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(Circulation. 2007;116:2315-2324.)
© 2007 American Heart Association, Inc.

Vascular Medicine

Metabolic Profiling of Arginine and Nitric Oxide Pathways Predicts Hemodynamic Abnormalities and Mortality in Patients With Cardiogenic Shock After Acute Myocardial Infarction

Stephen J. Nicholls, MBBS, PhD; Zeneng Wang, PhD; Robert Koeth, BA, BS; Bruce Levison, PhD; Brian DelFraino, MS; Vladimir Dzavik, MD; Owen W. Griffith, PhD; David Hathaway, MD, PhD; Julio A. Panza, MD; Steven E. Nissen, MD; Judith S. Hochman, MD; Stanley L. Hazen, MD, PhD

From the Department of Cardiovascular Medicine (S.J.N., S.E.N., S.L.H.) and Center for Cardiovascular Diagnostics and Prevention (S.J.N., Z.W., R.K., B.L., B.D., S.L.H.), Cleveland Clinic Foundation, Cleveland Ohio; Interventional Cardiology Program, Toronto General Hospital, Toronto, Canada (V.D.); Arginox Pharmaceuticals, Redwood City, Calif (O.W.G., D.H.); Coronary Care Unit, Washington Hospital Center, Washington, DC (J.A.P.); and Cardiovascular Clinical Research Center, New York University School of Medicine, New York (J.S.H.).

Correspondence to Stephen J. Nicholls, MBBS, PhD, Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic Foundation, 9500 Euclid Ave, NE-10, Cleveland OH, 44195. E-mail nichols1{at}ccf.org

Received May 4, 2006; accepted July 21, 2007.

Background— It is unclear whether abnormalities of arginine and nitric oxide metabolism are related to hemodynamic dysfunction and mortality in patients with cardiogenic shock (CS) after acute myocardial infarction.

Methods and Results— Plasma metabolites reflecting arginine bioavailability, nitric oxide metabolism, and protein oxidation were analyzed by mass spectrometry in patients with CS (n=79) and age- and gender-matched patients with coronary artery disease and normal left ventricular function (n=79). CS patients had higher levels of asymmetric dimethylarginine (ADMA; P<0.0001), symmetric dimethylarginine (P<0.0001), monomethylarginine (P=0.0003), nitrotyrosine (P<0.0001), and bromotyrosine (P<0.0001) and lower levels of arginine (P<0.0001), ratio of arginine to ornithine (P=0.03), and ratio of arginine to ornithine plus citrulline) (P=0.0003). CS patients with elevated ADMA levels were 3.5-fold (95% confidence interval, 1.4 to 11.3; P=0.02) more likely to die in 30 days than patients with low ADMA levels. ADMA remained the only independent predictor of mortality on multiple logistic regression analysis. In patients with normal renal function, symmetric dimethylarginine levels inversely correlated with mean arterial pressure and systemic vascular resistance, whereas levels of ADMA correlated with pulmonary capillary wedge pressure and both systolic and diastolic pulmonary artery pressures. Despite dramatic elevations, levels of protein oxidation products did not predict hemodynamic dysfunction or mortality in CS patients.

Conclusions— CS is characterized by an arginine-deficient and highly specific pro-oxidant state, with elevated levels of methylated arginine derivatives, including endogenous nitric oxide synthase inhibitors. Levels of methylated arginine derivatives strongly correlate with hemodynamic dysfunction. Among all clinical and laboratory parameters monitored, ADMA levels were the strongest independent predictor of 30-day mortality.

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