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.
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Lena
L
Vogl
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Johannes
J
Pohlhammer
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
Andreas
A
Meinitzer
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria; Department of Vascular Surgery, Medical University of Innsbruck, Innsbruck, Austria.
Barbara
B
Rantner
3rd Medical Department of Metabolic Diseases and Nephrology, Hietzing Hospital, Vienna, Austria; King's College London, Diabetes Research Group, London, United Kingdom.
Marietta
M
Stadler
3rd Medical Department of Metabolic Diseases and Nephrology, Hietzing Hospital, Vienna, Austria.
Slobodan
S
Peric
Central Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Innsbruck, Medical University of Innsbruck, Innsbruck, Austria.
Angelika
A
Hammerer-Lercher
Clinic for Angiology, HELIOS Klinikum Berlin-Buch, Berlin, Germany.
Peter
P
Klein-Weigel
Department of Vascular Surgery, Medical University of Innsbruck, Innsbruck, Austria.
Gustav
G
Fraedrich
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
Florian
F
Kronenberg
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: Barbara.Kollerits@i-med.ac.at.
Barbara
B
Kollerits
D000368:Aged; D001120:Arginine / Q000097:blood*; D001317:Austria; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002423:Cause of Death; D016009:Chi-Square Distribution; D003430:Cross-Sectional Studies; D018450:Disease Progression; D006709:Homoarginine / Q000097:blood*; D006801:Humans; D007383:Intermittent Claudication / Q000097:blood* / Q000175:diagnosis / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D058729:Peripheral Arterial Disease / Q000097:blood* / Q000175:diagnosis / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D013997:Time Factors
D015415:Biomarkers; D006709:Homoarginine; D001120:Arginine
ADMA; Cardiovascular disease; Mortality; Peripheral arterial disease; SDMA; l-arginine; l-homoarginine