Plasma Lipid Mediators Associate With Clinical Outcome After Successful Endovascular Thrombectomy in Patients With Acute Ischemic Stroke

Abstract

Background: Neuroinflammatory response contributes to early neurological deterioration (END) and unfavorable long-term functional outcome in patients with acute ischemic stroke (AIS) who recanalized successfully by endovascular thrombectomy (EVT), but there are no reliable biomarkers for their accurate prediction. Here, we sought to determine the temporal plasma profiles of the bioactive lipid mediators lipoxin A4 (LXA4), resolvin D1 (RvD1), and leukotriene B4 (LTB4) for their associations with clinical outcome.

Methods: We quantified levels of LXA4, RvD1, and LTB4 in blood samples retrospectively and longitudinally collected from consecutive AIS patients who underwent complete angiographic recanalization by EVT at admission (pre-EVT) and 24 hrs post-EVT. The primary outcome was unfavorable long-term functional outcome, defined as a 90-day modified Rankin Scale score of 3-6. Secondary outcome was END, defined as an increase in National Institutes of Health Stroke Scale (NIHSS) score ≥4 points at 24 hrs post-EVT.

Results: Eighty-one consecutive AIS patients and 20 healthy subjects were recruited for this study. Plasma levels of LXA4, RvD1, and LTB4 were significantly increased in post-EVT samples from AIS patients, as compared to those of healthy controls. END occurred in 17 (20.99%) patients, and 38 (46.91%) had unfavorable 90-day functional outcome. Multiple logistic regression analyses demonstrated that post-EVT levels of LXA4 (adjusted odd ratio [OR] 0.992, 95% confidence interval [CI] 0.987-0.998), ΔLXA4 (adjusted OR 0.995, 95% CI 0.991-0.999), LTB4 (adjusted OR 1.003, 95% CI 1.001-1.005), ΔLTB4 (adjusted OR 1.004, 95% CI 1.002-1.006), and post-EVT LXA4/LTB4 (adjusted OR 0.023, 95% CI 0.001-0.433) and RvD1/LTB4 (adjusted OR 0.196, 95% CI 0.057-0.682) ratios independently predicted END, and post-EVT LXA4 levels (adjusted OR 0.995, 95% CI 0.992-0.999), ΔLXA4 levels (adjusted OR 0.996, 95% CI 0.993-0.999), and post-EVT LXA4/LTB4 ratio (adjusted OR 0.285, 95% CI 0.096-0.845) independently predicted unfavorable 90-day functional outcome. These were validated using receiver operating characteristic curve analyses.

Conclusions: Plasma lipid mediators measured 24 hrs post-EVT were independent predictors for early and long-term outcomes. Further studies are needed to determine their causal-effect relationship, and whether the imbalance between anti-inflammatory/pro-resolving and pro-inflammatory lipid mediators could be a potential adjunct therapeutic target.

Keywords: acute ischemic stroke; cerebral ischemia-reperfusion injury; endovascular thrombectomy (EVT); futile recanalization; lipid mediator.

Figure 1

Plasma levels of LXA4 (A), RvD1 (B), LTB4 (C), ratio of LXA4/LTB4 (D), and ratio of RvD1/LTB4 (E) in healthy controls and EVT-treated AIS patients (pre- and 24 hrs post-EVT). Healthy controls were severed as baseline to analyze temporal profile of plasma lipid mediators in EVT-treated AIS patients. Data were presented as median and IQR. Differences between AIS patients and healthy controls were analyzed using the Mann-Whitney U test or independent-samples t-test (LTB4: healthy control vs. pre-EVT, RvD1: healthy control vs. post-EVT). The paired Wilcoxon signed-rank test was used to analyze dynamic changes of plasma levels of lipid mediators pre- and post-EVT. ^#p<0.05 and ^###p<0.001: healthy control vs. pre-EVT; *p<0.05, **p<0.01, and ***p<0.001: healthy control vs. post-EVT; ^$$$p<0.001: pre-EVT vs. post-EVT.

Figure 2

Plasma levels of lipid mediator parameters and END. (A) Plasma levels of lipid mediator parameters in EVT-treated AIS patients with or without END. ^aData were presented as median and IQR, and were analyzed by Mann-Whitney U test. ^bData were presented as mean ± SD, and were analyzed by independent-samples t-test. ^cFalse Discovery Rate (FDR)-correction was conducted to control the error rate under multiple testing. (B) Multivariate logistic regression of independent risk factors of END. Confounding factors: age and gender. (C) Receiver operator characteristic (ROC) curve analyses for lipid mediator parameters to predict END after successful EVT in patients with AIS. OR, odds ratio; CI, confidence interval. AUC, area under the curve.

Figure 3

Spearman correlation coefficient analyses of correlation between plasma lipid mediator parameter levels in EVT-treated AIS patients and 90-day mRS scores.

Figure 4

Plasma levels of lipid mediator parameters and 90-day functional outcome. (A) Plasma levels of lipid mediator parameters in EVT-treated AIS patients with favorable or unfavorable 90-day outcomes. ^aData were presented as median and IQR, and were analyzed by Mann-Whitney U test. ^bData were presented as mean ± SD, and were analyzed by independent-samples t-test. ^cFalse Discovery Rate (FDR)-correction was conducted to control the error rate under multiple testing. (B) Multivariate logistic regression of independent risk factors of unfavorable 90-day outcome. Confounding factors: age, frequency rate of female, diabetes and END, and admission NIHSS scores. (C) Receiver operator characteristic (ROC) curve analyses for lipid mediator parameters to predict unfavorable 90-day outcome after successful EVT in patients with AIS. OR, odds ratio; CI, confidence interval. END, early neurological deterioration. AUC, area under the curve.