CFTR Therapeutics Normalize Cerebral Perfusion Deficits in Mouse Models of Heart Failure and Subarachnoid Hemorrhage.
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ABSTRACT:
SUBMITTER: Lidington D
PROVIDER: S-EPMC6939007 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
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Project description:INTRODUCTION: Vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is thought to cause ischemia. To evaluate the contribution of vasospasm to delayed cerebral ischemia (DCI), we investigated the effect of vasospasm on cerebral perfusion and the relationship of vasospasm with DCI. METHODS: We studied 37 consecutive SAH patients with CT angiography (CTA) and CT perfusion (CTP) on admission and within 14 days after admission or at time of clinical deterioration. CTP values (cerebral blood volume, cerebral blood flow (CBF) and mean transit time), degree of vasospasm on CTA, and occurrence of DCI were recorded. Vasospasm was categorized as follows: no spasm (0-25% decrease in vessel diameter), moderate spasm (25-50% decrease), and severe spasm (>50% decrease). The correspondence of the flow territory of the most spastic vessel with the least perfused region was evaluated, and differences in perfusion values and occurrence of DCI between degrees of vasospasm were calculated with 95% confidence intervals (95% CI). RESULTS: Fourteen patients had no vasospasm, 16 were moderate, and seven were severe. In 65% of patients with spasm, the flow territory of the most spastic vessel corresponded with the least perfused region. There was significant CBF (milliliters per 100 g per minute) difference (-21.3; 95% CI, -37 <--> -5.3) between flow territories of severe and no vasospasm. Four of seven patients with severe, six of 16 with moderate, and three of 14 patients with no vasospasm had DCI. CONCLUSION: Vasospasm decreases cerebral perfusion, but corresponds with the least perfused region in only two thirds of our patients. Furthermore, almost half of patients with severe vasospasm do not have DCI. Thus, although severe vasospasm can decrease perfusion, it may not result in DCI.
| S-EPMC2773037 | biostudies-other
Project description:The diagnosis of cerebral vasospasm after Subarachnoid-Hemorrhage is currently very difficult, additional tools such as blood biomarkers are necessary. We tested the ability of gene expression profiles of blood cells to predict vasospasm. 32 patients suffering subarachnoid-hemorrhage were included in this prospective monocentre study. They were grouped according to have a complicated cerebral vasospasm (Vasospasm) or not (Control) and Paired according to age (+/- 10 years), sex, Fisher grade (+/- 1), location, smoking (at least 3 first parameters). Gene expression profiles of blood cells were determined using 25,000~gene microarray. Blood sample: 2.5 mL harvested in PAXgene® Blood RNA tubes (PreAnalytix) RNA extraction: PAXgene® Blood RNA kit (Qiagen). We used a Universel Reference RNA (Stratagene). RNA amplification and labelling: kit Amino Allyl MessageAmp II (Ambion). We hybridized 4 microarrays per patient using pangenomic microarrays from the "Réseau National des Génopôles" (Illkirch, France). 2 slides were hybridized with reference RNA labelled Cy3 and patient RNA labelled Cy5, and 2 slides were hybridized with reference RNA labelled Cy5 and patient RNA labelled Cy3. Hybridation : Agilent protocol with few modifications : 750 ng of each labelled RNA were hubriddized at 60°C during 17 hours in an Aglient hybridization oven. After washings, Slides were scanned with a GenePix 4000B scanner (Molecular Devices). Image intensity data were extracted with GenePix Pro 6.0 analysis software. Quantification of Cy3 and Cy5 and selection of good spots were performed using the MAIA software (Novikov E and Barillot E. Software package for automatic microarray image analysis (MAIA). The ACUITY software was then used to normalize log ratios Cy3/Cy5 with Lowess non linear normalization, to filter out genes not present in at least 3 slides out of 4, to evaluate the reproducibility of the 4 microarrays of each patient (hierarchical clustering, Self Organizing Maps). Statistical analyses to insure reproducibility was performed using Excel (correlation coefficients, ANOVA). Only slides that passed all reprocubility tests were validated.
2014-05-08 | E-GEOD-37924 | biostudies-arrayexpress
Project description:The diagnosis of cerebral vasospasm after Subarachnoid-Hemorrhage is currently very difficult, additional tools such as blood biomarkers are necessary. We tested the ability of gene expression profiles of blood cells to predict vasospasm.
2014-05-08 | GSE37924 | GEO
Project description:Background and purposeDCI is a serious complication following aneurysmal SAH leading to permanent neurologic deficits, infarction, and death. Our aim was to prospectively evaluate the diagnostic accuracy of CTP and to determine a quantitative threshold for DCI in aneurysmal SAH.Materials and methodsPatients with SAH were prospectively enrolled in a protocol approved by the institutional review board. CTP was performed during the typical time period for DCI, between days 6 and 8 following SAH. Quantitative CBF, CBV, and MTT values were obtained by using standard region-of-interest placement sampling of gray matter. The reference standard for DCI is controversial and consisted of clinical and imaging criteria in this study. In a subanalysis of vasospasm, DSA was used as the reference standard. ROC curves determined the diagnostic accuracy by using AUC. Optimal threshold values were calculated by using the patient population utility method.ResultsNinety-seven patients were included; 41% (40/97) had DCI. Overall diagnostic accuracy was 93% for CBF, 88% for MTT, and 72% for CBV. Optimal threshold values were 35 mL/100 g/min (90% sensitivity, 68% specificity) for CBF and 5.5 seconds (73% sensitivity, 79% specificity) for MTT. In the subanalysis (n = 57), 63% (36/57) had vasospasm. Overall diagnostic accuracy was 94% for CBF, 85% for MTT, and 72% for CBV. Optimal threshold values were 36.5 mL/100 g/min (95% sensitivity, 70% specificity) for CBF and 5.4 seconds (78% sensitivity, 70% specificity) for MTT.ConclusionsCBF and MTT have the highest overall diagnostic accuracy. Threshold values of 35 mL/100 g/min for CBF and 5.5-second MTT are suggested for DCI on the basis of the patient population utility method. Absolute threshold values may not be generalizable due to differences in scanner equipment and postprocessing methods.
| S-EPMC3237788 | biostudies-literature
Project description:Cerebral hypoperfusion is a key factor for determining the outcome after subarachnoid hemorrhage (SAH). A subset of SAH patients develop neurogenic stress cardiomyopathy (NSC), but it is unclear to what extent cerebral hypoperfusion is influenced by cardiac dysfunction after SAH. The aims of this study were to examine the association between cardiac function and cerebral perfusion in a murine model of SAH and to identify electrocardiographic and echocardiographic signs indicative of NSC. We quantified cortical perfusion by laser SPECKLE contrast imaging, and myocardial function by serial high-frequency ultrasound imaging, for up to 7 days after experimental SAH induction in mice by endovascular filament perforation. Cortical perfusion decreased significantly whereas cardiac output and left ventricular ejection fraction increased significantly shortly post-SAH. Transient pathological ECG and echocardiographic abnormalities, indicating NSC (right bundle branch block, reduced left ventricular contractility), were observed up to 3 h post-SAH in a subset of model animals. Cerebral perfusion improved over time after SAH and correlated significantly with left ventricular end-diastolic volume at 3, 24, and 72 h. The murine SAH model is appropriate to experimentally investigate NSC. We conclude that in addition to cerebrovascular dysfunction, cardiac dysfunction may significantly influence cerebral perfusion, with LVEDV presenting a potential parameter for risk stratification.
| S-EPMC7870815 | biostudies-literature
Project description:Background and purposeDCI is a serious complication following aneurysmal SAH and remains a leading cause of morbidity and mortality. Our aim was to evaluate CTP in aneurysmal SAH by using outcome measures of DCI.Materials and methodsThis was a retrospective study of consecutive patients with SAH enrolled in a prospective institutional review board-approved clinical accuracy trial. Qualitative CTP deficits were determined by 2 neuroradiologists blinded to clinical and imaging data. Quantitative CTP was performed by using a standardized protocol with region-of-interest placement sampling of the cortex. Primary outcome measures were permanent neurologic deficits and infarction. The secondary outcome measure was DCI, defined as clinical deterioration. CTP test characteristics (95% CI) were determined for each outcome measure. Statistical significance was calculated by using the Fisher exact and Student t tests. ROC curves were generated to determine accuracy and threshold analysis.ResultsNinety-six patients were included. Permanent neurologic deficits developed in 33% (32/96). CTP deficits were seen in 78% (25/32) of those who developed permanent neurologic deficits and 34% (22/64) of those without (P < .0001). CTP deficits had 78% (61%-89%) sensitivity, 66% (53%-76%) specificity, and 53% (39%-67%) positive and 86% (73%-93%) negative predictive values. Infarction occurred in 18% (17/96). CTP deficits were seen in 88% (15/17) of those who developed infarction and 41% (32/79) of those without (P = .0004). CTP deficits had an 88% (66%-97%) sensitivity, 59% (48%-70%) specificity, and 32% (20%-46%) positive and 96% (86%-99%) negative predictive values. DCI was diagnosed in 50% (48/96). CTP deficits were seen in 81% (39/48) of patients with DCI and in 17% (8/48) of those without (P < .0001). CTP deficits had 81% (68%-90%) sensitivity, 83% (70%-91%) specificity, and 83% (70%-91%) positive and 82% (69%-90%) negative predictive values. Quantitative CTP revealed significantly reduced CBF and prolonged MTT for DCI, permanent neurologic deficits, and infarction. ROC analysis showed that CBF and MTT had the highest accuracy.ConclusionsCTP may add prognostic information regarding DCI and poor outcomes in aneurysmal SAH.
| S-EPMC4004022 | biostudies-literature
Project description:Dynamic cerebral autoregulation to spontaneous fluctuations in cerebral perfusion pressure (CPP) is often assessed by transcranial Doppler (TCD) in the time domain, yielding primarily the mean flow index (Mx), or in the frequency domain using transfer function analysis (TFA), yielding gain and phase. For both domains, the measurement of blood pressure is critical. This study assessed the inter-method reliability of dynamic cerebral autoregulation using three different methods of pressure measurement. In 39 patients with aneurysmal subarachnoid hemorrhage, non-invasive arterial blood pressure (ABP), invasive ABP (measured in the radial artery) and CPP were recorded simultaneously with TCD. Intraclass correlation coefficient (ICC) was used to quantify reliability. Mx was higher when calculated using invasive ABP (0.39; 95% confidence interval [95% CI]: 0.33; 0.44) compared to non-invasive ABP, and CPP. The overall ICC showed poor to good reliability (0.65; 95% CI: 0.11; 0.84; n = 69). In the low frequency domain, the comparison between invasively measured ABP and CPP showed good to excellent (normalized gain, ICC: 0.87, 95CI: 0.81; 0.91; n = 96; non-normalized gain: 0.89, 95% CI: 0.84; 0.92; n = 96) and moderate to good reliability (phase, ICC: 0.69, 95% CI: 0.55; 0.79; n = 96), respectively. Different methods for pressure measurement in the assessment of dynamic cerebral autoregulation yield different results and cannot be used interchangeably.
| S-EPMC8958499 | biostudies-literature
Project description:Delayed cerebral ischemia (DCI) is at presentation a diagnosis per exclusionem, and can only be confirmed with follow-up imaging. For treatment of DCI a diagnostic tool is needed. We performed a systematic review to evaluate the value of CT perfusion (CTP) in the prediction and diagnosis of DCI. We searched PubMed, Embase, and Cochrane databases to identify studies on the relationship between CTP and DCI. Eleven studies totaling 570 patients were included. On admission, cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and time-to-peak (TTP) did not differ between patients who did and did not develop DCI. In the DCI time-window (4 to 14 days after subarachnoid hemorrhage (SAH)), DCI was associated with a decreased CBF (pooled mean difference -11.9 mL/100 g per minute (95% confidence interval (CI): -15.2 to -8.6)) and an increased MTT (pooled mean difference 1.5 seconds (0.9-2.2)). Cerebral blood volume did not differ and TTP was rarely reported. Perfusion thresholds reported in studies were comparable, although the corresponding test characteristics were moderate and differed between studies. We conclude that CTP can be used in the diagnosis but not in the prediction of DCI. A need exists to standardize the method for measuring perfusion with CTP after SAH, and optimize and validate perfusion thresholds.
| S-EPMC3915217 | biostudies-literature
Project description:INTRODUCTION: Delayed ischemic neurologic deficits secondary to vasospasm are a major cause of morbidity and mortality after subarachnoid hemorrhage (SAH). Treatment of vasospasm after SAH is associated with complications, and reliable techniques for evaluating effects of treatment of vasospasm in such patients are warranted. We present the use of perfusion computed tomography (PTC) to evaluate the effect of transluminal percutaneous angioplasty in a with SAH and vasospasm-induced ischemia. METHODS: Dynamic PCT with deconvolution produced maps of time-to-peak, mean transit time, regional cerebral blood flow, and regional cerebral blood volume, with a computerized automated map of the infarct and penumbra. CT scanners with quadruple detector array were used before and after angioplasty. RESULTS: Before angioplasty and intraarterial papaverine, PCT showed normal to decreased cerebral blood flow and increased cerebral blood volume and mean transit time in the middle cerebral artery territory of the left hemisphere. After angioplasty and intraarterial papaverine, PCT showed normalization of perfusion parameters. CONCLUSION: PCT can be a useful technique in monitoring angioplasty treatment effects in patients with vasospasm after SAH.
| S-EPMC2782106 | biostudies-other
Project description:Delayed cerebral ischemia and vasospasm are significant complications following SAH leading to cerebral infarction, functional disability, and death. In recent years, CTA and CTP have been used to increase the detection of delayed cerebral ischemia and vasospasm. Our aim was to perform comparative-effectiveness and cost-effectiveness analyses evaluating CTA and CTP for delayed cerebral ischemia and vasospasm in aneurysmal SAH from a health care payer perspective.We developed a decision model comparing CTA and CTP with transcranial Doppler sonography for detection of vasospasm and delayed cerebral ischemia in SAH. The clinical pathways were based on the "Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association" (2012). Outcome health states represented mortality and morbidity according to functional outcomes. Input probabilities of symptoms and serial test results from CTA and CTP, transcranial Doppler ultrasound, and digital subtraction angiography were directly derived from an SAH cohort by using a multinomial logistic regression model. Expected benefits, measured as quality-adjusted life years, and costs, measured in 2012 US dollars, were calculated for each imaging strategy. Univariable, multivariable, and probabilistic sensitivity analyses were performed to determine the independent and combined effect of input parameter uncertainty.The transcranial Doppler ultrasound strategy yielded 13.62 quality-adjusted life years at a cost of $154,719. The CTA and CTP strategy generated 13.89 quality-adjusted life years at a cost of $147,097, resulting in a gain of 0.27 quality-adjusted life years and cost savings of $7622 over the transcranial Doppler ultrasound strategy. Univariable and multivariable sensitivity analyses indicated that results were robust to plausible input parameter uncertainty. Probabilistic sensitivity analysis results yielded 96.8% of iterations in the right lower quadrant, representing higher benefits and lower costs.Our model results suggest that CTA and CTP are the preferred imaging strategy in SAH, compared with transcranial Doppler ultrasound, leading to improved clinical outcomes and lower health care costs.
| S-EPMC4161647 | biostudies-literature