Published Online
on October 29, 2007

A more recent version of this article appeared on November 13, 2007

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Submitted on May 4, 2006
Accepted on July 21, 2007

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, and 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.).

^* To whom correspondence should be addressed. E-mail: nichols1{at}ccf.org.

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.

Key words: myocardial infarction • nitric oxide • oxidative stress • shock

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