Apolipoprotein C3 and Necrotic Core Volume Are Correlated but Also Associated With Future Cardiovascular Events

We aimed to clarify the relationship between apolipoprotein C3 (apo-C3) and vascular composition of lesion plaque in stable coronary disease (SCD) before percutaneous coronary intervention (PCI) and to investigate major adverse cardiovascular events (MACEs) within 4 years. Data of 98 consecutive patients with SCD who underwent PCI between November 1, 2012, and March 10, 2015, were analyzed. Laboratory evaluation and virtual histology-intravascular ultrasound (VH-IVUS) examination of culprit lesions were conducted before PCI. Patients were divided according to the median apo-C3 value into low apo-C3 (≤8.5 mg/dL) and high apo-C3 (>8.5 mg/dL) groups. VH-IVUS data indicated that the percentage of necrotic core volume (%NC) was significantly higher in the high apo-C3 group than in the low apo-C3 group. Moreover, the %NC significantly correlated with the apo-C3 level (R=0.2109, P=0.037). Kaplan–Meier curve analysis revealed that freedom from MACEs decreased more in the high apo-C3 group than in the low apo-C3 group and in the high %NC group than in the low %NC group. Multivariate Cox hazards analysis showed that the %NC and high apo-C3 were independent predictors of 4-year MACEs. Apo-C3 may be a useful marker for future MACEs in patients with SCD after PCI and contribute to %NC growth.

Comparison of Two Automated Computed Tomography Perfusion Applications to Predict the Final Infarct Volume After Thrombolysis in Cerebral Infarction 3 Recanalization

Background and Purpose: Several automated computed tomography perfusion software applications have been developed to provide support in the definition of ischemic core and penumbra in acute ischemic stroke. However, the degree of interchangeability between software packages is not yet clear. Our study aimed to evaluate 2 commonly used automated perfusion software applications (Syngo.via and RAPID) for the indication of ischemic core with respect to the follow-up infarct volume (FIV) after successful recanalization and with consideration of the clinical impact. Methods: Retrospectively, 154 patients with large vessel occlusion of the middle cerebral artery or the internal carotid artery, who underwent endovascular therapy with a consequent Thrombolysis in Cerebral Infarction 3 result within 2 hours after computed tomography perfusion, were included. Computed tomography perfusion core volumes were assessed with both software applications with different thresholds for relative cerebral blood flow (rCBF). The results were compared with the FIV on computed tomography within 24 to 36 hours after recanalization. Bland-Altman was applied to display the levels of agreement and to evaluate systematic differences. Results: Highest correlation between ischemic core volume and FIV without significant differences was found at a threshold of rCBF<38% for the RAPID software ( r =0.89, P <0.001) and rCBF<25% for the Syngo software ( r =0.87, P <0.001). Bland-Altman analysis revealed best agreement in these settings. In the vendor default settings (rCBF<30% for RAPID and rCBF<20% for Syngo) correlation between ischemic core volume and FIV was also high (RAPID: r =0.88, Syngo: r =0.86, P <0.001), but mean differences were significant ( P <0.001). The risk of critical overestimation of the FIV was higher with rCBF<38% (RAPID) and rCBF<25% (Syngo) than in the default settings. Conclusions: By adjusting the rCBF thresholds, comparable results with reliable information on the FIV after complete recanalization can be obtained both with the RAPID and Syngo software. Keeping the software specific default settings means being more inclusive in patient selection, but forgo the highest possible accuracy in the estimation of the FIV.

Abstract 1122‐000167: Hyperintense Acute Reperfusion Marker and Hemorrhagic Conversion in Stroke Patients Undergoing Mechanical Reperfusion

Introduction : Endovascular thrombectomy (EVT) is a highly effective treatment to improve clinical outcome in patients with acute ischemic stroke due to large vessel occlusion (AIS‐LVO). However, blood‐brain barrier (BBB) disruption causing hemorrhagic transformation and reperfusion injury can potentially negate the beneficial effect of reperfusion. Studying determinants, frequency, and outcomes of the hyperintense acute reperfusion marker (HARM) sign, a biomarker of BBB disruption, would help to identify individual patients at increased risk, as well as developing therapies to prevent BBB breakdown. Methods : In consecutive AIS‐LVO patients with AIS‐LVO who underwent EVT followed by MRI within the next 24 hours, we evaluated frequency, determinants, and outcomes of HARM sign. Results : Among 81 patients meeting study criteria, age was 71.0 (SD 19.7), 58% female, mean NIHSS was 14.5 (SD 6.8), and time from last known well to treatment was 355 min (IQR 206.5 ‐ 664). HARM sign was observed in 64% (52/81) of patients. On multivariate logistic analysis, presence of HARM sign was independently associated with greater periventricular white matter hyperintensity, higher pre‐EVT ischemic core volume, more proximal target vessel occlusion, and achievement of successful reperfusion or better. Hemorrhagic conversion was seen in 31.8% of patients with HARM sign and 26.7% of patients without HARM sign. Multivariate analysis identified higher blood glucose, lower ASPECT, score and greater post‐EVT ischemic core volume as independent predictors of hemorrhagic conversion. HARM sign was identified to correlate with poor clinical outcome in bivariate analysis, but multivariate analysis only identified less neurological deficits, lower baseline systolic BP, lower degree of periventricular white matter hyperintensities, shorter time to device deployment and reduced post EVT ischemic core volume as independent predictors of good clinical outcome (mRS 0–2) upon discharge. Conclusions : The HARM sign indicating disruption of the blood‐brain barrier following EVT is common, present in about 6 of every 10 treated patients. Independent risk factors for HARM sign are chronic ischemic microangiopathy, greater acute ischemic core, and successful reperfusion. HARM sign presence is associated with worse functional outcome.

Low Baseline Ischemic Water Uptake is Directly Related to Overestimation of CT Perfusion-Derived Ischemic Core Volume

Background Computed-tomography perfusion (CTP) is frequently used to screen acute ischemic stroke (AIS) patients for endovascular treatment (EVT), despite known problems with ischemic “core” overestimation. This potentially leads to the unfair exclusion of patients from EVT. We propose that net water uptake (NWU) can be used in addition to CTP to more accurately assess the extent and/or stage of tissue infarction. Methods Patients treated for AIS between 06/2015-07/2020 were retrospectively analyzed. Baseline CTP-derived core volume (pCore) and NWU were determined. Logistic regression tested the relationship between baseline clinical and imaging variables and core-overestimation (primary outcome). The secondary outcomes comprised 90-day functional independence (modified Rankin score) and lesion growth. Results 284 patients were included. Median NWU was 7.2% (IQR:2.6–12.8). ASPECTS (RR:1.28,95%CI:1.09-1.51), NWU (RR:0.94,95%CI:0.89-0.98), onset to recanalization (RR:1.00,95%CI:0.99-1.00) and imaging (RR:1.00,95%CI1.00-1.00) times, and pCore (RR:1.02,95%CI:1.01-1.02) were significantly associated with core overestimation. Core-overestimation was more likely to occur in patients with large pCores and low NWU at baseline. NWU was significantly correlated with lesion growth. Conclusion NWU can be used as a supplemental tool to CTP during admission imaging to more accurately assess the extent of ischemia, particularly relevant for patients with large CTP-defined cores who would otherwise be excluded from treatment.

Abstract 1122‐000012: Study Design and Selection Criteria of a Large Core Thrombectomy Trial —— ANGEL‐ASPECT

Introduction : The ANGEL‐ASPECT trial (NCT 04551664) is an ongoing, multicenter, randomized controlled trial (RCT) currently being conducted in China. The goal of ANGEL‐ASPECT’s is to include the maximum patients with a true large core for whom EVT is not recommended under current guidelines with level 1 evidence. By enrolling patients with ASPECTS <6, expanding the window to 24h from stroke onset (beyond the windows in DAWN and DEFUSE3), and defining large core volume as >70 cc, ANGEL‐ASPECT maximizes the inclusion of patients with true large cores. What’s more, intracranial atherosclerotic disease (ICAD) is common in the Asian population while most of the previous trials have been performed in the Western world where ICAD is less prevalent. Methods : We reviewed the merits of ANGEL‐ASPECT’s design and suggest that it be included in the discussion of patient selection criteria in large core trials. Results : The primary goal of our trial is to determine whether EVT will benefit or harm AIS patients with LVO and a “large core” infarct. The inclusion criteria for ANGEL‐ASPECT are: 1. If ASPECTS is 3–5 and presentation is within 24 hours of onset, patients are enrolled without obtaining CTP. 2. If ASPECTS is >5 and presentation is beyond 6 hours of onset, only patients with relative cerebral blood flow (rCBF) of < 30% by CTP or apparent diffusion coefficient (ADC) of < 620 on MRI and estimated core volume of 70–100 cc are enrolled. 3. If ASPECTS is <3, only patients with rCBF < 30% or ADC on MRI < 620 and estimated core volume of 70–100 cc are enrolled. Patients are enrolled under a pre‐specified protocol. Each randomized patient is qualified by two core lab members who are available at all hours to calculate ASPECTS and infarct core volume using specialized, RAPID software. Conclusions : We believe that defining core volume using CTP can compensate for the inconsistencies of ASPECTS if we exclude patients with onset within six hours and core volume of 50–70 cc since these patients have already been shown to benefit from EVT in multiple RCTs. We believe that this decision captures more patients with true large core volumes for the trial. The ANGEL‐ASPECT inclusion criteria also eliminate the second group of “good ASPECTS + unfavorable CTP” . The sample size of our trial is calculated based on studies excluding these populations. The power of the trial was maintained for the relatively consistent large core volume patient population.

Mechanical Thrombectomy in Patients with a Large Ischemic Volume at Presentation: Systematic Review and Meta-Analysis

The benefits of mechanical thrombectomy (MT) for patients with acute ischemic stroke (AIS) and a large ischemic core (LIC) at presentation are uncertain. We aimed to obtain up-to-date aggregate estimates of the outcomes following MT in patients with volumetrically assessed LIC. We conducted a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-conformed, PROSPERO-registered, systematic review and meta-analysis of studies that included patients with AIS and a baseline LIC treated with MT, reported ischemic core volume quantitatively, and included patients with a LIC defined as a core volume ≥50 mL. The search was restricted to studies published between January 2015 and June 2020. Random-effects-meta-analysis was used to assess the effect of MT on 90-day unfavorable outcome (i.e., modified Rankin Scale [mRS] 3–6), mortality, and symptomatic intracranial hemorrhage (sICH) occurrence. Sensitivity analyses were performed for imaging-modality (computed tomography-perfusion or magnetic resonance-diffusion weighted imaging) and LIC-definition (≥50 or ≥70 mL). We analyzed 10 studies (954 patients), including six (682 patients) with a control group, allowing to compare 332 patients with MT to 350 who received best-medical-management alone. Overall, after MT the rate of patients with mRS 3–6 at 90 days was 74% (99% confidence interval [CI], 67 to 84; Z-value=7.04; I2=92.3%) and the rate of 90-day mortality was 36% (99% CI, 33 to 40; Z-value=–7.07; I2=74.5). Receiving MT was associated with a significant decrease in mRS 3–6 odds ratio (OR) 0.19 (99% CI, 0.11 to 0.33; P<0.01; Z-value=–5.92; I2=62.56) and in mortality OR 0.60 (99% CI, 0.34 to 1.06; P=0.02; Z-value=–2.30; I2=58.72). Treatment group did not influence the proportion of patients experiencing sICH, OR 0.96 (99% CI, 0.2 to 1.49; P=0.54; Z-value=–0.63; I2=64.74). Neither imaging modality for core assessment, nor LIC definition influenced the aggregated outcomes. Using aggregate estimates, MT appeared to decrease the risk of unfavorable functional outcome in patients with a LIC assessed volumetrically at baseline.

Cerebral Edema in Patients With Large Hemispheric Infarct Undergoing Reperfusion Treatment: A HERMES Meta-Analysis

Background and Purpose: Whether reperfusion into infarcted tissue exacerbates cerebral edema has treatment implications in patients presenting with extensive irreversible injury. We investigated the effects of endovascular thrombectomy and reperfusion on cerebral edema in patients presenting with radiological evidence of large hemispheric infarction at baseline. Methods: In a systematic review and individual patient-level meta-analysis of 7 randomized controlled trials comparing thrombectomy versus medical therapy in anterior circulation ischemic stroke published between January 1, 2010, and May 31, 2017 (Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration), we analyzed the association between thrombectomy and reperfusion with maximal midline shift (MLS) on follow-up imaging as a measure of the space-occupying effect of cerebral edema in patients with large hemispheric infarction on pretreatment imaging, defined as diffusion-magnetic resonance imaging or computed tomography (CT)-perfusion ischemic core 80 to 300 mL or noncontrast CT-Alberta Stroke Program Early CT Score ≤5. Risk of bias was assessed using the Cochrane tool. Results: Among 1764 patients, 177 presented with large hemispheric infarction. Thrombectomy and reperfusion were associated with functional improvement (thrombectomy common odds ratio =2.30 [95% CI, 1.32–4.00]; reperfusion common odds ratio =4.73 [95% CI, 1.66–13.52]) but not MLS (thrombectomy β=−0.27 [95% CI, −1.52 to 0.98]; reperfusion β=−0.78 [95% CI, −3.07 to 1.50]) when adjusting for age, National Institutes of Health Stroke Score, glucose, and time-to-follow-up imaging. In an exploratory analysis of patients presenting with core volume >130 mL or CT-Alberta Stroke Program Early CT Score ≤3 (n=76), thrombectomy was associated with greater MLS after adjusting for age and National Institutes of Health Stroke Score (β=2.76 [95% CI, 0.33–5.20]) but not functional improvement (odds ratio, 1.71 [95% CI, 0.24–12.08]). Conclusions: In patients presenting with large hemispheric infarction, thrombectomy and reperfusion were not associated with MLS, except in the subgroup with very large core volume (>130 mL) in whom thrombectomy was associated with increased MLS due to space-occupying ischemic edema. Mitigating cerebral edema-mediated secondary injury in patients with very large infarcts may further improve outcomes after reperfusion therapies.