Daniel Appel1, Miriam Seeberger2, Edzard Schwedhelm2,3, Patrick Czorlich4, Alwin E Goetz5, Rainer H Böger2,3, Juliane Hannemann2. 1. Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. d.appel@uke.de. 2. Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 3. DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Hamburg, Germany. 4. Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 5. Department of Anesthesiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Abstract
BACKGROUND: Delayed cerebral ischemia (DCI) is the major cause of lethality and neuronal damage in patients who survived the primary subarachnoid hemorrhage (SAH). Asymmetric and symmetric dimethylarginines (ADMA and SDMA) inhibit nitric oxide production from L-arginine via distinct mechanisms. Elevated ADMA levels are associated with vasospasm after SAH. We aimed to study the time course of ADMA and SDMA in plasma and ventricular cerebrospinal fluid (CSF) and their associations with DCI and outcome. METHODS: We measured ADMA and SDMA in 34 SAH patients with an external ventricular drain at admission and on days 3, 6, 8, 12, and 15 and followed them up for clinical status and neurological outcome until 30 days post-discharge. DCI was defined as the appearance of new infarctions on cerebral computed tomography or magnetic resonance imaging. RESULTS: ADMA and SDMA plasma concentrations did not differ significantly at baseline between patients who suffered DCI (N = 14; 41%) and not; however, plasma ADMA reached a peak on days 8 and 15 after hemorrhage in patients with DCI (0.81-0.91 µmol/l). Baseline plasma L-arginine/ADMA ratio was significantly lower in patients with DCI (57.1 [34.3; 70.8] vs. 68.7 [55.7; 96.2]; p < 0.05). ADMA and SDMA concentrations in CSF were significantly higher in patients with DCI than without. In multivariable-adjusted linear regression models, CSF ADMA was negatively associated with the incidence of DCI (OR 0.03 [0.02-0.70]; p = 0.04), whereas CSF SDMA on the day of hemorrhage predicted poor neurological outcome until 30 days after discharge (OR 22.4 [1.21-416.02]; p = 0.04). CONCLUSIONS: Our study shows that ADMA and the L-arginine/ADMA ratio are associated with the incidence of DCI after SAH. By contrast, SDMA was associated with initial neuronal damage and poor neurological outcome after SAH. These data support the hypothesis that ADMA and L-arginine affect the pathophysiology of cerebral ischemia after SAH, while SDMA is a biomarker of neurological outcome after SAH.
BACKGROUND:Delayed cerebral ischemia (DCI) is the major cause of lethality and neuronal damage in patients who survived the primary subarachnoid hemorrhage (SAH). Asymmetric and symmetric dimethylarginines (ADMA and SDMA) inhibit nitric oxide production from L-arginine via distinct mechanisms. Elevated ADMA levels are associated with vasospasm after SAH. We aimed to study the time course of ADMA and SDMA in plasma and ventricular cerebrospinal fluid (CSF) and their associations with DCI and outcome. METHODS: We measured ADMA and SDMA in 34 SAHpatients with an external ventricular drain at admission and on days 3, 6, 8, 12, and 15 and followed them up for clinical status and neurological outcome until 30 days post-discharge. DCI was defined as the appearance of new infarctions on cerebral computed tomography or magnetic resonance imaging. RESULTS:ADMA and SDMA plasma concentrations did not differ significantly at baseline between patients who suffered DCI (N = 14; 41%) and not; however, plasma ADMA reached a peak on days 8 and 15 after hemorrhage in patients with DCI (0.81-0.91 µmol/l). Baseline plasma L-arginine/ADMA ratio was significantly lower in patients with DCI (57.1 [34.3; 70.8] vs. 68.7 [55.7; 96.2]; p < 0.05). ADMA and SDMA concentrations in CSF were significantly higher in patients with DCI than without. In multivariable-adjusted linear regression models, CSF ADMA was negatively associated with the incidence of DCI (OR 0.03 [0.02-0.70]; p = 0.04), whereas CSF SDMA on the day of hemorrhage predicted poor neurological outcome until 30 days after discharge (OR 22.4 [1.21-416.02]; p = 0.04). CONCLUSIONS: Our study shows that ADMA and the L-arginine/ADMA ratio are associated with the incidence of DCI after SAH. By contrast, SDMA was associated with initial neuronal damage and poor neurological outcome after SAH. These data support the hypothesis that ADMA and L-arginine affect the pathophysiology of cerebral ischemia after SAH, while SDMA is a biomarker of neurological outcome after SAH.
Authors: E Sander Connolly; Alejandro A Rabinstein; J Ricardo Carhuapoma; Colin P Derdeyn; Jacques Dion; Randall T Higashida; Brian L Hoh; Catherine J Kirkness; Andrew M Naidech; Christopher S Ogilvy; Aman B Patel; B Gregory Thompson; Paul Vespa Journal: Stroke Date: 2012-05-03 Impact factor: 7.914
Authors: Michael N Diringer; Thomas P Bleck; J Claude Hemphill; David Menon; Lori Shutter; Paul Vespa; Nicolas Bruder; E Sander Connolly; Giuseppe Citerio; Daryl Gress; Daniel Hänggi; Brian L Hoh; Giuseppe Lanzino; Peter Le Roux; Alejandro Rabinstein; Erich Schmutzhard; Nino Stocchetti; Jose I Suarez; Miriam Treggiari; Ming-Yuan Tseng; Mervyn D I Vergouwen; Stefan Wolf; Gregory Zipfel Journal: Neurocrit Care Date: 2011-09 Impact factor: 3.210
Authors: R H Böger; S M Bode-Böger; A Szuba; P S Tsao; J R Chan; O Tangphao; T F Blaschke; J P Cooke Journal: Circulation Date: 1998-11-03 Impact factor: 29.690
Authors: Rainer H Böger; Lisa M Sullivan; Edzard Schwedhelm; Thomas J Wang; Renke Maas; Emelia J Benjamin; Friedrich Schulze; Vanessa Xanthakis; Ralf A Benndorf; Ramachandran S Vasan Journal: Circulation Date: 2009-03-16 Impact factor: 29.690
Authors: Carla S Jung; Brian A Iuliano; Judith Harvey-White; Michael G Espey; Edward H Oldfield; Ryszard M Pluta Journal: J Neurosurg Date: 2004-11 Impact factor: 5.115
Authors: Matthew Koch; Animesh Acharjee; Zsuzsanna Ament; Riana Schleicher; Matthew Bevers; Christopher Stapleton; Aman Patel; W Taylor Kimberly Journal: Neurosurgery Date: 2021-04-15 Impact factor: 4.654
Authors: Ernest Jan Bobeff; Malgorzata Bukowiecka-Matusiak; Konrad Stawiski; Karol Wiśniewski; Izabela Burzynska-Pedziwiatr; Magdalena Kordzińska; Konrad Kowalski; Przemyslaw Sendys; Michał Piotrowski; Dorota Szczesna; Ludomir Stefańczyk; Lucyna Alicja Wozniak; Dariusz Jan Jaskólski Journal: J Clin Med Date: 2022-01-13 Impact factor: 4.241
Authors: William S Dodd; Dimitri Laurent; Aaron S Dumont; David M Hasan; Pascal M Jabbour; Robert M Starke; Koji Hosaka; Adam J Polifka; Brian L Hoh; Nohra Chalouhi Journal: J Am Heart Assoc Date: 2021-07-30 Impact factor: 5.501