Effect of a Coordinated Community and Chronic Care Model Team Intervention vs Usual Care on Systolic Blood Pressure in Patients With Stroke or Transient Ischemic Attack: The SUCCEED Randomized Clinical Trial.

Importance: Few stroke survivors meet recommended cardiovascular goals, particularly among racial/ethnic minority populations, such as Black or Hispanic individuals, or socioeconomically disadvantaged populations. Objective: To determine if a chronic care model-based, community health worker (CHW), advanced practice clinician (APC; including nurse practitioners or physician assistants), and physician team intervention improves risk factor control after stroke in a safety-net setting (ie, health care setting where all individuals receive care, regardless of health insurance status or ability to pay). Design, Setting, and Participants: This randomized clinical trial included participants recruited from 5 hospitals serving low-income populations in Los Angeles County, California, as part of the Secondary Stroke Prevention by Uniting Community and Chronic Care Model Teams Early to End Disparities (SUCCEED) clinical trial. Inclusion criteria were age 40 years or older; experience of ischemic or hemorrhagic stroke or transient ischemic attack (TIA) no more than 90 days prior; systolic blood pressure (BP) of 130 mm Hg or greater or 120 to 130 mm Hg with history of hypertension or using hypertensive medications; and English or Spanish language proficiency. The exclusion criterion was inability to consent. Among 887 individuals screened for eligibility, 542 individuals were eligible, and 487 individuals were enrolled and randomized, stratified by stroke type (ischemic or TIA vs hemorrhagic), language (English vs Spanish), and site to usual care vs intervention in a 1:1 fashion. The study was conducted from February 2014 to September 2018, and data were analyzed from October 2018 to November 2020. Interventions: Participants randomized to intervention were offered a multimodal coordinated care intervention, including hypothesized core components (ie, ≥3 APC clinic visits, ≥3 CHW home visits, and Chronic Disease Self-Management Program workshops), and additional telephone visits, protocol-driven risk factor management, culturally and linguistically tailored education materials, and self-management tools. Participants randomized to the control group received usual care, which varied by site but frequently included a free BP monitor, self-management tools, and linguistically tailored information materials. Main Outcomes and Measures: The primary outcome was change in systolic BP at 12 months. Secondary outcomes were non-high density lipoprotein cholesterol, hemoglobin A1c, and C-reactive protein (CRP) levels, body mass index, antithrombotic adherence, physical activity level, diet, and smoking status at 12 months. Potential mediators assessed included access to care, health and stroke literacy, self-efficacy, perceptions of care, and BP monitor use. Results: Among 487 participants included, the mean (SD) age was 57.1 (8.9) years; 317 (65.1%) were men, and 347 participants (71.3%) were Hispanic, 87 participants (18.3%) were Black, and 30 participants (6.3%) were Asian. A total of 246 participants were randomized to usual care, and 241 participants were randomized to the intervention. Mean (SD) systolic BP improved from 143 (17) mm Hg at baseline to 133 (20) mm Hg at 12 months in the intervention group and from 146 (19) mm Hg at baseline to 137 (22) mm Hg at 12 months in the usual care group, with no significant differences in the change between groups. Compared with the control group, participants in the intervention group had greater improvements in self-reported salt intake (difference, 15.4 [95% CI, 4.4 to 26.0]; P = .004) and serum CRP level (difference in log CRP, -0.4 [95% CI, -0.7 to -0.1] mg/dL; P = .003); there were no differences in other secondary outcomes. Although 216 participants (89.6%) in the intervention group received some of the 3 core components, only 35 participants (14.5%) received the intended full dose. Conclusions and Relevance: This randomized clinical trial of a complex multilevel, multimodal intervention did not find vascular risk factor improvements beyond that of usual care; however, further studies may consider testing the SUCCEED intervention with modifications to enhance implementation and participant engagement. Trial Registration: ClinicalTrials.gov Identifier: NCT01763203.

The Left Atrial Septal Pouch: A New Stroke Risk Factor?

The left atrial septal pouch (LASP) occurs due to incomplete fusion of septa primum and secundum at the inter-atrial septum, creating an open flap that may serve as a thromboembolic source. Prior studies have demonstrated increased prevalence of LASP in cryptogenic strokes. The aim of the current study was to validate the above findings in a separate, larger group of stroke and non-stroke patients. We examined transesophageal echocardiograms (TEEs) performed between July 2011 and December 2018. LASP prevalence was determined in TEEs referred for ischemic stroke or transient ischemic attack ("stroke") and compared with LASP prevalence in patients undergoing TEEs for other reasons ("non-stroke"). Stroke subtyping was performed using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. There were 306 TEEs from 144 non-stroke and 162 stroke patients. Mean age and sex distribution were 56 ± 1 (mean ± SE) and 65% male in the non-stroke group and 58 ± 1 and 54% male in the stroke group. The overall prevalence of LASP was 31%. The prevalence of LASP was 28% (41/144) in non-stroke patients, 25% (24/95) in non-cryptogenic stroke patients, and 43% (29/67) in cryptogenic stroke patients. LASP prevalence was significantly higher in the cryptogenic subgroup compared with the non-cryptogenic subgroup (p = 0.02). These findings demonstrate a significant association of LASP with risk of cryptogenic stroke, suggesting that LASP may serve as a thromboembolic nidus. Additional studies are needed to determine the generalizability of these findings, and their therapeutic implications, supporting LASP as a stroke risk factor.

Factors Associated With Participation in the Chronic Disease Self-Management Program: Findings From the SUCCEED Trial.

BACKGROUND AND PURPOSE: Self-management programs may improve quality of life and self-efficacy for stroke survivors, but participation is low. In a randomized controlled trial of a complex, multidisciplinary, team-based secondary stroke prevention intervention, we offered participants Chronic Disease Self-Management Program (CDSMP) workshops in addition to clinic visits and home visits. To enhance participation, workshops were facilitated by community health workers who were culturally and linguistically concordant with most participants and scheduled CDSMP sessions at convenient venues and times. Over time, we implemented additional strategies such as free transportation and financial incentives. In this study, we aimed to determine factors associated with CDSMP participation and attendance. METHODS: From 2014 to 2018, 18 CDSMP workshop series were offered to 241 English and Spanish-speaking individuals (age ≥40 years) with recent stroke or transient ischemic attack. Zero-inflated Poisson regression was used to identify factors associated with participation and attendance (ie, number of sessions attended) in CDSMP. Missing values were imputed using multiple imputation methods. RESULTS: Nearly one-third (29%) of intervention subjects participated in CDSMP. Moderate disability and more clinic/home visits were associated with participation. Participants with higher numbers of clinic and home visits (incidence rate ratio [IRR], 1.06 [95% CI, 1.01-1.12]), severe (IRR, 2.34 [95% CI, 1.65-3.31]), and moderately severe disability (IRR, 1.55 [95% CI, 1.07-2.23]), and who enrolled later in the study (IRR, 1.12 [95% CI, 1.08-1.16]) attended more sessions. Individuals with higher chaos scores attended fewer sessions (IRR, 0.97 [95% CI, 0.95-0.99]). CONCLUSIONS: Less than one-third of subjects enrolled in the SUCCEED (Secondary Stroke Prevention by Uniting Community and Chronic Care Model Teams Early to End Disparities) intervention participated in CDSMP; however, participation improved as transportation and financial barriers were addressed. Strategies to address social determinants of health contributing to chaos and engage individuals in healthcare may facilitate attendance. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01763203.

Hospital and demographic characteristics associated with inpatient neurological services in the United States.

OBJECTIVE: To determine nationwide availability and factors associated with inpatient neurological services. PATIENTS AND METHODS: Using the 2011 American Hospital Association survey, we determined the proportion of hospitals that provided inpatient neurological services. Demographic and household data from the 2010 national census and survey results were utilized to determine regional factors associated with the availability of inpatient neurologic services. Using rate ratios, the association was estimated using Poisson regression. Hospitals lacking emergency departments or with a bed size of less than 25 beds were excluded to focus on acute care facilities with the potential to have subspecialty services. RESULTS: Of 3969 hospitals that completed the survey, 2017 (65%) provided inpatient neurological services. Hospitals with Joint Commission (JC) accreditation were 1.35 times more likely (95% CI: 1.16-1.57) to have inpatient neurological services. Compared to small hospitals (bed size 25-36), large hospitals (bed size 246-2264) were 4.53 times more likely (95% CI: 2.79-7.35) to provide inpatient neurological services. Hospitals that were the sole community provider or were non-federal governmental hospitals had a lower probability of providing inpatient neurological services with rate ratio of 0.65 (95% CI: 0.5-0.84) and 0.81 (95% CI: 0.7-0.94), respectively. CONCLUSIONS: Approximately two-thirds of hospitals in this nationwide survey provided hospital-based neurological services. Larger hospitals and those with JC accreditation were more likely to provide neurological services, whereas small hospitals, sole community providers, and non-federal governmental hospitals were less likely to provide them.

Depression Is Associated with a Higher Risk of Death among Stroke Survivors.

BACKGROUND: Poststroke depression is common, affecting approximately 1 in 3 stroke survivors. We aimed to evaluate the association between depression and mortality in adults with and without prior stroke. METHODS: Using the National Health and Nutrition Examination Survey (NHANES) I Epidemiologic Follow-up Study (1982-1992), we investigated the association between depression and all-cause mortality among adults aged 25-74 years with and without prior stroke, and stroke mortality among stroke survivors, adjusting for covariates. RESULTS: Among 9919 individuals, 121 (1.2%) reported prior stroke. The adjusted depression prevalence was 37.1% among stroke survivors and 17.3% among individuals without stroke. In persons aged 25-64 years, neither stroke nor depression was associated with all-cause mortality. The combination of depression and stroke was not associated with all-cause mortality (adjusted hazard ratio [HR] 2.83, 95% confidence interval [CI] .67-12.04). Among persons aged 65-74 years, depression alone (adjusted HR 1.24, 95% CI 1.04-1.47), stroke alone (adjusted HR 1.64, 95% CI 1.17-2.32), and the combination of depression and stroke (adjusted HR 2.28, 95% CI 1.79-2.90) were associated with all-cause mortality, consistent with an additive relationship. Among all ages, the combination of depression and stroke was associated with all-cause mortality (adjusted HR 1.93, 95% CI 1.28-2.92). Higher stroke mortality was only observed in those aged 65-74 years (adjusted HR 2.43, 95% CI 1.05-5.60). Compared with stroke survivors without depression, those with depression were ~35 times more likely to die from a stroke (adjusted HR 35.33, 95% CI 7.79-160.32). CONCLUSIONS: The combination of prior stroke and depression is associated with higher all-cause mortality than either condition alone. The presence of depression after stroke increases stroke mortality 35-fold, highlighting the importance of identifying and treating depression among stroke survivors.

Randomized controlled trial of a coordinated care intervention to improve risk factor control after stroke or transient ischemic attack in the safety net: Secondary stroke prevention by Uniting Community and Chronic care model teams Early to End Disparities (SUCCEED).

BACKGROUND: Recurrent strokes are preventable through awareness and control of risk factors such as hypertension, and through lifestyle changes such as healthier diets, greater physical activity, and smoking cessation. However, vascular risk factor control is frequently poor among stroke survivors, particularly among socio-economically disadvantaged blacks, Latinos and other people of color. The Chronic Care Model (CCM) is an effective framework for multi-component interventions aimed at improving care processes and outcomes for individuals with chronic disease. In addition, community health workers (CHWs) have played an integral role in reducing health disparities; however, their effectiveness in reducing vascular risk among stroke survivors remains unknown. Our objectives are to develop, test, and assess the economic value of a CCM-based intervention using an Advanced Practice Clinician (APC)-CHW team to improve risk factor control after stroke in an under-resourced, racially/ethnically diverse population. METHODS/DESIGN: In this single-blind randomized controlled trial, 516 adults (≥40 years) with an ischemic stroke, transient ischemic attack or intracerebral hemorrhage within the prior 90 days are being enrolled at five sites within the Los Angeles County safety-net setting and randomized 1:1 to intervention vs usual care. Participants are excluded if they do not speak English, Spanish, Cantonese, Mandarin, or Korean or if they are unable to consent. The intervention includes a minimum of three clinic visits in the healthcare setting, three home visits, and Chronic Disease Self-Management Program group workshops in community venues. The primary outcome is blood pressure (BP) control (systolic BP <130 mmHg) at 1 year. Secondary outcomes include: (1) mean change in systolic BP; (2) control of other vascular risk factors including lipids and hemoglobin A1c, (3) inflammation (C reactive protein [CRP]), (4) medication adherence, (5) lifestyle factors (smoking, diet, and physical activity), (6) estimated relative reduction in risk for recurrent stroke or myocardial infarction (MI), and (7) cost-effectiveness of the intervention versus usual care. DISCUSSION: If this multi-component interdisciplinary intervention is shown to be effective in improving risk factor control after stroke, it may serve as a model that can be used internationally to reduce race/ethnic and socioeconomic disparities in stroke in resource-constrained settings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01763203 .

Patterns and Predictors of Blood Pressure Treatment, Control, and Outcomes among Stroke Survivors in the United States.

BACKGROUND: Expert consensus guidelines recommend antihypertensive treatment to lower secondary stroke risk, but patterns and predictors of blood pressure (BP) treatment and control among stroke survivors in the United States remain unknown. Understanding predictors of poor control can facilitate development of targeted strategies. METHODS: We reviewed the prevalence and control of hypertension among adults 40 years or older with self-reported stroke who participated in the National Health and Nutrition Examination Surveys 1999-2004 with mortality follow-up through 2006. Predictors of poorly controlled BP (>140/90 mm Hg) and nontreatment were determined via logistic regression. Independent association between antihypertensive use and mortality was determined using Cox models. RESULTS: Among 9145 participants, 490 reported previous stroke; 72% had known hypertension, 8% had undiagnosed hypertension, and 47% had poorly controlled BP. In multivariable analyses, age (odds ratio [OR] per year 1.06, 95% confidence interval [CI] 1.03-1.09), female sex (OR 1.70, 95% CI 1.12-2.57), non-Mexican Hispanic ethnicity (OR 4.54, 95% CI 1.76-11.70), black race (OR 3.15, 95% CI 1.59-6.25), hypercholesterolemia (OR 2.46, 95% CI 1.44-4.21), and diabetes (OR 1.96, 95% CI 1.16-3.33) were associated with poorly controlled BP. Obesity was associated with lower odds of poorly controlled BP (OR .51, 95% CI .26-.99). Non-Mexican Hispanic ethnicity (OR 7.37, 95% CI 2.25-24.10) and black race (OR 3.13, 95% CI 1.05-9.34) were predictors of nontreatment, whereas diabetes was linked to treatment (OR 3.57, 95% CI 1.21-10.43). There was no association between antihypertensive treatment and mortality after adjustment for demographics and comorbidities. CONCLUSIONS: One in 2 stroke survivors in the United States has poorly controlled BP; the most vulnerable groups include women, non-Mexican Hispanics, blacks, diabetics, and older individuals. Understanding causes of this evidence-practice gap may assist in developing effective targeted interventions.

Vascular Neurologists as Directors of Stroke Centers in the United States.

BACKGROUND AND PURPOSE: Hospital certification as primary and comprehensive stroke center is associated with improvement in care. We aimed to characterize the leadership at stroke centers nationwide to determine the proportion led by vascular neurologists, a board-recognized subspecialty focusing on stroke care. METHODS: We identified hospitals in the United States holding primary and comprehensive stroke center designation as of September 2013. We contacted each hospital to identify the medical director and used data from relevant medical boards to determine specialization. Sex and date of medical school graduation were obtained from an online physician database. RESULTS: Of the 1167 primary and 50 comprehensive stroke center hospitals certified by the Joint Commission (n=1114), Det Norske Veritas (n=68), and Healthcare Facilities Accreditation Program (n=35), we identified the director in 940 (77%). Leadership was most often by a neurologist (n=745; 79%) followed by physicians in emergency medicine (n=58; 6%) and internal medicine (n=17; 2%). Vascular neurologists (n=319) led about one-third of stroke centers. Directors were mostly men (n=764; 81%), with a median number of years after medical school graduation of 25 (interquartile range, 18-34). Comprehensive stroke centers were more likely than primary stroke centers to have leadership by vascular neurologist (77%, n=37 versus 32%, n=282; P<0.001). CONCLUSIONS: Vascular neurologist led about one-third of stroke centers. There is opportunity for vascular neurologists to increase their role in stroke center directorship.

Cerebrovascular complications of pregnancy and the postpartum period.

Cerebrovascular complications of pregnancy, though uncommon, threaten women with severe morbidity or death, and they are the main causes of major long-term disability associated with pregnancy. In this review, we discuss the epidemiology, pathophysiology, presentation and diagnosis, and management and outcomes of ischemic and hemorrhagic stroke and cerebral venous thrombosis. We also discuss the posterior reversible encephalopathy syndrome, the reversible cerebral vasoconstriction syndrome including postpartum cerebral angiopathy, and their relationship as overlapping manifestations of pre-eclampsia-eclampsia.

Case misclassification in studies of spinal manipulation and arterial dissection.

BACKGROUND: Spinal manipulation has been associated with cervical arterial dissection and stroke but a causal relationship has been questioned by population-based studies. Earlier studies identified cases using International Classification of Diseases Ninth Revision (ICD-9) codes specific to anatomic stroke location rather than stroke etiology. We hypothesize that case misclassification occurred in these previous studies and an underestimation of the strength of the association. We also predicted that case misclassification would differ by patient age. METHODS: We identified cases in the Veterans Health Administration database using the same strategy as the prior studies. The electronic medical record was then screened for the word "dissection." The presence of atraumatic dissection was determined by medical record review by a neurologist. RESULTS: Of 3690 patients found by ICD-9 codes over a 30-month period, 414 (11.2%) had confirmed cervical artery dissection with a positive predictive value of 10.5% (95% confidence interval [CI] 9.6%-11.5%). The positive predictive value was higher in patients less than 45 years of age vs 45 years of age or older (41% vs 9%, P < .001). We reanalyzed a previous study, which reported no association between spinal manipulation and cervical artery dissection (odds ratio [OR] = 1.12, 95% CI .77-1.63) and recalculated an odds ratio of 2.15 (95% CI .98-4.69). For patients less than 45 years of age, the OR was 6.91 (95% CI 2.59-13.74). CONCLUSIONS: Prior studies grossly misclassified cases of cervical dissection and mistakenly dismissed a causal association with manipulation. Our study indicates that the OR for spinal manipulation exposure in cervical artery dissection is higher than previously reported.

Coma from wall suction-induced CSF leak complicating spinal surgery.

A 72-year-old woman was admitted for elective L4/L5 laminectomy. The operative procedure was extradural, and a Jackson-Pratt (JP) drain was placed in the tissue bed and set to wall suction during skin closure. During closure, the patient developed a 15 s period of asystole. The patient was haemodynamically stable, but was comatose for 3 days postoperatively. Cardiac enzymes and EEG were unrevealing. Head CT showed traces of subarachnoid haemorrhage and signs suggestive of cerebral anoxia. JP drain at the incision produced 170-210 mL/day of fluid, positive for ß-2 transferrin, indicating cerebrospinal fluid (CSF). The patient fully returned to baseline on hospital day 10. MRI on hospital day 8 normalised. The reversible coma and radiographic findings were most consistent with acute intracranial hypotension relating to acute loss of CSF. Because radiographic findings can mimic hypoxic-ischaemic injury, acute intracranial hypotension should be considered in the differential diagnosis of postoperative coma after cranial or spinal surgery.

Mitochondrial effects of estrogen are mediated by estrogen receptor alpha in brain endothelial cells.

Mitochondrial reactive oxygen species (ROS) and endothelial dysfunction are key contributors to cerebrovascular pathophysiology. We previously found that 17beta-estradiol profoundly affects mitochondrial function in cerebral blood vessels, enhancing efficiency of energy production and suppressing mitochondrial oxidative stress. To determine whether estrogen specifically affects endothelial mitochondria through receptor mechanisms, we used cultured human brain microvascular endothelial cells (HBMECs). 17beta-Estradiol treatment for 24 h increased mitochondrial cytochrome c protein and mRNA; use of silencing RNA for estrogen receptors (ERs) showed that this effect involved ERalpha, but not ERbeta. Mitochondrial ROS were determined by measuring the activity of aconitase, an enzyme with an iron-sulfur center inactivated by mitochondrial superoxide. 17beta-Estradiol increased mitochondrial aconitase activity in HBMECs, indicating a reduction in ROS. Direct measurement of mitochondrial superoxide with MitoSOX Red showed that 17beta-estradiol, but not 17alpha-estradiol, significantly decreased mitochondrial superoxide production, an effect blocked by the ER antagonist, ICI-182,780 (fulvestrant). Selective ER agonists demonstrated that the decrease in mitochondrial superoxide was mediated by ERalpha, not ERbeta. The selective estrogen receptor modulators, raloxifene and 4-hydroxy-tamoxifen, differentially affected mitochondrial superoxide production, with raloxifene acting as an agonist but 4-hydroxy-tamoxifen acting as an estrogen antagonist. Changes in superoxide by 17beta-estradiol could not be explained by changes in manganese superoxide dismutase. Instead, ERalpha-mediated decreases in mitochondrial ROS may depend on the concomitant increase in mitochondrial cytochrome c, previously shown to act as an antioxidant. Mitochondrial protective effects of estrogen in cerebral endothelium may contribute to sex differences in the occurrence of stroke and other age-related neurodegenerative diseases.

Estrogen suppresses brain mitochondrial oxidative stress in female and male rats.

Mitochondria are a major source of reactive oxygen species (ROS) and oxidative stress, key contributors to aging and neurodegenerative disorders. We report that gonadal hormones influence brain mitochondrial ROS production in both females and males. Initial experiments showed that estrogen decreases mitochondrial superoxide production in a receptor-mediated manner, as measured by MitoSOX fluorescence in differentiated PC-12 cells. We then assessed in vivo effects of gonadal hormones on brain mitochondrial oxidative stress in female and male rats. Brain mitochondria were isolated to measure a functional indicator of ROS, i.e., activity of the ROS-sensitive mitochondrial enzyme, aconitase. Gonadectomy of both males and females caused a decrease in aconitase activity, suggesting that endogenous gonadal hormones influence mitochondrial ROS production in the brain. In vivo treatment of gonadectomized animals with testosterone or dihydrotestosterone (DHT) had no effect, but estrogen replacement significantly increased aconitase activity in brain mitochondria from both female and male rats. This indicates that estrogen decreases brain mitochondrial ROS production in vivo. Sex hormone treatments did not affect protein levels of brain mitochondrial uncoupling proteins (UCP-2, 4, and 5). However, estrogen did increase the activity, but not the levels, of manganese superoxide dismutase (MnSOD), the mitochondrial enzyme that catalyzes superoxide radical breakdown, in brain mitochondria from both female and male rats. Thus, in contrast to the lack of effect of androgens on mitochondrial ROS, estrogen suppression of mitochondrial oxidative stress may influence neurological disease incidence and progression in both females and males.

Testosterone augments endotoxin-mediated cerebrovascular inflammation in male rats.

Activation of inflammatory mechanisms contributes to cerebrovascular pathophysiology. Male gender is associated with increased stroke risk, yet little is known about the effects of testosterone in the cerebral circulation. Therefore, we explored the impact of testosterone treatment on cerebrovascular inflammation with both in vivo and in vitro models of inflammation. We hypothesized that testosterone would augment the expression of two vascular markers of cellular inflammation, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Using four groups of male rats [intact, orchiectomized (ORX), and ORX treated with either testosterone (ORXT) or the testosterone metabolite 17beta-estradiol (ORXE)], we determined effects of the sex hormones on cerebrovascular inflammation after intraperitoneal LPS injection. Western blot analysis showed that induction of inflammatory markers was increased in cerebral blood vessels from ORXT rats compared with intact or ORX rats. In contrast, in cerebral blood vessels from ORXE rats, there was a significant decrease in endotoxin-induced COX-2 and iNOS protein levels. Confocal microscopy of cerebral blood vessels from ORXT rats showed increased COX-2 and iNOS immunoreactivity in both endothelial and smooth muscle cells after LPS treatment. In vitro incubation with LPS also induced COX-2 in pial vessels isolated from the four animal treatment groups, with the greatest induction observed in ORXT vessels compared with the ORX and ORXE groups. Production of PGE2, a principal COX-2-derived prostaglandin end product, was also greatest in cerebral vessels isolated from ORXT rats. In conclusion, testosterone increases cerebrovascular inflammation; this effect may contribute to stroke differences between men and women.