Aneurysmal ubarachnoid hemorrhage (aSAH) is a devastating disease with high rates of mortality, physical disability and neuropsychological impairment. One of the major complications of aSAH which contribute to morbidity and mortality is the development of delayed cerebral ischemia (DCI). Because DCI develops days after aSAH injury, there is a sufficient time window for therapeutic intervention. Yet, strategies to prevent DCI have had limited success primarily due the inability to identify patients at high risk to develop DCI. As a result, many studies have investigated the role of regulators of cerebrovascular tone in the development of DCI. Preclinical studies suggest that 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) are potent regulators of cerebrovascular tone that play an important role in the development of DCI and cerebral ischemic injury. Also, functional single nucleotide polymorphisms (SNPs) in the genes responsible for 20-HETE and EET formation and elimination have been associated with neurovascular and cardiovascular disease. Based on this evidence, we set out to explore the role of 20-HETE and EET in cerebrovascular complications after aSAH in humans. The focus of the research project is to identify the key gene variants which affect 20-HETE and EET concentrations in cerebrospinal fluid (CSF) and the risk of developing DCI in a large cohort of 275 aSAH patients.
Aim 1 is to determine the relationship between key gene variants and 20- HETE and EET concentrations in CSF of aSAH patients. Patients will be genotyped for candidate gene SNPs and 20-HETE and EET concentrations will be measured in CSF.
Aim 2 is to determine the relationship between key gene variants and cerebrovascular complications after aSAH and the mediating effects of CSF 20- HETE and EET concentrations. Cerebral vasospasm will be determined using cerebral angiography and transcranial Doppler ultrasound. DCI will be determined by concomitant presence of cerebral vasospasm and neurological deterioration. The long-term goal of this research is to elucidate novel mechanisms that may serve as targets for aSAH treatment and provide a rapid and effective method to determine aSAH patients at high risk for developing DCI. This research supports the goals of the National Institute of Nursing Research (NINR) to adopt, adapt and generate new technologies for better health care by identifying potential biomarkers that may predict SAH patients at high risk for DCI so that treatment can be modified to reduce ischemic complications and improve patient outcomes.
The overall prognosis of hemorrhagic stroke remains poor with high rates of mortality, physical disability and impairment. Currently, there are no established methods to identify hemorrhagic stroke patients at high risk of developing brain damage due to reduced blood flow after injury, an important and potentially preventable complication that develops in a high percentage of patients. The goal of this research is to identify new targets for therapy in hemorrhagic stroke patients and provide a rapid and effective method to determine patients at high risk for developing ischemic complications.
|Donnelly, Mark K; Crago, Elizabeth A; Conley, Yvette P et al. (2015) 20-HETE is associated with unfavorable outcomes in subarachnoid hemorrhage patients. J Cereb Blood Flow Metab 35:1515-22|