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.

Nimodipine-associated standard dose reductions and neurologic outcomes after aneurysmal subarachnoid hemorrhage: the era of pharmacogenomics.

Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.

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.

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.

Mesenchymal Stem Cell Therapy in Acute Intracerebral Hemorrhage: A Dose-Escalation Safety and Tolerability Trial.

BACKGROUND: We conducted a preliminary phase I, dose-escalating, safety, and tolerability trial in the population of patients with acute intracerebral hemorrhage (ICH) by using human allogeneic bone marrow-derived mesenchymal stem/stromal cells. METHODS: Eligibility criteria included nontraumatic supratentorial hematoma less than 60 mL and Glasgow Coma Scale score greater than 5. All patients were monitored in the neurosciences intensive care unit for safety and tolerability of mesenchymal stem/stromal cell infusion and adverse events. We also explored the use of cytokines as biomarkers to assess responsiveness to the cell therapy. We screened 140 patients, enrolling 9 who met eligibility criteria into three dose groups: 0.5 million cells/kg, 1 million cells/kg, and 2 million cells/kg. RESULTS: Intravenous administration of allogeneic bone marrow-derived mesenchymal stem/stromal cells to treat patients with acute ICH is feasible and safe. CONCLUSIONS: Future larger randomized, placebo-controlled ICH studies are necessary to validate this study and establish the effectiveness of this therapeutic approach in the treatment of patients with ICH.

Association between heart failure and cerebral collateral flow in large vessel occlusive ischemic stroke.

BACKGROUND: Cerebral collateral circulation plays a crucial role in determining the extent of brain ischemia in large vessel occlusive (LVO) stroke. Heart failure (HF) is known to cause cerebral hypoperfusion, yet the relationship between HF and robustness of collateral flow has not been well described. METHODS: Consecutive patients with middle cerebral and/or internal carotid LVO who underwent endovascular thrombectomy (EVT) between 2012 and 2020 were included. Single-phase head CTA prior to EVT was used to assess collateral status (poor <50 % filling; good ≥50 %). Classification of HF by left ventricular ejection fraction (LVEF) on echocardiogram was used where HF with reduced ejection fraction (HFrEF) had LVEF ≤40 %, HF with preserved EF (HFpEF) had LVEF ≥50 % with evidence of structural heart disease, and no HF had LVEF≥50 % without structural heart disease. Multivariable logistic regression analyses were performed to evaluate the association between HF and poor collaterals. RESULTS: We identified 235 patients, mean age was 69 ± 15 years; initial NIHSS was 18 ± 7. Of these, 107 (45.5 %) had HF and 105 (44.7 %) had poor collaterals. Those with HF were likely to have poor collaterals compared to those without HF (56.1 % vs 35.2 %, P = 0.001). There was a dose-dependent relationship between EF and poor collaterals: adjusted odds of poor collaterals were 1.63 and 2.45 in HFpEF and HFrEF, compared to those without HF (trend P = .018). CONCLUSION: Patients with HFrEF are more likely to have poor cerebral collaterals. Further study is needed to explore the pathomechanisms. Optimization of HF may improve cerebral collaterals and enhance EVT outcomes.

Differential associations between abnormal cardiac left ventricular geometry types and cerebral white matter disease.

OBJECTIVES: Reduced cardiac outflow due to left ventricular hypertrophy has been suggested as a potential risk factor for development of cerebral white matter disease. Our study aimed to examine the correlation between left ventricular geometry and white matter disease volume to establish a clearer understanding of their relationship, as it is currently not well-established. METHODS: Consecutive patients from 2016 to 2021 who were ≥18 years and underwent echocardiography, cardiac MRI, and brain MRI within one year were included. Four categories of left ventricular geometry were defined based on left ventricular mass index and relative wall thickness on echocardiography. White matter disease volume was quantified using an automated algorithm applied to axial T2 FLAIR images and compared across left ventricular geometry categories. RESULTS: We identified 112 patients of which 34.8 % had normal left ventricular geometry, 20.5 % had eccentric hypertrophy, 21.4 % had concentric remodeling, and 23.2 % had concentric hypertrophy. White matter disease volume was highest in patients with concentric hypertrophy and concentric remodeling, compared to eccentric hypertrophy and normal morphology with a trend-P value of 0.028. Patients with higher relative wall thickness had higher white matter disease volume (10.73 ± 10.29 cc vs 5.89 ± 6.46 cc, P = 0.003), compared to those with normal relative wall thickness. CONCLUSION: Our results showed that abnormal left ventricular geometry is associated with higher white matter disease burden, particularly among those with abnormal relative wall thickness. Future studies are needed to explore causative relationships and potential therapeutic options that may mediate the adverse left ventricular remodeling and its effect in slowing white matter disease progression.

Elevated triglycerides and treatment eligibility in patients with severe, asymptomatic carotid stenosis: CREST 2 Trials.

BACKGROUND: Data from the Centers for Disease Control show that approximately one-quarter of adults have elevated triglyceride (TG) levels. Some clinical trials, but not all, have demonstrated that pharmacologic treatment of high TG levels in patients already on statin therapy reduces the rate of major vascular events such as myocardial infarction and stroke. We assessed the prevalence of elevated TG levels in patients with asymptomatic carotid stenosis (CS), and medical conditions associated with high TG. METHODS: Baseline lipid profiles from patients enrolled in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST 2) were analyzed. to determine treatment eligibility for high TG levels using the criteria established by the REDUCE-IT trial (triglyceride levels ≥150 mg/dL with LDL managed by a statin to <100 mg/dL). Equally assessed was the percentage of patients who were using pharmacologic treatment for high TG levels at study entry. Demographic factors and baseline medical conditions associated with high (>150 mg/dl) TG values were also analyzed. Chi-square and t=tests were used to assess baseline factors and abnormal TG values. RESULTS: As of October 2023, of 2377 randomized CREST-2 patients, 2328 (98 %) (mean age 70.0 years, 63 % men) had baseline lipid profiles suitable for analysis. Among 1961 (84 %) patients who met REDUCE-IT criteria, analysis of lipid profiles revealed that 20.5 % of the patients were eligible for treatment of high triglycerides. Of the 1464 patients with fasting lipid profiles, 17.8 % were eligible for treatment. The median TG value was 205 (IQR 91) mg/dl in the total population. TG levels of 150 mg/dl or higher were strongly associated with hypertension, diabetes, obesity, high hemoglobin A1c, and reduced physical activity (all p<0.0001). CONCLUSIONS: Elevated TG levels are strongly associated with diabetes, hypertension, obesity, and reduced physical activity. Further research is needed on whether treatment of elevated TG levels in patients with asymptomatic carotid stenosis confers benefit.

Cerebral Small Vessel Disease-Related Dementia: More Questions Than Answers.

Cerebral small vessel disease (CSVD) has emerged as a common factor driving age-dependent diseases, including stroke and dementia. CSVD-related dementia will affect a growing fraction of the aging population, requiring improved recognition, understanding, and treatments. This review describes evolving criteria and imaging biomarkers for the diagnosis of CSVD-related dementia. We describe diagnostic challenges, particularly in the context of mixed pathologies and the absence of highly effective biomarkers for CSVD-related dementia. We review evidence regarding CSVD as a risk factor for developing neurodegenerative disease and potential mechanisms by which CSVD leads to progressive brain injury. Finally, we summarize recent studies on the effects of major classes of cardiovascular medicines relevant to CSVD-related cognitive impairment. Although many key questions remain, the increased attention to CSVD has resulted in a sharper vision for what will be needed to meet the upcoming challenges imposed by this disease.

When Will We Have What We Need to Advise Patients How to Manage Their Carotid Stenosis?: Lessons From SPACE-2.

The recently published SPACE-2 trial (Stent-Supported Percutaneous Angioplasty of the Carotid Artery Versus Endarterectomy-2) compared 3 treatments to prevent stroke in patients with asymptomatic carotid stenosis ≥70%: (1) carotid endarterectomy plus best medical treatment (BMT), (2) transfemoral carotid artery stenting plus BMT, or (3) BMT alone. Because of low enrollment, the findings of similar safety and efficacy for carotid endarterectomy, carotid artery stenting, or BMT alone were inconclusive. Publication of the CREST (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial)-2 results should provide level A evidence that has been lacking for 2 to 3 decades, to guide treatment of asymptomatic patients with severe carotid stenosis. For symptomatic patients with ≥70% stenosis, no trials are underway to update the degree of benefit reported for carotid endarterectomy by NASCET (North American Carotid Endarterectomy Trial) and ECST (European Carotid Surgery Trial), published in 1991. Subsequently, the use of cigarettes has plummeted, and major improvements in medical treatments and in carotid revascularization have emerged. These advances have coincided with abrupt decline in the clinical end points necessary for treatment comparisons in procedural trials. One of the advances in the invasive management of carotid disease has been transcarotid artery revascularization, already with limited approval by the US Food and Drug Administration. Establishing safety and efficacy of transcarotid artery revascularization compared with carotid endarterectomy, carotid artery stenting, or BMT alone may be challenging because of enrollment, regulatory, and funding barriers to design and complete an adequately powered randomized trial.

Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association.

Lacunar infarcts and vascular dementia are important phenotypic characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, the most common inherited cerebral small vessel disease. Individuals with the disease show variability in the nature and onset of symptoms and rates of progression, which are only partially explained by differences in pathogenic mutations in the NOTCH3 gene. Recognizing the disease early in its course and securing a molecular diagnosis are important clinical goals, despite the lack of proven disease-modifying treatments. The purposes of this scientific statement are to review the clinical, genetic, and imaging aspects of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, contrasting it with other inherited small vessel diseases, and to provide key prevention, management, and therapeutic considerations with the intent of reducing practice variability and encouraging production of high-quality evidence to support future treatment recommendations.

The relevance of rich club regions for functional outcome post-stroke is enhanced in women.

This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.

A Scoping Review of Simulation-Based Training Paradigms for Carotid Artery Endarterectomy and Carotid Artery Stenting.

BACKGROUND: Surgical simulation has come to the forefront to enhance the training of residents. The aim of our scoping review is to analyze the available simulation-based carotid revascularization techniques, including carotid endarterectomy (CEA) and carotid artery stenting (CAS) and suggest critical steps for evaluating competency in a standardized fashion. METHODS: A scoping review of all reports on simulation-based carotid revascularization techniques including CEA and CAS was performed in PubMed/MEDLINE, Scopus, Embase, Cochrane, Science Citation Index Expanded, Emerging Sources Citation Index, and Epistemonikos databases. Data were collected according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. The English language literature was searched from January 1, 2000 to January 9, 2022. The outcomes evaluated included measures of assessment of operator performance. RESULTS: Five CEA and 11 CAS manuscripts were included in this review. The methods of assessments employed by these studies to judge performance were comparable. The 5 CEA studies sought to validate and demonstrate improved performance with training or distinguish surgeons by their experience level, either through assessing operative performance or end-product results. The 11 CAS studies used 1 of 2 types of commercial simulators and focused on determining the efficacy of simulators as teaching tools. By examining the steps of the procedure associated with preventable perioperative complications, it provides a reasonable framework for determining which elements of the procedure should be emphasized most. Furthermore, using potential errors as a basis for assessment of competency could reliably distinguish operators based on level of experience. CONCLUSIONS: Competency-based simulation training is becoming more relevant as our surgical training paradigm shifts with the increased scrutiny within training programs of work-hour regulations and the need to develop a curriculum to assess our trainees' ability to perform specific operations competently during their stipulated training period. Our review has given us an insight into the current efforts in this space regarding 2 specific procedures that are key for all vascular surgeons to master. Although many competency-based modules are available, there is a lack of standardization in the grading/rating system of what surgeons consider vital steps of each procedure to assess these simulation-based modules. Therefore, the next steps of curriculum development should be based on standardization efforts for the different protocols available.

No Sex Differences in the Prevalence of Intracranial Aneurysms in Patients with Ascending Thoracic Aortic Aneurysms: A Multi-Center Experience.

BACKGROUND: Previous studies suggest a coprevalence of intracranial aneurysms (IA) in patients with infrarenal abdominal aortic aneurysms (AAA). We reviewed our multicenter experience in the detection/treatment of IAs in patients with ascending thoracic aortic aneurysms (ATAA) relative to patients without ATAA. METHODS: Surgical cases of ATAA repaired at 3 sites from January 1998 to December 2018 were retrospectively reviewed. Out of these patients, those with intracranial vascular imaging were selected for our study, and these individuals were concurrently randomly matched with a control group of patients who underwent intracranial vascular imaging without an ATAA in a 1:1 ratio by age, sex, smoking history, and year of intracranial vascular imaging. Conditional logistic regression was used to calculate odds ratios (OR). RESULTS: We reviewed 2176 ATAA repairs. 74% (n = 1,615) were men. Intracranial vascular imaging was available in 298 (13.7%) patients. Ninteen patients were found to have 22 IAs for a prevalence of 6.4%. Mean size of IA was 4.6 ± 3.3 mm; mean age at IA detection, 63.4 ± 12.1 years. IA was present on head imaging in 4.7% of male and 12.5% of female patients. Eleven (58%) patients were men. The OR of having IA in female versus male patients is 2.90, 95% confidence interval [CI] [1.08-7.50], P = 0.029. Time from IA diagnosis to ATAA repair was 1.7 ± 116.2 months. Two patients underwent treatment for IA, one ruptured and one unruptured. All were diagnosed before ATAA repair. Treatment included 1 clipping and 1 coiling with subsequent reintervention of the coiling using a flow diversion device. In the matched group of patients who had intracranial vascular imaging without ATAA, the rate of IA is 5.0%. IA was detected in 3.8% of males and 9.4% of female patients for an OR of 2.59, 95% CI [0.84-7.47], P = 0.083. Association within our study and matched groups, the OR of developing an IA with and without ATAA was not statistically significant 1.29, 95% CI [0.642.59], P = 0.48. There was also no evidence of sex differences in the association of ATAA with IA (interaction P = 0.88). The OR for the association of ATAA with IA was 1.33, 95% CI [0.46-3.84], P = 0.59 in females and 1.25, 95% CI [0.49-3.17], P = 0.64 in males. CONCLUSIONS: Our study found that IA was present in 6.4% of patients with ATAA who had intracranial vascular imaging available. The odds of IA were 1.29 times higher than a matched cohort of patients who had intracranial vascular imaging without ATAA but this failed to achieve statistical significance. We found that the odds of IA were more than 2 times higher in females than males for both those with ATAA (OR = 2.90) and those without ATAA (OR = 2.59); however, it only reached statistical significance in those with ATAA.

Systematic Review on Magnetic Resonance Angiography with Vessel Wall Imaging for the Characterization of Symptomatic Carotid Artery Plaque.

BACKGROUND: To perform a systematic literature review to assess the usefulness of performing magnetic resonance angiography (MRA) with vessel wall imaging (VWI) sequences for the assessment of symptomatic carotid artery plaques and the identification of risky plaque features predisposing for stroke. METHODS: We performed a systematic review of the literature pertaining to MRA with VWI techniques in patients with carotid artery disease, focusing on symptomatic patients' plaque features and morphology. Independent reviewers screened and analyzed data extracted from eligible studies, and a modified Newcastle-Ottawa Scale was used to appraise the quality of the design and content of the selected manuscripts to achieve an accurate interpretation. RESULTS: This review included nineteen peer-reviewed manuscripts, all of them including MRA and VWI assessments of the symptomatic carotid artery plaque. We focused on patients' comorbidities and reviewed plaque features, including intraplaque hemorrhage, a lipid-rich necrotic core, a ruptured fibrous cap, and plaque ulceration. CONCLUSIONS: MRA with VWI is a useful tool in the evaluation of carotid artery plaques. This imaging technique allows clinicians to identify plaques at risk of causing a neurovascular event. The presence of intraplaque hemorrhage, plaque ulceration, a ruptured fibrous cap, and a lipid-rich necrotic core are associated with neurovascular symptoms. The timely identification of these features could have a positive impact on neurovascular event prevention.

Association between left atrial enlargement and poor cerebral collaterals in large vessel occlusion.

OBJECTIVES: Left atrial enlargement (LAE) is a known risk factor for atrial fibrillation, a common cause of large vessel occlusion (LVO) leading to ischemic stroke. While robust cerebral collaterals protect penumbral tissue from infarction, the effect of structural heart disease on cerebral collaterals remains uncertain. This study aims to investigate the association between LAE and cerebral collaterals in patients with acute LVO stroke. MATERIALS AND METHODS: We conducted a retrospective study of consecutive patients with middle cerebral and/or internal carotid LVO who underwent endovascular thrombectomy (EVT) between 2012 to 2020. Consecutive patients with echocardiography and computed tomography angiography (CTA) of the head were included. Multivariate logistic regression analysis was performed to evaluate the relationship between LAE and poor cerebral collaterals, adjusting for demographics (age, sex, race) and vascular risk factors (hypertension, diabetes and smoking). RESULTS: The study included 235 patients with mean age of 69±15 years and an initial mean National Institutes of Health Stroke Scale score of 18. Of these, 89 (37.9 %) had LAE, and 105 (44.7 %) had poor collaterals. Patients with LAE were more likely to have poor collaterals compared to those without LAE (58.4 % vs 36.3 %, P = 0.001). LAE was independently associated with higher odds of poor collaterals (odds ratio, 2.47; P = 0.001), even after adjusting for covariables (odds ratio 1.84, P = 0.048). CONCLUSIONS: Our study demonstrated a significant association between LAE and poor cerebral collaterals in patients with LVO stroke undergoing EVT. Further research is warranted to explore potential shared mechanisms, such as endothelial dysfunction, underlying this heart-brain association.

Age-related macular degeneration is associated with probable cerebral amyloid angiopathy: A case-control study.

BACKGROUND: Age-related macular degeneration (AMD) is a common retinal degenerative disorder among older individuals. Amyloid deposits, a hallmark of cerebral amyloid angiopathy (CAA), may be involved in the pathogenesis of AMD. Since amyloid deposits may contribute to the development of both AMD and CAA, we hypothesized that patients with AMD have a higher prevalence of CAA. OBJECTIVE: To compare the prevalence of CAA in patients with or without AMD matched for age. METHODS: We conducted a cross-sectional, 1:1 age-matched, case-control study of patients ≥40 years of age at the Mayo Clinic who had undergone both retinal optical coherence tomography and brain MRI from 2011 to 2015. Primary dependent variables were probable CAA, superficial siderosis, and lobar and deep cerebral microbleeds (CMBs). The relationship between AMD and CAA was assessed using multivariable logistic regression and was compared across AMD severity (none vs early vs late AMD). RESULTS: Our analysis included 256 age-matched pairs (AMD 126, no AMD 130). Of those with AMD, 79 (30.9%) had early AMD and 47 (19.4%) had late AMD. The mean age was 75±9 years, and there was no significant difference in vascular risk factors between groups. Patients with AMD had a higher prevalence of CAA (16.7% vs 10.0%, p=0.116) and superficial siderosis (15.1% vs 6.2%, p=0.020), but not deep CMB (5.2% vs 6.2%, p=0.426), compared to those without AMD. After adjusting for covariates, having late AMD was associated with increased odds of CAA (OR 2.83, 95% CI 1.10-7.27, p=0.031) and superficial siderosis (OR 3.40, 95%CI 1.20-9.65, p=0.022), but not deep CMB (OR 0.7, 95%CI 0.14-3.51, p=0.669). CONCLUSIONS: AMD was associated with CAA and superficial siderosis but not deep CMB, consistent with the hypothesis that amyloid deposits play a role in the development of AMD. Prospective studies are needed to determine if features of AMD may serve as biomarkers for the early diagnosis of CAA.

Greater burden of white matter lesions and silent infarcts ipsilateral to carotid stenosis.

OBJECTIVES: Carotid stenosis may cause silent cerebrovascular disease (CVD) through atheroembolism and hypoperfusion. If so, revascularization may slow progression of silent CVD. We aimed to compare the presence and severity of silent CVD to the degree of carotid bifurcation stenosis by cerebral hemisphere. MATERIALS AND METHODS: Patients age ≥40 years with carotid stenosis >50% by carotid ultrasound who underwent MRI brain from 2011-2015 at Mayo Clinic were included. Severity of carotid stenosis was classified by carotid duplex ultrasound as 50-69% (moderate), 70-99% (severe), or occluded. White matter lesion (WML) volume was quantified using an automated deep-learning algorithm applied to axial T2 FLAIR images. Differences in WML volume and prevalent silent infarcts were compared across hemispheres and severity of carotid stenosis. RESULTS: Of the 183 patients, mean age was 71±10 years, and 39.3% were female. Moderate stenosis was present in 35.5%, severe stenosis in 46.5% and occlusion in 18.0%. Patients with carotid stenosis had greater WML volume ipsilateral to the side of carotid stenosis than the contralateral side (mean difference, 0.42±0.21cc, p=0.046). Higher degrees of stenosis were associated with greater hemispheric difference in WML volume (moderate vs. severe; 0.16±0.27cc vs 0.74±0.31cc, p=0.009). Prevalence of silent infarct was 23.5% and was greater on the side of carotid stenosis than the contralateral side (hemispheric difference 8.8%±3.2%, p=0.006). Higher degrees of stenosis were associated with higher burden of silent infarcts (moderate vs severe, 10.8% vs 31.8%; p=0.002). CONCLUSIONS: WML and silent infarcts were greater on the side of severe carotid stenosis.

Lessons From ACST-2.

The recent 130-center, international, second ACST trial (Asymptomatic Carotid Surgery Trial) involving 3625 patients found that regardless of whether a patient underwent stenting or endarterectomy, the periprocedural risk of disabling or fatal stroke was about 1% and the 5-year estimated risk of nonprocedural disabling or fatal stroke was 2.5%. With advances in technique, technology, and patient selection, stenting done by appropriately trained and experienced operators can achieve safety and efficacy comparable to endarterectomy for asymptomatic patients. The ongoing CREST-2 trial (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) will clarify whether revascularization, by either stenting or endarterectomy, remains an important therapeutic goal in the setting of modern intensive medical therapy.

Health Screening Program to Enhance Enrollment of Women and Minorities in CREST-2.

BACKGROUND AND PURPOSE: The CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) consists of 2 parallel randomized stroke prevention trials in patients with asymptomatic high-grade stenosis of the cervical carotid artery. The purpose of this report is to detail the outcomes of a health screening effort to increase trial enrollment of women and minorities. METHODS: Life Line screening (LLS) conducts nationwide screening for vascular disease. Screenings within a 50-mile radius of each CREST-2 center were identified for participation in a joint CREST-LLS program over the course of one year (November 2018 to October 2019) whereby patients with an abnormal carotid ultrasound were referred to the local CREST-2 center for further workup, management, and potential consideration for trial enrollment. RESULTS: LLS completed the screening of 588 198 individuals in 29 732 zip codes across the United States. Of those, 230 021 individuals were screened at events occurring near a CREST-2 clinical center and 646 (0.3%) were found to have abnormal carotid ultrasound findings. Each of the 646 individuals was contacted by CREST-LLS program staff for permission to be referred to their local CREST-2 center; 200 (31%) consented to be contacted by CREST-2. Of those, 39 (19.5%) agreed to be, and were, evaluated at their local CREST-2 center. High-grade stenosis was confirmed in 27 patients. A total of 3 patients were eligible for the trial and were enrolled, one woman but no racial/ethnic minorities. CONCLUSIONS: The LLS program appears to identify community-living individuals with high-grade carotid stenosis through ultrasonography. However, the prevalence of abnormal carotid findings was low. In addition, screening and offering participation into the CREST-2 trial had no substantial impact on the proportion of women and minorities enrolled in the trial. Additional innovative strategies are needed to promote enrollment of diverse patients with carotid stenosis into stroke prevention trials.