Symmetric dimethylarginine predicts all-cause mortality following ischemic stroke.
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 micromol/l vs. 0.50 micromol/l, p=0.015) and SDMA (0.56 micromol/l vs. 0.43 micromol/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 micromol/l vs. 0.50 micromol/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, beta-thromboglobulin, and von Willebrand factor.


CONCLUSIONS
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.
Schulze
Friedrich
F
Clinical Pharmacology Unit, Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Carter
Angela M
AM
Schwedhelm
Edzard
E
Ajjan
Ramzi
R
Maas
Renke
R
von Holten
Rouven-Alexander
RA
Atzler
Dorothee
D
Grant
Peter J
PJ
Böger
Rainer H
RH
D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007511:Ischemia / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000737:chemistry; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012307:Risk Factors; D020521:Stroke / Q000401:mortality / Q000473:pathology*; D001620:beta-Thromboglobulin / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D000418:Albumins; D004791:Enzyme Inhibitors; D001620:beta-Thromboglobulin; D014841:von Willebrand Factor; D009569:Nitric Oxide; C024917:symmetric dimethylarginine; D002097:C-Reactive Protein; D001120:Arginine; D019001:Nitric Oxide Synthase