Letter by Stuehlinger et al Regarding Article, “Metabolic Profiling of Arginine and Nitric Oxide Pathways Predicts Hemodynamic Abnormalities and Mortality in Patients With Cardiogenic Shock After Acute Myocardial Infarction”
To the Editor:
We read with great interest the article by Nicholls et al,1 which revealed alterations in the nitric oxide synthase pathway in patients with cardiogenic shock after myocardial infarction. Their intriguing data indicate that plasma concentrations of asymmetric dimethylarginine (ADMA, the endogenous nitric oxide synthase inhibitor) correlate with hemodynamic measurements in these patients. Moreover, of all clinical and laboratory parameters measured, plasma ADMA levels were the strongest determinant of 30-day mortality.1
We congratulate the authors for their important study, which provides more support for the role of endogenous ADMA in cardiovascular pathophysiology. However, the mechanism by which ADMA becomes elevated in this cohort remains unclear. The Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK-2) population was compared with patients with stable coronary artery disease but without evidence of heart failure or ischemia and before implementation of a reperfusion strategy. This comparison was useful because preexisting conditions (such as cardiovascular risk factors) that are known to elevate plasma ADMA were similar in the 2 groups. Plasma ADMA levels were more elevated in the patients with renal dysfunction, which is known to elevate plasma ADMA levels.2 However, even after consideration of creatinine clearance, ADMA was correlated to hemodynamic disturbances and mortality. Another cause contributing to the elevation of plasma ADMA in these individuals may be the effect of myocardial ischemia or reperfusion injury. Indeed, we recently found elevated plasma concentrations of ADMA in individuals with acute coronary syndromes without hemodynamic instability.3 Furthermore, we showed that ADMA accumulates transiently within the first hours of reperfusion in a rodent model.4 ADMA seems to be a very critical mediator of reperfusion injury, because lowering ADMA by ≈50% in a genetic mouse model was able to reduce the amount of damage from ischemia and reperfusion.4 Thus, the observed elevations of plasma ADMA in the SHOCK-2 trial may alternatively be explained by myocardial ischemia, reperfusion, or both in this population. It would therefore be very interesting to compare determinants of the nitric oxide synthase pathway in the SHOCK-2 population with matched patients after myocardial infarction but with normal hemodynamic function.
Dr Cooke is the inventor of patents owned by Stanford University for diagnostic and therapeutic applications of the NOS pathway, from which he receives royalties. The other authors report no conflicts.
Nicholls SJ, Wang Z, Koeth R, Levison B, Delfraino B, Dzavik V, Griffith OW, Hathaway D, Panza JA, Nissen SE, Hochman JS, Hazen SL. Metabolic profiling of arginine and nitric oxide pathways predicts hemodynamic abnormalities and mortality in patients with cardiogenic shock after acute myocardial infarction. Circulation. 2007; 116: 2315–2324.
Cooke JP. Asymmetrical dimethylarginine: the über marker? Circulation. 2004; 109: 1813–1818.
Bae SW, Stuhlinger MC, Yoo HS, Yu KH, Park HK, Choi BY, Lee YS, Pachinger O, Choi YH, Lee SH, Park JE. Plasma asymmetric dimethylarginine concentrations in newly diagnosed patients with acute myocardial infarction or unstable angina pectoris during two weeks of medical treatment. Am J Cardiol. 2005; 95: 729–733.
Stuhlinger MC, Conci E, Haubner BJ, Stocker EM, Schwaighofer J, Cooke JP, Tsao PS, Pachinger O, Metzler B. Asymmetric dimethyl L-arginine (ADMA) is a critical regulator of myocardial reperfusion injury. Cardiovasc Res. 2007; 75: 417–425.