eNOS polymorphisms and cerebral vasospasm after SAH. Cerebral vasospasm is a common complication of aneurysmal subarachnoid hemorrhage (SAH) and remains a major cause of death and disability after aneurysm rupture. The etiology of cerebral vasospasm is likely multi-factorial but eventually leads to altered cerebral blood flow (CBF) regulation by the vascular endothelium. Our data also supports the role of endothelial nitric oxide (eNOS) polymorphisms in increasing susceptibility for cerebral vasospasm. We propose to study the effect of polymorphisms in eNOS on blood flow regulation by measuring quantitative CBF and correlating with outcomes in patients with cerebral vasospasm after SAH. In our longitudinal cohort of 300 SAH patients (established in 2003), we have collected blood, serum, and CSF samples, and we have carefully characterized clinical and radiographic findings during the acute hospitalization. In addition, we have collected functional and cognitive outcomes up to two years after SAH. Further correlation of genetic susceptibility with an intermediate phenotype, quantitative CBF, and relevant clinical outcomes will form the basis of a future R01 grant application to investigate regulation of CBF in cerebral vasospasm and ischemia. In order to better understand the role of polymorphisms in eNOS in cerebral vasospasm, we will determine the association between eNOS polymorphisms, cerebral vasospasm and adverse neurological outcomes in our retrospective cohort. We will also perform a prospective pilot study to determine the association of the highest risk genotypes with physiologic alterations in CBF. The goal of this research is to provide evidence for genetic variation associated with altered NOS activity with clinical outcome. Further, we will develop a set of intermediate phenotypes that will enable us to better understand the biologic mechanisms that confer genetic susceptibility from eNOS polymorphisms. The long-term goals of this research are to understand the pathophysiology of cerebral vasospasm, to develop better predictive models for patients at risk, and to identify novel targets for intervention that will improve clinical outcomes.
