Samuel M Poloyac

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (84)334.62 Total impact

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    ABSTRACT: Levetiracetam (LEV) is an anti-epileptic targeting novel pathways. Coupled with a favorable safety profile and increasing empiric clinical use, it was the fifth drug tested by Operation Brain Trauma Therapy (OBTT). We assessed the efficacy of a single 15 min post-injury IV dose (54 or 170 mg/kg) on behavioral, histopathological, and biomarker outcomes after parasagittal fluid percussion brain injury (FPI), controlled cortical impact (CCI), and penetrating ballistic like brain injury (PBBI) in rats. In FPI, there was no benefit on motor function but on Morris water maze (MWM) both doses improved latencies and path lengths vs vehicle (p<0.05). On probe trial, the vehicle group was impaired vs sham, but both LEV treated groups did not differ vs sham, and the 54mg/kg group was improved vs vehicle (p<0.05). No histological benefit was seen. In CCI, there was a benefit on beam balance at 170mg/kg (p<0.05 vs vehicle). On MWM the 54 mg/kg dose was improved and not different from sham. Probe trial did not differ between groups for either dose. There was a reduction in hemispheric tissue loss (p<0.05 vs vehicle) with 170mg/kg. In PBBI there was no motor, cognitive or histological benefit from either dose. Regarding biomarkers, in CCI, 24h GFAP blood levels were lower in the 170mg/kg group vs vehicle (p<0.05). In PBBI, GFAP blood levels were increased in vehicle and 170mg/kg groups vs sham (p<0.05) but not in the 54mg/kg group. No treatment effects were seen for UCH-L1 across models. Early single IV LEV produced multiple benefits in CCI and FPI and reduced GFAP levels in PBBI. LEV achieved 10 points at each dose, is the most promising drug tested thus far by OBTT, and the only drug to improve cognitive outcome in any model. LEV has been advanced to testing in the micropig model in OBTT.
    No preview · Article · Dec 2015 · Journal of neurotrauma
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    ABSTRACT: Operation Brain Trauma Therapy (OBTT) is a fully operational, rigorous, and productive multi-center, pre-clinical drug and circulating biomarker screening consortium for the field of traumatic brain injury (TBI). In this manuscript, we synthesize the findings from the first five therapies tested by OBTT, and discuss both the current work that is ongoing and potential future directions. Based on the results generated from the first five therapies tested within the exacting approach used by OBTT, four (nicotinamide, erythropoietin, cyclosporine A, and simvastatin) performed below or well below what was expected based on the published literature. However, OBTT has identified the early post-TBI administration of levetiracetam as a promising agent and has advanced it to a gyrencephalic large animal model-- fluid percussion injury in micropigs. The 6th and 7th therapies have just completed testing (glibenclamide and Kollidon VA 64) and an 8th drug (AER 271) is in testing. Incorporation of circulating brain injury biomarker assessments into these pre-clinical studies suggests considerable potential for diagnostic and theranostic utility of glial fibrillary acidic protein (GFAP) in pre-clinical studies. Given the failures in clinical translation of therapies in TBI, rigorous multi-center, pre-clinical approaches to therapeutic screening such as OBTT may be important for the ultimate translation of therapies to the human condition.
    No preview · Article · Dec 2015 · Journal of neurotrauma

  • No preview · Article · Nov 2015 · Critical care medicine

  • No preview · Article · Nov 2015 · Critical care medicine
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    ABSTRACT: Simvastatin, the 4th drug selected for testing by OBTT, is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor used clinically to reduce serum cholesterol. Additionally, simvastatin has demonstrated potent anti-neuroinflammatory and brain edema reducing effects and has shown promise in promoting functional recovery in preclinical models of traumatic brain injury (TBI). The purpose of this study was to assess the potential neuroprotective effects of oral administration of simvastatin on neurobehavioral, biomarker and histopathological outcome measures compared across three pre-clinical TBI animal models. Adult male Sprague-Dawley rats were exposed to either moderate fluid percussion injury (FPI), controlled cortical impact injury (CCI) or penetrating ballistic-like brain injury (PBBI). Simvastatin (1 or 5 mg/kg) was delivered via oral gavage at 3 hours post-injury and continued once daily out to 14 days post-injury. Results indicated an intermediate beneficial effect of simvastatin on motor performance on the gridwalk (FPI), balance beam (CCI) and rotarod tasks (PBBI). However no significant therapeutic benefit was detected on cognitive outcome across the OBTT TBI models. In fact, MWM performance was actually worsened by treatment in the FPI model and scored full negative points for low dose in the MWM latency and swim distance to locate the hidden platform. A detrimental effect on cortical tissue loss was also seen in the FPI model and there were no benefits on histology across the other models. Simvastatin also produced negative effects on circulating GFAP biomarker outcomes that were evident in the FPI and PBBI models. Overall, the current findings do not support the beneficial effects of simvastatin administration over 2-weeks post-TBI using the oral route of administration and as such, it will not be further pursued by OBTT.
    No preview · Article · Nov 2015 · Journal of neurotrauma
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    ABSTRACT: Insufficient cerebral perfusion pressure (CPP) after aneurysmal subarachnoid hemorrhage can impair cerebral blood flow. We examined the temporal profiles of CPP change and tested whether these profiles were associated with delayed cerebral ischemia (DCI). CPP values were retrospectively reviewed for 238 subjects. Intracranial pressure and mean arterial pressure values were obtained every 2 hours for 14 days. Induced hypertension was utilized to prevent vasospasm. The linear and quadratic CPP changes over time were tested using growth curve analysis. Multivariable logistic regression was utilized to examine the association between DCI and percentages of CPP values of >110, >100, <70, and <60 mm Hg. DCI was defined as neurological deterioration because of impaired cerebral blood flow. Between-subject differences accounted for 39% of variation in CPP values. There was a significant linear increase in CPP values over time (β = 0.06, SE = 0.006, p < .001). The covariance (-0.52, SE = 0.09, p < .001) between initial CPP and linear parameter was negative, indicating that subjects with high CPP on admission had a slower rate of increase whereas those with low CPP had a faster rate of increase. For every 10% increase in the proportion of CPP of >100 or >110 mm Hg, the odds of DCI increased by 1.21 and 1.43, respectively (p < .05). The longer the time patients spent with high CPP, the greater the odds for DCI. When used prophylactically, induced hypertension contributes to higher CPP values. On the basis of the CPP trends and correlations observed, induced hypertension may not confer expected benefits in patients with aneurysmal subarachnoid hemorrhage.
    No preview · Article · Aug 2015
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    ABSTRACT: Whether delayed cerebral ischemia (DCI) mediates the relationship between Hunt and Hess grade and outcomes after aneurysmal subarachnoid hemorrhage remains unknown. To investigate the relationship between cerebral perfusion pressure, DCI, Hunt and Hess grade, and outcomes after aneurysmal subarachnoid hemorrhage. DCI was defined as neurological deterioration due to impaired cerebral blood flow. Relationships between minimum cerebral perfusion pressure and onset and occurrence of DCI were tested by using logistic regression and the accelerated failure time model. The mediation effect of DCI on relationships between Hunt and Hess grade and outcomes was tested by using the bootstrap confidence interval. Outcomes at 3 and 12 months included mortality and neuropsychological, functional, and physical outcomes. DCI occurred in 211 patients (42%). About one-third of the patients had poor functional outcome at 3 (32%) and 12 (30%) months. Impaired neuropsychological outcome was observed in 33% of patients at 3 months and 17% at 12 months. For every increase of 10 mm Hg in cerebral perfusion pressure, odds for DCI increased by 2.78 (95% CI, 2.00-3.87). High perfusion pressure was associated with earlier onset of DCI (P < .001). DCI does not mediate the relationship of Hunt and Hess grade to functional outcome or death. The relationship between cerebral perfusion pressure and DCI was most likely due to induced hypertension and hypervolemia. Clinical guidelines may need to include limits for induced hypertension. ©2015 American Association of Critical-Care Nurses.
    Full-text · Article · Jul 2015 · American Journal of Critical Care

  • No preview · Conference Paper · Jun 2015
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    ABSTRACT: Vasoconstrictive and vasodilatory eicosanoids generated after cardiac arrest (CA) may contribute to cerebral vasomotor disturbances and neurodegeneration. We evaluated the balance of vasodilator/vasoconstrictor eicosanoids produced by cytochrome P450 (CYP) metabolism, and determined their role on cortical perfusion, functional outcome, and neurodegeneration after pediatric asphyxial CA. Cardiac arrest of 9 and 12 minutes was induced in 16- to 18-day-old rats. At 5 and 120 minutes after CA, we quantified the concentration of CYP eicosanoids in the cortex and subcortical areas. In separate rats, we inhibited 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis after CA and assessed cortical cerebral blood flow (CBF), neurologic deficit score, neurodegeneration, and edema. After 9 minutes of CA, vasodilator eicosanoids markedly increased versus sham. Conversely, after 12 minutes of CA, vasoconstrictor eicosanoid 20-HETE increased versus sham, without compensatory increases in vasodilator eicosanoids. Inhibition of 20-HETE synthesis after 12 minutes of CA decreased cortical 20-HETE levels, increased CBF, reduced neurologic deficits at 3 hours, and reduced neurodegeneration and edema at 48 hours versus vehicle-treated rats. In conclusion, cerebral vasoconstrictor eicosanoids increased after a pediatric CA of 12 minutes. Inhibition of 20-HETE synthesis improved cortical perfusion and short-term neurologic outcome. These results suggest that alterations in CYP eicosanoids have a role in cerebral hypoperfusion and neurodegeneration after CA and may represent important therapeutic targets.Journal of Cerebral Blood Flow & Metabolism advance online publicatio
    No preview · Article · Jun 2015 · Journal of Cerebral Blood Flow & Metabolism
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    ABSTRACT: Vasoconstrictive and vasodilatory eicosanoids generated after cardiac arrest (CA) may contribute to cerebral vasomotor disturbances and neurodegeneration. We evaluated the balance of vasodilator/vasoconstrictor eicosanoids produced by cytochrome P450 (CYP) metabolism, and determined their role on cortical perfusion, functional outcome, and neurodegeneration after pediatric asphyxial CA. Cardiac arrest of 9 and 12 minutes was induced in 16- to 18-day-old rats. At 5 and 120 minutes after CA, we quantified the concentration of CYP eicosanoids in the cortex and subcortical areas. In separate rats, we inhibited 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis after CA and assessed cortical cerebral blood flow (CBF), neurologic deficit score, neurodegeneration, and edema. After 9 minutes of CA, vasodilator eicosanoids markedly increased versus sham. Conversely, after 12 minutes of CA, vasoconstrictor eicosanoid 20-HETE increased versus sham, without compensatory increases in vasodilator eicosanoids. Inhibition of 20-HETE synthesis after 12 minutes of CA decreased cortical 20-HETE levels, increased CBF, reduced neurologic deficits at 3 hours, and reduced neurodegeneration and edema at 48 hours versus vehicle-treated rats. In conclusion, cerebral vasoconstrictor eicosanoids increased after a pediatric CA of 12 minutes. Inhibition of 20-HETE synthesis improved cortical perfusion and short-term neurologic outcome. These results suggest that alterations in CYP eicosanoids have a role in cerebral hypoperfusion and neurodegeneration after CA and may represent important therapeutic targets.
    No preview · Article · Jun 2015 · Journal of Cerebral Blood Flow & Metabolism
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    ABSTRACT: Emerging evidence has suggested that patients experiencing aneurysmal subarachnoid hemorrhage (aSAH) develop vascular dysregulation as a potential contributor to poor outcomes. Preclinical studies have implicated the novel microvascular constrictor, 20-hydroxyeicosatetraenoic acid (20-HETE) in aSAH pathogenesis, yet the translational relevance of 20-HETE in patients with aSAH is largely unknown. The goal of this research was to determine the relationship between 20-HETE cerebrospinal fluid (CSF) levels, gene variants in 20-HETE synthesis, and acute/long-term aSAH outcomes. In all, 363 adult patients (age 18 to 75) with aSAH were prospectively recruited from the University of Pittsburgh Medical Center neurovascular Intensive Care Unit. Patients were genotyped for polymorphic variants and cytochrome P450 (CYP)-eicosanoid CSF levels were measured over 14 days. Outcomes included delayed cerebral ischemia (DCI), clinical neurologic deterioration (CND), and modified Rankin Scores (MRS) at 3 and 12 months. 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 2.5-, 2.1-, 3.1-, 3.3-, and 2.1-fold more likely to have unfavorable MRS at 3 months, unfavorable MRS at 12 months, mortality at 3 months, mortality at 12 months, and CND, respectively. These results showed that 20-HETE is associated with acute and long-term outcomes and suggest that 20-HETE may be a novel target in aSAH.Journal of Cerebral Blood Flow & Metabolism advance online publication, 29 April 2015; doi:10.1038/jcbfm.2015.75.
    No preview · Article · Apr 2015 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
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    ABSTRACT: Despite decades of basic and clinical research, treatments to improve outcomes after traumatic brain injury (TBI) are limited. However, based on the recent recognition of the prevalence of mild TBI, and its potential link to neurodegenerative disease, many new and exciting secondary injury mechanisms have been identified and several new therapies are being evaluated targeting both classic and novel paradigms. This includes a robust increase in both preclinical and clinical investigations. Using a mechanism-based approach the authors define the targets and emerging therapies for TBI. They address putative new therapies for TBI across both the spectrum of injury severity and the continuum of care, from the field to rehabilitation. They discussTBI therapy using 11 categories, namely, (1) excitotoxicity and neuronal death, (2) brain edema, (3) mitochondria and oxidative stress, (4) axonal injury, (5) inflammation, (6) ischemia and cerebral blood flow dysregulation, (7) cognitive enhancement, (8) augmentation of endogenous neuroprotection, (9) cellular therapies, (10) combination therapy, and (11) TBI resuscitation. The current golden age of TBI research represents a special opportunity for the development of breakthroughs in the field. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
    Full-text · Article · Feb 2015 · Seminars in Neurology
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    ABSTRACT: Splicing factors (SFs) coordinate nuclear intron/exon splicing of RNA. Splicing factor disturbances can cause cell death. RNA binding motif 5 (RBM5) and 10 (RBM10) promote apoptosis in cancer cells by activating detrimental alternative splicing of key death/survival genes. The role(s) of RBM5/10 in neurons has not been established. Here, we report that RBM5 knockdown in human neuronal cells decreases caspase activation by staurosporine. In contrast, RBM10 knockdown augments caspase activation. To determine whether brain injury alters RBM signaling, we measured RBM5/10 protein in mouse cortical/hippocampus homogenates after controlled cortical impact (CCI) traumatic brain injury (TBI) plus hemorrhagic shock (CCI+HS). The RBM5/10 staining was higher 48 to 72 hours after injury and appeared to be increased in neuronal nuclei of the hippocampus. We also measured levels of other nuclear SFs known to be essential for cellular viability and report that splicing factor 1 (SF1) but not splicing factor 3A (SF3A) decreased 4 to 72 hours after injury. Finally, we confirm that RBM5/10 regulate protein expression of several target genes including caspase-2, cellular FLICE-like inhibitory protein (c-FLIP), LETM1 Domain-Containing Protein 1 (LETMD1), and amyloid precursor-like protein 2 (APLP2) in neuronal cells. Knockdown of RBM5 appeared to increase expression of c-FLIP(s), LETMD1, and APLP2 but decrease caspase-2.Journal of Cerebral Blood Flow & Metabolism advance online publication, 14 January 2015; doi:10.1038/jcbfm.2014.242.
    No preview · Article · Jan 2015 · Journal of Cerebral Blood Flow & Metabolism
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    ABSTRACT: Biochemical mediators alter cerebral perfusion and have been implicated in delayed cerebral ischemia (DCI) and poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). Estrogens (estrone [E1] and estradiol [E2]) are mediators with neuroprotective properties that could play a role in DCI. This study explored associations between plasma estrogen levels and outcomes following aSAH. Plasma samples from 1-4, 4-6, and 7-10 days after hemorrhage from 99 adult aSAH patients were analyzed for estrogen levels using liquid chromatography tandem mass spectrometry. DCI was operationalized as radiographic/ultrasonic evidence of impaired cerebral blood flow accompanied by neurological deterioration. Outcomes were assessed using the Modified Rankin Scale at 3 and 12 months after hemorrhage. Statistical analysis included correlation, regression, and group-based trajectory. Higher E1 and E2 levels were associated with higher Hunt and Hess grade (E1, p = .01; E2, p = .03), the presence of DCI (E1, p = .02; E2, p = .02), and poor 3-month outcomes (E1, p = .002; E2, p = .002). Trajectory analysis identified distinct populations over time for E1 (61% E1 high) and E2 (68% E2 high). Patients in higher trajectory groups had higher Fisher grades (E1, p = .008; E2, p = .01), more frequent DCI (E1, p = .04; E2, p = .08), and worse 3-month outcomes (E1, p = .01; E2, p = .004) than low groups. These results provide the first clinical evidence that plasma E1 and E2 concentrations are associated with severity of injury and outcomes after aSAH. © The Author(s) 2014.
    No preview · Article · Dec 2014 · Biological Research for Nursing

  • No preview · Article · Dec 2014 · Critical Care Medicine

  • No preview · Article · Dec 2014 · Critical Care Medicine
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    ABSTRACT: Preclinical studies show that epoxyeicosatrienoic acids (EETs) regulate cerebrovascular tone and protect against cerebral ischemia. We investigated the relationship between polymorphic genes involved in EET biosynthesis/metabolism, cytochrome P450 (CYP) eicosanoid levels, and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage (aSAH). Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid (DHET) cerebrospinal fluid (CSF) levels, as well as acute outcomes defined by delayed cerebral ischemia (DCI) or clinical neurologic deterioration (CND), were assessed over 14 days. Long-term outcomes were defined by Modified Rankin Scale (MRS) at 3 and 12 months. CYP2C8*4 allele carriers had 44% and 36% lower mean EET and DHET CSF levels (P=0.003 and P=0.007) and were 2.2- and 2.5-fold more likely to develop DCI and CND (P=0.039 and P=0.041), respectively. EPHX2 55Arg, CYP2J2*7, CYP2C8*1B, and CYP2C8 g.36785A allele carriers had lower EET and DHET CSF levels. CYP2C8 g.25369T and CYP2C8 g.36755A allele carriers had higher EET levels. Patients with CYP2C8*2C and EPHX2 404del variants had worse long-term outcomes while those with EPHX2 287Gln, CYP2J2*7, and CYP2C9 g.816G variants had favorable outcomes. Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3-month outcomes. Dihydroxyeicosatetraenoic acids were not associated with outcomes. No associations passed Bonferroni multiple testing correction. These are the first clinical data demonstrating the association between the EET biosynthesis/metabolic pathway and the pathophysiology of aSAH.Journal of Cerebral Blood Flow & Metabolism advance online publication, 12 November 2014; doi:10.1038/jcbfm.2014.195.
    No preview · Article · Nov 2014 · Journal of Cerebral Blood Flow & Metabolism
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    ABSTRACT: Fatty liver disease is an emerging public health problem without effective therapies, and chronic hepatic inflammation is a key pathologic mediator in its progression. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory effects. Although promoting the effects of EETs elicits anti-inflammatory and protective effects in the cardiovascular system, the contribution of CYP-derived EETs to the regulation of fatty liver disease-associated inflammation and injury is unknown. Using the atherogenic diet model of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH), our studies demonstrated that induction of fatty liver disease significantly and preferentially suppresses hepatic CYP epoxygenase expression and activity, and both hepatic and circulating levels of EETs in mice. Furthermore, mice with targeted disruption of Ephx2 (the gene encoding soluble epoxide hydrolase) exhibited restored hepatic and circulating EET levels and a significantly attenuated induction of hepatic inflammation and injury. Collectively, these data suggest that suppression of hepatic CYP-mediated EET biosynthesis is an important pathological consequence of fatty liver disease-associated inflammation, and that the CYP epoxygenase pathway is a central regulator of the hepatic inflammatory response in NAFLD/NASH. Future studies investigating the utility of therapeutic strategies that promote the effects of CYP-derived EETs in NAFLD/NASH are warranted.
    Full-text · Article · Oct 2014 · PLoS ONE
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    ABSTRACT: Objectives: To examine the relationship between regional cerebral oxygen saturation (rSO2), delayed cerebral ischaemia (DCI), and outcomes after aneurysmal subarachnoid haemorrhage (aSAH). Research methodology: Subjects (n = 163) with aSAH, age 21-75 years, and Fisher grade >1 were included in the study. Continuous rSO2 monitoring was performed for 5-10 days after injury using near-infrared spectroscopy with sensors over the frontal/temporal cortex. rSO2<50 indicated desaturation. DCI was defined as neurological deterioration due to impaired cerebral blood flow. Three- and 12-month functional outcomes were assessed by the modified Rankin scale (MRS) as good (0-3) and poor (4-6). Results: DCI occurred in 57% of patients; of these 66% had rSO2<50. Overall, 56% had rSO2<50 on either side, 21% and 16% had poor MRS at 3 and 12 months. Subjects with rSO2 <50 were 3.25 times more likely to have DCI compared to those with rSO2 >50 (OR 3.25, 95%CI 1.58-6.69), positive predictive value (PPV) = 70%. Subjects with rSO2 <50 were 2.7 times more likely to have poor 3-month MRS compared to those with rSO2 >50 (OR 2.7, 95%CI 1.1-7.2), PPV = 70%. Conclusions: These results suggest that NIRS has the potential for detecting DCI after aSAH. This potential needs to be further explored in a larger prospective study.
    No preview · Article · Jun 2014 · Intensive & critical care nursing: the official journal of the British Association of Critical Care Nurses
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    ABSTRACT: Aneurysmal subarachnoid hemorrhage is a type of stroke with high morbidity and mortality. Increased endothelin-1 (ET-1) levels have been associated with increased risk of cerebral vasospasm, which is associated with increased morbidity. The purpose of this study was to investigate the relationships between ET-1 genotypes and ET-1 protein levels in cerebrospinal fluid (CSF) measured 72 hr before angiographic vasospasm measurement in subjects at high risk of cerebral vasospasm. Specifically, this study evaluated the differences between variant positive and variant negative groups of nine different ET-1 single-nucleotide polymorphisms (SNPs) in relationship with the ET-1 protein exposure rate. The CSF ET-1 protein levels were quantified using enzyme-linked immunosorbent assay. One functional SNP and eight ET-1 tagging SNPs were selected because they represent genetic variability in the entire ET-1 gene. The variant negative group of SNP rs2070699 was associated with a significantly higher ET-1 exposure rate than the variant positive group (p = 0.004), while the variant positive group of the rs5370 group showed a trend toward association with a higher ET-1 exposure rate (p = 0.051). Other SNPs were not informative. This is the first study to show differences in ET-1 exposure rate 72 hr before angiography in relation to ET-1 genotypes. These exploratory findings need to be replicated in a larger study; if replicated, these differences in genotypes may be a way to inform clinicians of those patients at a higher risk of increased ET-1 protein levels, which may lead to a higher risk of angiographic vasospasm.
    No preview · Article · May 2014 · Biological Research for Nursing