The Safety of Intra-arterial Tirofiban during Endovascular Therapy after Intravenous Thrombolysis.

BACKGROUND AND PURPOSE: The safety and efficacy of tirofiban during endovascular therapy in patients undergoing intravenous thrombolysis with recombinant IV tPA remain unclear. This study aimed to investigate the safety and efficacy of intra-arterial tirofiban use during endovascular therapy in patients treated with IV tPA. MATERIALS AND METHODS: Using a multicenter registry, we enrolled patients with acute ischemic stroke who underwent endovascular therapy. Safety outcomes included postprocedural parenchymal hematoma type 2 and/or thick subarachnoid hemorrhage, intraventricular hemorrhage, and 3-month mortality. Efficacy outcomes included the successful reperfusion rate, postprocedural reocclusion, and good outcomes at 3 months (mRS scores of 0-2). The tirofiban effect on the outcomes was evaluated using a multivariable analysis while adjusting for potential confounders. RESULTS: Among enrolled patients, we identified 314 patients with stroke (279 and 35 patients in the no tirofiban and tirofiban groups, respectively) due to an intracranial artery occlusion who underwent endovascular therapy with intravenous thrombolysis. A multivariable analysis revealed no association of intra-arterial tirofiban with postprocedural parenchymal hematoma type and/or thick subarachnoid hemorrhage (adjusted OR, 1.07; 95% CI, 0.20-4.10; P = .918), intraventricular hemorrhage (adjusted OR, 0.43; 95% CI, 0.02-2.85; P = .467), and 3-month mortality (adjusted OR, 0.38; 95% CI, 0.04-1.87; P = .299). Intra-arterial tirofiban was not associated with good outcome (adjusted OR, 2.22; 95% CI, 0.89 -6.12; P = .099). CONCLUSIONS: Using intra-arterial tirofiban during endovascular therapy after IV tPA could be safe.

Infarct Growth despite Successful Endovascular Reperfusion in Acute Ischemic Stroke: A Meta-analysis.

BACKGROUND: Infarct volume inversely correlates with good recovery in stroke. The magnitude and predictors of infarct growth despite successful reperfusion via endovascular treatment are not known. PURPOSE: We aimed to summarize the extent of infarct growth in patients with acute stroke who achieved successful reperfusion (TICI 2b-3) after endovascular treatment. DATA SOURCES: We performed a systematic review and meta-analysis by searching MEDLINE and Google Scholar for articles published up to October 31, 2020. STUDY SELECTION: Studies of >10 patients reporting baseline and post-endovascular treatment infarct volumes on MR imaging were included. Only patients with TICI 2b-3 were included. We calculated infarct growth at a study level as the difference between baseline and follow-up MR imaging infarct volumes. DATA ANALYSIS: Our search yielded 345 studies, and we included 10 studies reporting on 973 patients having undergone endovascular treatment who achieved successful reperfusion. DATA SYNTHESIS: The mean baseline infarct volume was 19.5 mL, while the mean final infarct volume was 37.5 mL. A TICI 2b reperfusion grade was achieved in 24% of patients, and TICI 2c or 3 in 76%. The pooled mean infarct growth was 14.8 mL (95% CI, 7.9-21.7 mL). Meta-regression showed higher infarct growth in studies that reported higher baseline infarct volumes, higher rates of incomplete reperfusion (modified TICI 2b), and longer onset-to-reperfusion times. LIMITATIONS: Significant heterogeneity among studies was noted and might be driven by the difference in infarct growth between early- and late-treatment studies. CONCLUSIONS: These results suggest considerable infarct growth despite successful endovascular treatment reperfusion and call for a faster workflow and the need for specific therapies to limit infarct growth.

Association between time to treatment and functional outcomes according to the Diffusion-Weighted Imaging Alberta Stroke Program Early Computed Tomography Score in endovascular stroke therapy.

BACKGROUND AND PURPOSE: The rate at which the chance of a good outcome of endovascular stroke therapy (EVT) decays with time when eligible patients are selected by baseline diffusion-weighted magnetic resonance imaging (DWI-MRI) and whether ischaemic core size affects this rate remain to be investigated. METHODS: This study analyses a prospective multicentre registry of stroke patients treated with EVT based on pretreatment DWI-MRI that was categorized into three groups: small [Diffusion-Weighted Imaging Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS)] (8-10), moderate (5-7) and large (<5) cores. The main outcome was a good outcome at 90 days (modified Rankin Scale 0-2). The interaction between onset-to-groin puncture time (OTP) and DWI-ASPECTS categories regarding functional outcomes was investigated. RESULTS: Ultimately, 985 patients (age 69 ± 11 years; male 55%) were analysed. Potential interaction effects between the DWI-ASPECTS categories and OTP on a good outcome at 90 days were observed (Pinteraction  = 0.06). Every 60-min delay in OTP was associated with a 16% reduced likelihood of a good outcome at 90 days amongst patients with large cores, although no associations were observed amongst patients with small to moderate cores. Interestingly, the adjusted rates of a good outcome at 90 days steeply declined between 65 and 213 min of OTP and then remained smooth throughout 24 h of OTP (Pnonlinearity  = 0.15). CONCLUSIONS: Our study showed that the probability of a good outcome after EVT nonlinearly decreased, with a steeper decline at earlier OTP than at later OTP. Discrepant effects of OTP on functional outcomes by baseline DWI-ASPECTS categories were observed. Thus, different strategies for EVT based on time and ischaemic core size are warranted.

Clot Burden Score and Early Ischemia Predict Intracranial Hemorrhage following Endovascular Therapy.

BACKGROUND AND PURPOSE: Intracranial hemorrhage is a known complication following endovascular thrombectomy. The radiologic characteristics of a CT scan may assist with hemorrhage risk stratification. We assessed the radiologic predictors of intracranial hemorrhage following endovascular therapy using data from the INTERRSeCT (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography) study. MATERIALS AND METHODS: Patients undergoing endovascular therapy underwent baseline imaging, postprocedural angiography, and 24-hour follow-up imaging. The primary outcome was any intracranial hemorrhage observed on follow-up imaging. The secondary outcome was symptomatic hemorrhage. We assessed the relationship between hemorrhage occurrence and baseline patient characteristics, clinical course, and imaging factors: baseline ASPECTS, thrombus location, residual flow grade, collateralization, and clot burden score. Multivariable logistic regression with backward selection was used to adjust for relevant covariates. RESULTS: Of the 199 enrolled patients who met the inclusion criteria, 46 (23%) had an intracranial hemorrhage at 24 hours. On multivariable analysis, postprocedural hemorrhage was associated with pretreatment ASPECTS (OR, 1.56 per point lost; 95% CI, 1.12-2.15), clot burden score (OR, 1.19 per point lost; 95% CI, 1.03-1.38), and ICA thrombus location (OR, 3.10; 95% CI, 1.07-8.91). In post hoc analysis, clot burden scores of ≤3 (sensitivity, 41%; specificity, 82%; OR, 3.12; 95% CI, 1.36-7.15) and pretreatment ASPECTS ≤ 7 (sensitivity, 48%; specificity, 82%; OR, 3.17; 95% CI, 1.35-7.45) robustly predicted hemorrhage. Residual flow grade and collateralization were not associated with hemorrhage occurrence. Symptomatic hemorrhage was observed in 4 patients. CONCLUSIONS: Radiologic factors, early ischemia on CT, and increased CTA clot burden are associated with an increased risk of intracranial hemorrhage in patients undergoing endovascular therapy.

Automated ASPECTS on Noncontrast CT Scans in Patients with Acute Ischemic Stroke Using Machine Learning.

BACKGROUND AND PURPOSE: Alberta Stroke Program Early CT Score (ASPECTS) was devised as a systematic method to assess the extent of early ischemic change on noncontrast CT (NCCT) in patients with acute ischemic stroke (AIS). Our aim was to automate ASPECTS to objectively score NCCT of AIS patients. MATERIALS AND METHODS: We collected NCCT images with a 5-mm thickness of 257 patients with acute ischemic stroke (<8 hours from onset to scans) followed by a diffusion-weighted imaging acquisition within 1 hour. Expert ASPECTS readings on DWI were used as ground truth. Texture features were extracted from each ASPECTS region of the 157 training patient images to train a random forest classifier. The unseen 100 testing patient images were used to evaluate the performance of the trained classifier. Statistical analyses on the total ASPECTS and region-level ASPECTS were conducted. RESULTS: For the total ASPECTS of the unseen 100 patients, the intraclass correlation coefficient between the automated ASPECTS method and DWI ASPECTS scores of expert readings was 0.76 (95% confidence interval, 0.67-0.83) and the mean ASPECTS difference in the Bland-Altman plot was 0.3 (limits of agreement, -3.3, 2.6). Individual ASPECTS region-level analysis showed that our method yielded κ = 0.60, sensitivity of 66.2%, specificity of 91.8%, and area under curve of 0.79 for 100 × 10 ASPECTS regions. Additionally, when ASPECTS was dichotomized (>4 and ≤4), κ = 0.78, sensitivity of 97.8%, specificity of 80%, and area under the curve of 0.89 were generated between the proposed method and expert readings on DWI. CONCLUSIONS: The proposed automated ASPECTS scoring approach shows reasonable ability to determine ASPECTS on NCCT images in patients presenting with acute ischemic stroke.

Role of the histone deacetylase inhibitor valproic acid in high-fat diet-induced hypertension via inhibition of HDAC1/angiotensin II axis.

BACKGROUND: Obesity is known as an epidemic worldwide because of consumption of westernized high-fat diets and one of the major risk factors of hypertension. Histone deacetylases (HDACs) control gene expression by regulating histone/non-histone protein deacetylation. HDAC inhibitors exert anti-cancer and anti-inflammatory effects and play a protective role in cardiovascular diseases. In the present study, we tested the effect of an FDA-approved pan-HDAC inhibitor valproic acid (VPA) on high-fat diet (HFD)-induced hypertension in mice. Furthermore, we examined the mechanism of VPA-induced prevention of hypertension. METHODS: Nine-week-old male C57BL/6 mice were fed either a normal diet (ND) or HFD. When the HFD group reached a pre-hypertensive phase (130-140 mm Hg systolic blood pressure), VPA was administered for 6 days (300 mg kg-1 per day). Body weights and blood pressure (BP), expression of renin-angiotensin system (RAS) components and HDAC1 were determined. The direct role of HDAC1 in the expression of RAS components was investigated using gene silencing. RESULTS: HFD accelerated the increase in body weight from 22.4±1.3 to 31.9±3.0 compared to in the ND group from 22.7±0.9 to 26.0±1.7 (P=0.0134 ND vs HFD), systolic BP from 118.5±5.7 to 145.0±3.0 (P<0.001), and diastolic BP from 91.0±13.6 to 121.0±5.0 (P=0.006); BP was not altered in the ND group. HFD increased RAS components and HDAC1 in the kidneys as well as leptin in the plasma. VPA administration prevented the progression of hypertension and inhibited the increase in expression of HDAC1 and RAS components. VPA did not affect plasma leptin level. Knockdown of HDAC1 in MDCK cells decreased the expression of angiotensinogen and type 1 angiotensin II receptor. CONCLUSIONS: VPA prevented HFD-induced hypertension by downregulating angiotensin II and its receptor via inhibition of HDAC1, offering a novel therapeutic option for HFD-induced hypertension.

Early reperfusion rates with IV tPA are determined by CTA clot characteristics.

BACKGROUND AND PURPOSE: An ability to predict early reperfusion with IV tPA in patients with acute ischemic stroke and intracranial clots can help clinicians decide if additional intra-arterial therapy is needed or not. We explored the association between novel clot characteristics on baseline CTA and early reperfusion with IV tPA in patients with acute ischemic stroke by using classification and regression tree analysis. MATERIALS AND METHODS: Data are from patients with acute ischemic stroke and proximal anterior circulation occlusions from the Calgary CTA data base (2003-2012) and the Keimyung Stroke Registry (2005-2009). Patients receiving IV tPA followed by intra-arterial therapy were included. Clot location, length, residual flow within the clot, ratio of contrast Hounsfield units pre- and postclot, and the M1 segment origin to the proximal clot interface distance were assessed on baseline CTA. Early reperfusion (TICI 2a and above) with IV tPA was assessed on the first angiogram. RESULTS: Two hundred twenty-eight patients (50.4% men; median age, 69 years; median baseline NIHSS score, 17) fulfilled the inclusion criteria. Median symptom onset to IV tPA time was 120 minutes (interquartile range = 70 minutes); median IV tPA to first angiography time was 70.5 minutes (interquartile range = 62 minutes). Patients with residual flow within the clot were 5 times more likely to reperfuse than those without it. Patients with residual flow and a shorter clot length (≤15 mm) were most likely to reperfuse (70.6%). Patients with clots in the M1 MCA without residual flow reperfused more if clots were distal and had a clot interface ratio in Hounsfield units of <2 (36.8%). Patients with proximal M1 clots without residual flow reperfused 8% of the time. Carotid-T/-L occlusions rarely reperfused (1.7%). Interrater reliability for these clot characteristics was good. CONCLUSIONS: Our study shows that clot characteristics on CTA help physicians estimate a range of early reperfusion rates with IV tPA.

CTA collateral status and response to recanalization in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Collateral status at baseline is an independent determinant of clinical outcome among patients with acute ischemic stroke. We sought to identify whether the association between recanalization after intra-arterial acute stroke therapy and favorable clinical response is modified by the presence of good collateral flow assessed on baseline CTA. MATERIALS AND METHODS: Data are from the Keimyung Stroke Registry, a prospective cohort study of patients with acute ischemic stroke from Daegu, South Korea. Patients with M1 segment MCA with or without intracranial ICA occlusions on baseline CTA from May 2004 to July 2009 who also had baseline MR imaging were included. Two readers blinded to all clinical information assessed baseline and follow-up imaging. Leptomeningeal collaterals on baseline CTA were assessed by consensus by use of the regional leptomeningeal score. RESULTS: Among 84 patients (mean age, 65.2 ± 13.2 years; median NIHSS score, 14; interquartile range, 8.5), median time from stroke onset to initial MR imaging was 164 minutes. TICI 2b-3 recanalization was achieved in 38.1% of patients and mRS 0-2 at 90 days in 35.8% of patients. In a multivariable model, the interaction between collateral status and recanalization was significant. Only patients with intermediate or good collaterals who recanalized showed a statistically significant association with good clinical outcome (rate ratio = 3.8; 95% CI, 1.2-12.1). Patients with good and intermediate collaterals who did not achieve recanalization and patients with poor collaterals, even if they achieved recanalization, did not do well. CONCLUSIONS: Patients with good or intermediate collaterals on CTA benefit from intra-arterial therapy, whereas patients with poor collaterals do not benefit from treatment.

Pharmacokinetics of liquiritigenin and its two glucuronides, M1 and M2, in rats with acute hepatitis induced by d-galactosamine/lipopolysaccharide or CCl(4).

Cytoprotective effects of liquiritigenin (LQ) against liver injuries have been reported, but its pharmacokinetics has not been studied in acute hepatitis. Thus, pharmacokinetics of LQ and its two conjugated glucuronide metabolites: 4'-O-glucuronide (M1) and 7-O-glucuronide (M2), in rats with acute hepatitis induced by d-galactosamine/lipopolysaccharide (GalN/LPS) rats or carbon tetrachloride-treated (CCl(4)-treated) rats were evaluated. LQ was administered intravenously (20 mg kg(-1)) and orally (50 mg kg(-1)) to control GalN/LPS and CCl(4)-treated rats. Expression of uridine 5'-diphospho-glucuronosyltransferases 1A (UGT1A) and in vitro metabolism of LQ in hepatic and intestinal microsomes were also measured. After intravenous administration of LQ, area under the plasma concentration-time curve (AUC) of LQ in GalN/LPS rats was significantly smaller than that in controls due to faster non-renal clearance, as a result of its greater free fraction in plasma and faster hepatic blood flow rate than the controls. In CCl(4)-treated rats, the AUC(M1, 0-8 h)/AUC(LQ) and AUC(M2, 0-8 h)/AUC(LQ) ratios were significantly greater than the controls due to decrease in biliary excretion of M1 and M2. However, no significant pharmacokinetic changes were observed in both acute hepatitis rats after oral administration due to comparable intestinal metabolism of LQ. Modification of oral dosage regimen of LQ may not be necessary in patients with acute hepatitis; but human studies are required.

Pharmacokinetics and first-pass effects of liquiritigenin in rats: low bioavailability is primarily due to extensive gastrointestinal first-pass effect.

Pharmacokinetics of liquiritigenin, a candidate for inflammatory liver disease, and its two glucuronide conjugates, M1 and M2, were evaluated in rats. The hepatic and gastrointestinal first-pass effects of liquiritigenin were also evaluated in rats. After oral administration of liquiritigenin at a dose of 20 mg kg(-1), 1.07% of the dose was not absorbed from the gastrointestinal tract up to 24 h, and the F-value was only 6.68%. In vitro metabolism of liquiritigenin in S9 fractions of rat tissues showed that the liver and intestine were major tissues responsible for glucuronidation of liquiritigenin. The hepatic and gastrointestinal first-pass effects of liquiritigenin were approximately 3.67% and 92.5% of the oral dose, respectively. Although the hepatic first-pass effect of liquiritigenin after absorption into the portal vein was 57.1%, the value was only 3.67% of the oral dose due to extensive gastrointestinal first-pass effect in rats. Therefore, the low F-value of liquiritigenin in rats was primarily attributable to an extensive gastrointestinal first-pass effect although liquiritigenin was well absorbed. Compared with rats, the higher F-value of liquiritigenin could be expected in humans.

Cerebellar infarction presenting isolated vertigo: frequency and vascular topographical patterns.

OBJECTIVE: To determine the frequency of cerebellar infarction mimicking vestibular neuritis (VN), the pattern of clinical presentation, and the territory of the cerebellar infarction when it simulates VN. METHODS: We studied 240 consecutive cases of isolated cerebellar infarction in the territories of the cerebellar arteries diagnosed by brain MRI from the acute stroke registry at the Keimyung University Dongsan Medical Center. RESULTS: We identified 25 patients (10.4%) with isolated cerebellar infarction who had clinical features suggesting VN. Two types of cerebellar infarction simulating VN were found: isolated spontaneous prolonged vertigo with imbalance as a sole manifestation of cerebellar infarction (n = 24) and isolated spontaneous prolonged vertigo with imbalance as an initial manifestation of cerebellar infarction (n = 1) followed by delayed neurologic deficits 2 days after the onset. The cerebellar infarction territory most commonly involved was the medial branch of the posterior inferior cerebellar artery territory (24/25: 96%), followed by the anterior inferior cerebellar artery territory (1/25: 4%). None of patients with infarcts in the territory of the superior cerebellar artery or multiple cerebellar arteries showed isolated spontaneous prolonged vertigo. CONCLUSIONS: Cerebellar infarction simulating vestibular neuritis is more common than previously thought. Early recognition of the pseudo-vestibular neuritis of vascular cause may allow specific management.