Meschia, James F.

Background: Data from the CDC show that approximately one-quarter of adults have elevated triglyceride (TG) levels. Recent trials 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 (REDUCE-IT trial). We sought to assess how often patients with asymptomatic carotid stenosis (CS) have elevated TG levels and factors associated with high TG values. Methods: Patients enrolled in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST 2) were analyzed. Baseline lipid profiles were evaluated to determine high TG treatment eligibility as per the REDUCE-IT trial. We also evaluated baseline use of pharmacologic treatment for high TG levels. Demographic factors and baseline medical conditions were studied in relation to high (>150 mg/dl) TG values. Chi square and t tests were used to assess baseline factors and abnormal TG values. Results: As of August 10, 2020, 1655 of 1689 randomized patients (mean age 69.7 years, 61% men) had baseline lipid profiles suitable for analysis. Treatment eligibility according to REDUCE-IT (LDL 41-100 mg/dl, TG>150 mg/dl) was present in 21% (345) of subjects. In these patients, the median TG value was 205 (IQR 93) mg/dl. Fibrate medications were used at baseline in 4.5% of patients. Analysis of demographic and medical history factors and TG values greater than 150 mg/dl is found in the Table. There was significant positive correlation between baseline hemoglobin A1C and triglyceride values (p<0.0001) Conclusions: One in five patients in CREST 2 has TG values that potentially justify pharmacologic treatment. Elevated TG levels are most correlated with diabetes, hypertension, obesity, decreased physical activity, and heart disease. Clinicians should investigate treatment of elevated TG levels as a component of intensive medical therapy for stroke prevention.

Introduction: Retinal microvascular abnormalities have been associated with stroke, but their association with dementia and death is less well described. We tested the hypothesis that retinopathy is associated with stroke, dementia, and age-adjusted mortality. Methods: Data were obtained from the US National Health and Nutrition Examination Surveys from 2005 to 2008, with linked mortality through 2015. Severity of retinopathy was defined as no retinopathy, mild nonproliferative retinopathy (NPR), moderate-severe NPR, and proliferative retinopathy. Logistic regression models were performed to evaluate the relationships between retinopathy, stroke, and dementia, respectively. Independent relationships between retinopathy and all-cause mortality were assessed using Cox regression models, before and after adjusting for covariates. All analyses were adjusted for the complex survey design. Results: Of 5,543 participants aged ≥18 years with gradable retinal imaging, 696 had retinopathy, 289 had stroke, and 597 had dementia. Mean age of subjects was 56.3 ± 11.7 years. Retinopathy was associated with higher risk of stroke (adj OR 2.39, P <0.001) and dementia (adj OR 1.68, P =0.005). Over a median duration of 118 months (IQR 111-125), there was a dose-dependent relationship between severity of retinopathy and all-cause mortality (adjusted hazard ratios were 1.0, 1.5, 2.4, 3.4 across retinopathy severity; P =0.021). The Figure shows the age-adjusted cumulative mortality curves by retinopathy severity. Conclusions: Participants with retinopathy have a greater than 2-fold increase in stroke risk and a 1.7-fold increase in dementia risk. Having more severe retinopathy confers a higher risk of death after adjusting for age and vascular risk factors. The retina may serve as a tissue biomarker in intervention trials for cerebrovascular and neurodegenerative diseases.

In the SPRINT (Systolic Blood Pressure Intervention Trial), the number of strokes did not differ significantly by treatment group. However, stroke subtypes have heterogeneous causes that could respond differently to intensive blood pressure control. SPRINT participants (N=9361) were randomized to target systolic blood pressures of <120 mm Hg (intensive treatment) compared with <140 mm Hg (standard treatment). We compared incident hemorrhage, cardiac embolism, large- and small-vessel infarctions across treatment arms. Participants randomized to the intensive arm had mean systolic blood pressures of 121.4 mm Hg in the intensive arm (N=4678) and 136.2 mm Hg in the standard arm (N=4683) at one year. Sixty-nine strokes occurred in the intensive arm and 78 in the standard arm when SPRINT was stopped. The breakdown of stroke subtypes across treatment arms included hemorrhagic (intensive treatment, n=6, standard treatment, n=7) and ischemic stroke subtypes (large artery atherosclerosis: intensive treatment n=11, standard treatment, n=13; cardiac embolism: intensive treatment n=11, standard treatment n=15; small artery occlusion: intensive treatment n=8, standard treatment n=8; other ischemic stroke: intensive treatment n=3, standard treatment n=1). Fewer strokes occurred among participants without prior cardiovascular disease in the intensive (n=43) than the standard arm (n=61), but the difference did not reach predefined statistical significance level of 0.05 ( P =0.09). The interaction between baseline cardiovascular risk factor status and treatment arm on stroke risk did not reach significance ( P =0.05). Similar numbers of stroke subtypes occurred in the intensive BP control and standard control arms of SPRINT.

Abstract Despite substantial advances in stroke care, vascular cognitive impairment remains a prominent source of disability. Unlike sensorimotor impairments, cognition often continues to decline after stroke. An aging population will increase the prevalence of vascular cognitive impairment, with stroke playing an important role. Ten percent of patients presenting with stroke have pre-stroke dementia; an additional 10% will develop incident dementia with a first stroke, and 30% with a recurrent stroke. While stroke increases the risk of cognitive impairment, the presence of cognitive impairment also impacts acute stroke treatment and increases risk of poor outcome by nearly twofold. There is substantial overlap in the clinical and pathological aspects of vascular and degenerative dementias in many patients. How they relate to one another is controversial. The treatment of vascular cognitive impairment remains supportive, focusing on treating vascular risk factors. Cognitive rehabilitation after stroke is an area of active research, and existing pharmacologic treatments have limited benefit. Heightened awareness of cognitive impairment in the setting of stroke is imperative for prognostication and management, impetus for research and, ultimately, the discovery of efficacious treatments.

Background and Purpose: To describe the neurological and cerebrovascular findings in patients who tested positive for SARS-CoV-2 and underwent head imaging in ambulatory and inpatient settings. Methods: Consecutive patients aged ≥18 years with SARS-CoV-2 infection diagnosed or treated at Mayo Clinic sites from 3/11/2020 to 7/23/2020 with head CT or brain MRI within 30 days of SARS-CoV-2 diagnosis were included. Demographics, medical history, indication for SARS-CoV-2 testing, neurologic symptoms, indication for brain imaging, neuroimaging findings, etiology of cerebrovascular events, and hospital course were abstracted from medical records. Results: Of 8,675 patients with SARS-CoV-2, 180 (2.07%) had head imaging. Mean age of the entire cohort was 42 ± 18 years, whereas mean age of those with head imaging was 62 ± 19 years. Common indications for imaging were headache (34.4%), encephalopathy (33.4%), focal neurologic symptom (16.7%), and trauma (13.9%). While 86.1% of patients who underwent head imaging had normal exams, cerebrovascular events occurred in 18 patients (0.21% of the total cohort). Of patients with cerebrovascular events, 8 (44.5%) had acute infarct; 6 (33.3%), acute intracranial hemorrhage; 5 (2.8%), subacute infarct; and 1 (0.6%) posterior reversible encephalopathy syndrome. In the thirteen patients with ischemic stroke, 6 (46.2%) had cryptogenic stroke; 3 (23.1%), other defined causes; 2 (15.4%), small vessel stroke; 1 (7.7%), large vessel stroke; and 1 (7.7%) cardioembolic stroke. Conclusion: In ambulatory and hospitalized patients with SARS-CoV-2 infection, the rate of head imaging is low, with common indications of encephalopathy and headache. Cerebrovascular events occurred rarely, and cryptogenic stroke was the most common stroke mechanism.

Plasma neurofilament light is a reliable, uniform marker to estimate neuroaxonal injury and forecast all-cause mortality across major stroke types.

Background and Purpose: The CREST2 trial (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis) is comparing intensive medical management (IMM) alone to IMM plus revascularization with carotid endarterectomy or transfemoral carotid artery stenting for preventing stroke or death within 44 days after randomization or ipsilateral ischemic stroke thereafter. There are extensive clinical trial data on outcomes after revascularization of asymptomatic carotid stenosis, but not for IMM. As such, the experimental treatment in CREST2 is IMM, which is described in this article. Methods: IMM consists of aspirin 325 mg/day and intensive risk factor management, primarily targeting systolic blood pressure <130 mm Hg (initially systolic blood pressure <140 mm Hg) and LDL (low-density lipoprotein) cholesterol <70 mg/dL. Secondary risk factor targets focus on tobacco smoking, non-HDL (high-density lipoprotein), HbA1c (hemoglobin A1c), physical activity, and weight. Risk factor management is performed by site personnel and a lifestyle coaching program delivered by telephone. We report interim risk factor data on 1618 patients at baseline and last follow-up through 24 months. Results: The mean baseline LDL of 80.5 mg/dL improved to 66.7 mg/dL. The mean baseline systolic blood pressure of 139.7 mm Hg improved to 130.3 mm Hg. The proportion of patients in-target improved from 43% to 61% for systolic blood pressure <130 mm Hg and from 45% to 67% for LDL<70 mg/dL (both changes P <0.001). Conclusions: The rigorous multimodal approach to intensive stroke risk factor management in CREST2 has resulted in significant improvements in risk factor control that will enable a comparison of cutting-edge medical care to revascularization in patients with asymptomatic carotid stenosis. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02089217.

AbstractThe study aims to review the sex differences with respect to transient ischemic attack (TIA)/stroke and death in the perioperative period and on long-term follow-up among asymptomatic patients treated with carotid stenting (CAS) in the vascular quality initiative (VQI). All cases reported to VQI of asymptomatic CAS (ACAS) patients were reviewed. The primary end point was risk of TIA/stroke and death in the in-hospital perioperative period and in the long-term follow-up. The secondary end point was to evaluate predictors of in-hospital perioperative TIA/stroke and mortality on long-term follow-up after CAS. There were 22,079 CAS procedures captured from January 2005 to April 2019. There were 5,785 (62.7%) patients in the ACAS group. The rate of in-hospital TIA/stroke was higher in female patients (2.7 vs. 1.87%, p = 0.005) and the rate of death was not significant (0.03 vs. 0.07%, p = 0.66). On multivariable logistic regression analysis, prior/current smoking history (odds ratio = 0.58 [95% confidence interval or CI = 0.39–0.87]; p = 0.008) is a predictor of in-hospital TIA/stroke in females. The long-term all-cause mortality is significantly higher in male patients (26.9 vs. 15.7%, p < 0.001). On multivariable Cox-regression analysis, prior/current smoking history (hazard ratio or HR = 1.17 [95% CI = 1.01–1.34]; p = 0.03), coronary artery disease or CAD (HR = 1.15 [95% CI = 1.03–1.28]; p = 0.009), chronic obstructive pulmonary disease or COPD (HR = 1.73 [95% CI = 1.55–1.93]; p < 0.001), threat to life American Society of Anesthesiologists (ASA) class (HR = 2.3 [95% CI = 1.43–3.70]; p = 0.0006), moribund ASA class (HR = 5.66 [95% CI = 2.24–14.29]; p = 0.0003), and low hemoglobin levels (HR = 0.84 [95% CI = 0.82–0.86]; p < 0.001) are the predictors of long-term mortality. In asymptomatic carotid disease patients, women had higher rates of in-hospital perioperative TIA/stroke and a predictor of TIA/stroke is a prior/current history of smoking. Meanwhile, long-term all-cause mortality is higher for male patients compared with their female counterparts. Predictors of long-term mortality are prior/current smoking history, CAD, COPD, higher ASA classification of physical status, and low hemoglobin level. These data should be considered prior to offering CAS to asymptomatic female and male patients and careful risks versus benefits discussion should be offered to each individual patient.

Background and Purpose: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. Methods: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. Results: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance ( P =4.62×10 −8 ) and an additional 29 variants with suggestive evidence of association ( P <1×10 −6 ), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10 −3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN ( P =8.18×10 −4 ) and METASTROKE ( P =1.72×10 −3 ) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. Conclusions: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.