Plaque Inflammation and Unstable Morphology Are Associated With Early Stroke Recurrence in Symptomatic Carotid Stenosis

Background and Purpose Although symptomatic carotid stenosis is associated with 3-fold increased risk of early stroke recurrence, the pathophysiologic mechanisms of high early stroke risk have not been established. We aimed to investigate the relationship between early stroke recurrence after initial symptoms and histological features of plaque inflammation and instability in resected carotid plaque. Methods Carotid endarterectomy tissue from consecutive patients with ipsilateral stenosis 50% and recent symptoms were analyzed using a validated histopathologic algorithm (Oxford Plaque Study [OPS] system). Nonprocedural stroke recurrence before carotid endarterectomy was ascertained at 7, 28, and 90 days after initial symptoms. Results Among 44 patients meeting eligibility criteria, 27.3% (12/44) had stroke recurrence after initial stroke/transient ischemic attack but before carotid endarterectomy. Compared with patients without recurrence, stroke recurrence was associated with dense macrophage infiltration (OPS grade 3; 91.7% versus 37.5%; P=0.002), extensive (>25%) fibrous cap disruption (90.9% versus 37%; P=0.004), neovascularization (OPS grade 2; 83.3% versus 43.8%; P=0.04), and low plaque fibrous content (OPS grade <2; 50% versus 6.3%; P=0.003). Early recurrence rates were 82.3% (confidence interval, 49.2%-98.8%) in patients with extensive plaque macrophage infiltration (OPS grade 3) compared with 22.2% (confidence interval, 3.5%-83.4%) in those with OPS grade <3 (log-rank P=0.009). On multivariable Cox regression, including OPS macrophage grade (3 or <3), age, and severity of stenosis (50%-69% or 70%), plaque inflammation was the only variable independently predicting stroke recurrence (adjusted hazard ratio, 9; confidence interval, 1.1-70.6; P=0.04). Conclusions Plaque inflammation and other vulnerability features were associated with highest risk of stroke recurrence and may represent therapeutic targets for future stroke prevention trials.