Variants of the endothelial nitric oxide gene and cerebral blood flow after severe traumatic brain injury

Abstract

Experimental studies suggest that nitric oxide produced by endothelial nitric oxide synthase (NOS3) plays a role in maintaining cerebral blood flow (CBF) after traumatic brain injury (TBI). The purpose of this study was to determine if common variants of the NOS3 gene contribute to hypoperfusion after severe TBI. Fifty-one patients with severe TBI were studied. Cerebral hemodynamics, including global CBF by the stable xenon computed tomography (CT) technique, internal carotid artery flow volume (ICA-FVol), and flow velocity in intracranial vessels, were measured within 12 h of injury, and at 48 h after injury. A blood sample was collected for DNA analysis, and genotyping of the following variants of the NOS3 gene was performed: -786T>C, 894G>T, and 27bp VNTR. Cerebral hemodynamics were most closely related to the-786T>C genotype. CBF averaged 57.7±3.0 mL/100 g/min with the normal T/T genotype, 47.0±2.5 mL/100 g/min with the T/C, and 37.3±8.8 mL/100 g/min with the C/C genotype (p=0.0146). Cerebrovascular resistance followed an inverse pattern with the highest values occurring with the C/C genotype (p=0.0027). The lowest ICA-FVol of 124±43 mL/min was found at 12 h post-injury in the more injured hemisphere of the patients with the C/C genotype (p=0.0085). The mortality rate was 20% in patients with the T/T genotype and 17% with the T/C genotype. In contrast, both of the patients with the C/C genotype were dead at 6 months post-injury (p=0.022). The findings in this study support the importance of NO produced by NOS3 activity in maintaining CBF after TBI, since lower CBF values were found in patients having the -786C allele. The study suggests that a patient's individual genetic makeup may contribute to the brain's response to injury and determine the patient's chances of surviving the injury. The results here will need to be studied in a larger number of patients, but could explain some of the variability in outcome that occurs following severe TBI.

FIG. 1.

The nitric oxide synthase 3 (NOS3) gene consists of 26 exons (vertical lines) spanning 21 kb on the chromosome. The three polymorphisms that were studied are indicated by the arrows. The −786T>C location is in the promoter region. The 27-bp VNTR location is in intron 4, and the 894G>T location is in exon 7.

FIG. 2.

Average cortical cerebral blood flow (CBF) by −786T>C genotype and by day (-786T>C genotype effect, p=0.0146).

FIG. 3.

Average cortical cerebral vascular resistance (CVR) by −786T>C genotype and by day (-786T>C genotype effect, p=0.0027; day effect, p=0.0149).

FIG. 4.

Internal carotid artery flow volume by −786T>C genotype and side of brain and day (genotype×side×day interaction, p=0.0085).

FIG. 5.

Middle cerebral artery flow velocity by 894G>T genotype and side of brain and day (genotype×side×day interaction, p=0.0005; †different from both G/G and T/T on same day and side [p<0.05]; *different from G/G on same side and day [p<0.05]).