 0.8, P=0.007), but not ADMA (adjusted OR 1.3, 95%CI 0.88 to 2.0, P=0.177) were associated with increased prevalence of significantly obstructive CAD. Elevated levels of SDMA (adjusted Hazard Ratio HR 2.4, 95%CI 1.2 to 4.6, P=0.009), ADMA (adjusted HR 2.2, 95%CI 1.2 to 4.0, P=0.015), as well as an integrated index of arginine methylation ArgMI=(ADMA+SDMA)/MMA (adjusted HR 2.4, 95%CI 1.3 to 4.5, P=0.006) were significant independent predictors of incident MACE. ArgMI was predictive of incident MACE even following adjustments for global arginine bioavailability, particularly within secondary prevention patients. CONCLUSIONS: ADMA, SDMA, and the integrated quantification of arginine methylation (in the form of a methylation index) provided independent risk prediction for both significantly obstructive CAD and incident MACE in stable patients undergoing cardiac evaluation. These results suggest that factors beyond direct NOS inhibition contribute to the clinical associations between methylarginines and CAD outcomes.