Low Plasma Arginine:Asymmetric Dimethyl Arginine Ratios Predict Mortality After Intracranial Aneurysm Rupture

Abstract

Background— Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, predicts mortality in cardiovascular disease and has been linked to cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). In this prospective study, we assessed whether circulating ADMA, arginine:ADMA ratio, and nitrite/nitrate levels were associated with survival and cerebral vasospasm in SAH patients. Methods— One hundred and eleven patients were observed day 1 to 15 after SAH, with serial measurements of transcranial Doppler flow velocities (V MCA ) and plasma biomarkers. Clinical status was assessed by the World Federation of Neurosurgical Societies grading scale. Results— Overall 30-day mortality was 18%, but differed between patients grouped by low, midrange, and high arginine:ADMA ratio in the first week after SAH. Mortality rates were 14/37, 1/37, and 5/37 in the 3 groups, respectively ( P -logrank=0.0003). Cox regression showed that low versus midrange or high arginine:ADMA was associated with a hazard ratio of 4.1 independent of World Federation of Neurosurgical Societies grade (95% confidence interval, 1.5–10.9; P =0.006). ADMA or arginine:ADMA had no association to V MCA , but there was an inverse relationship between V MCA and nitrite/nitrate levels ( P <0.0001). The NOS3 894G/G genotype was associated with 15% lower V MCA ( P =0.01). ATbG- NOS3 haplotype homozygosity was associated with up to 64% higher nitrite/nitrate levels ( P =0.003). Conclusions— This study suggests that plasma arginine:ADMA ratios predict mortality after SAH. Both clinical and physiological measures of changes in cerebral hemodynamics are coupled to the nitric oxide system.