Kathrin Cordts1, Ricarda Grzybowski2, Susanne Lezius3, Nicole Lüneburg4, Dorothee Atzler5, Axel Neu6, Sönke Hornig6, Rainer H Böger1, Christian Gerloff2, Tim Magnus2, Götz Thomalla2, Edzard Schwedhelm1, Peter J Grant7, Chi-Un Choe8. 1. Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; DZHK (Deutsches Zentrum für Herz-Kreislauf-Forschung e.V.), partner site Hamburg/Kiel/Lübeck, Germany. 2. Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. 3. Department of Medical Biometry and Epidemiology, University Medical Center Hamburg- Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. 4. Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. 5. Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, DZHK, partner site Munich Heart Alliance, Munich, Germany. 6. Experimental Neuropediatrics, ZMNH, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. 7. Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds, UK. 8. Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. Electronic address: cchoe@uke.de.
Abstract
INTRODUCTION: Guanidino compounds, including l-homoarginine (l-hArg), symmetric dimethylarginine (SDMA), asymmetric dimethylarginine (ADMA) and l-arginine (l-Arg) are associated with mortality, fatal strokes, stroke incidence, and atherosclerosis. OBJECTIVES: We aimed to study the association of guanidino compounds (l-hArg/ADMA and l-hArg/SDMA) with stroke etiology, internal carotid artery (ICA) stenosis and CHA2DS2-VASc score in patients with cerebrovascular disease. METHODS: We analyzed l-hArg, SDMA, ADMA, l-Arg, and compound molar ratios, i.e. l-hArg/ADMA and l-hArg/SDMA, in 272 patients with cerebrovascular disease in a cross-sectional discovery cohort and two cross-sectional validation cohorts of acute stroke patients from Germany (n = 137) and UK (n = 394). The guanidino compound levels were compared with clinical, imaging, and ultrasound parameters. RESULTS: Low l-hArg/ADMA and l-hArg/SDMA molar ratios predicted territorial infarcts (OR 1.74; 95% CI 1.34-2.26 and OR 1.64; 95% CI 1.26-2.15, respectively) and were associated with stroke subtypes due to large vessel disease or cardio-embolism (OR 1.52; 95% CI 1.12-2.06 and OR 2.01; 95% CI 1.35-3.00, respectively) in meta-analysis of the discovery and validation cohort data. In line with these results, a low l-hArg/ADMA and l-hArg/SDMA molar ratio was found in patients with ICA stenosis (OR 0.73; 95% CI 0.55-0.97 and OR 0.69; 95% CI 0.50-0.94, respectively) in the discovery and validation cohort. Furthermore, guanidino compound ratios (i.e. l-hArg/ADMA and l-hArg/SDMA) were strongly correlated with CHA2DS2-VASC score (p < .001) in all three cohorts. DISCUSSION: The results from these three cross-sectional studies reveal that guanidino compound ratios (i.e. l-hArg/ADMA and l-hArg/SDMA) can discriminate stroke etiologies, predict ICA stenosis and estimate risk prediction in patients with cerebrovascular disease.
INTRODUCTION:Guanidino compounds, including l-homoarginine (l-hArg), symmetric dimethylarginine (SDMA), asymmetric dimethylarginine (ADMA) and l-arginine (l-Arg) are associated with mortality, fatal strokes, stroke incidence, and atherosclerosis. OBJECTIVES: We aimed to study the association of guanidino compounds (l-hArg/ADMA and l-hArg/SDMA) with stroke etiology, internal carotid artery (ICA) stenosis and CHA2DS2-VASc score in patients with cerebrovascular disease. METHODS: We analyzed l-hArg, SDMA, ADMA, l-Arg, and compound molar ratios, i.e. l-hArg/ADMA and l-hArg/SDMA, in 272 patients with cerebrovascular disease in a cross-sectional discovery cohort and two cross-sectional validation cohorts of acute strokepatients from Germany (n = 137) and UK (n = 394). The guanidino compound levels were compared with clinical, imaging, and ultrasound parameters. RESULTS: Low l-hArg/ADMA and l-hArg/SDMA molar ratios predicted territorial infarcts (OR 1.74; 95% CI 1.34-2.26 and OR 1.64; 95% CI 1.26-2.15, respectively) and were associated with stroke subtypes due to large vessel disease or cardio-embolism (OR 1.52; 95% CI 1.12-2.06 and OR 2.01; 95% CI 1.35-3.00, respectively) in meta-analysis of the discovery and validation cohort data. In line with these results, a low l-hArg/ADMA and l-hArg/SDMA molar ratio was found in patients with ICA stenosis (OR 0.73; 95% CI 0.55-0.97 and OR 0.69; 95% CI 0.50-0.94, respectively) in the discovery and validation cohort. Furthermore, guanidino compound ratios (i.e. l-hArg/ADMA and l-hArg/SDMA) were strongly correlated with CHA2DS2-VASC score (p < .001) in all three cohorts. DISCUSSION: The results from these three cross-sectional studies reveal that guanidino compound ratios (i.e. l-hArg/ADMA and l-hArg/SDMA) can discriminate stroke etiologies, predict ICA stenosis and estimate risk prediction in patients with cerebrovascular disease.