Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade.

Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated" vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.

18F-Fluorodeoxyglucose-Positron Emission Tomography Imaging Detects Response to Therapeutic Intervention and Plaque Vulnerability in a Murine Model of Advanced Atherosclerotic Disease-Brief Report.

OBJECTIVE: This study sought to determine whether 18F-fluorodeoxyglucose-positron emission tomography/computed tomography could be applied to a murine model of advanced atherosclerotic plaque vulnerability to detect response to therapeutic intervention and changes in lesion stability. Approach and Results: To analyze plaques susceptible to rupture, we fed ApoE-/- mice a high-fat diet and induced vulnerable lesions by cast placement over the carotid artery. After 9 weeks of treatment with orthogonal therapeutic agents (including lipid-lowering and proefferocytic therapies), we assessed vascular inflammation and several features of plaque vulnerability by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography and histopathology, respectively. We observed that 18F-fluorodeoxyglucose-positron emission tomography/computed tomography had the capacity to resolve histopathologically proven changes in plaque stability after treatment. Moreover, mean target-to-background ratios correlated with multiple characteristics of lesion instability, including the corrected vulnerability index. CONCLUSIONS: These results suggest that the application of noninvasive 18F-fluorodeoxyglucose-positron emission tomography/computed tomography to a murine model can allow for the identification of vulnerable atherosclerotic plaques and their response to therapeutic intervention. This approach may prove useful as a drug discovery and prioritization method.

Editor's Choice - Distribution of Care and Hospital Incidence of Carotid Endarterectomy and Carotid Artery Stenting: A Secondary Analysis of German Hospital Episode Data.

OBJECTIVE: This is a description of the German healthcare landscape regarding carotid artery disease, assessment of hospital incidence time courses for carotid endarterectomy (CEA) and carotid artery stenting (CAS), and simulation of potential effects of minimum hospital caseload requirements for CEA and CAS. METHODS: The study is a secondary data analysis of diagnosis related group statistics data (2005-2016), provided by the German Federal Statistical Office. Cases encoded by German operation procedure codes for CEA or CAS and by International Classification of Diseases (ICD-10) codes for carotid artery disease were included. Hospitals were categorised into quartiles according to annual caseloads. Linear distances to the closest hospital fulfilling hypothetical caseload requirements were calculated. RESULTS: A total of 132 411 and 33 709 patients treated with CEA and CAS from 2012 to 2016 were included. CEA patients had lower rates of myocardial infarction (1.4% vs. 1.8%) and death (1.2% vs. 4.0%), and CAS patients were more often treated after emergency admission (38.1% vs. 27.1%). Age standardised annual hospital incidences were 67.2 per 100 000 inhabitants for CEA and 16.3 per 100 000 inhabitants for CAS. The incidence for CEA declined from 2005 to 2016, with CAS rising again until 2016 after having declined from 2010 to 2013. Regarding distance from home to hospital, centres offering CEA are distributed more homogeneously across Germany, compared with those performing CAS. Hypothetical introduction of minimum annual caseloads (> 20 for CEA; > 10 for CAS) imply that 75% of the population would reach their hospital after travelling 45 km for CEA and 70 km for CAS. CONCLUSION: Differences in spatial distribution mean that statutory minimum annual caseloads would have a greater impact on CAS accessibility than CEA in Germany. Presumably because of a decline in carotid artery disease and a transition towards individualised therapy for asymptomatic patients, hospital incidence for CEA has been declining.

Prospective Comparison of Duplex Ultrasound and Angiography for Intra-operative Completion Studies after Carotid Endarterectomy.

OBJECTIVE: The application of intra-operative completion studies may have contributed to the ongoing improvement of peri-operative outcomes in carotid surgery. METHODS: This prospective study aimed to compare angiography and duplex ultrasound (IDUS) as intra-operative completion studies after carotid endarterectomy (CEA) with respect to differences in the rating of vessel wall defects and interobserver reliability. Patients undergoing CEA for symptomatic or asymptomatic carotid stenosis were included. After CEA, angiography and IDUS were performed. Intra-operatively obtained video footage was evaluated at a later date by three independent and blinded raters with different levels of clinical experience. Rating was done according to a four step rating scale, with higher grades representing more severe defects. Standard statistical methods (Pearson's chi square test; permutation test; Wilcoxon signed rank test; Kendall's coefficient of concordance, Wt) were applied. RESULTS: In total, 150 patients (mean ± standard deviation age 72 ± 7 years, 68.7% male, 33.3% symptomatic) were enrolled between March 2016 and September 2017. Significantly more defects requiring intra-operative revision (grades 3 and 4 on rating scale) were detected by IDUS, which, in part, remained undetected by angiography: 22 (14.7%) vs. 10 (6.7%) (p = .040). Defects were also judged to be more severe with IDUS than with angiography: median rating grade 1: 74 (49.3%) vs. 102 (68.0%); grade 2: 54 (36.0%) vs. 38 (25.3%); grade 3: 21 (14.0%) vs. 9 (6.0%); grade 4: 1 (0.7%) vs.1 (0.7%) (p < .001). Furthermore, Wt was significantly higher for IDUS compared with angiography (0.70 vs. 0.57; p = .003). CONCLUSION: IDUS revealed more defects after CEA than angiography. Despite both techniques only showing moderate interobserver reliability, IDUS is less dependent on the surgeon's subjectivity than angiography. Taking into account the absence of procedure associated risks (i.e., adverse effects of iodinated contrast media and Xray), IDUS could be considered as an alternative intra-operative morphological assessment tool in carotid surgery.

Last neurologic event is associated with risk of in-hospital stroke or death after carotid endarterectomy or carotid artery stenting: Secondary data analysis of the German statutory quality assurance database.

OBJECTIVE: We sought to analyze the association between last neurologic event and the risk of stroke or death among patients treated with carotid endarterectomy (CEA) or carotid artery stenting (CAS) under routine conditions in Germany. METHODS: Secondary data analysis was performed based on the German statutory quality assurance database for carotid procedures. A total of 144,347 patients treated by CEA and 14,794 patients treated by CAS were included in the analysis. Primary outcome was any in-hospital stroke or death. To analyze the association between the last neurologic event and outcome, multilevel multivariable regression analysis was performed. RESULTS: In patients treated by CEA, raw risk for any in-hospital stroke or death was 2.0% (2923/144,347), with a risk of 1.4% in asymptomatic and 3.0% in symptomatic patients. In patients treated by CAS, raw risk for any in-hospital stroke or death was 3.6% (538/14,794), with a risk of 1.7% in asymptomatic and 6.1% in symptomatic patients. Regression analysis revealed that increasing severity of last neurologic event was significantly associated with an increasing risk of any in-hospital stroke or death in patients treated by both CEA and CAS (P < .004). However, the risk of any stroke or death did not significantly differ between asymptomatic patients and patients with amaurosis fugax before CEA or CAS (P = .219 for CEA, P = .124 for CAS). CONCLUSIONS: Increasing severity of last neurologic event is associated with an increasing risk of any in-hospital stroke or death in patients treated by CEA and CAS. The risk of any stroke or death did not differ between asymptomatic patients and patients with amaurosis fugax.

Age but not sex is associated with higher risk of in-hospital stroke or death after carotid artery stenting in symptomatic and asymptomatic carotid stenosis.

OBJECTIVE: The aim of this study was to analyze the correlation of age and sex with the outcome after carotid artery stenting (CAS). We used the statutory nationwide quality assurance database in Germany, in which, among others, all endovascular procedures on the extracranial carotid artery are filed. METHODS: We performed a secondary data analysis of all CAS procedures (N = 13,086) between 2012 and 2014 in Germany. The primary outcome was defined as any in-hospital stroke or death; the secondary outcomes were defined as in-hospital stroke (alone) and in-hospital death (alone). Descriptive analyses as well as multilevel multivariable analyses were applied. RESULTS: About 70% of the patients were male, and the mean age of all patients was 69.7 ± 9.3 years. Carotid stenosis was symptomatic in 36% of all patients. The primary outcome occurred in 2.4% (n = 317) of patients (2.5% of women, 2.4% in men, 1.7% of asymptomatic patients, and 3.7% of symptomatic patients). Multivariable regression analysis indicated that age (linear effect per 10-year increase) was significantly correlated with a higher risk of in-hospital stroke or death after CAS (risk ratio [RR], 1.54; 95% confidence interval [CI], 1.35-1.75). The risks of stroke alone (RR, 1.47; 95% CI, 1.26-1.72) and death alone (RR, 1.62; 95% CI, 1.01-2.58) were also significantly associated with age in CAS patients. Sex did not significantly alter the age effect and was not associated with the primary outcome rate (RR, 0.99; 95% CI, 0.78-1.26). CONCLUSIONS: Age but not sex is correlated with a higher risk of in-hospital stroke or death in asymptomatic and symptomatic patients after CAS under routine conditions. The primary outcome rate was fueled to a comparable magnitude by both components of the composite outcome.

Different perioperative antiplatelet therapies for patients treated with carotid endarterectomy in routine practice.

OBJECTIVE: There is currently no clear consensus regarding the optimal perioperative antiplatelet therapy regimen for carotid surgery. Therefore, associations between different antiplatelet therapies and the risk of stroke or death and perioperative complications after carotid endarterectomy on a national level in Germany were analyzed. METHODS: Overall, 117,973 elective carotid endarterectomies for asymptomatic or symptomatic carotid artery stenosis between 2010 and 2014 were included. Data were extracted from the statutory nationwide quality assurance database. The primary outcome was any in-hospital stroke or death until discharge from the hospital. Secondary outcomes were any major stroke or death, death alone, stroke, myocardial infarction, local bleeding, and any local complications (cranial nerve palsy, severe bleeding, acute occlusion). Descriptive statistics and multilevel multivariable regression analyses were applied. Single-agent therapy with aspirin was used as reference. RESULTS: Patients were predominantly male (68%), with a mean age of 71 years. Carotid stenosis was symptomatic in 40%. Of all patients, 82.8% were treated perioperatively by monotherapy with aspirin alone, 2.7% received other platelet inhibitors, and 4.8% of the patients were operated on under dual antiplatelet therapy. The primary outcome occurred in 1.8% of all patients. Multilevel multivariable regression analysis revealed that the combined stroke and death rate of patients with no perioperative antiplatelet therapy was significantly higher (risk ratio [RR], 1.21; 95% confidence interval [CI], 1.04-1.42) compared with the group of patients receiving monotherapy. The same was true for the major stroke and death rate (RR, 1.23; 95% CI, 1.02-1.48). In contrast, dual antiplatelet therapy was associated with a lower risk of death alone (RR, 0.67; 95% CI, 0.51-0.88) but with a significantly higher rate of secondary bleeding requiring reoperation (RR, 2.16; 95% CI, 1.88-2.50). CONCLUSIONS: This study shows that the risk of stroke or death was significantly higher in patients without any perioperative antiplatelet therapy. In contrast, dual antiplatelet therapy vs aspirin monotherapy was associated with a lower risk only of perioperative death but with a higher risk of neck bleeding until discharge. Perioperative antiplatelet therapy was significantly associated with a decreased in-hospital stroke and death risk. Further studies are needed to evaluate the risk-benefit ratio of single vs dual antiplatelet therapy.

Patient characteristics and in-hospital outcomes of emergency carotid endarterectomy and carotid stenting after stroke in evolution.

OBJECTIVE: The objective of this study was to describe characteristics and in-hospital outcomes of patients treated with carotid endarterectomy (CEA) and carotid artery stenting (CAS) for stroke in evolution (SIE) under routine conditions in Germany. METHODS: This secondary data analysis is based on the German statutory quality assurance database for carotid revascularization procedures. Patients with SIE who had undergone CEA or CAS were included. The primary outcome was any new stroke or all-cause death until hospital discharge. Descriptive statistics were calculated using statistical standard methods. To identify factors that are associated with the primary or secondary outcomes, a multilevel multivariable regression analysis was performed (exploratory approach). RESULTS: Between 2009 and 2014, a total of 5058 patients (mean age, 70 ± 11 years; 68% male) with SIE were treated with CEA (n = 3176) or percutaneous transluminal angioplasty/CAS (n = 1882). The primary outcome occurred in 9.0% and 11.7% after CEA and CAS, respectively. The multivariable regression analysis revealed that age (per 10-year increase: risk ratio [RR], 1.30; 95% confidence interval [CI], 1.12-1.50), American Society of Anesthesiologists (ASA) class (ASA class 4 and 5 vs ASA class 3: RR, 2.34; 95% CI, 1.65-3.32), ipsilateral degree of stenosis (occlusion vs severe stenosis: RR, 1.90; 95% CI, 1.29-2.79; low grade vs severe stenosis: RR, 3.06; 95% CI, 1.55-6.02), and neurologic deficit on admission (modified Rankin scale score of 3-5 vs 0-2: RR, 1.48; 95% CI, 1.04-2.10) are significantly associated with the risk of stroke or death after emergency CEA for SIE. In patients treated with CAS, only age (per 10-year increase: RR, 1.58; 95% CI, 1.37-1.82), ASA class (ASA class 1 and 2 vs ASA class 3: RR, 0.66; 95% CI, 0.46-0.95; ASA class 4 and class 5 vs ASA class 3: RR, 1.91; 95% CI, 1.31-2.78), and ipsilateral degree of stenosis (moderate vs severe stenosis: RR, 0.19; 95% CI, 0.04-0.77; occlusion vs severe stenosis: RR, 1.63; 95% CI, 1.18-2.25) were significantly associated with the primary outcome rate. CONCLUSIONS: Emergency carotid revascularization is associated with a combined stroke or death rate of about 10% under routine conditions in Germany. Lower age, lower ASA class, moderate to high-grade stenosis, and less severe neurologic deficit preceding CEA potentially serve as protective factors.

Intraoperative Completion Studies, Local Anesthesia, and Antiplatelet Medication Are Associated With Lower Risk in Carotid Endarterectomy.

BACKGROUND AND PURPOSE: In Germany, all surgical and endovascular procedures on the carotid bifurcation must be documented in a statutory nationwide quality assurance database. We aimed to analyze the association between procedural and perioperative variables and in-hospital stroke or death rates after carotid endarterectomy. METHODS: Between 2009 and 2014, overall 142 074 elective carotid endarterectomy procedures for asymptomatic or symptomatic carotid artery stenosis were documented in the database. The primary outcome of this secondary data analysis was in-hospital stroke or death. Major stroke or death, stroke, and death, each until discharge were secondary outcomes. Adjusted relative risks (RRs) were assessed by multivariable multilevel regression analyses. RESULTS: The primary outcome occurred in 1.8% of patients, with a rate of 1.4% in asymptomatic and 2.5% in symptomatic patients, respectively. In the multivariable analysis, lower risks of stroke or death were independently associated with local anesthesia (versus general anesthesia: RR, 0.85; 95% confidence interval [CI], 0.75-0.95), carotid endarterectomy with patch plasty compared with primary closure (RR, 0.71; 95% CI, 0.52-0.97), intraoperative completion studies by duplex ultrasound (RR, 0.74; 95% CI, 0.63-0.88) or angiography (RR, 0.80; 95% CI, 0.71-0.90), and perioperative antiplatelet medication (RR, 0.83; 95% CI, 0.71-0.97). No shunting and a short cross-clamp time were also associated with lower risks; however, these are suspected to be confounded. CONCLUSIONS: Local anesthesia, patch plasty compared with primary closure, intraoperative completion studies by duplex ultrasound or angiography, and perioperative antiplatelet medication were independently associated with lower in-hospital stroke or death rates after carotid endarterectomy.

A short time interval between the neurologic index event and carotid endarterectomy is not a risk factor for carotid surgery.

OBJECTIVE: Current guidelines recommend that carotid endarterectomy (CEA) be performed as early as possible after the neurologic index event in patients with 50% to 99% carotid artery stenosis. However, recent registry data showed that patients treated ≤48 hours had a significantly increased perioperative risk. Therefore, the aim of this single-center study was to determine the effect of the time interval between the neurologic index event and CEA on the periprocedural complication rate at our institution. METHODS: Prospectively collected data for 401 CEAs performed between 2004 and 2014 for symptomatic carotid stenosis were analyzed. Patients were divided into four groups according to the interval between the last neurologic event and surgery: group I, 0 to 2 days; group II, 3 to 7 days; group III, 8 to 14 days; and group IV, 15 to 180 days. The primary end point was the combined rate of in-hospital stroke or mortality. Data were analyzed by way of χ2 tests and multivariable regression analysis. RESULTS: The patients (68% men) had a median age of 70 years (interquartile range, 63-76 years). The index events included transient ischemic attack in 43.4%, amaurosis fugax in 25.4%, and an ipsilateral stroke in 31.2%. CEA was performed using the eversion technique in 61.1% of patients, and 50.1% were treated under locoregional anesthesia. The perioperative combined stroke and mortality rate was 2.5% (10 of 401), representing a perioperative mortality rate of 1.0% and stroke rate of 1.5%. Overall, myocardial infarction, cranial nerve injuries, and postoperative bleeding occurred in 0.7%, 2.2%, and 1.7%, respectively. We detected no significant differences for the combined stroke and mortality rate by time interval: 3% in group I, 3% in group II, 2% in group III, and 2% in group IV. Multivariable regression analysis showed no significant effect of the time interval on the primary end point. CONCLUSIONS: The combined mortality and stroke rate was 2.5% and did not differ significantly between the four different time interval groups. CEA was safe in our cohort, even when performed as soon as possible after the index event.

Short Time Interval Between Neurologic Event and Carotid Surgery Is Not Associated With an Increased Procedural Risk.

BACKGROUND AND PURPOSE: Guidelines recommend that carotid endarterectomy should be performed within 2 weeks in patients with a symptomatic carotid stenosis. Because a Swedish register study indicated that patients treated within the first days after a stroke or transient ischemic attack might have an increased perioperative stroke and mortality risk, this study aimed to find out whether these findings are also true under everyday conditions in Germany. METHODS: Secondary data analysis including 56 336 elective carotid endarterectomy procedures performed for symptomatic carotid stenosis under everyday conditions between 2009 and 2014. The patient cohort was divided into 4 groups according to time interval between index event and surgery (I: 0-2, II: 3-7, III: 8-14, and IV: 14-180 days). Primary outcome was any in-hospital stroke or death. For risk-adjusted analyses, a multilevel multivariable regression model was used. RESULTS: Mean patients' age was 71.1±9.6 years; 67.5% were men. Overall rate of any stroke or death was 2.5% (n=1434). Risk of any in-hospital stroke or death was 3.0% in group I, 2.5% in group II, 2.6% in group III, and 2.3% in group IV. Multivariable regression analysis revealed that the time interval was not significantly associated with the primary outcome. CONCLUSIONS: The time interval between the index event and carotid endarterectomy was not associated with the risk of any in-hospital stroke or death in patients with symptomatic carotid stenosis in Germany. In clinically stable patients, carotid endarterectomy might, therefore, be performed safely as soon as possible after the neurological index event.

Impact of sex and age on carotid plaque instability in asymptomatic patients-results from the Munich Vascular Biobank.

BACKGROUND: It is still a controversial issue whether carotid endarterectomy (CEA) for asymptomatic carotid stenosis is superior to best medical treatment. The aim of this study was therefore to analyze the impact of sex and age on carotid plaque instability in asymptomatic patients undergoing CEA. PATIENTS AND METHODS: Atherosclerotic plaques from 465 asymptomatic patients with high-grade carotid artery stenosis (2004 - 2013) at the Munich Vascular Biobank were analyzed. Ascertainment of lesion stability/instability was performed on formalin-fixed paraffin-embedded tissue samples using hematoxylin-eosin and elastic van Gieson staining. Unstable plaques were considered lesions with a fibrous cap < 200 µm overlaying lipid-rich atheroma. RESULTS: The average age of the patients was 69.3 ± 8.2 years. Independent of age, asymptomatic men had in total more frequently unstable plaques in contrast to women (41 % versus 52%, p = 0.042). No differences were found in plaque instability between age-related quartiles (< 65, 65- 69, 70 - 74, > 74 years) for female sex (p = 0.422). In men, a continuous increase in plaque instability with age was observed, without achieving statistical significance (p = 0.125). The greatest differences between male and female sex were found in the last quartile (> 74 years), without achieving statistical significance (p = 0.053). The chance of unstable carotid plaques in men was significantly higher than in women (OR = 1.562, p = 0.040). The probability of age-associated quartiles related to the first quartile demonstrated significant increase in plaque instability in the group of 65- to 69-year-old patients (OR 1.867, p = 0.024) and for patients older than 74 years (OR 1.740, p = 0.040). CONCLUSIONS: Asymptomatic men had in total more frequently unstable plaques in contrast to women. Thus, male sex seems to be an additional risk factor for ischemic stroke.

Carotid Plaque Morphology Is Significantly Associated With Sex, Age, and History of Neurological Symptoms.

BACKGROUND AND PURPOSE: The purpose of this study was to analyze the association between morphological characteristics of human carotid plaques and patient's sex, age, and history of neurological symptoms. METHODS: The study included 763 atherosclerotic plaques from patients treated surgically for carotid stenosis between 2004 and 2013. Histological analyses of carotid plaques were performed to assess the type of plaque (American Heart Association classification), the stability of the plaque, the extent of calcification, inflammation, and neovascularization, as well as the deposition of collagen and elastin. According to the scale of outcome measurement, logistic regression, ordinal regression, and multinomial regression analyses were applied. All results were adjusted for common risk factors of atherosclerosis. RESULTS: Male sex was associated with more cellularity (odds ratio [OR], 1.56; P=0.003), more inflammatory infiltrates (OR, 1.75; P<0.001), and more neovascularization (OR, 1.47; P=0.010), but less calcification (OR, 0.78; P=0.090). Symptomatic patients were more likely to have a lower amount of elastin (OR, 0.71; P=0.057). Higher age was associated with increased calcification (OR, 1.23; P=0.009). Unstable plaques were found more frequently in symptomatic patients (OR, 1.60; 95% confidence interval, 1.14-2.25; P=0.007). A multinomial regression model revealed that age, sex, and history of neurological symptoms were significantly associated with specific plaque types (P=0.009, P<0.001, and P=0.017, respectively). CONCLUSIONS: Plaque morphology differed between men and women and varied with age. Certain types of plaques (VI and VI/VII) as well as unstable plaques were significantly associated with a history of neurological symptoms. Thus, individual approaches (eg, in detection of plaque hemorrhage or thin fibrous caps) especially based on sex and age should be considered to identify patients at increased risk of stroke.

Intraoperative completion studies in carotid endarterectomy: systematic review and meta-analysis of techniques and outcomes.

BACKGROUND: Declining perioperative stroke and death rates over the past 3 decades have been paralleled by an increasing use of intraoperative completion studies (ICS) following carotid endarterectomy (CEA). Techniques applied include angiography, intraoperative duplex ultrasound (IDUS), flowmetry, and angioscopy. This systematic review and meta-analysis is aiming on providing an overview of techniques and corresponding outcomes. METHODS: A PubMed based systematic literature review comprising the years 1980 through 2020 was performed using predefined keywords to identify articles on different ICS techniques. Pooled analyses and meta-analyses estimating risk ratios (RR) and 95% confidence intervals (CI) were performed to compare outcomes of different ICS modes to nonapplication of any ICS. I2 values were assessed to quantify study heterogeneities. RESULTS: Identification of 34 studies including patients undergoing CEA with angiography (n=53,218), IDUS (n=20,030), flowmetry (n=16,812), and angioscopy (n=2,291). Corresponding rates of perioperative stroke were 1.5%, 1.8%, 3.6%, and 1.5%, perioperative stroke or death occurred in 1.7%, 1.9%, 2.2%, and 2.0%. Intraoperative surgical revision rates were 6.2%, 5.9%, and 7.9% after CEA with angiography, IDUS, and angioscopy, respectively. Compared to nonapplication of any ICS, the pooled analysis revealed angiography to be significantly associated with lower rates of stroke (RR 0.47; 95% CI, 0.36-0.62; P<0.0001) and stroke or death (RR 0.76; 95% CI, 0.70-0.83; P<0.0001). IDUS was significantly associated with lower rates of stroke (RR 0.56; 95% CI, 0.43-0.73; P<0.0001) and stroke or death (RR 0.83; 95% CI, 0.74-0.93; P=0.0018), whereas angioscopy showed a significant association with a lower stroke rate (RR 0.48; 95% CI, 0.033-0.68; P=0.0001), but no effect on the combined stroke or death rate. Angioscopy was associated with a higher intraoperative revision rate compared to angiography (RR 1.29; 95% CI, 1.07-1.54; P=0.006). The meta-analyses confirmed lower perioperative stroke or death rates for angiography (RR 0.83; 95% CI, 0.76-0.91) and IDUS (RR 0.86; 95% CI, 0.76-0.98) compared to non-application of any ICS, whereas flowmetry showed no significant association. CONCLUSIONS: This study represents the first systematic literature review and meta-analysis on usage of ICSs in CEA. Data strongly indicate a significant beneficial effect of angiography, IDUS, and angioscopy on perioperative CEA outcomes. Any carotid surgeon should consider implementation of ICSs in his routine armamentarium.

Chitinase 3 like 1 is a regulator of smooth muscle cell physiology and atherosclerotic lesion stability.

AIMS: Atherosclerotic cerebrovascular disease underlies the majority of ischaemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals. METHODS AND RESULTS: Using two independent human endarterectomy biobanks, we found that the understudied glycoprotein, chitinase 3 like 1 (CHI3L1), is up-regulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumour suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity. CONCLUSION: CHI3L1 is up-regulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke.

Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis.

Atherosclerosis is the process that underlies heart attack and stroke. A characteristic feature of the atherosclerotic plaque is the accumulation of apoptotic cells in the necrotic core. Prophagocytic antibody-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells; however, these therapies can cause off-target clearance of healthy tissues, which leads to toxicities such as anaemia. Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of the antiphagocytic CD47-SIRPα signalling axis. We demonstrate that these single-walled carbon nanotubes accumulate within the atherosclerotic plaque, reactivate lesional phagocytosis and reduce the plaque burden in atheroprone apolipoprotein-E-deficient mice without compromising safety, and thereby overcome a key translational barrier for this class of drugs. Single-cell RNA sequencing analysis reveals that prophagocytic single-walled carbon nanotubes decrease the expression of inflammatory genes linked to cytokine and chemokine pathways in lesional macrophages, which demonstrates the potential of 'Trojan horse' nanoparticles to prevent atherosclerotic cardiovascular disease.