Symmetric dimethylarginine predicts all-cause mortality following ischemic stroke

• Published in: Atherosclerosis Vol. 208; no. 2; pp. 518 - 523
• Main Authors: Schulze, Friedrich, Carter, Angela M, Schwedhelm, Edzard, Ajjan, Ramzi, Maas, Renke, von Holten, Rouven-Alexander, Atzler, Dorothee, Grant, Peter J, Böger, Rainer H
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01.02.2010; Elsevier
• Subjects: Aged; Aged, 80 and over; Albumins - metabolism; Arginine - analogs & derivatives; Arginine - chemistry; Arginine - metabolism; Atherosclerosis (general aspects, experimental research); Atrial fibrillation; beta-Thromboglobulin - metabolism; Biological and medical sciences; Blood and lymphatic vessels; C-Reactive Protein - metabolism; Cardiology. Vascular system; Cardiovascular; Endothelium, Vascular - metabolism; Enzyme Inhibitors - pharmacology; Female; Glomerular Filtration Rate; Haemostasis; Humans; Ischemia - mortality; Ischemia - pathology; Male; Medical sciences; Middle Aged; Neurology; Nitric oxide; Nitric Oxide - chemistry; Nitric Oxide Synthase - antagonists & inhibitors; Prognosis; Renal function; Risk Factors; Risk marker; Stroke - mortality; Stroke - pathology; Vascular diseases and vascular malformations of the nervous system; von Willebrand Factor - metabolism; Prognosis; Renal function; Risk marker; Haemostasis; Nitric oxide; Atrial fibrillation; Cerebral infarction; Nervous system diseases; Stroke; Arrhythmia; Mortality; Cardiovascular disease; Excitability disorder; Cerebral disorder; Vascular disease; Heart disease; Central nervous system disease; Atherosclerosis; Risk factor; Brain ischemia; Cerebrovascular disease
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2009.06.039

Abstract Objective Methylarginines have been shown to interfere with nitric oxide (NO) formation by inhibiting NO synthase (asymmetric dimethylarginine, ADMA, and monomethylarginine, NMMA) and the cellular l -arginine uptake system (ADMA, NMMA and symmetric dimethylarginine, SDMA), thereby causing endothelial dysfunction. ADMA is a predictor of cardiovascular events and mortality in diverse populations. Methods We investigated whether methylarginines are predictors of mortality in 394 patients after acute ischemic stroke during 7.4 years of follow-up. Results Patients who died ( N = 231) were older and more frequently had one of the traditional risk factors for stroke (previous stroke/TIA, atrial fibrillation, prevalent ischemic heart disease, peripheral vascular disease, each p < 0.05). ADMA (0.52 μmol/l vs. 0.50 μmol/l, p = 0.015) and SDMA (0.56 μmol/l vs. 0.43 μmol/l, p < 0.001) were higher in patients who died. In multivariable-adjusted hazard models, SDMA but not ADMA or NMMA was an independent predictor of all-cause mortality after stroke (SDMA, hazard ratio 2.41 (1.55–3.72), p < 0.001; ADMA, hazard ratio 1.43 (0.99–2.07), p = 0.06). SDMA was significantly associated with atrial fibrillation (0.55 μmol/l vs. 0.50 μmol/l, p = 0.03) but there was no significant interaction between SDMA and AF in relation to mortality ( p = 0.81). SDMA remained significantly associated with mortality after adjusting for eGFR and also additionally adjusting for C-reactive protein, albumin, β-thromboglobulin, and von Willebrand factor. Conclusion Our study demonstrates that SDMA is an independent predictor of total mortality after acute stroke irrespective of renal function. SDMA is associated with atrial fibrillation, endothelial and platelet activation, and may therefore play a previously unknown role in the pathophysiology of stroke.