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Background— The major complication of carotid angioplasty is embolic stroke, which may occur after balloon inflation and deflation or in the early postintervention period. Platelet adhesion and aggregation to the angioplasty site with subsequent embolization seems to plays a major role in early postangioplasty embolization and stroke. During this period, asymptomatic embolic signals can be detected in patients by transcranial Doppler ultrasound despite aspirin and heparin treatment. S -Nitrosoglutathione (GSNO) is a nitric oxide donor that appears to have relative platelet specificity. We evaluated its effectiveness in reducing embolization after carotid angioplasty. Methods and Results— Sixteen patients undergoing carotid angioplasty and stenting for symptomatic ≥70% internal carotid artery stenosis were randomized in a double-blind manner to GSNO or placebo given after surgery for 90 minutes. All patients were pretreated with aspirin and given heparin for 24 hours after the procedure. Transcranial Doppler recordings were made from the ipsilateral middle cerebral artery for 1 hour before treatment and at 0 to 3, 6, and 24 hours after treatment. GSNO resulted in a rapid reduction in the frequency of embolic signals of 95% at 0 to 3 hours and 100% at 6 hours ( P =0.007 and P =0.01 versus placebo, respectively). In the placebo group, 2 patients experienced ipsilateral stroke after the angioplasty. No cerebrovascular events occurred in the GSNO group. Conclusions— S -Nitrosoglutathione was highly effective in rapidly reducing the frequency of embolic signals after endovascular treatment for symptomatic high-grade carotid stenosis.

We thank Dr Zhang for his interest in our article “Early Dual Versus Mono Antiplatelet Therapy for Acute Non-Cardioembolic Ischemic Stroke or Transient Ischemic Attack: An Updated Systematic Review and Meta-Analysis.”1 We agree that the results of the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) study and this meta-analysis may change the guidelines for stroke and transient ischemic attack treatment in future. However, we are not aware of any recent …

Background — l -Arginine reduces platelet aggregation and adhesion in ex vivo studies, but there is no evidence as yet that it has a therapeutic effect on clinical end points. Doppler ultrasound can detect cerebral emboli noninvasively. Such embolic signals are common after carotid endarterectomy, and their frequency predicts risk of stroke recurrence. We used this situation to determine the antiplatelet efficacy of l -arginine and S -nitrosoglutathione (GSNO), a physiological nitric oxide donor with possible platelet specificity. Methods and Results —Patients undergoing carotid endarterectomy were randomized in a double-blind manner between l -arginine (n=14), GSNO (n=14), or placebo (n=14) administered intravenously for 90 minutes, starting 30 minutes after skin closure. All patients were pretreated with aspirin and given heparin during surgery. Transcranial Doppler recordings were made from the ipsilateral middle cerebral artery for 4 hours after surgery, beginning 30 minutes after skin closure, and also at 6 and 24 hours. There were highly significant reductions in the number of Doppler embolic signals in the l -arginine and GSNO groups; first 4 hours, median (range) number of embolic signals, placebo 44.7 (6 to 778), l -arginine 9.5 (0 to 225), and GSNO 0.8 (0 to 8), both P Conclusions —Intravenous l -arginine and GSNO attenuate Doppler embolic signals in humans. Modulation of the NO system with these agents may have applications in the treatment of thromboembolic disease. This study demonstrates the potential application of ultrasonic embolic signal detection to examine the efficacy of new antiplatelet agents in relatively small numbers of patients.

Background —Chronic Chlamydia pneumoniae infection has been implicated in the pathogenesis of atherosclerosis but whether it plays a role at an early stage in the disease is uncertain. An early estimate of atherosclerosis can be obtained by ultrasonic imaging of the carotid artery to determine intima-media thickness (IMT) and the thickness of any atheroma plaques. Methods and Results —In 983 normal population individuals aged 30 to 70 years, we measured common carotid artery (CCA) and carotid bulb IMT, and also carotid plaque thickness and the degree of internal carotid artery (ICA) stenosis. C. pneumoniae IgA titers of ≥16 and IgG titers of ≥64 were taken as positive. There was no association between C. pneumoniae IgA or IgG seropositivity with right, left, or mean CCA or bulb IMT, or with the presence of carotid plaques. There was a significant association between IgA seropositivity and >50% mean carotid stenosis with an odds ratio of 5.24 (95% CI 1.24 to 22.21, P =0.0245) after controlling for age and sex; after controlling for other cardiovascular risk factors, this was not significant 3.96 (95% CI 0.84 to 18.78, P =0.082). No association was found between IgA or IgG seropositivity and markers of fibrinogen, log C-reactive protein, or leukocyte count. Conclusions —We found no evidence that serological evidence of C. pneumoniae infection is associated with early atherosclerosis. It is possible that IgA seropositivity is associated with more advanced disease but this hypothesis needs to be examined in a population with a higher prevalence of advanced atherosclerosis. We found no evidence that C. pneumoniae results in a chronic systemic inflammatory state.

Background —Antiplatelet agents presently used in the secondary prevention of cardiovascular disease fail to prevent the majority of cases of recurrent stroke and systemic embolization. An evaluation of the efficacy of new agents is hampered by a lack of in vivo models in humans. Asymptomatic cerebral embolic signals (ES) may be detected with the use of transcranial Doppler ultrasonography. These signals are particularly common after carotid endarterectomy, and this provides a situation in which new antiplatelet agents can be evaluated. With this model, we determined the effectiveness of S -nitrosoglutathione (GSNO), a nitric oxide donor with relative platelet specificity, in reducing cerebral embolization. Methods and Results —Transcranial Doppler ultrasound recordings from the ipsilateral middle cerebral artery were made after carotid endarterectomy in 12 control patients and 12 patients receiving intravenous GSNO from the induction of anesthesia until 2 hours after skin closure. Recording times were 0.5 to 3.5, 6 to 7, and 24 to 25 hours after skin closure. The Doppler signal was recorded onto tape, and analysis for ES was performed, with the investigators blinded to treatment group. All patients received aspirin 300 mg/d before surgery and 5000 IU of heparin during surgery. The median (range) number of ES detected during the initial 3-hour postoperative recording was markedly reduced in the GSNO group compared with the control group: 7.5 (0 to 61) versus 38.5 (1 to 219) ( P =0.018). This difference persisted until 6 hours after surgery. Conclusions —Despite the administration of aspirin and heparin, frequent embolization occurred and was markedly reduced after the administration of GSNO. This demonstrates the potential use of platelet-specific nitric oxide donors in the treatment of thromboembolic disease. This model of cerebral embolism may allow determination of the effectiveness of new antiplatelet agents in humans.

Background— Emerging studies suggest that early administration of dual antiplatelet therapy may be better than monotherapy for prevention of early recurrent stroke and cardiovascular outcomes in acute ischemic stroke and transient ischemic attack (TIA). We performed a meta-analysis of randomized, controlled trials evaluating dual versus mono antiplatelet therapy for acute noncardioembolic ischemic stroke or TIA. Methods and Results— We assessed randomized, controlled trials investigating dual versus mono antiplatelet therapy published up to November 2012 and the CHANCE trial (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events), for efficacy and safety outcomes in adult patients with acute noncardioembolic ischemic stroke or TIA with treatment initiated within 3 days of ictus. In total, 14 studies of 9012 patients were included in the systematic review and meta-analysis. Dual antiplatelet therapy significantly reduced risk of stroke recurrence (risk ratio, 0.69; 95% confidence interval, 0.60–0.80; P P P =0.37). Analyses restricted to the CHANCE Trial or the 7 double-blind randomized, controlled trials showed similar results. Conclusions— For patients with acute noncardioembolic ischemic stroke or TIA, dual therapy was more effective than monotherapy in reducing risks of early recurrent stroke. The results of the CHANCE study are consistent with previous studies done in other parts of the world.

We have known since the 17th century that emboli can cause stroke but, despite their occasional visualisation in the retinal circulation, a diagnosis of embolic stroke is usually one of “guilt by association,” which is made by the detection of an appropriate embolic source in a patient with stroke. Frequently, >1 potential embolic source exists; determining which is clinically relevant may be impossible. The indirect diagnosis of embolic stroke also results in management difficulties in stroke prevention. For example, in atrial fibrillation, treatment failure can only be determined by the onset of stroke or systemic embolization. Recently, studies have evaluated a technique that allows the direct visualisation of circulating emboli. This offers exciting potential applications in both the diagnosis and management of patients at risk of cerebral and systemic embolism. Since the 1960s, we have known that gaseous emboli can be detected in blood using Doppler ultrasound. The large acoustic impedance difference between air and blood results in a scattering of ultrasound at the blood-air interface and a marked increase in received ultrasound intensity as the bubble passes. This results in a brief, high-intensity signal. This technique was applied to develop safe decompression limits in divers and to investigate air embolism during cardiopulmonary bypass. In 1990, while recording for air emboli during carotid endarterectomy, similar signals, but of lower intensity, were noted during manipulation of the carotid bifurcation.1 This was before arterial opening and, therefore, these signals could not represent air emboli; it was suggested that they represented thrombus and platelet emboli. Despite initial scepticism that these signals represented anything other than artifacts or flow turbulence, it has been clearly demonstrated experimentally that thrombus, platelet, and atheroma emboli result in these characteristic Doppler signals.2 The technique is highly sensitive and specific, and similar signals cannot be produced by …

Background— Determining whether the distribution of stroke subtypes differs between ethnic groups is important in understanding the mechanisms of the increased stroke incidence in black patients. Methods and Results— In this study, 600 black and 600 white patients with stroke were prospectively and consecutively recruited to determine differences in stroke subtypes. The pathophysiological Trial of Org 10172 (TOAST) classification was used and compared with a clinical (Oxfordshire Community Stroke Project) subtype classification. Stroke subtypes were determined by one investigator by review of original imaging. Black patients with stroke were significantly younger and had higher prevalences of hypertension, diabetes, and obesity. They were less likely to be smokers and had lower prevalences of myocardial infarction and atrial fibrillation. In the black patients, 33% of stroke was due to cerebral small vessel disease compared with 14% in the white stroke cohort (odds ratio, 2.94; 95% confidence interval, 1.97 to 4.39; P P =0.007) and cardioembolic disease (odds ratio, 0.54; 95% confidence interval, 0.37 to 0.80; P =0.002). Using a classification based on clinical syndrome alone gave a higher estimate of the frequency of small vessel disease stroke, particularly in white patients. Conclusions— A relative excess of small vessel disease was observed in black patients with stroke compared with an excess of extracranial atherosclerosis and cardioembolic stroke in white patients with stroke that was independent of conventional risk factors and social class. Whether these excesses are due to differences in genetic susceptibility or as-yet undetermined differences in environmental risk remains to be determined.

We thank Dr Rundek and her coauthors for their contribution on this very important issue. As plaque formation represents a later stage of atherosclerosis than diffuse intima-media thickening, it is likely that plaque formation is more predictive for vascular events than intima-media thickness (IMT), although formal comparisons between the 2 measurements in terms of risk relations are limited. For example, van der Meer et al1 indicated that plaques show a somewhat higher risk estimate than IMT, but the differences are small. In addition, one should bear in mind that in several studies, IMT is used as …

Background— Carotid intima-media thickness (IMT) is increasingly used as a surrogate marker for atherosclerosis. Its use relies on its ability to predict future clinical cardiovascular end points. We performed a systematic review and meta-analysis of data to examine this association. Methods and Results— Using a prespecified search strategy, we identified 8 relevant studies and compared study design, measurement protocols, and reported data. We identified sources of heterogeneity between studies. The assumption of a linear relationship between IMT and risk was challenged by use of a graphical technique. To obtain a pooled estimate of the relative risk per IMT difference, we performed a meta-analysis based on random effects models. The age- and sex-adjusted overall estimates of the relative risk of myocardial infarction were 1.26 (95% CI, 1.21 to 1.30) per 1–standard deviation common carotid artery IMT difference and 1.15 (95% CI, 1.12 to 1.17) per 0.10-mm common carotid artery IMT difference. The age- and sex-adjusted relative risks of stroke were 1.32 (95% CI, 1.27 to 1.38) per 1–standard deviation common carotid artery IMT difference and 1.18 (95% CI, 1.16 to 1.21) per 0.10-mm common carotid artery IMT difference. Major sources of heterogeneity were age distribution, carotid segment definition, and IMT measurement protocol. The relationship between IMT and risk was nonlinear, but the linear models fitted relatively well for moderate to high IMT values. Conclusions— Carotid IMT is a strong predictor of future vascular events. The relative risk per IMT difference is slightly higher for the end point stroke than for myocardial infarction. In future IMT studies, ultrasound protocols should be aligned with published studies. Data for younger individuals are limited and more studies are required.

Background— Evidence for efficacy of dual antiplatelet therapy in stroke is limited. Symptomatic carotid stenosis patients are at high risk of early recurrent stroke. In this group, asymptomatic microembolic signals (MES), detected by transcranial Doppler ultrasound (TCD), are markers of future stroke and transient ischemic attack (TIA) risk. They offer a surrogate marker to evaluate antiplatelet therapy, but no multicenter study has evaluated the feasibility of this approach. Methods and Results— Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) is a randomized, double-blind study in subjects with recently symptomatic ≥50% carotid stenosis. Patients were screened with TCD, and if MES were detected, they were randomized to clopidogrel and aspirin or aspirin monotherapy. Repeated TCD recordings were made on days 2 and 7. MES were detected in 110 of 230 patients by online analysis at baseline, of whom 107 were randomized. Intention-to-treat analysis revealed a significant reduction in the primary end point: 43.8% of dual-therapy patients were MES positive on day 7, as compared with 72.7% of monotherapy patients (relative risk reduction 39.8%; 95% CI, 13.8 to 58.0; P =0.0046). The secondary end point of MES frequency per hour was reduced (compared with baseline) by 61.4% (95% CI, 31.6 to 78.2; P =0.0013) in the dual-therapy group at day 7 and by 61.6% (95% CI, 34.9 to 77.4; P =0.0005) on day 2. There were 4 recurrent strokes and 7 TIAs in the monotherapy group versus no stroke and 4 TIAs in the dual-therapy group that were treatment emergent and ipsilateral to the qualifying carotid stenosis; 2 additional ipsilateral TIAs occurred before treatment started. MES frequency was greater in the 17 patients with recurrent ipsilateral events compared with the 90 without (mean±SD: 24.4±27.7 versus 8.9±11.5 per hour; P =0.0003). Conclusions— In patients with recently symptomatic carotid stenosis, combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing asymptomatic embolization. Doppler MES detection is a feasible method to evaluate the efficacy of antiplatelet therapy in multicenter studies.

Background — Current antiplatelet regimens fail to prevent the majority of recurrent strokes. Asymptomatic circulating emboli can be detected by transcranial Doppler ultrasound, are frequent in patients with symptomatic carotid stenosis, and predict recurrent stroke risk. S -Nitrosoglutathione (GSNO) is a nitric oxide donor that appears to have relative platelet specificity. We evaluated its effectiveness in reducing embolization in patients with symptomatic carotid stenosis who already were taking aspirin. Methods and Results — Twenty patients with ≥50% internal carotid artery stenosis and with ≥3 embolic signals detected during a half-hour screening recording were recruited. All had taken aspirin for at least 7 days. They were randomly assigned in a double-blind fashion to either GSNO (4.4 mmol/kg per minute) or saline placebo for 90 minutes. Transcranial Doppler recordings were made from the ipsilateral middle cerebral artery for 1 hour before treatment and at 0 to 3, 6, and 24 hours after treatment. Before treatment, the mean (range) of embolic signals per hour was 6.9 (3 to 13) in the GSNO group and 7.3 (4 to 12) in the placebo group ( P =0.68). GSNO resulted in a rapid reduction in the frequency of embolic signals of 84% at 0 to 3 hours, 95% at 6 hours, and 100% at 24 hours ( P P =0.003, and P Conclusions — Continued embolization is common in patients with carotid stenosis despite aspirin therapy. GSNO was highly effective in rapidly reducing the frequency of embolic signals in this patient group. Despite its short administration time and its short half-life, it resulted in therapeutic effects lasting 24 hours.