Biomarkers of Unfavorable Outcome in Acute Ischemic Stroke Patients with Successful Recanalization by Endovascular Thrombectomy

Abstract

<b><i>Background:</i></b> We aimed to identify plasma markers of unfavorable outcomes for patients with acute ischemic stroke (AIS) after recanalization by endovascular thrombectomy (EVT). <b><i>Methods:</i></b> From November 2017 to May 2019, we prospectively collected 61 AIS patients due to anterior large vessel occlusion who achieved recanalization by EVT. Plasma samples were obtained between 18 and 24 h after recanalization. Unfavorable outcomes included futile recanalization at 90 days and overall early complications within 7 days after EVT. <b><i>Results:</i></b> After adjustment for age and initial National Institute of Health Stroke Scale (NIHSS), matrix metalloproteinase-9 (MMP-9), tenascin-C, thioredoxin, ADAMTS13, and gelsolin were independently associated with both futile recanalization and overall early complications significantly (all <i>p</i> < 0.05), while C-reactive protein (CRP) was independently associated with overall early complications (<i>p</i> = 0.031) but at the limit of significance for futile recanalization (<i>p</i> = 0.051). The baseline clinical model (BCM) (including age and initial NIHSS) demonstrated discriminating ability to indicate futile recanalization (area under the curve [AUC] 0.807, 95% confidence interval [CI] 0.693–0.921) and overall early complications (AUC 0.749, 95% CI 0.611–0.887). BCM+MMP-9+thioredoxin enhanced discrimination (AUC 0.908, 95% CI 0.839–0.978, <i>p</i> = 0.043) and reclassification (net reclassification improvement [NRI] 67.2%, <i>p</i> < 0.001) to indicate futile recanalization. With respect to overall early complications, BCM+MMP-9+tenascin-C, BCM+MMP-9+CRP, BCM+MMP-9+ADAMTS13, BCM+tenascin-C+ADAMTS13, and BCM+CRP+ADAMTS13, all improved discrimination (AUC [95% CI]: 0.868 [0.766–0.970], 0.882 [0.773–0.990], 0.886 [0.788–0.984], 0.880 [0.783–0.977], and 0.863 [0.764–0.962], respectively, all <i>p</i> < 0.05 by the DeLong method) and reclassification (NRI 59.1%, 71.8%, 51.1%, 67.4%, and 38.3%, respectively, all <i>p</i> < 0.05). <b><i>Conclusions:</i></b> The increased levels of MMP-9, tenascin-C, CRP, thioredoxin, and decreased levels of ADAMTS13 and gelsolin were independent predictors of futile recanalization in AIS patients after recanalization by EVT.

Annexin A1 protects against cerebral ischemia–reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway

“…Biomarkers detected in the peripheral blood of patients could have better predictive values because they are often related to pathophysiological response to EVT recanalization. In this regard, matrix metalloprotease-9 [ 6 ] and low-density lipoprotein cholesterol [ 33 ] have been associated with clinical outcomes in EVT-treated AIS patients. Senchenkova et al [ 20 ] have shown that plasma levels of ANXA1 were lower in AIS patients than healthy controls, but the study did not link the finding to clinical outcomes of the AIS patients and those with EVT.…”

“…In this study, we used a well-established mouse model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) and an in vitro OGD/R model to study the role of Ac2-26 in I/R-induced microglia/macrophage activation and polarization, and the subsequent inflammatory injuries. In addition, few biomarkers have been reported to predict the unfavorable outcome/futile recanalization after EVT [ 6 ]. We therefore measured dynamic changes of plasma levels of ANXA1 in longitudinal samples from patients with AIS who received successful recanalization in order to determine whether ANXA1 predicts the unfavorable outcome/futile recanalization of AIS patients after EVT.…”

“…However, many AIS patients who achieved successful recanalization develop early complications (e.g., secondary infarct growth, symptomatic hemorrhagic transformation, and malignant edema), and~50% of these patients remain disabled several months post-EVT. This condition is now termed as "futile recanalization" [4][5][6]. It has been widely recognized that rapid reperfusion itself induced cerebral ischemia-reperfusion (I/R) injury is a major cause of futile recanalization [7][8][9].…”

Timely and Blood-Based Multiplex Molecular Profiling of Acute Stroke

“…Consequently, stroke chameleon patients have the worst outcomes at 12 months [ 10 ]; The reperfusion treatments would be hastened. Thrombolytic iv treatment would start right after the first encounter of the paramedic team with the patient, saving over 15 min, depending on the time and distance from the scene to hospital [ 70 ], at a significantly lower cost than specialized stroke ambulances with portable imaging devices [ 112 ]; Biomarkers able to anticipate successful recanalization (e.g., reduced levels of inflammation-associated α2-antiplasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) or C-Reactive Protein) [ 113 , 114 , 115 ], could guide adjuvant therapies (e.g., growth factors administration) [ 116 ] to improve the efficacy of thrombolytic iv treatment in centers where mechanical thrombectomy is not readily available or when thrombectomy is not recommended (distal clots with low NIHSS at presentation and high pretreatment modified Rankin scale) [ 117 ]. In addition, biomarkers that predict the risk of hemorrhagic transformation after iv thrombolysis or mechanical recanalization (e.g., cellular Fibronectin (c-Fn)) could be measured with POC diagnostic platforms preventing damaging interventions [ 79 ]; The identification of the stroke subtype in the pre-hospital setting would be more sensitive.…”

“…Biomarkers able to anticipate successful recanalization (e.g., reduced levels of inflammation-associated α2-antiplasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) or C-Reactive Protein) [ 113 , 114 , 115 ], could guide adjuvant therapies (e.g., growth factors administration) [ 116 ] to improve the efficacy of thrombolytic iv treatment in centers where mechanical thrombectomy is not readily available or when thrombectomy is not recommended (distal clots with low NIHSS at presentation and high pretreatment modified Rankin scale) [ 117 ]. In addition, biomarkers that predict the risk of hemorrhagic transformation after iv thrombolysis or mechanical recanalization (e.g., cellular Fibronectin (c-Fn)) could be measured with POC diagnostic platforms preventing damaging interventions [ 79 ];…”