High Plasma Dimethylarginine Levels are Associated with Adverse Clinical Outcome After Stroke

Abstract

Aim: Increased levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been observed in patients with cardiovascular risk factors and atherosclerosis and in patients with a history of stroke. The role of ADMA and its analogue symmetric dimethylarginine (SDMA) in acute ischemic stroke is yet unclear. We hypothesized that plasma dimethylarginine levels increase in the hyper-acute phase after ischemic stroke and that their time course is related to stroke outcome. Methods: Plasma dimethylarginines ADMA and SDMA and L-arginine levels were measured in 67 patients at 6, 12, 24 hours, as well as 3 and 7 days after stroke onset using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS). Data were compared to control data from 32 age-adjusted healthy volunteers. Clinical outcome was assessed using the modified Rankin Scale (mRS) at 90 days after stroke. Results: At baseline, plasma ADMA levels were higher in stroke patients than in controls, whereas plasma SDMA and L-arginine levels did not differ from control subjects. The time courses of ADMA and SDMA were related to the clinical outcome. Binary logistic regression analysis showed that ADMA levels of ≥ 0.566 mol/L at day 3, ≥ 0.530 mol/L at day 7 and SDMA levels of ≥ 0.59 mol/L at 24 hours predicted an unfavorable clinical outcome. Conclusions: An increase of both ADMA and SDMA plasma levels within the first 72 hours after the onset of ischemic stroke predicts a poor outcome. J Atheroscler Thromb, 2011; 18:753-761.

Subarachnoid haemorrhage induces an inflammatory response followed by a delayed persisting increase in asymmetric dimethylarginine

“…In a clinical study of patients with aneurysmal SAH, a strong correlation between ADMA concentrations in CSF and degree of cerebral vasospasm was found, but ADMA concentrations in serum remained unchanged during the study period [17]. This is in contrast to the rapid increase in plasma concentrations of ADMA after ischemic stroke reported by Worthmann et al [14]. In a small study on patients with SAH caused by aneurysmal bleeding or trauma, increased concentrations of ADMA were shown both in both plasma and CSF [18].…”

“…A massive systemic inflammatory response is triggered by SAH and induces an increase in inflammatory markers such as C-Reactive Protein (CRP) [12]. High ADMA concentrations after ischemic stroke has been associated to un-favourable outcome, and elevated concentrations of ADMA can be lowered by anti-inflammatory treatment with statins [13,14]. However, the timing of ADMA and CRP as markers for inflammatory response after SAH remains to be elucidated [15].…”

Letter by Tsuda Regarding Article, “Low Plasma Arginine:Asymmetric Dimethyl Arginine Ratios Predict Mortality After Intracranial Aneurysm Rupture”

“…It was reported that higher SDMA levels in the cerebrospinal fluid were correlated with a poor outcome at 3 months after stroke onset. 4 Worthmann et al 5 demonstrated that an increase of both plasma ADMA and SDMA levels within the first 72 hours after the onset of ischemic stroke may predict a poor outcome. In this context, it is strongly suggested that both ADMA and SDMA could be the biomarkers referring to endothelial dysfunction and disturbed cerebrovascular circulation.…”

Asymmetric Dimethylarginine in Response to Recombinant Tissue-Type Plasminogen Activator and Erythropoietin in Acute Stroke

“…This is in line with previous data from a clinical stroke study that did not include subgroup analysis for acute stroke treatment. 9 Considering data from animal models and endothelial cell cultures, we hypothesized that elevation of ADMA levels might be pronounced in patients who received EPO or EPO+rtPA compared with those with placebo. 15,16 However, we could not prove this hypothesis.…”

“…ADMA increase after acute stroke is associated with adverse outcome. [9][10][11] It is suggested that ADMA might significantly contribute to brain injury after stroke by decreasing cerebral perfusion and triggering oxidative stress and inflammation. [12][13][14] Treatment with EPO increased ADMA levels in both, cell cultures and experimental animals.…”