Serum concentrations of L-arginine and L-homoarginine in male patients with intermittent claudication: A cross-sectional and prospective investigation in the CAVASIC Study

Background: High serum concentrations of L-arginine and L-homoarginine increase nitric oxide (NO) availability and thereby improve endothelial function. Information about the association of these markers with peripheral arterial disease (PAD) and related outcomes is sparse. Methods: L-arginine, its metabolites and L-homoarginine were analyzed in the CAVASIC Study including 232 male patients diagnosed with intermittent claudication and 246 age- and diabetes-matched controls. After the baseline investigation PAD patients were prospectively followed (median 7 years). The association of these markers with symptomatic PAD at baseline, incident cardiovascular events and all-cause mortality was assessed. Results: At baseline each increase of ln-L-homoarginine and L-arginine by one standard deviation was associated with symptomatic PAD: OR = 0.75, 95% CI 0.59-0.96, P = 0.02 and OR = 1.36, 95% CI 1.07-1.73, P = 0.01, respectively (both models adjusted for ln-CRP, GFR, HDL cholesterol, and current smoking). Only L-arginine remained significant after additional adjustment for ln-NT-proBNP and hs-cTnT: OR = 1.49, P = 0.002. In the Cox regression analysis elevated ln-L-homoarginine significantly reduced the risk to die (n = 38) even independent from ln-NT-proBNP and hs-cTnT: HR = 0.59, 95% CI 0.41-0.84, P = 0.004. L-arginine was significantly predicting incident cardiovascular events (n = 65): HR = 1.68, 95% CI 1.35-2.10, P < 0.001. Conclusions: This study in male patients with intermittent claudication and age-and diabetes-matched controls showed an association of L-homoarginine and L-arginine with PAD. During follow-up, L-arginine was associated with incident cardiovascular events probably due to its primary role in NO metabolism and impact on endothelial integrity. L-homoarginine was related to all-cause mortality implying a broader role in metabolic processes besides endothelial function. (C) 2015 Elsevier Ireland Ltd. All rights reserved.