Diminished Global Arginine Bioavailability and Increased Arginine Catabolism as Metabolic Profile of Increased Cardiovascular Risk

• Published in: Journal of the American College of Cardiology Vol. 53; no. 22; pp. 2061 - 2067
• Main Authors: Tang, W.H. Wilson, MD, Wang, Zeneng, PhD, Cho, Leslie, MD, Brennan, Danielle M., MS, Hazen, Stanley L., MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 02-06-2009; Elsevier; Elsevier Limited
• Subjects: Acute coronary syndromes; Aged; arginine; Arginine - analogs & derivatives; Arginine - blood; Arginine - metabolism; Atherosclerosis (general aspects, experimental research); Bioavailability; Biological and medical sciences; Biological Availability; Blood and lymphatic vessels; C-Reactive Protein; Cardiology; Cardiology. Vascular system; Cardiovascular; Cardiovascular disease; Cholesterol; Citrulline - blood; Confidence Intervals; coronary artery disease; Coronary Artery Disease - blood; Coronary Artery Disease - metabolism; Coronary Artery Disease - mortality; Coronary vessels; Deoxyribonucleic acid; Diabetes; DNA; Female; Heart attacks; Humans; Hypertension; Internal Medicine; Intubation; Male; Medical sciences; Middle Aged; Nitric oxide; Nitric Oxide Synthase - blood; Nitric Oxide Synthase - metabolism; Odds Ratio; Ornithine - blood; Ornithine - metabolism; Population; Prognosis; Prospective Studies; Risk Assessment; Risk Factors; coronary artery disease; NO; nitric oxide; CAD; myocardial infarction; major adverse cardiovascular event(s); ADMA; high-sensitivity C-reactive protein; GABR; prognosis; arginine; MACE; hsCRP; global arginine bioavailability ratio; MI; asymmetric dimethylarginine; Vascular disease; Arginine; Atherosclerosis; Risk factor; Cardiovascular risk; Cardiovascular disease; Catabolism; Circulatory system; Bioavailability; Cardiology; Profile
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2009.02.036

Objectives We hypothesized that an integrated assessment of arginine with its catabolic products might better predict cardiovascular risks than arginine levels alone. Background Arginine is the sole nitrogen source for nitric oxide (NO) synthesis. The major catabolic products of arginine are ornithine and citrulline. Methods Plasma levels of free arginine, ornithine, citrulline, and the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) were measured with liquid chromatography coupled with tandem mass spectrometry. We examined the relationship of global arginine bioavailability ratio (GABR) (defined as arginine/[ornithine + citrulline]) versus arginine and its catabolic metabolites to prevalence of significantly obstructive coronary artery disease (CAD) and incidence of major adverse cardiovascular events (MACE) (death, myocardial infarction, stroke) over a 3-year follow-up in 1,010 subjects undergoing elective cardiac catheterization. Results Patients with significantly obstructive CAD had significantly lower GABR (median [interquartile range]: 1.06 [0.75 to 1.31] vs. 1.27 [0.96 to 1.73], p < 0.001) and arginine levels [mean: 68 ± 20 μmol/l vs. 74 ± 24 μmol/l, p < 0.001) than those without significantly obstructive CAD. After adjusting for Framingham risk score, C-reactive protein, and renal function, lower GABR (but not arginine levels) and higher citrulline levels remained significantly associated with both the prevalence of significantly obstructive CAD (adjusted odds ratio: 3.93, p < 0.001, and 5.98, p < 0.001, respectively) and 3-year risk for the incidence of MACE (adjusted hazard ratio: 1.98, p = 0.025, and 2.40, p = 0.01, respectively) and remained significant after adjusting for ADMA. Conclusions GABR might serve as a more comprehensive concept of reduced NO synthetic capacity compared with systemic arginine levels. Diminished GABR and high citrulline levels are associated with both development of significantly obstructive atherosclerotic CAD and heightened long-term risk for MACE.