Collateral is brain: Low perfusion triggers spreading depolarization and futile reperfusion after acute ischemic stroke.

Futile reperfusion is a phenomenon of inadequate perfusion despite successful recanalization after acute ischemic stroke (AIS). It is associated with poor patient outcomes and has received increasing interest due to its clinical diagnosis becoming more common. However, the underlying mechanisms remain elusive, and experimental studies are focused on the pathological background of futile reperfusion. Our recent study has confirmed that poor primary collateralization plays a crucial role in the insufficiency of reperfusion after AIS in mice. Specifically, the absence of primary collaterals in the circle of Willis (CoW) promoted the development of spreading depolarizations (SDs) during AIS. In our experimental stroke model, the occurrence of SDs during ischemia always predicted futile reperfusion. Conversely, in mice with a complete CoW, no SDs were observed, and reperfusion was complete. Importantly, the human CoW displays variation in the primary collaterals in approximately 50% of the population. Therefore, futile reperfusion may result from SD evolution in AIS patients. Our purpose here is to emphasize the crucial role of SD in the development of futile reperfusion. We propose that adequate collateral recruitment can prevent SD occurrence, leading to improved reperfusion and AIS outcomes.

U-shaped association between low-density lipoprotein cholesterol levels and risk of futile reperfusion mediated by stroke-associated pneumonia in acute ischemic stroke after endovascular thrombectomy.

OBJECTIVE: Futile reperfusion (FR) is becoming a major challenge in the treatment of patients with acute ischaemic stroke (AIS) undergoing endovascular thrombectomy. This study aims to determine the dose-response relationship between low-density lipoprotein cholesterol (LDL-C) levels and the risk of FR in patients with AIS undergoing endovascular thrombectomy and to investigate potential mediators. METHODS: A total of 614 patients with AIS undergoing endovascular thrombectomy were enrolled and divided into five groups according to quintiles of LDL-C levels: Q1(≤2.27 mmol/l), Q2 (2.27-2.5 mmol/l), Q3 (2.5-2.59 mmol/l), Q4 (2.59-2.97 mmol/l) and Q5 (≥2.97 mmol/l). Associations between LDL-C levels and the risk of FR and stroke-associated pneumonia (SAP) were estimated using multivariate logistic regression models. Restricted cubic spline curves were used to describe the dose-response relationship between LDL-C levels and the risk of FR and SAP. Mediation effect analysis was performed in R software with 100 bootstrap samples. RESULTS: After adjustment for confounders, both low and high LDL-C levels were significantly associated with a higher risk of FR compared with the reference group (Q3). We observed a U-shaped association between LDL-C levels and the risk of FR (P for nonlinear =0.012). Mediation analysis showed that the association between LDL-C levels and the risk of FR was 29.7 % (95 % CI: 2.96 %-75.0 %, P=0.02) mediated by SAP. CONCLUSIONS: We found a U-shaped association between LDL-C levels and the risk of FR that was mediated by SAP. Clinicians should note that in AIS patients undergoing endovascular thrombectomy, lower LDL-C levels are not always better.

A CT texture-based nomogram for predicting futile reperfusion in patients with intraparenchymal hyperdensity after endovascular thrombectomy for acute anterior circulation large vessel occlusion.

Background: Post-thrombectomy intraparenchymal hyperdensity (PTIH) in patients with acute anterior circulation large vessel occlusion is a common CT sign associated with a higher incidence of futile reperfusion (FR). We aimed to develop a nomogram to predict FR specifically in patients with PTIH. Methods: We retrospectively collected information on patients with acute ischemic stroke who underwent endovascular thrombectomy (EVT) at two stroke centers. A total of 398 patients with PTIH were included to develop and validate the nomogram, including 214 patients in the development cohort, 92 patients in the internal validation cohort and 92 patients in the external validation cohort. The nomogram was developed according to the independent predictors obtained from multivariate logistic regression analysis, including clinical factors and CT texture features extracted from hyperdense areas on CT images within half an hour after EVT. The performance of the nomogram was evaluated with integrated discrimination improvement (IDI), category-free net reclassification improvement (NRI), the area under the receiver operating characteristic curve (AUC-ROC), calibration plots, and decision curve analyses for discrimination, calibration ability, and clinical net benefits, respectively. Results: Our nomogram was constructed based on three clinical factors (age, NIHSS score and ASPECT score) and two CT texture features (entropy and kurtosis), with AUC-ROC of 0.900, 0.897, and 0.870 in the development, internal validation, and external validation cohorts, respectively. NRI and IDI further validated the superior predictive ability of the nomogram compared to the clinical model. The calibration plot revealed good consistency between the predicted and the actual outcome. The decision curve indicated good positive net benefit and clinical validity of the nomogram. Conclusion: The nomogram enables clinicians to accurately predict FR specifically in patients with PTIH within half an hour after EVT and helps to formulate more appropriate treatment plans in the early post-EVT period.

Impacts of futile reperfusion and reperfusion injury in acute ischemic stroke.

Acute ischemic stroke (AIS) remains to be a challenging cerebrovascular disease. The mainstay of AIS management is endovascular reperfusion therapy, including thrombectomy and thrombolysis. However, ineffective (futile) reperfusion (FR) or reperfusion injury (RI) can be seen in a significant number of patients undergoing reperfusion strategy. In this article, we discuss two clinically relevant concepts known as "time window" and "tissue window" that can impact the clinical outcome of reperfusion therapy. We also explore patient risk factors, leading to FR and RI as well as an emerging concept of "no-reflow phenomenon" seen in ineffective reperfusion. These fundamental concepts provide insight into the clinical management of AIS patients and provide references for future research.

Association between uric acid levels and the risk of futile reperfusion in stroke after thrombectomy: A propensity score matching study.

INTRODUCTION: Currently, futile reperfusion (FR) is becoming a major challenge in the endovascular treatment of patients with acute ischemic stroke (AIS). The relationship between serum uric acid (SUA) and FR has not been investigated. This study aims to determine the relationship between SUA and FR using propensity score matching (PSM) analysis. METHODS: A total of 441 patients with AIS undergoing mechanical thrombectomy (MT) between August 2017 and January 2023 were included and divided into two groups based on the median SUA (297.4 µmol/L). Two groups were balanced using PSM analysis at a 1:1 ratio. The standardized mean difference (SMD) were used to assess the efficacy of the matching. Finally, 158 patients with low SUA (≤ 297.4 µmol/L) were matched with 158 patients with high SUA (>297.4 µmol/L). Predictors of FR were analyzed by multivariate logistic regression analysis in the PSM cohort. RESULTS: After PSM, patients with low SUA (≤ 297.4 µmol/L) had a significant higher incidence of FR (72.8 %, 115/158) than patients with high SUA (>297.4 µmol/L) (48.1 %, 76/158) (P<0.001). Multivariate logistic regression analysis in the PSM cohort showed that low SUA (≤ 297.4 µmol/L) was an independent risk factor for the efficacy of reperfusion (OR: 6.403, 95 % CI: 3.123-13.129, P<0.001), suggesting that patients with SUA ≤ 297.4 µmol/L have a 6.403 times higher risk of FR than patients with SUA>297.4 µmol/L. CONCLUSION: The results of this study suggest that low SUA (≤ 297.4 µmol/L) at admission increases the risk of FR in AIS patients undergoing MT by PSM analysis.

Effects of prior antiplatelet use on futile reperfusion in patients with acute ischemic stroke receiving endovascular treatment.

Introduction: We evaluated the effects of prior antiplatelet use (APU) on futile reperfusion (FR) after endovascular treatment (EVT) in acute ischemic stroke. Material and methods: We consecutively collected data of 9369 patients with acute ischemic stroke from four university-affiliated multicenter registry databases over 92 months. We enrolled 528 patients with acute stroke receiving EVT. Among them, we defined FR in subjects as a 3-month modified Rankin Scale score of >2 despite successful reperfusion after EVT. We classified patients into two groups: prior APU and no prior APU. We used propensity score matching (PSM) to overcome the imbalance in multiple covariates between the two groups. After PSM, we compared the baseline characteristics between the two groups and performed multivariate analysis to determine whether prior APU affected FR and other stroke outcomes. Results: The overall FR rate in the present study was 54.2%. In the PSM cohort, the FR was lower in the prior APU group than that in the no prior APU group (66.2% vs 41.5%, p < 0.001). In the multivariate analysis using the PSM cohort, prior APU significantly reduced the risk of FR (odds ratio (OR), 0.32; 95% confidence interval (CI), 0.18-0.55; p = 0.001) and stroke progression (OR, 0.38; 95% CI, 0.15-0.93; p = 0.03). Prior APU was not associated with symptomatic hemorrhagic transformation in this study. Conclusion: Prior APU potentially reduced FR and stroke progression. Further, prior APU was not associated with symptomatic hemorrhagic transformation in patients receiving EVT. APU pretreatment can be a modifiable predictor of FR in clinical practice.

Advances in Futile Reperfusion following Endovascular Treatment in Acute Ischemic Stroke due to Large Vessel Occlusion.

BACKGROUND: Futile reperfusion (FR) is becoming an urgent issue for acute ischemic stroke patients who underwent endovascular treatment (EVT). Although the recanalization rate has improved after EVT, it is far from translating to increased tissue reperfusion and functional independence. SUMMARY: Many underlying mechanisms including the "no-reflow" phenomenon, poor collateral flow, venous dysfunction, and inflammation were proposed, but the pathophysiology of FR is still unclear. Clinically, reliable predictors are still yet to be identified, and ongoing trials on shortening the time delay and cytoprotection may provide novel ideas for interventions of FR. KEY MESSAGES: This review will summarize the latest advances in FR and hopefully shed light on potential interventions.

Cerebral Small Vessel Disease Burden and Futile Reperfusion after Endovascular Treatment for Patients with Acute Ischemic Stroke.

INTRODUCTION: Cerebral small vessel disease (SVD) burden includes increased risk of poor functional outcomes after acute ischemic stroke (AIS). We aimed to investigate the impact of cerebral SVD on 3-month functional outcomes in patients with AIS who received endovascular treatment (EVT) and to determine whether SVD is associated with futile reperfusion (FR). METHODS: Using a multicenter stroke registry, we analyzed consecutive patients with AIS with either intracranial and/or extracranial anterior circulation large artery occlusion, who were treated with EVT and achieved successful reperfusion (thrombolysis in cerebral infarction grade 2b-3). The cerebral SVD burden was evaluated using baseline brain magnetic resonance imaging using a modified Fazekas score (mFS). The main outcome variable was FR, defined as poor functional outcomes (modified Rankin scale 3-6) at 3 months after stroke, despite successful recanalization. Secondary outcomes included stroke progression/recurrence and any hemorrhagic transformation. RESULTS: Among 10,890 patients with AIS, 577 (5.3%) received EVT within 12 h of onset, including 354 who met study eligibility criteria. FR was observed in 191 patients (53.5%) and was positively associated with SVD burden. After adjustment for covariates including age, sex, stroke etiology, initial stroke severity, collateral status, Alberta stroke program early CT score, initial serum glucose, systemic blood pressure, and vascular risk factors, mFS grade 3 was significantly associated with FR (odds ratio: 3.93, 95% confidence interval: 1.602-9.619; p = 0.003). CONCLUSIONS: We demonstrated that cerebral SVD assessed with baseline brain MRI is associated with the futility of successful recanalization after EVT and any hemorrhagic transformation but not with early stroke progression or recurrence. Nevertheless, our findings do not justify withholding EVT in otherwise eligible patients with AIS based on the presence of severe SVD.

Futile reperfusion and predicted therapeutic benefits after successful endovascular treatment according to initial stroke severity.

BACKGROUND: Futile reperfusion (poor functional status despite successful reperfusion) was observed in up to 67% of patients enrolled in recent endovascular treatment (EVT) clinical trials. We investigated the impact of baseline stroke severity on both futile reperfusion and therapeutic benefit of successful EVT. METHODS: Using a prospective multicenter stroke registry, we identified consecutive ischemic stroke patients with anterior circulation large artery occlusion, who were reperfused successfully by EVT (Thrombolysis in Cerebral Infarction grade 2b-3). The rate of futile reperfusion was assessed across the initial National Institutes of Health Stroke Scale (NIHSS) scores. The frequency of poor outcomes (modified Rankin scale [mRS] 3-6) according to NIHSS scores was compared between patients revascularized successfully by EVT and those who did not receive EVT, after standardizing for age. RESULTS: Among 21,591 patients with ischemic stroke, 972 (4.5%) received EVT within 12 h of onset, including 440 who met study eligibility criteria. Futile reperfusion was observed in 226 of the 440 study-eligible patients (51.4%) and was associated with stroke severity: 20.9% in NIHSS scores ≤5, 34.6% in 6-10, 58.9% in 11-20, and 63.8% in > 20 (p < 0.001). Nonetheless, the therapeutic benefit of EVT also increased with increasing stroke severity (p for interaction < 0.001): 0.1% in NIHSS ≤5, 18.6% in 6-10, 28.7% in 11-20, and 34.3% in > 20. CONCLUSIONS: EVT is more beneficial with increasing stroke severity, although futile reperfusion also increases with higher stroke severity.