Management of atherosclerotic extracranial carotid artery stenosis

Atherosclerosis leading to stenosis of the internal carotid artery is the underlying cause of 8–15% of ischaemic strokes (symptomatic carotid stenosis). 1–2% of the adult population have asymptomatic carotid stenosis. Clinical trials in patients with symptomatic carotid stenosis showed a higher procedural risk of non-disabling stroke with stenting versus endarterectomy, but a higher risk of myocardial infarction, cranial nerve palsy, and access site haematoma with endarterectomy. Apart from procedural complications, both treatments are equally effective in preventing stroke and recurrent severe carotid stenosis in the medium-to-long term. Endarterectomy has a modest effect in preventing stroke among patients with asymptomatic carotid stenosis, whereas the role of stenting remains to be established. With advances in medical therapy against atherosclerosis, benefit from invasive therapy has become uncertain. Risk modelling, with the inclusion of brain and carotid plaque imaging, will become increasingly important in selecting patients for interventions

Incidence, impact, and predictors of cranial nerve palsy and haematoma following carotid endarterectomy in the international carotid stenting study.

OBJECTIVE: Cranial nerve palsy (CNP) and neck haematoma are complications of carotid endarterectomy (CEA). The effects of patient factors and surgical technique were analysed on the risk, and impact on disability, of CNP or haematoma in the surgical arm of the International Carotid Stenting Study (ICSS), a randomized controlled clinical trial of stenting versus CEA in patients with symptomatic carotid stenosis. MATERIALS AND METHODS: A per-protocol analysis of early outcome in patients receiving CEA in ICSS is reported. Haematoma was defined by the surgeon. CNP was confirmed by an independent neurologist. Factors associated with the risk of CNP and haematoma were investigated in a binomial regression analysis. RESULTS: Of the patients undergoing CEA, 45/821 (5.5%) developed CNP, one of which was disabling (modified Rankin score = 3 at 1 month). Twenty-eight (3.4%) developed severe haematoma. Twelve patients with haematoma also had CNP, a significant association (p 14 days (RR 3.33, 95% CI 1.05 to 10.57). The risk of haematoma was increased in women, by the prescription of anticoagulant drugs pre-procedure and in patients with atrial fibrillation, and was decreased in patients in whom a shunt was used and in those with a higher baseline cholesterol level. CONCLUSIONS: CNP remains relatively common after CEA, but is rarely disabling. Women should be warned about an increased risk. Attention to haemostasis might reduce the incidence of CNP. ICSS is a registered clinical trial: ISRCTN 25337470

Long Term Restenosis Rate After Carotid Endarterectomy: Comparison of Three Surgical Techniques and Intra-Operative Shunt Use

OBJECTIVE: Closure of the artery during carotid endarterectomy (CEA) can be done with or without a patch, or performed with the eversion technique, while the use of intra-operative shunts is optional. The influence of these techniques on subsequent restenosis is uncertain. Long term carotid restenosis rates and risk of future ipsilateral stroke with these techniques were compared. METHODS: Patients who underwent CEA in the International Carotid Stenting Study were divided into patch angioplasty, primary closure, or eversion endarterectomy. Intra-operative shunt use was reported. Carotid duplex ultrasound was performed at each follow up. Primary outcomes were restenosis of ≥ 50% and ≥ 70%, and ipsilateral stroke after the procedure to the end of follow up. RESULTS: In total, 790 CEA patients had restenosis data at one and five years. Altogether, 511 (64.7%) had patch angioplasty, 232 (29.4%) primary closure, and 47 (5.9%) eversion endarterectomy. The cumulative incidence of ≥ 50% restenosis at one year was 18.9%, 26.1%, and 17.7%, respectively, and at five years it was 25.9%, 37.2%, and 30.0%, respectively. There was no difference in risk between the eversion and patch angioplasty group (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.45 - 1.81; p = .77). Primary closure had a higher risk of restenosis than patch angioplasty (HR 1.45, 95% CI 1.06 - 1.98; p = .019). The cumulative incidence of ≥ 70% restenosis did not differ between primary closure and patch angioplasty (12.1% vs. 7.1%, HR 1.59, 95% CI 0.88 - 2.89; p = .12) or between patch angioplasty and eversion endarterectomy (4.7%, HR 0.45, 95% CI 0.06 - 3.35; p = .44). There was no effect of shunt use on the cumulative incidence of restenosis. Post-procedural ipsilateral stroke was not more common in either of the surgical techniques or shunt use. CONCLUSION: Restenosis was more common after primary closure than conventionally with a patch closure. Shunt use had no effect on restenosis. Patch closure is the treatment of choice to avoid restenosis

Исследование обобщающих характеристик пузырей подводных газовых факелов

Objective: To decrease the procedural risk of carotid revascularisation it is crucial to understand the mechanisms of procedural stroke. This study analysed the features of procedural strokes associated with carotid artery stenting (CAS) and carotid endarterectomy (CEA) within the International Carotid Stenting Study (ICSS) to identify the underlying pathophysiological mechanism. Materials and methods: Patients with recently symptomatic carotid stenosis (1,713) were randomly allocated to CAS or CEA. Procedural strokes were classified by type (ischaemic or haemorrhagic), time of onset (intraprocedural or after the procedure), side (ipsilateral or contralateral), severity (disabling or non-disabling), and patency of the treated artery. Only patients in whom the allocated treatment was initiated were included. The most likely pathophysiological mechanism was determined using the following classification system: (1) carotid-embolic, (2) haemodynamic, (3) thrombosis or occlusion of the revascularised carotid artery, (4) hyperperfusion, (5) cardio-embolic, (6) multiple, and (7) undetermined. Results: Procedural stroke occurred within 30 days of revascularisation in 85 patients (CAS 58 out of 791 and CEA 27 out of 819). Strokes were predominately ischaemic (77; 56 CAS and 21 CEA), after the procedure (57; 37 CAS and 20 CEA), ipsilateral to the treated artery (77; 52 CAS and 25 CEA), and non-disabling (47; 36 CAS and 11 CEA). Mechanisms of stroke were carotid-embolic (14; 10 CAS and 4 CEA), haemodynamic (20; 15 CAS and 5 CEA), thrombosis or occlusion of the carotid artery (15; 11 CAS and 4 CEA), hyperperfusion (9; 3 CAS and 6 CEA), cardio-embolic (5; 2 CAS and 3 CEA) and multiple causes (3; 3 CAS). In 19 patients (14 CAS and 5 CEA) the cause of stroke remained undetermined. Conclusion: Although the mechanism of procedural stroke in both CAS and CEA is diverse, haemodynamic disturbance is an important mechanism. Careful attention to blood pressure control could lower the incidence of procedural stroke. </p

End-stage kidney disease in patients with clinically manifest vascular disease; incidence and risk factors: results from the UCC-SMART cohort study

Background: Patients with cardiovascular disease (CVD) are at increased risk of end-stage kidney disease (ESKD). Insights into the incidence and role of modifiable risk factors for end-stage kidney disease may provide means for prevention in patients with cardiovascular disease. Methods: We included 8402 patients with stable cardiovascular disease. Incidence rates (IRs) for end-stage kidney disease were determined stratified according to vascular disease location. Cox proportional hazard models were used to assess the risk of end-stage kidney disease for the different determinants. Results: Sixty-five events were observed with a median follow-up of 8.6 years. The overall incidence rate of end-stage kidney disease was 0.9/1000 person-years. Patients with polyvascular disease had the highest incidence rate (1.8/1000 person-years). Smoking (Hazard ratio (HR) 1.87; 95% CI 1.10–3.19), type 2 diabetes (HR 1.81; 95% CI 1.05–3.14), higher systolic blood pressure (HR 1.37; 95% CI 1.24–1.52/10 mmHg), lower estimated glomerular filtration rate (eGFR) (HR 2.86; 95% CI 2.44–3.23/10 mL/min/1.73 m ) and higher urine albumin/creatinine ratio (uACR) (HR 1.19; 95% CI 1.15–1.23/10 mg/mmol) were independently associated with elevated risk of end-stage kidney disease. Body mass index (BMI), waist circumference, non-HDL-cholesterol and exercise were not independently associated with risk of end-stage kidney disease. Conclusions: Incidence of end-stage kidney disease in patients with cardiovascular disease varies according to vascular disease location. Several modifiable risk factors for end-stage kidney disease were identified in patients with cardiovascular disease. These findings highlight the potential of risk factor management in patients with manifest cardiovascular disease. Graphic abstract: [Figure not available: see fulltext.].

Common Variants Associated With OSMR Expression Contribute to Carotid Plaque Vulnerability, but Not to Cardiovascular Disease in Humans

Background and Aims: Oncostatin M (OSM) signaling is implicated in atherosclerosis, however the mechanism remains unclear. We investigated the impact of common genetic variants in OSM and its receptors, OSMR and LIFR, on overall plaque vulnerability, plaque phenotype, intraplaque OSMR and LIFR expression, coronary artery calcification burden and cardiovascular disease susceptibility. Methods and Results: We queried Genotype-Tissue Expression data and found that rs13168867 (C allele) was associated with decreased OSMR expression and that rs10491509 (A allele) was associated with increased LIFR expression in arterial tissues. No variant was significantly associated with OSM expression. We associated these two variants with plaque characteristics from 1,443 genotyped carotid endarterectomy patients in the Athero-Express Biobank Study. After correction for multiple testing, rs13168867 was significantly associated with an increased overall plaque vulnerability (β = 0.118 ± s.e. = 0.040, p = 3.00 × 10−3, C allele). Looking at individual plaque characteristics, rs13168867 showed strongest associations with intraplaque fat (β = 0.248 ± s.e. = 0.088, p = 4.66 × 10−3, C allele) and collagen content (β = −0.259 ± s.e. = 0.095, p = 6.22 × 10−3, C allele), but these associations were not significant after correction for multiple testing. rs13168867 was not associated with intraplaque OSMR expression. Neither was intraplaque OSMR expression associated with plaque vulnerability and no known OSMR eQTLs were associated with coronary artery calcification burden, or cardiovascular disease susceptibility. No associations were found for rs10491509 in the LIFR locus. Conclusions: Our study suggests that rs1316887 in the OSMR locus is associated with increased plaque vulnerability, but not with coronary calcification or cardiovascular disease risk. It remains unclear through which precise biological mechanisms OSM signaling exerts its effects on plaque morphology. However, the OSM-OSMR/LIFR pathway is unlikely to be causally involved in lifetime cardiovascular disease susceptibility

Stent Design, Restenosis and Recurrent Stroke After Carotid Artery Stenting in the International Carotid Stenting Study

BACKGROUND AND PURPOSE: Open-cell carotid artery stents are associated with a higher peri-procedural stroke risk than closed-cell stents. However, the effect of stent design on long-term durability of carotid artery stenting (CAS) is unknown. We compared the medium- to long-term risk of restenosis and ipsilateral stroke between patients treated with open-cell stents versus closed-cell stents in the ICSS (International Carotid Stenting Study). METHODS: Patients with symptomatic carotid stenosis were randomized to CAS or endarterectomy and followed with duplex ultrasound for a median of 4.0 years. We analyzed data from patients with completed CAS procedures, known stent design, and available ultrasound follow-up. The primary outcome, moderate or higher restenosis (≥50%) was defined as a peak systolic velocity of >1.3 m/s on ultrasound or occlusion of the treated internal carotid artery and analyzed with interval-censored models. RESULTS: Eight hundred fifty-five patients were allocated to CAS. Seven hundred fourteen patients with completed CAS and known stent design were included in the current analysis. Of these, 352 were treated with open-cell and 362 with closed-cell stents. Moderate or higher restenosis occurred significantly less frequently in patients treated with open-cell (n=113) than closed-cell stents (n=154; 5-year risks were 35.5% versus 46.0%; unadjusted hazard ratio, 0.68; 95% CI, 0.53–0.88). There was no significant difference in the risk of severe restenosis (≥70%) after open-cell stenting (n=27) versus closed-cell stenting (n=43; 5-year risks, 8.6% versus 12.7%; unadjusted hazard ratio, 0.63; 95% CI, 0.37–1.05). The risk of ipsilateral stroke beyond 30 days after treatment was similar with open-cell and closed-cell stents (hazard ratio, 0.78; 95% CI, 0.35–1.75). CONCLUSIONS: Moderate or higher restenosis after CAS occurred less frequently in patients treated with open-cell stents than closed-cell stents. However, both stent designs were equally effective at preventing recurrent stroke during follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com/. Unique identifier: ISRCTN25337470

The influence of baseline risk on the relation between HbA1c and risk for new cardiovascular events and mortality in patients with type 2 diabetes and symptomatic cardiovascular disease.

Background Strict glycaemic control in patients with type 2 diabetes has proven to have microvascular benefits while the effects on CVD and mortality are less clear, especially in high risk patients. Whether strict glycaemic control would reduce the risk of future CVD or mortality in patients with type 2 diabetes and pre-existing CVD, is unknown. This study aims to evaluate whether the relation between baseline HbA1c and new cardiovascular events or mortality in patients with type 2 diabetes and pre-existing cardiovascular disease (CVD) is modified by baseline vascular risk. Methods A cohort of 1096 patients with type 2 diabetes and CVD from the Second Manifestations of ARTerial Disease (SMART) study was followed. The relation between HbA1c at baseline and future vascular events (composite of myocardial infarction, stroke and vascular mortality) and all-cause mortality was evaluated with Cox proportional hazard analyses in a population that was stratified for baseline risk for vascular events as calculated with the SMART risk score. The mean follow-up duration was 6.9 years for all-cause mortality and 6.4 years for vascular events, in which period 243 and 223 cases were reported, respectively. Results A 1 % increase in HbA1c was associated with a higher risk for all-cause mortality (HR 1.18, 95 % CI 1.06–1.31). This association was also found in the highest SMART risk quartile (HR 1.33, 95 % CI 1.11–1.60). There was no relation between HbA1c and the occurrence of cardiovascular events during follow-up (HR 1.03, 95 % CI 0.91–1.16). The interaction term between HbA1c and SMART risk score was not significantly related to any of the outcomes. Conclusion In patients with type 2 diabetes and CVD, HbA1c is related to the risk of all-cause mortality, but not to the risk of cardiovascular events. The relation between HbA1c and all-cause mortality in patients with type 2 diabetes and vascular disease is not dependent on baseline vascular risk

Absence of Consistent Sex Differences in Outcomes From Symptomatic Carotid Endarterectomy and Stenting Randomized Trials.

BACKGROUND AND PURPOSE: CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) reported a higher periprocedural risk for any stroke, death, or myocardial infarction for women randomized to carotid artery stenting (CAS) compared with women randomized to carotid endarterectomy (CEA). No difference in risk by treatment was detected for women relative to men in the 4-year primary outcome. We aimed to conduct a pooled analysis among symptomatic patients in large randomized trials to provide more precise estimates of sex differences in the CAS-to-CEA risk for any stroke or death during the 120-day periprocedural period and ipsilateral stroke thereafter. METHODS: Data from the Carotid Stenosis Trialists' Collaboration included outcomes from symptomatic patients in EVA-3S (Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis), SPACE (Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients), ICSS (International Carotid Stenting Study), and CREST. The primary outcome was any stroke or death within 120 days after randomization and ipsilateral stroke thereafter. Event rates and relative risks were estimated using Poisson regression; effect modification by sex was assessed with a sex-by-treatment-by-trial interaction term, with significant interaction defined a priori as P≤0.10. RESULTS: Over a median 2.7 years of follow-up, 433 outcomes occurred in 3317 men and 1437 women. The CAS-to-CEA relative risk of the primary outcome was significantly lower for women compared with men in 1 trial, nominally lower in another, and nominally higher in the other two. The sex-by-treatment-by-trial interaction term was significant (P=0.065), indicating heterogeneity among trials. Contributors to this heterogeneity are primarily differences in periprocedural period. When the trials are nevertheless pooled, there were no significant sex differences in risk in any follow-up period. CONCLUSIONS: There were significant differences between trials in the magnitude of sex differences in treatment effect (CAS-to-CEA relative risk), indicating pooling data from these trials to estimate sex differences might not be valid. Whether sex is acting as an effect modifier of the CAS-to-CEA treatment effect in symptomatic patients remains uncertain. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00190398 (EVA-3S) and NCT00004732 (CREST). URL: https://www.isrctn.com; Unique identifier: ISRCTN57874028 (SPACE) and ISRCTN25337470 (ICSS)

Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

RATIONALE: Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed. OBJECTIVE: Using single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis. METHODS AND RESULTS: We performed single-cell RNA and single-cell ATAC sequencing on human carotid atherosclerotic plaques to define the cells at play and determine their transcriptomic and epigenomic characteristics. We identified 14 distinct cell populations including endothelial cells, smooth muscle cells, mast cells, B cells, myeloid cells, and T cells and identified multiple cellular activation states and suggested cellular interconversions. Within the endothelial cell population, we defined subsets with angiogenic capacity plus clear signs of endothelial to mesenchymal transition. CD4+ and CD8+ T cells showed activation-based subclasses, each with a gradual decline from a cytotoxic to a more quiescent phenotype. Myeloid cells included 2 populations of proinflammatory macrophages showing IL (interleukin) 1B or TNF (tumor necrosis factor) expression as well as a foam cell-like population expressing TREM2 (triggering receptor expressed on myeloid cells 2) and displaying a fibrosis-promoting phenotype. ATACseq data identified specific transcription factors associated with the myeloid subpopulation and T cell cytokine profiles underlying mutual activation between both cell types. Finally, cardiovascular disease susceptibility genes identified using public genome-wide association studies data were particularly enriched in lesional macrophages, endothelial, and smooth muscle cells. CONCLUSIONS: This study provides a transcriptome-based cellular landscape of human atherosclerotic plaques and highlights cellular plasticity and intercellular communication at the site of disease. This detailed definition of cell communities at play in atherosclerosis will facilitate cell-based mapping of novel interventional targets with direct functional relevance for the treatment of human diseas