Carotid plaque inflammation in stroke assessed by PET: a burning issue?

Despite recent advances in medical and surgical treatments to prevent arterial stroke, the cerebrovascular burden of atherosclerosis remains high. Factors associated with a high risk for arterial stroke include stenosis .50% and ulcerated plaque. Given the important role of inflammation in atherosclerotic plaque progression and rupture, a measure of plaque inflammation may help stratify arterial stroke risk. Indeed, inflammatory markers have been associated with arterial stroke. A noninvasive imaging method to characterize atherosclerotic plaque inflammation could add to the assessment of plaque vulnerability and rupture risk. In this issue of Neurology®, Ní Chróinín et al. evaluated the association between serum lipids and carotid plaque fluorodeoxyglucose F (FDG) uptake. The authors measured FDG uptake by PET-CT across 10 regions of plaque in 61 patients with acutely symptomatic carotid stenosis. Increased FDG uptake in plaque was associated with increased low-density lipoprotein (LDL), cholesterol, and triglycerides, and decreased high-density lipoprotein. After adjusting for age, sex, stenosis severity, statin use, and smoking, both LDL and cholesterol remained associated with plaque FDGuptake. FDG is a glucose analog that contains a radioactive fluorine-18 isotope. Increased FDG uptake indicates cells with high metabolic activity. Coregistering FDG-PET images with anatomic images from CT scan allows determination of the location of FDG uptake. Increasing evidence indicates a role of FDG-PET to assess vascular inflammation and atherosclerosis. Indeed, FDG uptake correlates with atherosclerotic plaque inflammation and macrophage accumulation in animal and human studies. The current study suggests that increased LDL and cholesterol may contribute to inflammation in human carotid plaque as measured by FDG uptake. This is consistent with a number of studies indicating increased FDG uptake correlates with the atherosclerotic lipid core, macrophage infiltration, and matrix metalloproteinase immunoreactivity. In addition, modifying atherosclerosis with statins and other antiatherogenic therapy reduces plaque FDG uptake. The study also examined whether patients with increased carotid FDG uptake are at increased risk for recurrent stroke. Twelve of the 61 patients (19.7%) had recurrent stroke by 90 days, most within the first 2 weeks of the index event. Recurrent stroke occurred more frequently in those with increased FDG uptake (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.2–11.1, p5 0.02) even after adjusting for age, carotid stenosis severity, and LDL (OR 5.6, 95% CI 1.5–22.3, p 5 0.01). Despite the small sample size, these data suggest that inflammation measured by FDG-PET may reflect plaque instability. Thus, FDG-PETmay have utility to stratify risk in patients with carotid stenosis. Identifying factors associated with acute atherosclerotic plaque rupture in humans may reveal potential targets to prevent rupture and ischemic vascular events. The study byNí Chróinín et al. indicates that inflammation is increased in recently symptomatic carotid plaques. However, asymptomatic carotid arteries also showed increased FDG uptake. This may suggest that increased FDG uptake may represent a general process of inflammatory atherosclerotic disease rather than a specific process in acutely symptomatic carotid plaques. All patients studied had recent symptomatic carotid plaques. Thus, if plaque inflammation is the central factor to plaque rupture, one might expect increased FDG uptake in all patients. FDG uptake differed among participants, potentially reflecting multiple aspects of carotid plaque inflammation, including plaque progression, repair, and rupture. Future studies should consider other factors relevant to plaque inflammation. For example, the time from index event to PET-CT may be important, because inflammation measured within the first few days after stroke may have greater relevance to risk of acute plaque rupture. In addition, comparing patients with symptomatic and asymptomatic carotid stenosis may further delineate differences in human carotid plaque inflammation. This study raises a number of questions that require further evaluation. For instance, further study may determine whether or not increased carotid FDG uptake can identify a group of stroke patients in whom more intensive stroke prevention therapy could be targeted or a group with a different risk-benefit profile for carotid revascularization. Further studies are also needed to determine