Elizabeth Crago

Elevated Cardiac Troponin I and Relationship to Persistence of Electrocardiographic and Echocardiographic Abnormalities After Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— Cardiac injury persistence after aneurysmal subarachnoid hemorrhage (aSAH) is not well described. We hypothesized that post-aSAH cardiac injury, detected by elevated cardiac troponin I (cTnI), is related to aSAH severity and associated with electrocardiographic and structural echocardiographic abnormalities that are persistent. Methods— Prospective longitudinal study was conducted of patients with aSAH with Fisher grade ≥2 and/or Hunt/Hess grade ≥3. Serum cTnI was collected on Days 1 to 5; cohort dichotomized into peak cTnI ≥0.3 ng/mL (elevated) or cTnI <0.3 ng/mL. Relationships among cTnI and aSAH severity, 12-lead electrocardiography early (≤4 days) and late (≥7 days), Holter monitoring on Days 1 to 5, and transthoracic echocardiogram (left ventricular ejection fraction and regional wall motion abnormalities) early (Days 0 to 5) and late (Days 5 to 12) were evaluated. Results— Of 204 subjects, 31% had cTnI ≥0.3 ng/mL. cTnI ≥0.3 ng/mL was incrementally related to aSAH severity by admission symptoms (Hunt/Hess P=0.001) and blood load (Fisher P=0.028). More patients with cTnI ≥0.3 ng/mL had prolonged QTc on early (63% versus 30%, P<0.0001) and late electrocardiography (24% versus 7%, P=0.024). On Holter monitoring, more patients with cTnI ≥0.3 ng/mL had ventricular tachycardia/fibrillation (22% versus 9%, P=0.018) but not atrial fibrillation/flutter (P=0.241). Cardiac troponin I ≥0.3 ng/mL was associated with both early ejection fraction <50% (44% versus 5%, P<0.0001) and regional wall motion abnormalities (44% versus 4%, P<0.0001). Regional wall motion abnormalities predominated in basal and midventricular segments and persisted to some degree in 73% of patients affected, whereas ejection fraction <50% persisted in 59% of patients affected. Conclusions— Cardiac injury is incrementally worse with increasing aSAH severity and associated with persistent QTc prolongation and ventricular arrhythmias. Regional wall motion abnormalities and depressed ejection fraction persist to some degree in the majority of those affected.

Rapid, simultaneous quantitation of mono and dioxygenated metabolites of arachidonic acid in human CSF and rat brain

Currently, there are few biomarkers to predict the risk of symptomatic cerebral vasospasm (SV) in subarachnoid hemorrhage (SAH) patients. Mono and dioxygenated arachidonic acid metabolites, involved in the pathogenesis of ischemic injury, may serve as indicators of SV. This study developed a quantitative UPLC-MS/MS method to simultaneously measure hydroxyeicosatetraenoic acid (HETE), dihydroxyeicosatrienoic acid (DiHETrE), and epoxyeicosatrienoic acid (EET) metabolites of arachidonic acid in cerebrospinal fluid (CSF) samples of SAH patients. Additionally, we determined the recovery of these metabolites from polyvinylchloride (PVC) bags used for CSF collection. Linear calibration curves ranging from 0.208 to 33.3 ng/ml were validated. The inter-day and intra-day variance was less than 15% at most concentrations with extraction efficiency greater than 73%. The matrix did not affect the reproducibility and reliability of the assay. In CSF samples, peak concentrations of 8,9-DiHETrE, 20-HETE, 15-HETE, and 12-HETE ranged from 0.293 to 24.9 ng/ml. In rat brain cortical tissue samples, concentrations of 20-, 15-, 12-HETE, 8,9-EET, and 14,15-, 11,12-DiHETrE ranged from 0.57 to 23.99 pmol/g wet tissue. In rat cortical microsomal incubates, all 10 metabolites were measured with formation rates ranging from 0.03 to 7.77 pmol/mg/min. Furthermore, 12-HETE and EET metabolites were significantly altered by contact with PVC bags at all time points evaluated. These data demonstrate that the simultaneous measurement of these compounds in human CSF and rat brain can be achieved with a UPLC-MS/MS system and that this method is necessary for evaluation of these metabolites as potential quantitative biomarkers in future clinical trials.

In-stent thrombosis and stenosis after neck-remodeling device-assisted coil embolization of intracranial aneurysms.

BACKGROUND: Intrinsic thrombosis and stenosis are complications associated with the use of neck-remodeling devices in the treatment of intracranial aneurysms. OBJECTIVE: To examine the technical and anatomic factors that predict short- and long-term stent patency. METHODS: We undertook a retrospective review of 161 patients who underwent coil embolization of 168 ruptured and unruptured aneurysms assisted by the use of a neck-remodeling device. One hundred twenty-seven patients had catheter-based angiographic follow-up to evaluate 133 stent-coil constructs (mean, 15.4 months; median, 12.7 months). The technique of microcatheter jailing was used in a majority of patients; nonstandard stent configurations were also used. RESULTS: Clinical follow-up for all patients who had catheter-based angiograms demonstrated that among 133 stent constructs, a total of 9 (6.8%) had an in-stent event: 6 acute or subacute thrombosis (4.5%) and 3 delayed stenosis or occlusion (2.3%). Seven of these constructs were associated with a symptomatic event (5.3%). A significantly higher rate of in-stent events was seen with the use of constructs to treat anterior communicating artery aneurysms. When all patients are considered, including those who did not receive catheter-based follow-up imaging, 2 of 168 procedures (1.2%) resulted in the death of a patient, and procedural morbidity was 14.9%. CONCLUSION: From these results and those in the published literature, in-stent complication rates are low in carefully selected patients. The use of dual antiplatelet therapy, sensitivity assays, and glycoprotein IIb/IIIa inhibitors may decrease the rate of acute and chronic in-stent complications.

The impact of cardiac complications on outcome in the SAH population

Objectives –  To determine the impact of cardiac complications (CdCs) on outcomes in patients with acute subarachnoid hemorrhage (SAH).

Cerebrospinal Fluid 20-HETE Is Associated With Delayed Cerebral Ischemia and Poor Outcomes After Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— Delayed cerebral ischemia (DCI) is a major complication after aneurysmal subarachnoid hemorrhage (aSAH); it is manifested by changes in cerebral blood flow accompanied by neurological decline, and it results in long-term functional and neuropsychological impairment. Preclinical evidence has demonstrated that the arachidonic acid metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), affects cerebral microvascular tone and cerebral blood flow after aSAH. The purpose of this study was to determine whether cerebrospinal fluid 20-HETE levels were associated with DCI and long-term neuropsychological outcomes in aSAH patients. Methods— Cerebrospinal fluid samples were collected twice daily through 14 days after hemorrhage on 108 acute, adult, aSAH patients. Samples were analyzed for 20-HETE via HPLC MSQ single quadrupole mass spectrometry. DCI was defined as the presence of impaired cerebral blood flow (angiographic vasospasm, elevated transcranial Dopplers, abnormal computed tomography or magnetic resonance perfusion scans) accompanied by neurological deterioration. Outcomes, including death and neuropsychological testing, were completed at 3 months after hemorrhage. Results— Detectable 20-HETE levels were observed in 31% of patient samples and were associated with severity of hemorrhage (Hunt & Hess [HH], P=0.04; Fisher, P=0.05). Detection of 20-HETE was not associated with angiographic vasospasm (P=0.34); however, detectable 20-HETE was significantly associated with DCI (P=0.016). Our data also suggest that detectable 20-HETE was associated with decreased performance in 5 neuropsychological domains. Conclusions— These results provide the first clinical evidence that cerebrospinal fluid 20-HETE concentrations are associated with DCI and poor outcomes, and this provides impetus for future studies to elucidate the clinical utility of inhibiting 20-HETE formation as a novel therapeutic intervention in patients with aSAH.

Elevated Cardiac Troponin I and Functional Recovery and Disability in Patients After Aneurysmal Subarachnoid Hemorrhage

BACKGROUND Patients with aneurysmal subarachnoid hemorrhage experience myocardial injury at the time of rupture, but its effect on functional recovery and disability is unclear. OBJECTIVE To describe the prevalence of myocardial injury, as indicated by high serum levels of cardiac troponin I (≥0.3 ng/mL), within the first 5 days after aneurysmal subarachnoid hemorrhage and the effect of the injury on 3-month functional recovery and disability. METHODS In a prospective longitudinal study, 239 patients with Hunt/Hess grade 3 or greater and/or Fisher grade 2 or greater at admission had serum level of troponin I measured on days 0 to 5. Patients were interviewed at 3 months to evaluate functional recovery (Glasgow Outcome Scale) and functional disability (Modified Rankin Scale). Statistics included χ² analysis, t tests, and binary logistic regression. RESULTS Troponin values were elevated in 33.5% of the patients, and few patients in either group had a history of coronary artery disease (7.4% with troponin levels ≥0.3 ng/mL vs 2.7% with levels <0.3 ng/mL, P = .12). Higher troponin levels were significantly related to age and Hunt/Hess and Fisher grades, but not race, and were significantly associated with poorer functional recovery (P < .001) and more functional disability (P < .001). Even after controls for age, race, and more severe Hunt/Hess grades, higher levels remained a significant predictor of poorer functional recovery (P = .04) and disability (P = .01). CONCLUSION Elevated levels of cardiac troponin I after aneurysmal subarachnoid hemorrhage are common in patients with no cardiac history, are associated with severity of the hemorrhage, and are independently predictive of poorer functional recovery and increased disability.

Haptoglobin genotype and functional outcome after aneurysmal subarachnoid hemorrhage

OBJECT Haptoglobin allele heterogeneity has been implicated in differential reactive oxidant inhibition and inflammation. Haptoglobin α2-α2 has a lower affinity for binding hemoglobin, and when bound to hemoglobin, is cleared less easily by the body. The authors hypothesized that haptoglobin α2-α2 genotype should be less protective for downstream injury after aneurysmal subarachnoid hemorrhage (aSAH) and should portend a worse outcome. METHODS Patients with Fisher Grade 2 or higher aSAH were enrolled in the study. Genotyping for haptoglobin genotype was performed from blood and/or CSF. Demographic information, medical condition variables, and hospital course were abstracted from the medical record upon enrollment into the study. Outcome data (modified Rankin Scale score, Glasgow Outcome Scale score, and mortality) were collected at 3 months posthemorrhage. RESULTS The authors enrolled 193 patients who ranged in age from 18 to 75 years. Only Caucasians were used in this analysis to minimize bias from variable haptoglobin allele frequencies in populations of different ancestral backgrounds. The sample had more women than men (overall mean age 54.45 years). Haptoglobin α2 homozygotes were older than the other individuals in the study sample (57.27 vs 53.2 years, respectively; p = 0.02) and were more likely to have Fisher Grade 3 SAH (p = 0.02). Haptoglobin α2-α2 genotype, along with Fisher grade and Hunt and Hess grade, was associated with a worse 3-month outcome compared to those with the haptoglobin α1-α1 genotype according to modified Rankin Scale score after controlling for covariates (OR 4.138, p = 0.0463). CONCLUSIONS Patients with aSAH who carry the haptoglobin α2-α2 genotype had a worse outcome. Interestingly, the presence of a single α-2 allele was associated with worse outcome, suggesting that the haptoglobin α-2 protein may play a role in the pathology of brain injury following aSAH, although the mechanism for this finding requires further research. The haptoglobin genotype may provide additional information on individual risk of secondary injury and recovery to guide care focused on improving outcomes.

Anatomic results and complications of stent-assisted coil embolization of intracranial aneurysms

The purpose of this study was to evaluate and report our anatomic results and complications associated with stent-assisted coil embolization of intracranial aneurysms using the Neuroform stent. From September 2003 to August 2007, 127 consecutive patients (ruptured 50, 39.4%; unruptured 77, 60.6%) underwent 129 stent-assisted coil embolization procedures to treat 136 aneurysms at our institution. Anatomic results at follow-up, procedure-related complications, and morbidity/mortality were retrospectively reviewed. Stent deployment was successful in 128 out of 129 procedures (99.2%). Forty-seven patients presented with 53 procedure-related complications (37.0%, 47/127). Thromboembolic events (n = 17, 13.4%) were the most common complications, followed by intraoperative rupture (n = 8, 6.3%), coil herniation (n = 5, 3.9%), and postoperative rupture (n = 4, 3.1%). For thromboembolic events, acute intra-procedural in-stent thromboses were observed in two patients and subacute or delayed in-stent thromboses in three patients. Overall mortality rate was 16.5% (21/127) and procedure-related morbidity and mortality rates were 5.5% (7/127) and 8.7% (11/127) retrospectively. Patients with poor grade subarachnoid hemorrhage (Hunt and Hess grade IV or V; 25/127, 19.7%) exhibited 56% (14/25) overall mortality rate and 24% (6/25) procedure-related mortality rate. Immediate angiographic results showed complete occlusion in 31.7% of aneurysms, near-complete occlusion in 45.5%, and partial occlusion in 22.8%. Sixty nine patients in 70 procedures with 77 aneurysms underwent angiographic follow-up at six months or later. Mean follow-up period was 13.7 months (6 to 45 months). Complete occlusion was observed in 57 aneurysms (74.0%) and significant in-stent stenosis was not found. Thromboembolism and intra/postoperative aneurysm ruptures were the most common complications and the main causes of procedure-related morbidity and mortality. Patients with poor grade subarachnoid hemorrhage showed poor clinical outcomes. Since most complications were induced by stent manipulation and deployment, it is mandatory to utilize these devices selectively and cautiously. While the follow-up angiographic results are promising, further studies are essential to evaluate safety, efficacy, and durability of the Neuroform stent.

Risk of Hemorrhage in Combined Neuroform Stenting and Coil Embolization of Acutely Ruptured Intracranial Aneurysms

Stenting as adjuvant therapy for the coiling of acutely ruptured aneurysms remains controversial due to the necessity of anticoagulation and antiplatelet medications. We report our experience using the Neuroform stent in the management of 41 aneurysms in 40 patients over a period of three years. For aneurysms whose open surgical risk remains excessive with a morphology that would preclude complete embolization, the risks of stenting may be warranted.

Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage.

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.