William M. Feinberg Lecture: Asymptomatic Carotid Stenosis: Current and Future Considerations.

Asymptomatic high-grade carotid stenosis is an important therapeutic target for stroke prevention. For decades, the ACAS (Asymptomatic Carotid Atherosclerosis Study) and ACST (Asymptomatic Carotid Surgery Trial) trials provided most of the evidence supporting endarterectomy for patients with asymptomatic high-grade stenosis who were otherwise good candidates for surgery. Since then, transfemoral/transradial carotid stenting and transcarotid artery revascularization have emerged as alternatives to endarterectomy for revascularization. Advances in treatments against atherosclerosis have driven down the rates of stroke in patients managed without revascularization. SPACE-2 (Stent-Protected Angioplasty Versus Carotid Endarterectomy-2), a trial that included endarterectomy, stenting, and medical arms, failed to detect significant differences in stroke rates among treatment groups, but the study was stopped well short of its recruitment goal. CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) will be able to clarify whether revascularization by stenting or endarterectomy remains efficacious under conditions of intensive medical management. Transcarotid artery revascularization has a favorable periprocedural risk profile, but randomized trials comparing it to intensive medical management are lacking. Features like intraplaque hemorrhage on MRI and echolucency on B-mode ultrasonography can identify patients at higher risk of stroke with asymptomatic stenosis. High-grade stenosis with poor collaterals can cause hemispheric hypoperfusion, and unstable plaque can cause microemboli, both of which may be treatable risk factors for cognitive impairment. Evidence that there are patients with carotid stenosis who benefit cognitively from revascularization is presently lacking. New risk factors are emerging, like exposure to microplastics and nanoplastics. Strategies to limit exposure will be important without specific medical therapies.

Transcarotid Arterial Revascularization of Symptomatic Internal Carotid Artery Disease: A Systematic Review and Study-Level Meta-Analysis.

BACKGROUND: Transcarotid artery revascularization (TCAR) is an interventional therapy for symptomatic internal carotid artery disease. Currently, the utilization of TCAR is contentious due to limited evidence. In this study, we evaluate the safety and efficacy of TCAR in patients with symptomatic internal carotid artery disease compared with carotid endarterectomy (CEA) and carotid artery stenting (CAS). METHODS: A systematic review was conducted, spanning from January 2000 to February 2023, encompassing studies that used TCAR for the treatment of symptomatic internal carotid artery disease. The primary outcomes included a 30-day stroke or transient ischemic attack, myocardial infarction, and mortality. Secondary outcomes comprised cranial nerve injury and major bleeding. Pooled odds ratios (ORs) for each outcome were calculated to compare TCAR with CEA and CAS. Furthermore, subgroup analyses were performed based on age and degree of stenosis. In addition, a sensitivity analysis was conducted by excluding the vascular quality initiative registry population. RESULTS: A total of 7 studies involving 24 246 patients were analyzed. Within this patient cohort, 4771 individuals underwent TCAR, 12 350 underwent CEA, and 7125 patients underwent CAS. Compared with CAS, TCAR was associated with a similar rate of stroke or transient ischemic attack (OR, 0.77 [95% CI, 0.33-1.82]) and myocardial infarction (OR, 1.29 [95% CI, 0.83-2.01]) but lower mortality (OR, 0.42 [95% CI, 0.22-0.81]). Compared with CEA, TCAR was associated with a higher rate of stroke or transient ischemic attack (OR, 1.26 [95% CI, 1.03-1.54]) but similar rates of myocardial infarction (OR, 0.9 [95% CI, 0.64-1.38]) and mortality (OR, 1.35 [95% CI, 0.87-2.10]). CONCLUSIONS: Although CEA has traditionally been considered superior to stenting for symptomatic carotid stenosis, TCAR may have some advantages over CAS. Prospective randomized trials comparing the 3 modalities are needed.

Diagnostic Performance of Carotid Ring Sign on CT-Angiography in Internal Carotid True Occlusion.

BACKGROUND: To differentiate between pseudo occlusion (PO) and true occlusion (TO) of internal carotid artery (ICA) is important in thrombectomy treatment planning for patients with acute ischemic stroke. Although delayed contrast filling has been differentiated carotid PO from TO, its application has been limited by the implementations of multiphasic computed tomography angiography. In this study, we hypothesized that carotid ring sign, which is readily acquired from single-phasic CTA, can sufficiently differentiate carotid TO from PO. METHODS: One thousand four hundred and twenty patients with anterior circulation stroke receiving endovascular therapy were consecutively recruited through a hospital- and web-based registry. Two hundred patients with nonvisualization of the proximal ICA were included in the analysis after a retrospective screening. Diagnosis of PO or TO of the cervical segment of ICA was made based on digital subtraction angiography. Diagnostic performances of carotid ring sign on arterial-phasic CTA and delayed contrast filling on multiphasic computed tomography angiography were evaluated and compared. RESULTS: One-hundred twelve patients had ICA PO and 88 had TO. Carotid ring sign was more common in patients with TO (70.5% versus 6.3%; P<0.001), whereas delayed contrast filling was more common in PO (94.9% versus 7.7%; P<0.001). The sensitivity and specificity of carotid ring sign in diagnosing carotid TO were 0.70 and 0.94, respectively, whereas sensitivity and specificity of delayed contrast filling was 0.95 and 0.92 in judging carotid PO. CONCLUSIONS: Carotid ring sign is a potent imaging marker in diagnosing ICA TO. Carotid ring sign could be complementary to delayed contrast filling sign in differentiating TO from PO, in particular in centers with only single-phasic CTA.

Microglial TLR4 Mediates White Matter Injury in a Combined Model of Diesel Exhaust Exposure and Cerebral Hypoperfusion.

BACKGROUND: Air pollution particulate matter exposure and chronic cerebral hypoperfusion (CCH) contribute to white matter toxicity through shared mechanisms of neuroinflammation, oxidative stress, and myelin breakdown. Prior studies showed that exposure of mice to joint particulate matter and CCH caused supra-additive injury to corpus callosum white matter. This study examines the role of TLR4 (toll-like receptor 4) signaling in mediating neurotoxicity and myelin damage observed in joint particulate matter and CCH exposures. METHODS: Experiments utilized a novel murine model of inducible monocyte/microglia-specific TLR4 knockout (i-mTLR4-ko). Bilateral carotid artery stenosis (BCAS) was induced surgically to model CCH. TLR4-intact (control) and i-mTLR4-ko mice were exposed to 8 weeks of either aerosolized diesel exhaust particulate (DEP) or filtered air (FA) in 8 experimental groups: (1) control/FA (n=10), (2) control/DEP (n=10), (3) control/FA+BCAS (n=9), (4) control/DEP+BCAS (n=10), (5) i-mTLR4-ko/FA (n=9), (6) i-mTLR4-ko/DEP (n=8), (7) i-mTLR4-ko/FA+BCAS (n=8), and (8) i-mTLR4-ko/DEP+BCAS (n=10). Corpus callosum levels of 4-hydroxynonenal, 8-Oxo-2'-deoxyguanosine, Iba-1 (ionized calcium-binding adapter molecule 1), and dMBP (degraded myelin basic protein) were assayed via immunofluorescence to measure oxidative stress, neuroinflammation, and myelin breakdown, respectively. RESULTS: Compared with control/FA mice, control/DEP+BCAS mice exhibited increased dMBP (41%; P<0.01), Iba-1 (51%; P<0.0001), 4-hydroxynonenal (100%; P<0.0001), and 8-Oxo-2'-deoxyguanosine (65%; P<0.05). I-mTLR4 knockout attenuated responses to DEP/BCAS for all markers. CONCLUSIONS: i-mTLR4-ko markedly reduced neuroinflammation and oxidative stress and attenuated white matter degradation following DEP and CCH exposures. This suggests a potential role for targeting TLR4 signaling in individuals with vascular cognitive impairment, particularly those exposed to substantial ambient air pollution.

Surveillance duplex ultrasound prompted interventions after carotid endarterectomy.

OBJECTIVE: Current societal guidelines recommend duplex ultrasound (DUS) surveillance beyond 30 days after carotid endarterectomy (CEA) for patients with risk factors for restenosis or who underwent primary closure. However, the appropriate duration of this surveillance has not yet been identified, and the rate at which DUS surveillance prompts intervention is unknown. Multiple calls for decreasing health care spending that does not provide value, including unnecessary testing, have been made. The purpose of this study was to examine the rate of intervention prompted by surveillance DUS on the ipsilateral or contralateral carotid artery after CEA and determine the value of continued surveillance by determining the rate of DUS-prompted intervention. METHODS: A single-center, retrospective chart review of all patients older than 18 years who had undergone CEA from August 2009 to July 2022 was performed. Patients with at least one postoperative duplex in our Intersocietal Accreditation Council-accredited ultrasound lab were included. Exclusion criteria were patients with incomplete medical charts or patients who underwent a concomitant procedure. The primary end point was return to the operating room for subsequent intervention based on abnormal surveillance DUS findings. Secondary end points were the number of postoperative surveillance duplexes, duration of surveillance, and incidence of perioperative stroke. The study participant data were queried for patients who had a diagnosis of stroke that occurred following their procedure. RESULTS: A total 767 patients, accounting for 771 procedures, were included in this study, which resulted in 2145 ultrasound scans. A total of 40 (5.2%) patients required 44 subsequent interventions that were prompted by DUS surveillance scans. The average number of ultrasound scans per patient was 2.8 (range: 0-14), and the average duration of surveillance was 26.4 months (range: 0-155 months). Of the 767 patients, 669 (87.2%) had a unilateral CEA. A total of 62 of 767 (8.1%) patients had planned endarterectomies on the contralateral side based on initial imaging, not prompted by interval DUS surveillance scans. Of 767 patients, 28 (3.7%) patients who underwent CEA had a subsequent procedure for progression of contralateral disease, which was prompted by duplex surveillance scans. The average duration between index CEA and intervention on contralateral carotid was 29.57 months (range: 3-81 months). A total of 11 patients, accounting for 12 procedures, underwent a subsequent procedure for restenosis of their ipsilateral carotid, prompted by duplex surveillance scans. The average duration between index CEA and reintervention on the ipsilateral carotid was 17.9 months (range: 4-70 months). Three of 767 (0.4%) patients in total were identified as having a perioperative stroke. CONCLUSIONS: The overall rate of ipsilateral reintervention after CEA is low. A small percentage of patients will progress their contralateral disease, ultimately requiring surgical intervention. These data suggest that regular duplex surveillance after CEA is warranted for patients with at least moderate contralateral disease; however, the yield is low for ipsilateral restenosis after 36 months based on this single institution study. Further study is needed to better delineate which patients need follow-up to decrease unnecessary testing while still targeting patients most at risk of restenosis or contralateral progression of disease.

Impact of head and neck radiation on long-term outcomes after carotid revascularization.

OBJECTIVE: Radiation-induced carotid artery stenosis (RICS) is a well-described phenomenon seen after head and neck cancer radiation. Previously published literature suggests that, compared with atherosclerotic disease, RICS may result in worse long-term outcomes and early restenosis. This study aims to evaluate the effect of radiation on long-term outcomes after various carotid revascularization techniques using a multi-center registry database. METHODS: Patients in the Society for Vascular Surgery (SVS) Vascular Quality Initiative (VQI) registry for carotid artery intervention (carotid endarterectomy [CEA]; transfemoral carotid artery stenting [CAS]; transcarotid artery revascularization [TCAR]), who are 65 years or older were included in the study. VQI Vascular Implant Surveillance and Interventional Outcomes Network (VISION) Medicare-linked database was used to obtain long-term procedure-specific outcomes. Primary endpoints were 3-year death, stroke, and reintervention. We performed propensity matching between patients with prior radiation and those without. Kaplan-Meier analysis and a multivariate logistic regression model were used to analyze the outcome variables. RESULTS: A total of 56,472 patients had undergone carotid revascularization (CEA, n = 48,307; TCAR, n = 4593; CAS, n = 3572), 1244 patients with prior radiation and 54,925 patients without prior radiation. The prior radiation group was more likely to be male (71.9% vs 60.3%; P < .01), to receive a stent (47.5% vs 13.5%; P < .01), and to be on P2Y12 inhibitor (55.2% vs 38.3%; P < .01). Propensity matching was performed on 1223 patients (CEA, n = 655; TCAR, n = 292; CAS, n = 287). There were no significant differences in 30-day outcomes for death, stroke, or major adverse cardiovascular events for all three procedures. The prior radiation group had higher rates of cranial nerve injury (3.7% vs 1.8%; P = .04) and 90-day readmission (23.5% vs 18.3%; P = .01) after CEA. For long-term outcomes, prior radiation significantly increased mortality risk for CEA and CAS (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.38-2.27 and HR, 1.56; 95% CI, 1.02-2.36, respectively). The 3-year risk of stroke for CEA in radiated patients was also significantly higher (HR, 1.47; 95% CI, 1.03-2.09) compared with non-radiated patients. Prior radiation did not significantly affect death and stroke in patients undergoing TCAR. Prior radiation also did not impact the rates of short and long-term reintervention after CEA, CAS, or TCAR. CONCLUSIONS: Prior head and neck radiation significantly increases the risk for mortality and stroke for CEA and the risk for mortality after CAS. Long-term outcomes for TCAR are not significantly affected by prior radiation. TCAR may be the preferred treatment modality for patients with radiation-induced carotid stenosis.

An international, multispecialty, expert-based Delphi Consensus document on controversial issues in the management of patients with asymptomatic and symptomatic carotid stenosis.

OBJECTIVE: Despite the publication of various national/international guidelines, several questions concerning the management of patients with asymptomatic (AsxCS) and symptomatic (SxCS) carotid stenosis remain unanswered. The aim of this international, multi-specialty, expert-based Delphi Consensus document was to address these issues to help clinicians make decisions when guidelines are unclear. METHODS: Fourteen controversial topics were identified. A three-round Delphi Consensus process was performed including 61 experts. The aim of Round 1 was to investigate the differing views and opinions regarding these unresolved topics. In Round 2, clarifications were asked from each participant. In Round 3, the questionnaire was resent to all participants for their final vote. Consensus was reached when ≥75% of experts agreed on a specific response. RESULTS: Most experts agreed that: (1) the current periprocedural/in-hospital stroke/death thresholds for performing a carotid intervention should be lowered from 6% to 4% in patients with SxCS and from 3% to 2% in patients with AsxCS; (2) the time threshold for a patient being considered "recently symptomatic" should be reduced from the current definition of "6 months" to 3 months or less; (3) 80% to 99% AsxCS carries a higher risk of stroke compared with 60% to 79% AsxCS; (4) factors beyond the grade of stenosis and symptoms should be added to the indications for revascularization in AsxCS patients (eg, plaque features of vulnerability and silent infarctions on brain computed tomography scans); and (5) shunting should be used selectively, rather than always or never. Consensus could not be reached on the remaining topics due to conflicting, inadequate, or controversial evidence. CONCLUSIONS: The present international, multi-specialty expert-based Delphi Consensus document attempted to provide responses to several unanswered/unresolved issues. However, consensus could not be achieved on some topics, highlighting areas requiring future research.

Cognitive impairment in asymptomatic carotid artery stenosis is associated with abnormal segments in the Circle of Willis.

OBJECTIVE: Our group has previously demonstrated that patients with asymptomatic carotid artery stenosis (ACAS) demonstrate cognitive impairment. One proposed mechanism for cognitive impairment in patients with ACAS is cerebral hypoperfusion due to flow-restriction. We tested whether the combination of a high-grade carotid stenosis and inadequate cross-collateralization in the Circle of Willis (CoW) resulted in worsened cognitive impairment. METHODS: Twenty-four patients with high-grade (≥70% diameter-reducing) ACAS underwent carotid duplex ultrasound, cognitive assessment, and 3D time-of-flight magnetic resonance angiography. The cognitive battery consisted of nine neuropsychological tests assessing four cognitive domains: learning and recall, attention and working memory, motor and processing speed, and executive function. Raw cognitive scores were converted into standardized T-scores. A structured interpretation of the magnetic resonance angiography images was performed with each segment of the CoW categorized as being either normal or abnormal. Abnormal segments of the CoW were defined as segments characterized as narrowed or occluded due to congenital aplasia or hypoplasia, or acquired atherosclerotic stenosis or occlusion. Linear regression was used to estimate the association between the number of abnormal segments in the CoW, and individual cognitive domain scores. Significance was set to P < .05. RESULTS: The mean age of the patients was 66.1 ± 9.6 years, and 79.2% (n = 19) were male. A significant negative association was found between the number of abnormal segments in the CoW and cognitive scores in the learning and recall (ß = -6.5; P = .01), and attention and working memory (ß = -7.0; P = .02) domains. There was a trend suggesting a negative association in the motor and processing speed (ß = -2.4; P = .35) and executive function (ß = -4.5; P = .06) domains that did not reach significance. CONCLUSIONS: In patients with high-grade ACAS, the concomitant presence of increasing occlusive disease in the CoW correlates with worse cognitive function. This association was significant in the learning and recall and attention and working memory domains. Although motor and processing speed and executive function also declined numerically with increasing abnormal segments in the CoW, the relationship was not significant. Since flow restriction at a carotid stenosis compounded by inadequate collateral compensation across a diseased CoW worsens cerebral perfusion, our findings support the hypothesis that cerebral hypoperfusion underlies the observed cognitive impairment in patients with ACAS.

Female and male patients have similar outcomes after transcarotid artery revascularization in prospective trials.

OBJECTIVE: Sex disparities in outcomes after carotid revascularization have long been a concern, with several studies demonstrating increased postoperative death and stroke for female patients after either carotid endarterectomy or transfemoral stenting. Adverse events after transfemoral stenting are higher in female patients, particularly in symptomatic cases. Our objective was to investigate outcomes after transcarotid artery revascularization (TCAR) stratified by patient sex hypothesizing that the results would be similar between males and females. METHODS: We analyzed prospectively collected data from the Safety and Efficacy Study for Reverse Flow Used During Carotid Artery Stenting Procedure (ROADSTER)1 (pivotal), ROADSTER2 (US Food and Drug Administration indicated postmarket), and ROADSTER Extended Access TCAR trials. All patients had verified carotid stenosis meeting criteria for intervention (≥80% for asymptomatic patients and ≥50% in patient with symptomatic disease), and were included based on anatomical or clinical high-risk criteria for carotid stenting. Neurological assessments (National Institutes of Health Stroke Scale, Modified Rankin Scale) were obtained before and within 24 hours from procedure end by an independent neurologist or National Institutes of Health Stroke Scale-certified nurse. Patients were stratified by sex (male vs female). Baseline demographics were compared using χ2 and Fisher's exact tests where appropriate; primary outcomes were combination stroke/death (S/D) and S/D/myocardial infarction (S/D/M) at 30 days, and secondary outcomes were the individual components of S/D/M. Univariate logistic regression was conducted. RESULTS: We included 910 patients for analysis (306 female [33.6%], 604 male [66.4%]). Female patients were more often <65 years old (20.6% vs 15%) or ≥80 years old (22.6% vs 20.2%) compared with males, and were more often of Black/African American ethnicity (7.5% vs 4.3%). There were no differences by sex in term of comorbidities, current or prior smoking status, prior stroke, symptomatic status, or prevalence of anatomical and/or clinical high-risk criteria. General anesthetic use, stent brands used, and procedure times did not differ by sex, although flow reversal times were longer in female patients (10.9 minutes male vs 12.4 minutes female; P = .01), as was more contrast used in procedures for female patients (43 mL male vs 48.9 mL female; P = .049). The 30-day S/D and S/D/M rates were similar between male and female patients (S/D, 2.7% male vs 1.6% female [P = .34]; S/D/M, 3.6% male vs 2.6% female [P = .41]), which did not differ when stratified by symptom status. Secondary outcomes did not differ by sex, including stroke rates at 30 days (2.2% male vs 1.6% female; P = .80), nor were differences seen with stratification by symptom status. Univariate analysis demonstrated that history of a prior ipsilateral stroke was associated with increased odds of S/D (odds ratio [OR], 4.19; P = .001) and S/D/M (OR, 2.78; P = .01), as was symptomatic presentation with increased odds for S/D (OR, 2.78; P = .02). CONCLUSIONS: Prospective TCAR trial data demonstrate exceptionally low rates of S/D/MI, which do not differ by patient sex.

Outcomes of carotid revascularization stratified by procedure in patients with an estimated glomerular filtration rate of <30 and dialysis patients.

OBJECTIVE: Renal failure is a predictor of adverse outcomes in carotid revascularization. There has been debate regarding the benefit of revascularization in patients with severe chronic kidney disease or on dialysis. METHODS: Patients in the Vascular Quality Initiative undergoing transcarotid artery revascularization (TCAR), transfemoral carotid artery stenting (tfCAS), or CEA between 2016 and 2023 with an estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m2 or on dialysis were included. Patients were divided into cohorts based on procedure. Additional analyses were performed for patients on dialysis only and by symptomatology. Primary outcomes were perioperative stroke/death/myocardial infarction (MI) (SDM). Secondary outcomes included perioperative death, stroke, MI, cranial nerve injury, and stroke/death. Inverse probability of treatment weighting was performed based on treatment assignment to TCAR, tfCAS, and CEA patients and adjusted for demographics, comorbidities, and preoperative symptoms. The χ2 test and multivariable logistic regression analysis were used to evaluate the association of procedure with perioperative outcomes in the weighted cohort. Five-year survival was evaluated using Kaplan-Meier and weighted Cox regression. RESULTS: In the weighted cohort, 13,851 patients with an eGFR of <30 (2506 on dialysis) underwent TCAR (3639; 704 on dialysis), tfCAS (1975; 393 on dialysis), or CEA (8237; 1409 on dialysis) during the study period. Compared with TCAR, CEA had higher odds of SDM (2.8% vs 3.6%; adjusted odds ratio [aOR], 1.27; 95% confidence interval [CI], 1.00-1.61; P = .049), and MI (0.7% vs 1.5%; aOR, 2.00; 95% CI, 1.31-3.05; P = .001). Compared with TCAR, rates of SDM (2.8% vs 5.8%), stroke (1.2% vs 2.6%), and death (0.9% vs 2.4%) were all higher for tfCAS. In asymptomatic patients CEA patients had higher odds of MI (0.7% vs 1.3%; aOR, 1.85; 95% CI, 1.15-2.97; P = .011) and cranial nerve injury (0.3% vs 1.9%; aOR, 7.23; 95% CI, 3.28-15.9; P < .001). Like in the primary analysis, asymptomatic tfCAS patients demonstrated higher odds of death and stroke/death. Symptomatic CEA patients demonstrated no difference in stroke, death, or stroke/death. Although tfCAS patients demonstrated higher odds of death, stroke, MI, stroke/death, and SDM. In both groups, the 5-year survival was similar for TCAR and CEA (eGFR <30, 75.1% vs 74.2%; aHR, 1.06; P = .3) and lower for tfCAS (eGFR <30, 75.1% vs 70.4%; aHR, 1.44; P < .001). CONCLUSIONS: CEA and TCAR had similar odds of stroke and death and are both a reasonable choice in this population; however, TCAR may be better in patients with an increased risk of MI. Additionally, tfCAS patients were more likely to have worse outcomes after weighting for symptom status. Finally, although patients with a reduced eGFR have worse outcomes than their healthy peers, this analysis shows that the majority of patients survive long enough to benefit from the potential stroke risk reduction provided by all revascularization procedures.

Evaluating the influence of altered cerebral hemodynamics on cognitive performance in asymptomatic carotid artery stenosis: A systematic review.

OBJECTIVE: Substantial controversy exists regarding asymptomatic carotid stenosis (ACS) and its potential role in the pathophysiology of cognitive impairment. If proven, this hypothesis may suggest an additional definition for symptomatic carotid disease that would alter current management. This study aimed to synthesize the literature evaluating the relationship between impaired cerebral hemodynamics and cognition in patients with ACS. METHODS: A literature search was performed using MEDLINE, Embase, and EBM Reviews through May 2022. We included prospective case-control studies that used validated, objective measure(s) of either global cognition or one or more domains of cognitive function and assessed cerebrovascular reserve (CVR). RESULTS: Five studies were included, comprising a total of 782 patients with moderate (50%-69%) to severe (70%-99%) ACS. Patients with ACS and impaired ipsilateral CVR demonstrated significant cognitive impairment compared with controls. Patients with unilateral or bilateral ACS and normal CVR had cognitive scores similar to controls. Those with bilateral CVR impairment demonstrated the lowest cognitive scores. CONCLUSIONS: This review lends support to the claim that cognitive impairment, likely the result of impaired cerebral hemodynamics, is an under-recognized morbidity in patients with ACS. CVR may serve as an additional tool to determine whether patients are in fact symptomatic from their carotid stenosis and warrant consideration for intervention.

Recent advances and controversial issues in the optimal management of asymptomatic carotid stenosis.

OBJECTIVE: The optimal management of patients with asymptomatic carotid stenosis (AsxCS) is enduringly controversial. We updated our 2021 Expert Review and Position Statement, focusing on recent advances in the diagnosis and management of patients with AsxCS. METHODS: A systematic review of the literature was performed up to August 1, 2023, using PubMed/PubMed Central, EMBASE and Scopus. The following keywords were used in various combinations: "asymptomatic carotid stenosis," "carotid endarterectomy" (CEA), "carotid artery stenting" (CAS), and "transcarotid artery revascularization" (TCAR). Areas covered included (i) improvements in best medical treatment (BMT) for patients with AsxCS and declining stroke risk, (ii) technological advances in surgical/endovascular skills/techniques and outcomes, (iii) risk factors, clinical/imaging characteristics and risk prediction models for the identification of high-risk AsxCS patient subgroups, and (iv) the association between cognitive dysfunction and AsxCS. RESULTS: BMT is essential for all patients with AsxCS, regardless of whether they will eventually be offered CEA, CAS, or TCAR. Specific patient subgroups at high risk for stroke despite BMT should be considered for a carotid revascularization procedure. These patients include those with severe (≥80%) AsxCS, transcranial Doppler-detected microemboli, plaque echolucency on Duplex ultrasound examination, silent infarcts on brain computed tomography or magnetic resonance angiography scans, decreased cerebrovascular reserve, increased size of juxtaluminal hypoechoic area, AsxCS progression, carotid plaque ulceration, and intraplaque hemorrhage. Treatment of patients with AsxCS should be individualized, taking into consideration individual patient preferences and needs, clinical and imaging characteristics, and cultural, ethnic, and social factors. Solid evidence supporting or refuting an association between AsxCS and cognitive dysfunction is lacking. CONCLUSIONS: The optimal management of patients with AsxCS should include BMT for all individuals and a prophylactic carotid revascularization procedure (CEA, CAS, or TCAR) for some asymptomatic patient subgroups, additionally taking into consideration individual patient needs and preference, clinical and imaging characteristics, social and cultural factors, and the available stroke risk prediction models. Future studies should investigate the association between AsxCS with cognitive function and the role of carotid revascularization procedures in the progression or reversal of cognitive dysfunction.

Comparative assessment of racial disparity in 30-day outcomes for Asian Americans undergoing carotid endarterectomy.

OBJECTIVE: Carotid endarterectomy (CEA) is an effective treatment for carotid stenosis. All previous studies on racial disparity of CEA outcomes omitted Asian Americans. This study aimed to address this gap by investigating racial disparities in 30-day outcomes following CEA among Asian Americans. METHODS: Asian American and Caucasian patients who underwent CEA were identified in the American College of Surgeons National Surgical Quality Improvement Program targeted database from 2011 to 2021. Patients with age less than 18 years old were excluded. Patients with symptomatic and asymptomatic carotid stenosis were examined separately. A 1:5 propensity-score matching was used to address preoperative differences. Thirty perioperative outcomes were assessed. RESULTS: There were 380 Asian Americans (2.27%) and 13,250 Caucasians (79.18%) with symptomatic carotid stenosis who underwent CEA. Also, 289 Asian Americans (1.40%) and 18,257 Caucasians (88.14%) with asymptomatic carotid stenosis had CEA. Asian Americans undergoing CEA presented with higher comorbid burdens and more severe symptomology. Also, asymptomatic Asian Americans were more likely to undergo surgeries for mild stenosis (<50%), which is not in line with practice guidelines. After 1:5 propensity-matching, all symptomatic Asian Americans were matched to 1550 Caucasian patients, and all asymptomatic Asian Americans were matched to 1445 Caucasians; preoperative differences were addressed. Asian Americans exhibited low overall 30-day mortality (symptomatic, 1.61%; asymptomatic, 0.35%) and stroke (symptomatic, 2.26%; asymptomatic, 0.69%). All perioperative outcomes were comparable to Caucasians, with the exception that Asian Americans experienced longer operation times. CONCLUSIONS: Evidence suggested that Asian Americans with asymptomatic stenosis were underrepresented in CEA. After propensity-score matching, Asian Americans demonstrated comparable 30-day outcomes to Caucasians. These suggest that, when afforded equal access to quality health care, CEA serves as an effective treatment for carotid stenosis among Asian Americans. Therefore, efforts may be aimed at addressing health care access, potentially in the screening for asymptomatic carotid stenosis in Asian Americans. This would ensure they have equitable benefits from CEA. Nevertheless, the exact preoperative differences and long-term CEA outcomes in Asian Americans should warrant further examination in future studies.

Learning curve of transfemoral carotid artery stenting in the Vascular Quality Initiative registry.

OBJECTIVE: With the recent expansion of the Centers for Medicare and Medicaid Services coverage, transfemoral carotid artery stenting (tfCAS) is expected to play a larger role in the management of carotid disease. Existing research on the tfCAS learning curve, primarily conducted over a decade ago, may not adequately describe the current effect of physician experience on outcomes. Because approximately 30% of perioperative strokes/deaths post-CAS occur after discharge, appropriate thresholds for in-hospital event rates have been suggested to be <4% for symptomatic and <2% for asymptomatic patients. This study evaluates the tfCAS learning curve using Vascular Quality Initiative (VQI) data. METHODS: We identified VQI patients who underwent tfCAS between 2005 and 2023. Each physician's procedures were chronologically grouped into 12 categories, from procedure counts 1-25 to 351+. The primary outcome was in-hospital stroke/death rate; secondary outcomes were in-hospital stroke/death/myocardial infarction (MI), 30-day mortality, in-hospital stroke/transient ischemic attack (stroke/TIA), and access site complications. The relationship between outcomes and procedure counts was analyzed using the Cochran-Armitage test and a generalized linear model with restricted cubic splines. Our results were then validated using a generalized estimating equations model to account for the variability between physicians. RESULTS: We analyzed 43,147 procedures by 2476 physicians. In symptomatic patients, there was a decrease in rates of in-hospital stroke/death (procedure counts 1-25 to 351+: 5.2%-1.7%), in-hospital stroke/death/MI (5.8%-1.7%), 30-day mortality (4.6%-2.8%), in-hospital stroke/TIA (5.0%-1.1%), and access site complications (4.1%-1.1%) as physician experience increased (all P values < .05). The in-hospital stroke/death rate remained above 4% until 235 procedures. Similarly, in asymptomatic patients, there was a decrease in rates of in-hospital stroke/death (2.1%-1.6%), in-hospital stroke/death/MI (2.6%-1.6%), 30-day mortality (1.7%-0.4%), and in-hospital stroke/TIA (2.8%-1.6%) with increasing physician experience (all P values <.05). The in-hospital stroke/death rate remained above 2% until 13 procedures. CONCLUSIONS: In-hospital stroke/death and 30-day mortality rates after tfCAS decreased with increasing physician experience, showing a lengthy learning curve consistent with previous reports. Given that physicians' early cases may not be included in the VQI, the learning curve was likely underestimated. Nevertheless, a substantially high rate of in-hospital stroke/death was found in physicians' first 25 procedures. With the recent Centers for Medicare and Medicaid Services coverage expansion for tfCAS, a significant number of physicians would enter the early stage of the learning curve, potentially leading to increased postoperative complications.

The effect of the collateral cerebrovascular circulation on tolerance to carotid artery cross-clamping and on early outcome after carotid endarterectomy.

OBJECTIVE: The Circle of Willis (CoW) serves as the primary source of contralateral blood supply in patients who undergo carotid artery cross-clamping (CC) for carotid endarterectomy (CEA). It has been suggested that the CoW's anatomy influences CEA outcomes. The aim of this study was to evaluate associations between the cerebral collateral circulation, a positive awake test for intraoperative neurologic deficit after carotid CC, and postoperative adverse neurologic events. METHODS: A systematic review was conducted searching MEDLINE, Cochrane, and Web of Science databases for studies that assessed the cerebral circulation, including CoW variations, using neuroimaging techniques in patients who underwent carotid CC. For the metanalytical incidence, the statistical technique used was weight averaging. Otherwise, descriptive analysis was used due to the excessive heterogeneity of the studies. RESULTS: Eight publications, seven cohort and one case-controlled study, involving 1313 patients who underwent carotid artery CC under loco-regional anesthesia, were included in the systematic review. The incidence of positive awake test in the cohort studies ranged from 4.4% to 19.7%. Carotid artery CC resulted in positive awake test in 5% to 91% of patients with alterations in the anterior portion and in 27% to 74% with alterations in the posterior portion of the CoW. A positive awake test in patients with contralateral carotid stenosis or occlusion ranged from 5.8% to 45.7%. Contralateral carotid stenosis >70% or occlusion were associated with a positive awake test (P < .001). Patients with incomplete CoW did not have statistically significant correlation with intraoperative neurological deficits after CC. Data were insufficient to evaluate the effect of the collateral circulation on early outcome after CEA. CONCLUSIONS: In this systematic review, contralateral carotid artery stenosis or occlusion, but not CoW abnormalities, were associated with a positive awake test after carotid artery CC. Further research is needed to evaluate which specific CoW anomaly predicts neurologic deficit after CC and to confirm association between a positive awake test and clinical outcome after CEA.

Carotid endarterectomy and transcarotid artery revascularization can be performed with acceptable morbidity and mortality in patients with chronic kidney disease.

OBJECTIVE: Patients with chronic kidney disease (CKD) are considered a high-risk population, and the optimal approach to the treatment of carotid disease remains unclear. Thus, we compared outcomes following carotid revascularization for patients with CKD by operative approach of carotid endarterectomy (CEA), transfemoral carotid artery stenting (TFCAS), and transcarotid arterial revascularization (TCAR). METHODS: The Vascular Quality Initiative was analyzed for patients undergoing carotid revascularizations (CEA, TFCAS, and TCAR) from 2016 to 2021. Patients with normal renal function (estimated glomular filtration rate >90 mL/min/1.72 m2) were excluded. Asymptomatic and symptomatic carotid stenosis were assessed separately. Preoperative demographics, operative details, and outcomes of 30-day mortality, stroke, myocardial infarction (MI), and composite variable of stroke/death were compared. Multivariable analysis adjusted for differences in groups, including CKD stage. RESULTS: A total of 90,343 patients with CKD underwent revascularization (CEA, n = 66,870; TCAR, n = 13,459; and TFCAS, n = 10,014; asymptomatic, 63%; symptomatic, 37%). Composite 30-day mortality/stroke rates were: asymptomatic: CEA, 1.4%; TCAR, 1.2%; TFCAS, 1.8%; and symptomatic: CEA, 2.7%; TCAR, 2.3%; TFCAS, 3.7%. In adjusted analysis, TCAR had lower 30-day mortality compared with CEA (asymptomatic: adjusted odds ratio [aOR], 0.4; 95% confidence interval [CI], 0.3-0.7; symptomatic: aOR, 0.5; 95% CI, 0.3-0.7), and no difference in stroke, MI, or the composite outcome of stroke/death in both symptom cohorts. TCAR had lower risk of other cardiac complications compared with CEA in asymptomatic patients (aOR, 0.7; 95% CI, 0.6-0.9) and had similar risk in symptomatic patients. Compared with TFCAS, TCAR patients had lower 30-day mortality (asymptomatic: aOR, 0.5; 95% CI, 0.2-0.95; symptomatic: aOR, 0.3; 95% CI, 0.2-0.4), stroke (symptomatic: aOR, 0.7; 95% CI, 0.5-0.97), and stroke/death (asymptomatic: aOR, 0.7; 95% CI, 0.5-0.97; symptomatic: aOR, 0.6; 95% CI, 0.4-0.7), but no differences in MI or other cardiac complications. Patients treated with TFCAS had higher 30-day mortality (aOR, 1.8; 95% CI, 1.2-2.5) and stroke risk (aOR, 1.3; 95% CI, 1.02-1.7) in symptomatic patients compared with CEA. There were no differences in MI or other cardiac complications. CONCLUSIONS: Among patients with CKD, TCAR and CEA showed rates of stroke/death less than 2% for asymptomatic patients and less than 3% for symptomatic patients. Given the increased risk of major morbidity and mortality, TFCAS should not be performed in patients with CKD who are otherwise anatomic candidates for TCAR or CEA.

Diagnostics Accuracy of Magnetic Resonance Imaging in Detection of Atherosclerotic Plaque Characteristics in Carotid Arteries Compared to Histology: A Systematic Review.

Carotid plaque composition represents one of the main risk factors of future ischemic stroke. MRI provides excellent soft tissue contrast that can distinguish plaque characteristics. Our objective was to analyze the diagnostic accuracy of MRI imaging in the detection of carotid plaque characteristics compared to histology in patients with symptomatic and asymptomatic carotid atherosclerosis through a systematic review. After prospective registration in PROSPERO (ID CRD42022329690), Medline Ovid, Embase.com, Cochrane Library, and Web of Science Core were searched without any search limitation up to May 27, 2022 to identify eligible articles. Of the 8168 studies, 53 (37 × 1.5 T MRI, 17 × 3 T MRI) evaluated MRI accuracy in the detection of 13 specific carotid plaque characteristics in 169 comparisons. MRI demonstrated high diagnostic accuracy for detection of calcification (3 T MRI: mean sensitivity 92%/mean specificity 90%; 1.5 T MRI: mean sensitivity 81%/mean specificity 91%), fibrous cap (1.5 T: 89%/87%), unstable plaque (1.5 T: 89%/87%), intraplaque hemorrhage (1.5 T: 86%/88%), and lipid-rich necrotic core (1.5 T: 89%/79%). MRI also proved to have a high level of tissue discrimination for the carotid plaque characteristics investigated, allowing potentially for a better risk assessment and follow-up of patients who may benefit from more aggressive treatments. These results emphasize the role of MRI as the first-line imaging modality for comprehensive assessment of carotid plaque morphology, particularly for unstable plaque. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Cerebral Blood Flow Patterns in Patients With Low-Flow Carotid Artery Stenosis, a 4D-PCMRI Assessment.

BACKGROUND: Compromised cerebral blood flow can contribute to future ischemic events in patients with symptomatic carotid artery disease. However, there is limited knowledge of the effects on cerebral hemodynamics resulting from a reduced internal carotid artery (ICA) blood flow rate (BFR). PURPOSE: Investigate how reduced ICA-BFR, relates to BFR in the cerebral arteries. STUDY TYPE: Prospective. SUBJECTS: Thirty-eight patients, age 72 ± 6 years (11 female). FIELD STRENGTH/SEQUENCE: 3-Tesla, four-dimensional phase-contrast magnetic resonance imaging (4D-PCMRI). ASSESSMENT: Patients with ischemic stroke or transient ischemic attack were evaluated regarding the degree of stenosis. 4D-PCMRI was used to measure cerebral BFR in 38 patients with symptomatic carotid stenosis (≥50%). BFR in the cerebral arteries was assessed in two subgroups based on symptomatic ICA-BFR: reduced ICA-flow (<160 mL/minutes) and preserved ICA-flow (≥160 mL/minutes). BFR laterality was defined as a difference in the paired ipsilateral-contralateral arteries. STATISTICAL TESTS: Patients were grouped based on ICA-BFR (reduced vs. preserved). Statistical tests (independent sample t-test/paired t-test) were used to compare groups and hemispheres. Significance was determined at P < 0.05. RESULTS: The degree of stenosis was not significantly different, 80% (95% confidence interval [CI] = 73%-87%) in the reduced ICA-flow vs. 72% (CI = 66%-76%) in the preserved ICA-flow; P = 0.09. In the reduced ICA-flow group, a significantly reduced BFR was found in the ipsilateral middle cerebral artery and anterior cerebral artery (A1), while significantly increased in the contralateral A1. Retrograde BFR was found in the posterior communicating artery and ophthalmic artery. Significant BFR laterality was present in all paired arteries in the reduced ICA-flow group, contrasting the preserved ICA-flow group (P = 0.14-0.93). DATA CONCLUSIONS: 4D-PCMRI revealed compromised cerebral BFR due to carotid stenosis, not possible to detect by solely analyzing the degree of stenosis. In patients with reduced ICA-flow, collaterals were not sufficient to maintain symmetrical BFR distribution to the two hemispheres. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Limb-Shaking Transient Ischemic Attacks in Patients with Carotid Occlusion or Stenosis: A Systematic Review and Individual Patient Data Meta-Analysis.

BACKGROUND: Limb-shaking transient ischemic attack (LSTIA) is a rare neurological condition which presents with involuntary jerky movements of the arm or leg, often because of carotid stenosis or occlusion. Due to the rarity of the condition, the epidemiology of LSTIA is poorly understood and the disease is frequently misdiagnosed. There is no standard treatment to date. The purpose of this study was to provide an overview of the epidemiology of LSTIA and its current treatment options. METHODS: Embase, MEDLINE, Web of Science, Cochrane Central Register of Controlled Trials for randomized controlled trials, and Google Scholar were searched from database inception to December 30, 2023 for articles containing information on the epidemiology and treatment of LSTIA. An individual patient data meta-analysis (IPD-MA) was performed using data extracted from the included articles. Inclusion criteria were description of both the epidemiology and treatment of LSTIA in patients over the age of 18 with carotid stenosis/occlusion, confirmed by radiographic imaging. Exclusion criteria were studies focusing on pediatrics, no epidemiological data, internal carotid artery (ICA) stenosis/occlusion not radiologically confirmed, full text unavailable, full text not in English or Dutch, and non-original articles. RESULTS: Of the 8,855 articles screened, 55 articles containing 251 patients were included. Fifty articles harboring 81 patients were included in the IPD-MA, and 7 articles harboring 187 patients were included in the cohort analysis. The results of the IPD-MA showed that LSTIA was caused by unilateral ICA stenosis/occlusion in 29 patients (36%) and most often from bilateral ICA stenosis/occlusion in 52 patients (64%). Limb-shaking was unilateral in 66 patients (83%) and was accompanied by weakness in 27 patients (33%). The intervention with the highest success rate was endovascular intervention (carotid stenting or balloon angioplasty), as all 10 patients remained asymptomatic after treatment. The cohort analysis showed that LSTIA can be caused by both unilateral and bilateral carotid stenosis or occlusion. The prevalence within cohorts of TIA patients of LSTIA varied considerably from 3.5 to 29%. CONCLUSION: A large international clinical registry is warranted to gain a better understanding of the epidemiology of LSTIA. There is insufficient evidence available to suggest a standard treatment.

Interleukin-6 Predicts Carotid Plaque Severity, Vulnerability, and Progression.

BACKGROUND: IL-6 (interleukin-6) has important roles in atherosclerosis pathophysiology. To determine if anti-IL-6 therapy warrants evaluation as an adjuvant stroke prevention strategy in patients with carotid atherosclerosis, we tested whether circulating IL-6 levels predict carotid plaque severity, vulnerability, and progression in the prospective population-based CHS (Cardiovascular Health Study). METHODS: Duplex carotid ultrasound was performed at baseline and 5 years. Baseline plaque severity was scored 0 to 5 based on North American Symptomatic Carotid Endarterectomy Trial grade of stenosis. Plaque vulnerability at baseline was the presence of markedly irregular, ulcerated, or echolucent plaques. Plaque progression at 5 years was a ≥1 point increase in stenosis severity. The relationship of baseline plasma IL-6 levels with plaque characteristics was modeled using multivariable linear (severity) or logistic (vulnerability and progression) regression. Risk factors of atherosclerosis were included as independent variables. Stepwise backward elimination was used with P>0.05 for variable removal. To assess model stability, we computed the E-value or minimum strength of association (odds ratio scale) that unmeasured confounders must have with log IL-6 and the outcome to suppress the association. We performed internal validation with 100 bootstrap samples. RESULTS: There were 4334 participants with complete data (58.9% women, mean age: 72.7±5.1 years), including 1267 (29.2%) with vulnerable plaque and 1474 (34.0%) with plaque progression. Log IL-6 predicted plaque severity (ß=0.09, P=1.3×10-3), vulnerability (OR, 1.21 [95% CI, 1.05-1.40]; P=7.4×10-3, E-value=1.71), and progression (OR, 1.44 [95% CI, 1.23-1.69], P=9.1×10-6, E-value 2.24). In participants with >50% predicted probability of progression, mean log IL-6 was 0.54 corresponding to 2.0 pg/mL. Dichotomizing IL-6 levels did not affect the performance of prediction models. CONCLUSIONS: Circulating IL-6 predicts carotid plaque severity, vulnerability, and progression. The 2.0 pg/mL cutoff could facilitate the selection of individuals that would benefit from anti-IL-6 drugs for stroke prevention.