Dimethylarginines in patients with intracerebral hemorrhage: association with outcome, hematoma enlargement, and edema

Abstract

BackgroundAsymmetric dimethylarginine (ADMA)––the most potent endogenous NO-synthase inhibitor, has been regarded as mediator of endothelial dysfunction and oxidative stress. Considering experimental data, levels of ADMA and its structural isomer symmetric dimethylarginine (SDMA) might be elevated after intracerebral hemorrhage (ICH) and associated with clinical outcome and secondary brain injury.MethodsBlood samples from 20 patients with acute ICH were taken at ≤ 24 h and 3 and 7 days after the event. Nine patients had favorable (modified Rankin Scale (mRS) at 90 days 0–2) outcome, and 11 patients unfavorable outcome (mRS 3–6). Patients’ serum ADMA, SDMA, and L-arginine levels were determined by high-performance liquid chromatography–tandem mass spectrometry. Levels were compared to those of 30 control subjects without ICH. For further analysis, patients were grouped according to outcome, hematoma and perihematomal edema volumes, occurrence of hematoma enlargement, and cytotoxic edema as measured by computed tomography and serial magnetic resonance imaging.ResultsLevels of ADMA––but not SDMA and L-arginine––were elevated in ICH patients compared to controls (binary logistic regression analysis: ADMA ≤ 24 h, p = 0.003; 3 days p = 0.005; 7 days p = 0.004). If patients were grouped according to outcome, dimethylarginines were increased in patients with unfavorable outcome. The binary logistic regression analysis confirmed an association of SDMA levels ≤ 24 h (p = 0.048) and at 3 days (p = 0.028) with unfavorable outcome. ADMA ≤ 24 h was increased in patients with hematoma enlargement (p = 0.003), while SDMA ≤ 24 h was increased in patients with large hematoma (p = 0.029) and perihematomal edema volume (p = 0.023).ConclusionsOur data demonstrate an association between dimethylarginines and outcome of ICH. However, further studies are needed to confirm this relationship and elucidate the mechanisms behind.

Intrathecal and systemic alterations of L-arginine metabolism in patients after intracerebral hemorrhage

“…A significant drop in plasma L-arginine after ICH has been described before 17,18 but, similar to our findings, only showed a trend to decrease in a different study. 19 Furthermore, significant decreases for L-citrulline and L-ornithine after ICH have been measured as well. 17 Similarly, significantly decreased plasma levels of L-arginine, L-citrulline and L-ornithine without changes in dimethylarginines have been reported after severe traumatic brain injury.…”

“…18 However, this is in contrast to a study by Worthmann et al describing elevated ADMA levels through day seven after ICH. 19…”

“…17 Dimethylarginine levels after ICH have only been measured in two studies that exclusively reported their peripheral blood levels but not CSF concentrations. 18,19 Results were discrepant: Wanby and co-workers observed no changes in dimethylarginine levels, 18 whereas Worthmann et al observed elevated ADMA levels and an independent association of SDMA concentration with outcome. 19 No comprehensive analysis of intrathecal metabolites of L-arginine catabolism after ICH has been reported yet.…”

“…18,19 Results were discrepant: Wanby and co-workers observed no changes in dimethylarginine levels, 18 whereas Worthmann et al observed elevated ADMA levels and an independent association of SDMA concentration with outcome. 19 No comprehensive analysis of intrathecal metabolites of L-arginine catabolism after ICH has been reported yet. Moreover, CSF data on these metabolic pathways is also sparse for other acute neurological disorders.…”

Plasma Dimethylarginine Levels and Carotid Intima–Media Thickness are related to Atrial Fibrillation in Patients with Embolic Stroke

“…ADMA is an inhibitor of nitric oxide (NO) synthesis as it competes with its analogue L-arginine at the NO-synthase. Several studies have described an association of ADMA with cardiovascular risk [12], carotid intima–media thickness (CIMT) [13], and pathologies like ischemic [14,15] and hemorrhagic stroke [16]. Symmetric dimethylarginine (SDMA), which is an isomer of ADMA, modulates the synthesis of NO via inhibition of cellular uptake of L-arginine.…”