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Background and Purpose— Histopathologic evaluation of occlusive thrombi retrieved from cerebral arteries using endovascular therapy is possible. We investigated the relationship between successful reperfusion after thrombectomy and histopathologic characteristics of retrieved thrombi. Methods— Among consecutive patients with acute ischemic stroke treated with endovascular therapy at our institute from December 2010 to July 2015, we retrospectively reviewed those with acute major arterial occlusion from which retrieved thrombi were evaluated histopathologically. Obtained thrombi were assessed for the existence of atheromatous gruel, organization, and the ratios of erythrocyte and fibrin/platelet components. Successful reperfusion was defined as the modified Treatment in Cerebral Ischemia grade of 2b to 3. Results— Of 83 patients studied, 58 (70%) underwent successful reperfusion. Atheromatous gruel was less frequently identified (3% versus 20%; P =0.024), and the proportion of erythrocyte components was higher (57±23% versus 47±24%; P =0.042) in thrombi retrieved from the reperfused than the unreperfused group. On multivariate logistic regression analysis, atheromatous gruel was inversely related (odds ratio, 0.062; 95% confidence interval, 0.002–0.864), and >64% erythrocyte components (cutoff obtained from receiver operating characteristic curve) were positively related (odds ratio, 4.352; 95% confidence interval, 1.185–19.363) to successful reperfusion. Conclusions— Successful reperfusion could be associated with the histopathology of occlusive thrombi, including the existence of atheromatous gruel and proportion of erythrocyte components. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02251665.

Background: The ulcerated atheroma of the carotid artery is a risk factor of ipsilateral ischemic stroke. Contrast-enhanced ultrasound (CEUS) is a novel noninvasive technique useful for evaluating the morphology of carotid plaques, and can detect small disruptions on plaque surface. However, it remains unclear whether the disrupted carotid plaque detected by CEUS is related to the symptomatic internal carotid artery stenosis (ICS). Methods: A total of 79 ICS patients who underwent carotid endarterectomy (CEA) were enrolled from July 2010 to July 2015. Before operation, ICA lesions were examined by color Doppler ultrasound (CDUS) and CEUS using perflubutane. The ulceration was diagnosed when both of the color Doppler signal on CDUS and the pooling of microbubbles on CEUS were observed within the plaque. The disruption was diagnosed only by CEUS when microbubbles pooled through the fissured surface, unlike the linear delineation of neovessels. We validated findings on ultrasound compared with the histopathological findings of ulceration and present/recent plaque rupture. The associations between ulceration/disruption on ultrasound and symptomatic ICS (with a history of ipsilateral transient ischemic attack and/or ischemic stroke) were investigated. Results: Of 79 subjects (mean age 71.2±6.8 years old, 78 men), 55 had symptomatic ICS. The ulceration by CEUS and CDUS was recognized in 20 patients (25%), and the disruption on plaque surface was seen by CEUS solitary in 26 patients (33%). The sensitivity and specificity of detecting plaque ulceration or disruption using CEUS compared with histopathological findings were 0.57 (45/66) and 1.00 (13/13), respectively. The detection rate of ulceration or disruption using CEUS was higher in symptomatic ICS than in asymptomatic ICS (66% vs 42%, P=0.049). Compared to plaques without ulceration/disruption on ultrasound, prevalence of symptomatic ICS was higher in plaques with the disruption (88% vs 58%, P=0.01), whereas it was similar in plaques with the ulceration (65% vs 58%, P=0.77) Conclusion: Small disruptions on carotid plaque surface detected by CEUS were significantly related to symptomatic ICS and this results may help the detailed assessment of plaque vulnerability.

Background: Cerebrovascular accidents (CVAs), including ischemic stroke, transient ischemic attack, and intracranial hemorrhage, are major and devastating complications of left ventricular assist devices (LVADs). However, little is known about their incidence and risk factors. Materials and methods: We retrospectively reviewed the medical records of 75 consecutive cases supported with a LVAD (mean age of 39 years, 60 men, paracorporeal pulsatile-flow LVAD in 31, implantable centrifugal-flow in 18, and implantable axial-flow in 26) in our institution between December 2009 and June 2014. The incidence rate of CVAs was estimated as events per patient-year, and baseline characteristics (age, sex, etiologies of heart failure, comorbid diseases, and types of LVAD) were assessed to determine their contribution to the incidences of total, ischemic and hemorrhagic CVAs. Results: During 113.7 patient-years of observation, a total of 59 CVA events (26 hemorrhagic and 33 ischemic) were identified in 31 cases, yielding an incidence rate of 0.52 events per patient-year. Univariate negative binomial regression (NBR) analysis demonstrated that patients with an axial-flow LVAD had significantly lower incidence of total CVAs [incidence rate ratio (IRR) 0.29, 95% confidence interval (CI) 0.10 - 0.88, p=0.03] and subsignificantly of both of ischemic (0.30, 0.05 - 1.69, p=0.17) and hemorrhagic CVAs (0.29, 0.08 - 1.02, p=0.05) than those with a paracorporeal LVAD (reference), whereas those with a centrifugal-flow LVAD did not. Patients with diabetes had a significantly higher incidence of total CVAs (IRR 2.39, 95% CI 1.03 - 5.57, p=0.04) and ischemic CVAs (4.01, 1.31 - 12.2, p=0.02) than those without diabetes but not of hemorrhagic CVAs (1.41, 0.54 - 3.66, p=0.48). Results of multivariate NBR analysis were similar with those of univariate analysis. Conclusion: Among patients on LVAD support, CVA occurred at a rate of 0.52 events per patient-year. Axial-flow LVADs reduced the incidence of CVAs, regardless of ischemic or hemorrhagic subtype, compared with paracorporeal LVADs. Diabetes was associated with an increased risk of CVAs, but the influence was different between ischemic and hemorrhagic CVAs.

Background and Purpose— The primary results of the Japan Adult Moyamoya Trial revealed the statistically marginal superiority of bypass surgery over medical treatment alone in preventing rebleeding in moyamoya disease. The purpose of this analysis is to test the prespecified subgroup hypothesis that the natural course and surgical effects vary depending on the hemorrhagic site at onset. Methods— The hemorrhagic site, classified as either anterior or posterior, was the only stratifying variable for randomization. Statistical analyses were focused on the assessment of effect modification according to the hemorrhagic site and were based on tests of interaction. Results— Of 42 surgically treated patients, 24 were classified as anterior hemorrhage and 18 as posterior hemorrhage; of 38 medically treated patients, 21 were classified as anterior and 17 as posterior. The hazard ratio of the primary end points (all adverse events) for the surgical group relative to the nonsurgical group was 0.07 (95% confidence interval, 0.01–0.55) for the posterior group, as compared with 1.62 (95% confidence interval, 0.39–6.79) for the anterior group ( P =0.013 for interaction). Analysis within the nonsurgical group revealed that the incidence of the primary end point was significantly higher in the posterior group than in the anterior group (17.1% per year versus 3.0% per year; hazard ratio, 5.83; 95% confidence interval, 1.60–21.27). Conclusions— Careful interpretation of the results suggests that patients with posterior hemorrhage are at higher risk of rebleeding and accrue greater benefit from surgery, subject to verification in further studies. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/index.htm . Unique identifier: C000000166.

Background and Purpose: Vulnerable plaques of carotid arteries are characterized as the presence of large necrotic core, intraplaque hemorrhage (IPH), intraplaque neovascularization (IPN), and active inflammation with thin fibrous cap. MRI is widely used for the qualitative evaluation of the plaques in vivo and the high-intensity plaques (HIP) on magnetization-prepared rapid acquisition with gradient echo (MPRAGE) images indicate containing necrotic cores with IPH, which indicates vulnerable plaques. However, we encounter the symptomatic cases without the presence of HIP on MPRAGE in clinical practice. Recent studies showed the efficacy for the evaluation of IPN using contrast-enhanced ultrasound (CEUS). We aimed to assess the vulnerability of the plaques without high intensity on MPRAGE images using CEUS. Methods: Between July 2010 and June 2014, we enrolled 69 patients with internal carotid artery stenosis who underwent carotid endarterectomy (CEA) and preoperatively examined CEUS and MRI (MPRAGE). All plaques were evaluated with CEUS and the contrast effects were classified semi-quantitatively (grade 0: absent, 1: small, 2: large, 3: extensive). We also divided the plaques into two groups (HIP group or non-HIP group) based on the signal intensity of the plaques on MPRAGE images. The results of MRI and CEUS were compared with histopathological findings of CEA specimens. Results: Fifty-eight plaques of all 69 patients showed HIP (41 were symptomatic), and eleven plaques were non-HIP (five were symptomatic: amaurosis fugax in three, cerebral infarction in two). In non-HIP group, symptomatic plaques were more enhanced (three in grade 2, two in grade 3) than asymptomatic plaques (one in grade 0, five in grade 1) using CEUS. Histopathological findings of all five CEA specimens from symptomatic patients showed that extensive IPN, large necrotic core, and active inflammation with thin fibrous cap which indicated vulnerable plaques, but small amount of IPH. These histological findings were compatible with the results of CEUS and MRI findings. Conclusion: CEUS may be useful for diagnosis of vulnerable plaques without high intensity on MPRAGE images.

Background and Purpose— About one half of those who develop adult-onset moyamoya disease experience intracranial hemorrhage. Despite the extremely high frequency of rebleeding attacks and poor prognosis, measures to prevent rebleeding have not been established. The purpose of this study is to determine whether extracranial–intracranial bypass can reduce incidence of rebleeding and improve patient prognosis. Methods— This study was a multicentered, prospective, randomized, controlled trial conducted by 22 institutes in Japan. Adult patients with moyamoya disease who had experienced intracranial hemorrhage within the preceding year were given either conservative care or bilateral extracranial–intracranial direct bypass and were observed for 5 years. Primary and secondary end points were defined as all adverse events and rebleeding attacks, respectively. Results— Eighty patients were enrolled (surgical, 42; nonsurgical, 38). Adverse events causing significant morbidity were observed in 6 patients in the surgical group (14.3%) and 13 patients in the nonsurgical group (34.2%). Kaplan–Meier survival analysis revealed significant differences between the 2 groups (3.2%/y versus 8.2%/y; P =0.048). The hazard ratio of the surgical group calculated by Cox regression analysis was 0.391 (95% confidence interval, 0.148–1.029). Rebleeding attacks were observed in 5 patients in the surgical group (11.9%) and 12 in the nonsurgical group (31.6%), significantly different in the Kaplan–Meier survival analysis (2.7%/y versus 7.6%/y; P =0.042). The hazard ratio of the surgical group was 0.355 (95% confidence interval, 0.125–1.009). Conclusions— Although statistically marginal, Kaplan–Meier analysis revealed the significant difference between surgical and nonsurgical group, suggesting the preventive effect of direct bypass against rebleeding. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/index.htm . Unique identifier: C000000166.

Background and Purpose— A prospective, multicenter, observational cohort study was conducted to clarify the association between major bleeding events and blood pressure (BP) levels during follow-up before development of bleeding events in antithrombotic users. Methods— A total of 4009 patients taking oral antithrombotic agents for cardiovascular or cerebrovascular diseases (2728 men, 69±10 years old) were followed. Changes in systolic and diastolic BPs between entry and the last clinic visit before intracranial hemorrhage (ICH) or extracranial hemorrhage were assessed. Results— Over a median follow-up of 19 months, ICH developed in 31 patients and extracranial hemorrhage developed in 77. Entry BP levels were similar among patients with ICH, those with extracranial hemorrhage, and those without hemorrhagic events. Both systolic BP and diastolic BP were relatively high during follow-up as compared with the levels at entry in patients with ICH, whereas they showed plateaus in patients with extracranial hemorrhage and patients without hemorrhagic events. Average systolic BP levels between 1 and 6 months (hazard ratio, 1.45; 95% CI, 1.08 to 1.92 per 10-mm Hg increase) and between 7 and 12 months (hazard ratio, 1.47; 95% CI, 1.05 to 2.01) as well as average diastolic BP levels between 7 and 12 months (hazard ratio, 2.05; 95% CI, 1.15 to 3.62) were independently associated with development of ICH after adjustment for established ICH predictors. The optimal cutoff BP level to predict impending risk of ICH was ≥130/81 mm Hg using receiver operating characteristic curve analysis. Conclusions— An increase in BP levels during antithrombotic medication was positively associated with development of ICH, suggesting the importance of adequate BP control for avoiding ICH. BP levels did not appear to be associated with extracranial hemorrhage.

Background and Purpose— We sought to determine the incidence and severity of bleeding events in patients with stroke and cardiovascular diseases who were taking oral antithrombotic agents in Japan, where the incidence of hemorrhagic stroke is higher than in Western countries. Methods— A prospective, multicenter, observational study was conducted; 4009 patients who were taking oral antithrombotic agents for stroke and cardiovascular diseases were enrolled. The patients were classified into 4 groups according to their antithrombotic treatment: the single antiplatelet agent group (47.2%); the dual antiplatelet agent group (8.7%); the warfarin group (32.4%); and the warfarin plus antiplatelet agent group (11.7%). The primary end point was life-threatening or major bleeding according to the MATCH trial definition. Results— During a median follow-up of 19 months, there were 57 life-threatening and 51 major bleeding events, including 31 intracranial hemorrhages. The annual incidence of the primary end point was 1.21% in the single antiplatelet agent group, 2.00% in the dual antiplatelet agent group, 2.06% in the warfarin group, and 3.56% in the warfarin plus antiplatelet agent group ( P Conclusions— The incidence of bleeding events during antithrombotic therapy in Japan was similar to that reported for Western countries, although the trials used different study designs. Dual antithrombotic therapy was independently related to an increased risk of bleeding events.