News:Arginine metabolite found to predict mortality in patients with cardiogenic shock

November 4, 2007 By Benjamin A. Olenchock, M.D. Ph.D. [mailto:bolenchock@partners.org]

Arginine metabolites were measured in baseline plasma samples from 79 patients in the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK-2) trial, a trial which examined the effect of a nitric oxide synthetase inhibitor Tilarginine in patients with cardiogenic shock after acute myocardial infarction (MI). That trial, and the larger TRIUMPH trial, both showed that Tilarginine improved blood pressure but not mortality in this patient population.

The authors used liquid chromatography/tandem mass spectrometry to quantify levels of 13 different arginine metabolites in 79 patients. They found that arginine levels were depleted in patients with cardiogenic shock, while levels of methylated arginine metabolites were increased. A multivariate analysis was performed to determine whether high levels of different metabolites could independently predict mortality in cardiogenic shock after MI. While levels of almost every arginine metabolite were altered in patients with cardiogenic shock, ADMA levels stood alone as the only statistically significant independent predictor of mortality, with an OR of 3.19 (CI 1.02-12.81; p<0.05). The effect of elevated ADMA levels was much greater than that of other known predictors, including age and creatinine clearance. The authors mention that age was excluded from the multivariate analysis because it was clearly not associated with mortality in this study.

It would be interesting to know how different clinical signs of end-organ malperfusion such as oliguria and acidemia correlate with levels of arginine metabolites. It is impossible to predict to what extent altered arginine metabolism is a result of tissue malperfusion vs. a contributor to poor vascular tone and cardiac function. There are two important questions that arise from this interesting study. First, can ADMA levels contribute prognostic information in patients with cardiogenic shock? Further study of ADMA levels in other patient cohorts will be needed to answer this question. Spurious findings become an issue when a large number of statistical analyses are performed in a small patient cohort, and careful interpretation appears warranted in this instance. Secondly, would targeting ADMA levels improve outcomes in patients with cardiogenic shock after AMI? ADMA is an inhibitor of nitric oxide synthetase, so at first glance one might expect elevated ADMA levels to improve vascular tone and cardiac contractility. The relative importance of arginine deficiency, nitric oxide synthetase activity, and activity of different nitric oxide synthetase enzymes is quite complex, however. Future work will likely follow-up on this exciting work and answer these important questions.


 * 1) ref1 pmid=17967979