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Donnelly, Mark K. (2014) ROLE OF CYTOCHROME P450 FATTY ACID METABOLISM IN THE PATHOPHYSIOLOGY OF SUBARACHNOID HEMORRHAGE. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Subarachnoid hemorrhage (SAH) stroke is associated with high rates of morbidity and mortality. One of the major complications of SAH is the development of delayed cerebral ischemia (DCI) due to vasospasm of the cerebrovasculature that typically occurs days after the hemorrhage. Currently, there are no established prognostic indicators of DCI and long-term outcomes in SAH patients. 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) are eicosanoids formed from the oxidation of arachidonic acid by cytochrome P450 (CYP) enzymes. 20-HETE constricts cerebral arteries and contributes to cerebral ischemic injury after SAH. Conversely, EETs dilate the cerebrovasculature and attenuate cerebral ischemic injury. EETs biological action is regulated by its metabolism to inactive DHETs. Human polymorphisms in CYP eicosanoid biosynthesis/metabolism genes are reported to alter enzyme function in vitro/in vivo. Thus, we hypothesized that polymorphisms in genes involved in CYP eicosanoid biosynthesis and metabolism will lead to increased 20-HETE or decreased EET concentrations in CSF resulting in the development of ischemic complications and unfavorable long-term functional outcomes in 363 patients with SAH. Patients were genotyped and CYP-eicosanoid CSF levels were measured over 14 days after hemorrhage. Acute outcomes assessed included delayed cerebral ischemia (DCI) and clinical neurological deterioration (CND) over 14 days. Modified Rankin Score (MRS) at 3 and 12 months were obtained for long-term outcome assessment. Multivariate analysis controlled for age, sex, race, and Fisher grade or Hunt & Hess score. Patients with CND and unfavorable 3-month MRS had ~2.2- and 2.7-fold higher mean 20-HETE CSF levels, respectively. Patients in high/moderate 20-HETE trajectory groups (35.7%) were 2.1-, 2.5-, and 2.1-fold more likely to have CND and unfavorable MRS at 3 and 12 months. CYP2C8*4 allele-carriers had 44% and 36% lower mean EET and DHET CSF levels and were 2.2- and 2.5-fold more likely to develop DCI and CND, respectively. Multiple loss-of-function SNPs were associated with lower CYP eicosanoid CSF levels and altered risk for unfavorable outcomes. Several CYP4F2 genotype frequencies differed from Hapmap database indicating putative genetic markers for SAH risk. These are the first clinical data demonstrating an association between genetic polymorphisms, CYP eicosanoid CSF levels, and outcomes in SAH patients.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Donnelly, Mark K.mkd14@pitt.eduMKD140000-0002-5649-0104
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorPoloyac, Samuel M.poloyac@pitt.eduPOLOYAC
Committee MemberVenkataramanan, Ramanrv@pitt.eduRV
Committee MemberBies, Robert.
Committee MemberGibbs, Robert Bgibbsr@pitt.eduGIBBSR
Committee MemberConley, Yvette P.yconley@pitt.eduYCONLEY
Date: 12 December 2014
Date Type: Publication
Defense Date: 9 September 2014
Approval Date: 12 December 2014
Submission Date: 12 December 2014
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 261
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: subarachnoid hemorrhage eicosanoids fatty acids cerebral blood flow 20-hydroxyeicosatetraenoic acid (20-HETE) epoxyeicosatrienoic acids (EET)
Date Deposited: 12 Dec 2014 13:07
Last Modified: 15 Nov 2016 14:26


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