High levels of arginine, citrulline and ADMA are independent predictors of cardiovascular disease

Abstract

Purpose: Arginine is the sole nitrogen source for Nitric Oxide (NO) synthesis and citrulline is the major catabolic product of arginine. Arginine restores endothelial function in atherosclerotic patients, in whom there are elevated levels of Asymmetric Dimethylarginine (ADMA), an endogenous inhibitor of Nitric Oxide Synthase (NOS). In this study we investigated the relationships among plasma arginine levels, its catabolic end-product citrulline and the competitive inhibitor of NO biosynthesis (ADMA) and subclinical measures of atherosclerosis and as well incident Cardiovascular Disease (CVD). Methods: We performed a matched case-control study derived from the population-based Malmo Diet and Cancer Cardiovascular Cohort (MDC-CC), all included subjects were without history of CVD at baseline. During 12 years of follow-up, 253 individuals had a CVD event and were matched for age, sex and Framingham risk score with 253 controls. Arginine, citrulline and ADMA were profiled in baseline plasma samples using liquid chromatography-tandem mass spectrometry and relationship to incident CVD was assessed using conditional logistic regression. We further examined whether arginine, citrulline and ADMA correlated with anatomical (plaque formation) abnormalities. Results: After adjustment for traditional risk factors, inflammation (hs-CRP), diabetes status and insulin resistance (HOMA-index) at baseline, each 1SD increase of arginine (1.65, 1.21-2.26; p=0.002), citrulline (1.43, 1.13-1.80; p=0.003), and ADMA (1.34, 1.04-1.72; p=0.024), were all significantly associated with increased risk of CVD after 12 years of follow-up. Furthermore, increased levels (in quartiles) of arginine, citrulline and ADMA were cross-sectionally related with presence of more than 50% stenosis of the carotid artery; (Ptrend=0.006 for arginine, Ptrend = 0.001 for citrulline and Ptrend = 0.025 for ADMA). Conclusion: This study identifies arginine, citrulline and ADMA as independent early predictors of CVD, after taking traditional risk factors for CVD, inflammation and insulin resistance into account.