Asymptomatic High-grade Carotid Stenosis Research Articles

Independent Factors Influencing Changes in Baroreceptor Sensitivity after Carotid Endarterectomy

ObjectiveCarotid endarterectomy (CEA) is a well-established standard therapy for patients with symptomatic or asymptomatic high-grade carotid stenosis. The aim of carotid endarterectomy is to decrease the risk of stroke and avoid relevant functional loss. However, carotid endarterectomy is known to be associated with haemodynamic dysregulation. In this study we compared eversion CEA (E-CEA) and conventional CEA (C-CEA) regarding postoperative blood pressure values as well as preoperative and postoperative baroreceptor sensitivity in the first 7 days after surgery. The aim was to find possible factors influencing changes in baroreceptor sensitivity. MethodsPatients (111 patients were enrolled, of which 50 patients received C-CEA and 61 patients E-CEA) were prospectively enrolled in this study. For the measurement of baroreceptor sensitivity, a non-invasive Finometer measuring device from Finapres Medical System B.V. (Amsterdam, The Netherlands) was used. Measurements were performed one day before surgery (PRE), directly after surgery (F1), on day 1 (F2), day 2 (F3) and on day 7 (F4) postoperatively. ResultsPostoperative blood pressure values were significantly higher in the E-CEA group on the day of surgery (F1) (p<0.001) and on day 1 (F2) (p<0.001). From day 2 (F3, F4) postoperatively, no significant difference was found between the two groups. The invasive blood pressure measurement in the postoperative recovery room showed significantly higher systolic blood pressure values in the E-CEA group (p=0.001). The need of acute antihypertensive therapy was significantly higher in the recovery room in the E-CEA group (p=0.020). With regard to changes in baroreceptor sensitivity, significantly lower baroreceptor sensitivity (BRS) values were recorded in the E-CEA group at 1 day (F2) postoperatively (p=0.005). The regression analysis showed that the applied surgical technique and the patients age were significant factors influencing changes in baroreceptor sensitivity. ConclusionsIn this study we could confirm higher blood pressure levels after E-CEA in the first two days after surgery. Additionally, we identified two factors possibly influencing baroreceptor sensitivity: surgical technique and age. Based on the data obtained in this study, haemodynamic dysregulation after CEA (E-CEA, C-CEA) is temporary and short-term. Already after the second postoperative day there was no significant difference between the E-CEA and E-CEA groups, this effect remained stable after 7 days.

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.

Increasing Occlusive Disease in the Circle of Willis Correlates with Worse Cognitive Function in Patients with High-grade Asymptomatic Carotid Stenosis

Increasing Occlusive Disease in the Circle of Willis Correlates with Worse Cognitive Function in Patients with High-grade Asymptomatic Carotid Stenosis

Cortical Thinning in High-Grade Asymptomatic Carotid Stenosis.

High-grade carotid artery stenosis may alter hemodynamics in the ipsilateral hemisphere, but consequences of this effect are poorly understood. Cortical thinning is associated with cognitive impairment in dementia, head trauma, demyelination, and stroke. We hypothesized that hemodynamic impairment, as represented by a relative time-to-peak (TTP) delay on MRI in the hemisphere ipsilateral to the stenosis, would be associated with relative cortical thinning in that hemisphere. We used baseline MRI data from the NINDS-funded Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis-Hemodynamics (CREST-H) study. Dynamic contrast susceptibility MR perfusion-weighted images were post-processed with quantitative perfusion maps using deconvolution of tissue and arterial signals. The protocol derived a hemispheric TTP delay, calculated by subtraction of voxel values in the hemisphere ipsilateral minus those contralateral to the stenosis. Among 110 consecutive patients enrolled in CREST-H to date, 45 (41%) had TTP delay of at least 0.5 seconds and 9 (8.3%) subjects had TTP delay of at least 2.0 seconds, the maximum delay measured. For every 0.25-second increase in TTP delay above 0.5 seconds, there was a 0.006-mm (6 micron) increase in cortical thickness asymmetry. Across the range of hemodynamic impairment, TTP delay independently predicted relative cortical thinning on the side of stenosis, adjusting for age, sex, hypertension, hemisphere, smoking history, low-density lipoprotein cholesterol, and preexisting infarction (P=0.032). Our findings suggest that hemodynamic impairment from high-grade asymptomatic carotid stenosis may structurally alter the cortex supplied by the stenotic carotid artery.

Carotid endarterectomy is safe for octogenarians

Carotid endarterectomy (CEA) has demonstrated superior results in stroke risk reduction for patients with symptomatic and asymptomatic high-grade carotid stenosis. However, this benefit has long been questioned for the elderly and high-risk populations. In the present study, we aimed to provide high-volume, single-institution data with long-term follow-up examining the risk factors for postoperative stroke and stroke-free survival stratified by age for asymptomatic and symptomatic patients undergoing CEA. A single-institution retrospective review of 840 consecutive patients who had undergone CEA from 2011 to 2018 was performed, inclusive of both symptomatic and asymptomatic operative indications. The primary end point was perioperative stroke within 30days of surgery. The secondary end points were late stroke, death, and myocardial infarction. Patients aged >80years were compared with those aged<80years to examine freedom from stroke and death. Statistically significant differences were defined as those with P< .05. A total of 840 patients were evaluated with a median follow-up of 416± 1244days. Of the 840 patients, 499 (59%) were men, and 604 (72%) were White. The mean age was 72± 9years, with 202 (24%) aged ≥80years. CEA was performed for symptomatic disease in 305 patients (36%), of whom 143 (47%) had had strokes and 162 (53%) had had transient ischemic attacks. The overall 30-day postoperative stroke rate was 1.0% (eight patients; 0.6% for asymptomatic and 1.6% for symptomatic; P= .147). Compared with younger patients, octogenarians had had a similar stroke rate after CEA (1.5% vs 0.8%; P= .407). Hispanic race was an independent risk factor for postoperative stroke. White race and preoperative statin use both appeared to be protective. Kaplan-Meier survival curves demonstrated decreased a 5-year stroke-free survival in patients aged ≥80years (P= .031). However, overall, the estimated 5-year survival was similar to the U.S. general population across both age groups. CEA for octogenarians is safe and effective for both symptomatic and asymptomatic populations with excellent 30-day outcomes and long-term survival mirroring that of the general population.

Elevated EMMPRIN Serum Levels Indicate Plaque Vulnerability in Patients With Asymptomatic High Grade Carotid Stenosis

Carotid atherosclerosis is an important cause of cerebral ischaemic stroke. Sonographic plaque characteristics are inappropriate for exact prediction of possible future ischaemic events. Additional markers are needed to predict the clinical outcome in high grade carotid stenosis. This study aimed to test extracellular matrix metalloproteinase inducer (EMMPRIN), due to its involvement in plaque formation and destabilisation, as a potential marker of high risk vulnerable plaques. EMMPRIN was analysed in pre-operative serum samples from patients with symptomatic and asymptomatic carotid artery stenosis by a specific ELISA. Pre-operative duplex sonography classified the atherosclerotic plaque due to echogenicity. Histopathological analysis of vulnerable and non-vulnerable plaques was based on the American Heart Association (AHA) classification. The study included 265 patients undergoing carotid endarterectomy: 90 (m:f, 69:21) patients with symptomatic and 175 (m:f, 118:57) with asymptomatic disease. Analysis of circulating EMMPRIN revealed significantly higher levels in patients with echolucent plaques (4 480; IQR 3 745, 6 144 pg/mL) compared with echogenic plaques (4 159; IQR 3 418, 5 402 pg/mL; p= .025). Asymptomatic patients with vulnerable plaques had significantly higher levels of EMMPRIN (4 875; IQR 3 850, 7 016 pg/mL) compared with non-vulnerable plaques (4 109; IQR 3 433, 5 402 pg/mL; p < .001). In logistic regression analysis, duplex sonography combined with age, gender, and clinical risk factors predicted vulnerable plaques in asymptomatic patients with an AUC of 0.71 (95% CI 0.61 - 0.80). EMMPRIN significantly improved the AUC in asymptomatic patients (AUC 0.79; 95% CI 0.71 - 0.87; p= .014). Patients with high risk plaques according to ultrasound and histopathological characteristics demonstrated increased serum EMMPRIN levels. EMMPRIN on top of clinical risk factors, including age, gender, and duplex sonography may be used for pre-operative risk stratification in asymptomatic patients.

Comprehensive Evaluation of Cerebral Hemodynamics and Oxygen Metabolism in Revascularization of Asymptomatic High-Grade Carotid Stenosis

IntroductionRevascularization procedures in carotid artery stenosis have shown a positive effect in the restoration of cerebral oxygen metabolism as assessed by T2’ (T2 prime) imaging as well as capillary homeostasis by measurement of capillary transit time heterogeneity (CTH); however, data in patients with asymptomatic carotid stenosis without manifest brain lesions are scarce.Patients and MethodsThe effect of revascularization on the hemodynamic profile and capillary homeostasis was evaluated in 13 patients with asymptomatic high-grade carotid stenosis without ischemic brain lesions using dynamic susceptibility contrast perfusion imaging and oxygenation-sensitive T2’ mapping before and 6–8 weeks after revascularization by endarterectomy or stenting. The cognitive performance at both timepoints was further assessed.ResultsPerfusion impairment at baseline was accompanied by an increased CTH (p = 0.008) in areas with a time to peak delay ≥ 2 s in the affected hemisphere compared to contralateral regions. Carotid intervention improved the overall moderate hemodynamic impairment at baseline by leading to an increase in normalized cerebral blood flow (p = 0.017) and a decrease in mean transit time (p = 0.027), oxygen extraction capacity (OEC) (p = 0.033) and CTH (p = 0.048). The T2’ values remained unchanged.ConclusionThis study presents novel evidence of a state of altered microvascular function in patients with high-grade carotid artery stenosis in the absence of ischemic brain lesions, which shows sustained normalization after revascularization procedures.

Non-Adherence to Antihypertensive Guidelines in Patients with Asymptomatic Carotid Stenosis

ImportanceHypertension and carotid stenosis are both risk factors for stroke, but the presence of carotid stenosis might dampen enthusiasm for tight control of hypertension because of concerns for hypoperfusion. ObjectiveTo determine the extent to which there are opportunities to potentially improve pharmacotherapy for hypertension in patients known to have asymptomatic high-grade carotid stenosis. DesignWe examined anti-hypertensive medication prescription and adherence to evidence-based hypertension treatment guidelines in a cross-sectional analysis of baseline data of patients enrolled in a clinical trial. SettingThe Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) is a multicenter prospective randomized open blinded end-point clinical trial of intensive medical management with or without revascularization by endarterectomy or stenting for asymptomatic high-grade carotid stenosis. Participants1479 participants (38.6% female; mean age 69.8 years) from 132 clinical centers enrolled in the CREST-2 trial as of April 6, 2020 who were taking ≥1 antihypertensive drug at baseline. ExposuresPharmacotherapy for hypertension. Main outcomeAdherence to evidence-based guidelines for treating hypertension. ResultsOf 1458 participants with complete data, 26% were on one, 31% on 2, and 43% on ≥3 antihypertensive medications at trial entry. Thirty-two percent of participants were prescribed thiazide; 74%, angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB); 38%, calcium channel blocker (CCB); 56%, a beta blocker; 11%, loop diuretic; and 27%, other. Of those prescribed a single antihypertensive medication, the proportion prescribed thiazide was 5%; ACEI or ARB, 55%, and CCB, 11%. The prevalence of guideline-adherent regimens was 34% (95% CI, 31-36%). Conclusions and relevanceIn a diverse cohort with severe carotid disease and hypertension, non-adherence to hypertension guidelines was common. All preferred classes of antihypertensive drug were under-prescribed. Using staged iterative guideline-based care for hypertension, CREST-2 will characterize drug tolerance and stroke rates under these conditions. Trial registrationClinicalTrials.gov Number NCT02089217.

Preoperative Dependent Functional Status Is Associated With Poor Outcomes After Carotid Endarterectomy and Carotid Stenting in Both Symptomatic and Asymptomatic Patients

BackgroundBoth Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are the most common procedures to treat patients with symptomatic, and asymptomatic high-grade carotid stenosis. Poor preoperative functional status (FS) is increasingly being recognized as predictor for postoperative outcomes. The purpose of this study is to determine the impact of preoperative functional status on the outcomes of patients who undergo CEA or CAS. MethodsData was obtained from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from the years 2011–2018. All patients in the database who underwent CEA or CAS during this time period were identified. Patients were then further divided into 2 subgroups: FS-Independent and FS-dependent. Bivariate and multivariate analyses was performed for pre, intra and post-operative variables with functional status. Outcomes for treatment of symptomatic carotid disease were compared to those with asymptomatic disease among the cohort of functionally dependent patients. ResultsA total of 27,163 patients (61.2% Males, 38.8% Females) underwent CEA (n = 26,043) or CAS (n = 1,120) from 2011–2018. Overall, primary outcomes were as follows: mortality 0.77% (n = 210) and stroke 1.87% (n = 507).Risk adjusted multivariate analysis showed that FS-D patients undergoing CEA had higher mortality (AOR 3.06, CI 1.90–4.92, P < 0.001), longer operative times (AOR 1.36, CI 1.17–1.58, P< 0.001) higher incidence of unplanned reoperation (AOR 1.68, CI 1.19–2.37, P = 0.003), postoperative pneumonia (AOR 5.43, CI 1.62 – 18.11, P = 0.006) and ≥3 day LOS (AOR 3.05, CI 2.62–3.56, P < 0.001) as compared to FS-I patients. FS-D patients undergoing CAS had higher incidence of postoperative pneumonia (AOR 20.81, CI 1.66–261.54, P = 0.019) and higher incidence of LOS ≥3 days (AOR 2.18, CI 1.21–3.93, P < .01) as compared to FS-I patients. Survival analysis showed that the best 30-day survival was observed in FS-I patients undergoing CEA, followed by FS-I patients undergoing CAS, followed by FS-D patients undergoing CEA, followed by FS-D patients undergoing CAS. FS-D status increased mortality after CEA by 2.11%. When the outcomes of CAS and CEA were compared to each other for the cohort of FS-D patients, CAS was associated with higher incidence of stroke (AOR 3.46, CI 0.32–1.97, P= 0.046), shorter operative times (AOR 0.25, CI 0.12–0.52, P < 0.001) and higher incidence of pneumonia (AOR 11.29, CI 1.32–96.74, P = 0.027). Symptomatic patientsundergoing CEA had higher LOS as compared to symptomatic patients undergoing CAS, and asymptomatic patients undergoing CEA or CAS. ConclusionsFS-D patients, undergoing CEA have higher mortality as compared to FS-I patients undergoing CAS. FS-D patients undergoing CAS have higher incidence of postoperative pneumonia and longer LOS as compared to FS-I patients. For the cohort of FS-D patients undergoing either CEA or CAS, CAS was associated with higher risk of stroke and reduced operative times. Risk benefit ratio for any carotid intervention should be carefully assessed before offering it to FS-D patients.Preoperative Dependent Functional Status Is Associated with Poor Outcomes After Carotid Endarterectomy and Carotid Stenting in Both Symptomatic and Asymptomatic Patients

Brain blood flow matters

Compromise in cognitive function in patients with carotid bifurcation disease is well documented. This might result from hypoperfusion of the affected hemisphere. However, not every patient with asymptomatic high-grade carotid stenosis will have compromised blood flow because collateral blood flow, via the circle of Willis, might provide adequate compensation. In their previous reports, Lal et al1 and Gray et al2 showed a clear correlation between carotid stenosis and impaired cognitive function but did not provide a mechanism.

Low rates of restenosis in primary lateral carotid artery endarterectomy

Carotid artery endarterectomy (CAE) is a treatment of choice for symptomatic and asymptomatic high-grade carotid stenosis, showing great results in reducing stroke morbidity. The optimal technique of the arterial closure is, however, still under discussion, with both patch angioplasty and primary closure having numerous advantages and pitfalls. The definite evidence is still lacking. The aim of this study was to evaluate the results of the modified primary closure technique during CEA. Incidence of restenosis more than 8 months after the surgery was measured. A retrospective observational study to evaluate modified primary internal carotid artery closure was conducted in Republican Vilnius University Hospital from January 1st, 2014 to December 31st, 2018. The patients were enrolled in the trial during their routine follow-up by their surgeon. During the visit, after an informed consent was signed, a qualified investigator performed carotid duplex ultrasound scan, documenting the restenosis rates. Patients also filled in the comorbidity assessment questionnaire, which included their smoking habits, history of hypertension and their adherence to antihypertensive medication as well as cholesterol levels and statin therapy, additional related comorbidities. Out of 342 patients that underwent CAE with primary closure in the Republican Vilnius university hospital from 2014 to 2018, 42 patients were identified as deceased, therefore a follow-up was impossible. Out of planned 150 (50%) consequently selected patients, 125 gave an informed consent to be enrolled into the study. Out of those 6 pre-occlusions were established during the review of the patient medical data and therefore were excluded from the study. In general, we analyzed the data of 119 patients and 125 CAE with a modified primary suture closure. The mean follow-up time was 35.78 months (SE 0.992; SD 11,046). At the time of a follow up, 3 (2,4%) carotid artery occlusions were identified and promptly evaluated. Restenosis rates varied: 5,6% of patients had low grade (&lt;50%), 5,6% had moderate grade (50-69%) and 1,6% had high grade (70-99%) stenosis. The modified lateral CAE with primary closure technique, used in our hospital’s contemporary practice has shown to be a promising alternative to the classical primary suture, due to reduced restenosis rates. More prospective and randomized studies are needed to evaluate this technique in comparison to other CAE closure techniques.

Balance and Mobility Function Improve After Revascularization for Asymptomatic Carotid Stenosis

Asymptomatic carotid stenosis (ACS) has recently been associated with cognitive impairment. We have found that approximately 50% of patients with ACS demonstrate cognitive impairment with deficits seen in working memory, attention, and learning. Based on these findings, we studied the association between carotid stenosis and mobility function. We found similar impairments in balance and mobility that worsened with increasing degrees of stenosis. Because these deficits were associated with concomitant stenosis-related impairment in cerebrovascular hemodynamics, we hypothesized that carotid revascularization in patients with high-grade (≥70% diameter-reducing) ACS would lead to improved balance and mobility function.

Normalization of reduced functional connectivity after revascularization of asymptomatic carotid stenosis

Internal carotid artery stenosis is a risk factor for ischemic stroke. Even in the absence of visible structural brain changes, patients with asymptomatic stenosis are prone to cognitive impairment. On a neuronal level, it was suggested that stenosis may lead to disturbed functional brain connectivity. If so, carotid revascularization should have an effect on hypothesized brain network disturbances. We studied functional connectivity in a motor network by resting-state electroencephalography in 12 patients with high grade asymptomatic carotid stenosis before and after interventional or surgical revascularization as compared to 23 controls. In patients with stenosis, functional connectivity of neural oscillations was significantly decreased prior and improved returning to normal connectivity after revascularization. In a subgroup of patients, also studied by contrast perfusion magnetic resonance imaging, reduced connectivity was associated with decreased regional brain perfusion reflected by increased mean transit time in the middle cerebral artery borderzone. Cognitive testing revealed only minor differences between patients and controls. In summary, we identified oscillatory connectivity changes in patients with asymptomatic carotid stenosis correlating with regional hypoperfusion, which both normalized after revascularization. Hence, electrophysiological changes might be a reversible precursor preceding macroscopic structural brain damage and behavioral impairment in patients with asymptomatic carotid stenosis.

Carotid revascularization and medical management for asymptomatic carotid stenosis - Hemodynamics (CREST-H): Study design and rationale.

For patients with asymptomatic high-grade carotid stenosis, clinical investigations have focused on preventing cerebral infarction, yet stenosis that reduces cerebral blood flow may independently impair cognition. Whether revascularization of a hemodynamically significant carotid stenosis can alter the course of cognitive decline has never been investigated in the context of a randomized clinical trial. Among patients randomized in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis (CREST-2) trials, the magnitude of treatment differences (revascularization versus medical management alone) with regard to cognition will differ between those with flow impairment compared to those without flow impairment. We will enroll approximately 500 patients from CREST-2, of which we anticipate 100 will have hemodynamic impairment. We estimate 93% power to detect a clinically meaningful treatment difference of 0.5 SD. We will use perfusion-weighted magnetic resonance imaging to stratify by hemodynamic status. Linear regression will compare treatment differences, controlling for baseline cognitive status, age, depression, prior cerebral infarcts, silent infarction, white matter hyperintensity volume, and cerebral microbleeds. The primary outcome is change in cognition at one year. Secondary outcomes include silent infarction, change in white matter hyperintensity volume, number of cerebral microbleeds, and cortical thickness over one year. If cognitive impairment can be shown to be reversible by revascularization, then we can redefine "symptomatic carotid stenosis" to include cognitive impairment and identify a new population of patients likely to benefit from revascularization. US National Institutes of Health (NIH) clinicaltrials.gov NCT03121209.

Duplex ultrasound in cerebrovascular disease - asymptomatic carotid stenosis

Duplex ultrasound in cerebrovascular disease - asymptomatic carotid stenosis Abstract. Distal embolization originating from an ipsilateral asymptomatic carotid stenosis (ACS) is the cause of a substantial proportion of first-ever ischemic strokes. Duplex ultrasound is recommended as first-line imaging method to detect and to evaluate the extent and severity of such extracranial carotid stenoses. All patients with ACS need best cardiovascular medical therapy including smoking cessation strategies, implementation of statins, antihypertensive drugs and antiplatelet therapy. The annual stroke rate in patients with ACS has significantly declined during the last years due to improvement in medical therapy. Therefore, surgical prophylactic carotid endarterectomy or carotid stenting no longer are recommended routinely in all patients with high-grade ACS. Several studies demonstrated that not only the grade of stenosis based on hemodynamic criteria on Duplex ultrasound increases the ipsilateral stroke risk, but also morphological characteristics on B-mode ultrasound and contrast-enhanced ultrasound are associated with more vulnerable ACS with higher risk of stroke. These additional morphological features may be useful to select a subgroup of patients with ACS who may benefit from interventions. There is some evidence that a high progression rat of the grade of stenosis on duplex ultrasound, hypoechogenicity, higher plaque area, surface irregularities and ulceration on B-mode ultrasound as well as intraplaque vascularization on contrast-enhanced ultrasound of the carotid stenosis are predictors of such a vulnerable ACS. This review article gives an overview of ultrasound based and other features of ACS, which are associated with an increased ipsilateral stroke risk.

Circulating inflammation-resolving lipid mediators RvD1 and DHA are decreased in patients with acutely symptomatic carotid disease

BackgroundEfficient biomarkers for early prediction and diagnosis of an acutely symptomatic carotid plaque rupture event are currently lacking, impairing the ability to diagnose and treat patients with an acute plaque rupture events in a timely fashion. Resolvins are endogenous inflammation-resolving lipid mediators that are induced by inflammatory insults. We hypothesized that resolvin and other lipid profiles in sera likely mark the process towards plaque rupture. MethodsCirculating lipids associated with plaque rupture events were quantitatively profiled via targeted mediator-lipidomics using ultraperformance liquid chromatography tandem mass spectrometry in patients with acutely symptomatic and asymptomatic carotid disease. ResultsResolvin D1 (RvD1, 82 ± 11pM vs. 152 ± 17pM, p = 0.001) and docosahexaenoic acid (DHA) (0.052 ± 0.007µM versus 0.076 ± 0.008µM, p = 0.025) levels are decreased in the sera of patients presenting with an acutely symptomatic carotid plaque rupture event (n = 21) compared to patients with asymptomatic (n = 24) high-grade carotid stenosis. Circulating arachidonic acid (AA) levels, however, were higher (0.429 ± 0.046µM versus 0.257 ± 0.035µM, p < 0.01) in acutely symptomatic compared to asymptomatic carotid patients. ROC curve analysis demonstrates that the serum ratio AA:RvD1 (AUC 0.84, sensitivity 0.71, specificity 0.92) and AA:DHA (AUC 0.86, sensitivity 0.90, specificity 0.71) are biomarkers for the risk of atherosclerotic plaque rupture. ConclusionsA circulating pro-inflammatory lipid profile, characterized by high AA:RvD1 and AA:DHA, is associated with acutely symptomatic carotid disease and stroke.

Carotid revascularization and medical management for asymptomatic carotid stenosis: Protocol of the CREST-2 clinical trials.

Rationale Trials conducted decades ago demonstrated that carotid endarterectomy by skilled surgeons reduced stroke risk in asymptomatic patients. Developments in carotid stenting and improvements in medical prevention of stroke caused by atherothrombotic disease challenge understanding of the benefits of revascularization. Aim Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) will test whether carotid endarterectomy or carotid stenting plus contemporary intensive medical therapy is superior to intensive medical therapy alone in the primary prevention of stroke in patients with high-grade asymptomatic carotid stenosis. Methods and design CREST-2 is two multicenter randomized trials of revascularization plus intensive medical therapy versus intensive medical therapy alone. One trial randomizes patients to carotid endarterectomy plus intensive medical therapy versus intensive medical therapy alone; the other, to carotid stenting plus intensive medical therapy versus intensive medical therapy alone. The risk factor targets of centrally directed intensive medical therapy are LDL cholesterol <70 mg/dl and systolic blood pressure <140 mmHg. Study outcomes The primary outcome is the composite of stroke and death within 44 days following randomization and stroke ipsilateral to the target vessel thereafter, up to four years. Change in cognition and differences in major and minor stroke are secondary outcomes. Sample size Enrollment of 1240 patients in each trial provides 85% power to detect a treatment difference if the event rate in the intensive medical therapy alone arm is 4.8% higher or 2.8% lower than an anticipated 3.6% rate in the revascularization arm. Discussion Management of asymptomatic carotid stenosis requires contemporary randomized trials to address whether carotid endarterectomy or carotid stenting plus intensive medical therapy is superior in preventing stroke beyond intensive medical therapy alone. Whether carotid endarterectomy or carotid stenting has favorable effects on cognition will also be tested. Trial registration United States National Institutes of Health Clinicaltrials.gov NCT02089217.

Evaluation by Magnetic Resonance Imaging of Silent Brain Infarcts in Preoperative and Postoperative Asymptomatic Carotid Surgery

To report the prevalence of silent brain infarcts (SBI) at magnetic resonance imaging (MRI) before and after surgery for asymptomatic high grade carotid stenosis. This is a single center retrospective observational study. Asymptomatic patients who underwent carotid endarterectomy between October 2012 and October 2014 were included. The preoperative assessment included a Doppler and a computed tomographic (CT) scan dating less than 3months. A neurological examination was performed during the anesthesia consultation and in the 15days before surgery. An MRI angiography was performed the day before and 3 days after surgery and was analyzed by an independent neuroradiologist. Preoperative analysis focused on the presence of ischemic events at MRI. The type of plaque, the supra aortic trunk lesions, and the quality of the circle of Willis were analyzed using Doppler and CT scanning. Postoperatively, we searched for signs of postoperative ischemic events at MRI. Forty-one patients were included (85.4% of men), and the mean age was 72.4±8.3years. We noted 7 (17.1%) contralateral stenoses (>50%) and 2 (4.9%) contralateral thromboses, 6 (14.6%) vertebral stenoses, and 7 (17.1%) abnormalities of the circle of Willis. The morphological analysis described 6 unstable plaques including 4 ulcerated, 1 pseudodissection, and 1 intraplaque hemorrhage. Preoperatively, we noted the presence of 21 (51.2%) ischemic lesions including 9 (21.9%) multiple lacunar ischemic events and 12 (29.3%) silent arterial territory infarcts. Eversion was performed for all patients except for 6 (14.6%), for whom a bypass was necessary. No deaths or major complications were observed in the 30 postoperative days. Postoperatively, MRI showed 3 (7.3%) asymptomatic recent ischemic strokes, 1 ipsilateral middle cerebral artery (MCA) stroke, and 2 contralateral (cerebellar and MCA) strokes. Patients with asymptomatic significant carotid stenosis show many preoperative SBI indicating a significant embolic risk. It is difficult to conclude about intraoperative embolic risk, but we hope that more data could demonstrate the importance of MRI for the preoperative evaluation of carotid plaques and brain parenchyma, to identify high-risk embolic patients.

Clinical need, design, and goals for the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis trial

Prior clinical trials produced evidence-based treatment recommendations for patients with asymptomatic carotid stenosis that may not be appropriate for clinical decision-making today. High-quality patient outcomes data to allow informed decision making regarding the optimal management of high-grade asymptomatic internal carotid artery stenosis is lacking. The results of the Asymptomatic Carotid Atherosclerosis Study were published in 1995 based on a randomized patient enrollment in the 1990s. Outcomes after endarterectomy, stenting, and medical treatment for these patients have all improved in the subsequent 2 decades. Therefore, the time has come to test whether contemporary intensive medical therapy is an acceptable alternative to contemporary endarterectomy or stenting and is the rationale for the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis (CREST-2) trial. This National Institute of Neurological Disorders and Stroke−sponsored prospective, multicenter clinical trial has the investigators, study teams, asymptomatic patients, and robust study design needed to provide these answers. Two randomized clinical trials are planned: carotid revascularization and intensive medical management versus medical management alone in patients with asymptomatic high-grade carotid stenosis randomize in a 1:1 ratio; the other trial will randomize patients in a 1:1 ratio to carotid stenting with embolic protection versus no stenting. ClinicalTrials.gov Identifier: NCT02089217.

Anatomic criteria determining high-risk carotid surgery patients.

Based on randomized trials, carotid endarterectomy (CEA) is the standard procedure for patients with a 50-99% symptomatic carotid stenosis and carefully selected patients with an asymptomatic high-grade carotid stenosis. Carotid artery stenting (CAS) is a technical alternative for patients with a high surgical risk or difficult anatomic conditions (e.g., recurrent stenosis). This study aims to provide an overview of anatomic factors associated with a higher risk of CEA complications. The current literature was analyzed using a hierarchical approach. Firstly, carotid guidelines published between 2010 and 2015 and their recommendations or statements concerning anatomic risks for CEA were examined. Secondly, the retrieved full-text articles of the cited literature were assessed in detail. Thirdly, we searched the MEDLINE databank using the key words "recurrent stenosis" OR "high carotid bifurcation" OR "irradiation" OR "tracheostomy" OR "neck dissection" OR "contralateral paralysis of the recurrent laryngeal nerve" AND "carotid endarterectomy" OR "carotid surgery". Finally, the available data were summarized, as was information on each defined anatomic risk factor for CEA complications. The whole analysis is descriptive; no statistics were used. No evidence was found for a higher incidence of cranial nerve injuries after carotid surgery due to a high carotid lesion. CEA can be performed if the carotid stenosis is accessible by ultrasound. Restenosis and irradiation were not associated with a higher risk of stroke or death, but were associated with a higher incidence of cranial nerve injuries. No literature is available on the influence of neck dissection, contralateral paralysis of the recurrent nerve, or tracheostomy on the CEA surgical risk. Anatomic criteria determining high-risk carotid surgery patients have been defined as high or low carotid stenosis, restenosis after CEA, previous radical neck dissection or cervical irradiation, contralateral laryngeal nerve palsy, and tracheostomy. Most of the defined criteria are based on expert opinion. Therefore, individual treatment based on carotid imaging and the local skin and soft tissue conditions is recommended.