Summary Background Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14·7%) of 224 patients in the stenting group and 13 (5·8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. Methods We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70–99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between-group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00576693. Findings During a median follow-up of 32·4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0·0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7·1% at year 1 (95% CI 0·2 to 13·8%; p=0·0428), 6·5% at year 2 (−0·5 to 13·5%; p=0·07) and 9·0% at year 3 (1·5 to 16·5%; p=0·0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 [26%] of 224 patients vs 42 [19%] of 227 patients; p=0·0468) and major haemorrhage (29 [13%] of 224 patients vs 10 [4%] of 227 patients; p=0·0009). Interpretation The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis.

Human apolipoprotein E is the major apolipoprotein expressed in the brain and exists as three isoforms, designated E2, E3, and E4. Although evidence suggests that apolipoprotein E plays an important role in modifying systemic and brain inflammatory responses, there is little data investigating apoE isoform-specific effects in vivo. In this study, we compared the inflammatory responses of targeted-replacement mice expressing the human APOE3 and APOE4 genes after intravenous administration of lipopolysaccharide. Animals expressing the E4 allele had significantly greater systemic and brain elevations of the pro-inflammatory cytokines TNFalpha and IL-6 as compared with their APOE3 counterparts, suggesting an isoform-specific effect of the immunomodulatory properties of apoE. Furthermore, intravenous administration of a small apoE-mimetic peptide derived from the receptor-binding region of the apoE holoprotein (apoE-(133-149)) similarly suppressed both systemic and brain inflammatory responses in mice after lipopolysaccharide administration. These results suggest that apoE plays an isoform-specific role in mediating the systemic and brain inflammatory responses. Moreover, because exogenous administration of this apoE mimetic peptide is effective at suppressing both systemic and brain inflammation, it may represent a novel therapeutic strategy for diseases characterized by systemic or central nervous system inflammation, such as septic shock, multiple sclerosis, and traumatic brain injury.

Background and Purpose-Endothelial nitric oxide synthase (eNOS) activity is decreased after subarachnoid hemorrhage (SAH). Simvastatin increases eNOS activity. We hypothesized that simvastatin would increase eNOS protein and ameliorate SAH-induced cerebral vasospasm. Methods-Mice were treated with subcutaneous simvastatin or vehicle for 14 days and then subjected to endovascular perforation of the right anterior cerebral artery or sham surgery. Three days later, neurological deficits were scored (5 to 27; 27ϭnormal), and middle cerebral artery diameter and eNOS protein were measured. The study was repeated, but simvastatin treatment was started after SAH or sham surgery. Results-In SAH mice, simvastatin pretreatment increased middle cerebral artery diameter (SAH-simvastatinϭ74Ϯ22 m, SAH-vehicleϭ52Ϯ18 m, Pϭ0.03; sham-simvastatinϭ102Ϯ8 m, sham-vehicleϭ105Ϯ6 m). Pretreatment reduced neurological deficits Pϭ0.005;. Simvastatin pretreatment also increased eNOS protein. Simvastatin posttreatment caused a modest increase in middle cerebral artery diameter in SAH mice (SAH-simvastatinϭ56Ϯ12 m, SAH-vehicleϭ45Ϯ4 m, Pϭ0.03; sham-simvastatinϭ92Ϯ13 m, sham-vehicleϭ99Ϯ10 m) and reduced neurological deficits (SAH-simvastatinϭ21Ϯ1, Pϭ0.009). Simvastatin posttreatment did not significantly increase eNOS protein. Conclusions-Simvastatin treatment before or after SAH attenuated cerebral vasospasm and neurological deficits in mice.The mechanism may be attributable in part to eNOS upregulation. Key Words: HMG-CoA reductase inhibitors Ⅲ simvastatin Ⅲ subarachnoid hemorrhage Ⅲ vasospasm Ⅲ mice D elayed cerebral vasospasm is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). Current medical treatments fail to consistently prevent or reverse vasospasm. 1 The etiology of vasospasm may result from an imbalance of vasodilation and vasoconstriction. 2 Vascular endothelium regulates smooth muscle tone by generating nitric oxide (NO) 3 and endothelial-derived constriction factors. 4 Disruption of endothelium or its relaxing factors may alter this balance, initiating vasospasm. 5 SAH has been associated with histopathological damage to cerebrovascular endothelium and impaired endothelium-dependent relaxation responses to pharmacological challenge. 1,6 NO depletion accompanies these changes, suggesting that SAH-induced endothelial dysfunction contributes to loss of NO. Furthermore, NO replacement reverses cerebral vasospasm in animal studies. 7 However, it is not clear whether decreased endogenous NO production or increased NO breakdown underlies these changes in NO bioavailability.NO synthase, the primary source of NO in vascular tone regulation, metabolizes L-arginine to NO and citrulline. The endothelial isoform (eNOS) is constitutively expressed in cerebrovascular endothelium. Immunoreactivity for eNOS mRNA and protein has been shown to decrease after SAH. 8 Although the mechanism of eNOS reduction is not known, it likely causes reduction of NO production and disruption of endothelial-depen...