Gert Jan de Borst

Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis : the International Carotid Stenting Study (ICSS) randomised trial

Summary Background Stenting is an alternative to endarterectomy for treatment of carotid artery stenosis, but long-term efficacy is uncertain. We report long-term data from the randomised International Carotid Stenting Study comparison of these treatments. Methods Patients with symptomatic carotid stenosis were randomly assigned 1:1 to open treatment with stenting or endarterectomy at 50 centres worldwide. Randomisation was computer generated centrally and allocated by telephone call or fax. Major outcomes were assessed by an independent endpoint committee unaware of treatment assignment. The primary endpoint was fatal or disabling stroke in any territory after randomisation to the end of follow-up. Analysis was by intention to treat ([ITT] all patients) and per protocol from 31 days after treatment (all patients in whom assigned treatment was completed). Functional ability was rated with the modified Rankin scale. This study is registered, number ISRCTN25337470. Findings 1713 patients were assigned to stenting (n=855) or endarterectomy (n=858) and followed up for a median of 4·2 years (IQR 3·0–5·2, maximum 10·0). Three patients withdrew immediately and, therefore, the ITT population comprised 1710 patients. The number of fatal or disabling strokes (52 vs 49) and cumulative 5-year risk did not differ significantly between the stenting and endarterectomy groups (6·4% vs 6·5%; hazard ratio [HR] 1·06, 95% CI 0·72–1·57, p=0·77). Any stroke was more frequent in the stenting group than in the endarterectomy group (119 vs 72 events; ITT population, 5-year cumulative risk 15·2% vs 9·4%, HR 1·71, 95% CI 1·28–2·30, p<0·001; per-protocol population, 5-year cumulative risk 8·9% vs 5·8%, 1·53, 1·02–2·31, p=0·04), but were mainly non-disabling strokes. The distribution of modified Rankin scale scores at 1 year, 5 years, or final follow-up did not differ significantly between treatment groups. Interpretation Long-term functional outcome and risk of fatal or disabling stroke are similar for stenting and endarterectomy for symptomatic carotid stenosis. Funding Medical Research Council, Stroke Association, Sanofi-Synthélabo, European Union.

Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection

Spontaneous intracranial artery dissection is an uncommon and probably underdiagnosed cause of stroke that is defined by the occurrence of a haematoma in the wall of an intracranial artery. Patients can present with headache, ischaemic stroke, subarachnoid haemorrhage, or symptoms associated with mass effect, mostly on the brainstem. Although intracranial artery dissection is less common than cervical artery dissection in adults of European ethnic origin, intracranial artery dissection is reportedly more common in children and in Asian populations. Risk factors and mechanisms are poorly understood, and diagnosis is challenging because characteristic imaging features can be difficult to detect in view of the small size of intracranial arteries. Therefore, multimodal follow-up imaging is often needed to confirm the diagnosis. Treatment of intracranial artery dissections is empirical in the absence of data from randomised controlled trials. Most patients with subarachnoid haemorrhage undergo surgical or endovascular treatment to prevent rebleeding, whereas patients with intracranial artery dissection and cerebral ischaemia are treated with antithrombotics. Prognosis seems worse in patients with subarachnoid haemorrhage than in those without.

Interleukin-6 receptor pathways in abdominal aortic aneurysm

Methods We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo. Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach. Results Up to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25–0.66, I2 = 70%, P = 1.1 × 10–5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80–0.89, I2 = 0%, P = 2.7 × 10–11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers. Conclusions A Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management.

Stenting Versus Surgery in Patients With Carotid Stenosis After Previous Cervical Radiation Therapy Systematic Review and Meta-Analysis

Background and Purpose— Patients with both carotid stenosis and previously cervical radiation therapy are considered “high risk” for carotid endarterectomy (CEA). Carotid angioplasty and stenting (CAS) seems a reasonable alternative, but neither the operative risk for CEA nor the effectiveness of CAS has been proven. The purpose of this study was to evaluate perioperative and long-term outcome of both procedures in patients with radiation therapy. Methods— A systematic search strategy with the synonyms “carotid artery stenosis” and “cervical irradiation” was conducted in MEDLINE and EMBASE databases. To provide and compare estimates of outcomes, pooled and metaregression analyses were performed. Results— Twenty-seven articles comprising 533 patients undergoing radiation therapy (361 CAS and 172 CEA) fulfilled our inclusion criteria. Pooled analysis showed perioperative risk for “any cerebrovascular adverse event” (CVE) of 3.9% (95% CI, 2.3%–6.7%) in CAS studies against 3.5% (95% CI, 1.5%–8.0%) in CEA studies (P=0.77). Risk for cranial nerve injury (CNI) after CEA was 9.2% (95% CI, 3.7%–21.1%) versus none after CAS. Late outcome showed rates of CVE favoring CEA (P=0.014). The rate of restenosis >50% was significantly higher in patients treated with CAS compared with CEA (P<0.003). Conclusions— Both CAS and CEA proved to be feasible revascularization techniques with low risk for CVE. Although patients undergoing CEA had more temporary CNI, higher rates of late CVE and restenosis were identified after CAS.

Asymptomatic Carotid Artery Stenosis and the Risk of Ischemic Stroke According to Subtype in Patients With Clinical Manifest Arterial Disease

Background and Purpose— Because best medical treatment is improving, the risk of stroke in asymptomatic carotid artery stenosis (ACAS) may decline. We evaluated the risk of ischemic stroke and stratified it according to stroke subtype in patients with ACAS during long-term follow-up. Methods— In total, 4319 consecutive patients in the Second Manifestations of Arterial disease study with clinically manifest arterial disease or specific risk factors, but without a history of cerebrovascular disease, were included. Degree of stenosis was evaluated with duplex ultrasound scanning. Strokes during follow-up were classified according to subtype. Cox-proportional hazard-regression models were used to evaluate the relationship between ACAS and future stroke. Results— We identified 293 (6.8%) patients with ACAS 50% to 99%, of whom 193 had 70% to 99% stenosis. In these subgroups, mean follow-up was 6.2 and 6.0 years, respectively. In total, 94 ischemic strokes occurred, of which 8 in ACAS 50% to 99% patients. The any territory annual ischemic stroke risk was 0.4% in 50% to 99% ACAS and 0.5% per year for 70% to 99% ACAS patients. The risk of ischemic stroke was not significantly increased in patients with ACAS 70% to 99% (hazard ratio, 1.5; 95% confidence interval, 0.7–3.5). Patients with ACAS 50% to 99% and ACAS 70% to 99% tended to have nonsignificantly more large vessel disease strokes (hazard ratio, 1.5; 95% confidence interval, 0.5–4.2 and hazard ratio, 1.7; 95% confidence interval, 0.5–5.6). Conclusions— Patients with clinically manifest arterial disease or type 2 diabetes mellitus have a low risk of developing ischemic stroke, irrespective of its subtype and independent of the degree of ACAS stenosis.

Time-Dependent Changes in Atherosclerotic Plaque Composition in Patients Undergoing Carotid Surgery

Background— Time-dependent trends in the incidence of cardiovascular disease have been reported in high-income countries. Because atherosclerosis underlies the majority of cardiovascular diseases, we investigated temporal changes in the composition of atherosclerotic plaques removed from patients undergoing carotid endarterectomy. Methods and Results— The Athero-Express study is an ongoing, longitudinal, vascular biobank study that includes the collection of atherosclerotic plaques of patients undergoing primary carotid endarterectomy in the province of Utrecht from 2002 to 2011. Histopathologic features of plaques of 1583 patients were analyzed in intervals of 2 years. The analysis included quantification of collagen, calcifications, lipid cores, plaque thrombosis, macrophages, smooth muscle cells, and microvessels. Large atheroma, plaque thrombosis, macrophages, and calcifications were less frequently observed over time, with adjusted odds ratios of 0.72 (95% confidence interval, 0.650-0.789), 0.62 (95% confidence interval, 0.569-0.679), 0.87 (95% confidence interval, 0.800-0.940), and 0.75 (95% confidence interval, 0.692-0.816) per 2-year increase in time, respectively. These changes in plaque characteristics were consistently observed in patient subgroups presenting with stroke, transient ischemic attack, ocular symptoms, and asymptomatic patients. Concomitantly, risk factor management and secondary prevention strategies among vascular patients scheduled for carotid endarterectomy significantly improved over the past decade. Conclusions— In conclusion, over the past decade, atherosclerotic plaques harvested during carotid endarterectomy show a time-dependent change in plaque composition characterized by a decrease in features currently believed to be causal for plaque instability. This appears to go hand in hand with improvements in risk factor management.

Symptomatic Carotid Atherosclerotic Disease Correlations Between Plaque Composition and Ipsilateral Stroke Risk

Background and Purpose— For symptomatic patients with carotid artery stenosis, the risk benefit for surgical intervention may vary among patient groups. Various modalities of plaque imaging have been promoted as potential tools for additional risk stratification, particularly in patients with moderate stenosis. However, it remains uncertain to what extent carotid plaque components predict risk of future ipsilateral ischemic stroke. Methods— In 2 large atherosclerotic carotid plaque biobank studies, we related histological characteristics of 1640 carotid plaques with a validated risk model for the prediction of individual 1- and 5-year stroke risk. Results— No significant heterogeneity between the studies was found. Predicted 5-year stroke risk (top versus bottom quartile) was related to plaque thrombus (odds ratio, 1.42; 95% confidence interval, 1.11–1.89; P=0.02), fibrous content (0.65; 0.49–0.87; P=0.004), macrophage infiltration (1.41; 1.05–1.90; P=0.02), high microvessel density (1.49; 1.05–2.11; P=0.03), and overall plaque instability (1.40; 1.05–1.87; P=0.02). This association was not observed for cap thickness, calcification, intraplaque hemorrhage, or lymphocyte infiltration. Plaques removed within 30 days of most recent symptomatic event were most strongly correlated with predicted stroke risk. Conclusions— Features of the vulnerable carotid plaque, including plaque thrombus, low fibrous content, macrophage infiltration, and microvessel density, correlate with predicted stroke risk. This study provides a basis for plaque imaging studies focused on stroke risk stratification.

Symptomatic Carotid Artery Stenosis: Impairment of Cerebral Autoregulation Measured at the Brain Tissue Level with Arterial Spin-labeling MR Imaging

PURPOSE To measure the cerebral autoregulatory status of the brain tissue supplied by the individual brain-feeding arteries in patients with symptomatic stenosis of the internal carotid artery (ICA) by using arterial spin-labeling (ASL) magnetic resonance (MR) imaging and to compare this status with that in healthy controls. MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. Twenty-three patients (mean age, 69.3 years +/- 8.0 [standard deviation]) with unilateral symptomatic stenosis of the ICA and 20 healthy controls (mean age, 66.8 years +/- 6.3 [standard deviation]) underwent perfusion and flow territory-selective ASL MR imaging before and after intravenous administration of acetazolamide. Cerebrovascular reactivity was measured throughout the brain in the gray matter that is supplied by the individual ICAs and the basilar artery. Data were analyzed with paired and unpaired t tests. RESULTS In patients with symptomatic stenosis of the ICA, the flow territory of the symptomatic ICA was smaller than that of the asymptomatic ICA. After administration of acetazolamide, a significant increase in cerebral blood flow at the brain tissue level was measured in both control subjects and patients in all perfusion territories. Mean cerebrovascular reactivity values were 35.9% +/- 3.0% (standard error) and 44.6% +/- 3.5% (standard error) in the flow territories of the patients with symptomatic ICAs and those with asymptomatic ICAs, respectively, and 47.9% +/- 3.1% (standard error) in the control subjects. Cerebrovascular reactivity was lower in the flow territory of the symptomatic ICA than in the arteries of control participants (mean difference, -12.0%; 95% confidence interval: -20.7%, -3.3%). CONCLUSION In patients with symptomatic stenosis of the ICA, vasodilatory capacity in the flow territories of the major cerebral arteries can be visualized and quantified at the brain tissue level with ASL MR imaging.

The potential benefits and the role of cerebral monitoring in carotid endarterectomy.

Purpose of review The benefit of carotid endarterectomy (CEA) in patients with symptomatic severe carotid stenosis is highly dependent on the perioperative stroke rate. Cerebral monitoring plays an important role in reducing the perioperative stroke rate as it allows detection of the main causes of perioperative stroke, being embolism, intraoperative hypoperfusion and postoperative hyperperfusion syndrome. However, some physicians doubt about the benefit of cerebral monitoring and consider it costly and time consuming. The aim of this review is to provide an overview of the available cerebral monitoring modalities and their role in CEA. Recent findings Electroencephalography, transcranial Doppler, stump pressure and sensory-evoked potentials, are known and used for years. Near-infrared spectroscopy is a relatively new valuable technique, as it is noninvasive, easy to apply and applicable in all CEA patients, but remains to be validated. Summary In our opinion, cerebral monitoring during CEA is essential because it provides direct information regarding new neurological deficits, which might otherwise be missed. Intraoperative cerebral monitoring provides immediate feedback to the treating physician allowing prompt correction in tissue handling. Several monitoring modalities are available for cerebral monitoring in CEA, but no single test is comprehensive. Therefore, a combination of several monitoring modalities with each specific strength not only during but also after CEA is recommended to cover all needs and reduce the perioperative stroke rate.

Mast cells in human carotid atherosclerotic plaques are associated with intraplaque microvessel density and the occurrence of future cardiovascular events

AIMS Human autopsy, animal, and cell culture studies together have merged in a concept suggesting participation of mast cells (MCs) in the generation of atherosclerotic plaques. More specifically, these studies have suggested MC-induced intraplaque neovascularization as one mechanism by which MCs may render the plaques vulnerable. The present study was designed to assess the association between MC numbers and neovascularization in human atherosclerotic plaques, and to relate the abundance of plaque MCs to the occurrence of adverse cardiovascular events during the follow-up. METHODS AND RESULTS Atherosclerotic plaques of 270 patients suffering from carotid artery stenosis were stained for the presence of MCs (MC tryptase). Furthermore, during a follow-up of 3 years, cardiovascular-related endpoints were assessed in 253 patients. On average a high number of MCs were observed per plaque cross-section [median 108 (55-233) cells per section]. Plaques with high MC numbers revealed an unstable lipid-rich inflammatory phenotype and were associated with symptomatic patients. In addition, MC numbers were positively associated with microvessel density (r = 0.416, P < 0.001). Patients with high intraplaque MC numbers showed significantly more cardiovascular events during the follow-up (58/142 vs. 31/111 events, P = 0.029). In a multivariate analysis with correction for the main risk factors of cardiovascular diseases, MCs remained independently associated with adverse cardiovascular events (P = 0.025). CONCLUSION Mast cells are highly prevalent in human carotid atherosclerotic lesions and associated with plaque microvessel density. Furthermore, intraplaque MC numbers associate with future cardiovascular events.