Brown, Robert D.

Introduction: Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke; however the causal mechanisms are unknown. Understanding etiology of stroke in OSA patients may: (1) aid in ascertaining how OSA exerts its influence in increasing stroke risk, and (2) facilitate tailoring recurrent stroke prevention management strategies in OSA patients. Our study compares stroke subtypes in OSA cases versus controls without significant sleep disordered breathing. Hypothesis: We hypothesized cardioembolic (CE) strokes would occur more frequently in OSA cases than in controls. Methods: Consecutive patients were identified who underwent polysomnography (PSG) at Mayo Clinic and suffered an ischemic stroke within one year after PSG. Patients with an apnea-hypopnea index (AHI) ≤ 10 were classified as controls; AHI > 10 classified as OSA cases. Mechanism of stroke was determined using (1) the Causative Classification System for Ischemic Stroke (CCS) and (2) the phenotype definitions used in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Information on cardiovascular risk factors, neuroimaging, and echocardiography data were collected on each patient. Results: In 53 total subjects, CE strokes were more common among OSA cases (72% vs 33%, p=0.01). Large artery atherosclerosis and small vessel occlusion strokes were more common in controls. Atrial fibrillation (AF) was more frequent in OSA patients (59% vs 24%, p=0.01). Frequency of CE stroke increased with OSA severity. The association between OSA and CE stroke remained significant after controlling for AF (p=0.03, OR 4.5). Echocardiogram data revealed CE stroke risk factors were more frequent in OSA cases (84% vs 52% p=0.02). There were no significant differences between groups for left ventricular ejection fraction, left atrial volume index, or right ventricular systolic pressure. Conclusions: The results demonstrate a strong association between OSA and CE stroke. In OSA patients presenting with cryptogenic stroke, high clinical suspicion for cardioembolism is warranted. This may lead to consideration of further studies (eg, transesophageal echocardiography, Holter monitoring, or extended cardiac monitoring) to identify cardioembolic risk factors such as paroxysmal AF.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia in current clinical practice. Yet, contemporary community data on adverse outcomes, such as ischemic stroke (IS) and heart failure (HF), are scarce. Methods: We assembled a community-based cohort of incident AF among Olmsted County, MN residents ≥18 years of age from 2000-2010. IS, transient ischemic attack (TIA), and incident HF occurring through 12/31/2012 were identified using diagnosis codes and were manually validated. Cox proportional hazards regression was used to determine age- and sex-adjusted predictors of IS/TIA and HF, as well as the association of year of AF diagnosis with these outcomes after adjustment for demographics and comorbidities. Results: Among 3315 incident AF (mean age 72.6 years, 52% male), 346 (10%) developed a subsequent IS (n=230) or TIA (n=116) over a mean follow-up of 4.2 years. In the 2807 AF patients without prior HF, 782 (28%) developed HF over a mean of 3.9 years. Differences in the predictors of subsequent IS/TIA and HF were observed (Figure). Increasing age, female sex, and prior IS/TIA were associated with an increased risk of IS/TIA, whereas increasing age, obesity, smoking, prior myocardial infarction, diabetes, chronic obstructive pulmonary disease, peripheral vascular disease, prior IS/TIA, and renal disease predicted the development of HF after AF. The risk of subsequent IS/TIA or HF did not differ by year of AF diagnosis. Compared to those diagnosed with AF in 2000-2003, the adjusted hazard ratios (HR) (95% CI) for ischemic IS/TIA were 0.84 (0.65-1.08) and 1.02 (0.76-1.36) for those diagnosed with AF in 2004-2007 and 2008-2010, respectively (P time trend =0.58); similar results were observed for IS alone. The corresponding HRs for HF were 0.99 (0.83-1.16) and 0.93 (0.76-1.13) for those diagnosed with AF in 2004-2007 and 2008-2010 compared to 2000-2003 (P time trend =0.43). Conclusions: In the community, adverse outcomes are frequent after AF, and HF occurs more frequently than IS/TIA. Risk factors differed for IS/TIA and HF, suggesting that pathways to the occurrence of these outcomes, as well as prevention strategies, may differ. Finally, the occurrence of these outcomes did not decline over the last decade, highlighting the importance of continued rigorous surveillance of adverse outcomes in AF.

Purpose: The safety of revascularization for asymptomatic carotid stenosis, and the efficacy of medical therapy for stroke prevention have improved. Therefore, results of prior randomized trials may not apply to current treatment decisions. The NINDS-funded CREST-2 will compare carotid endarterectomy and intensive medical therapy (IMT) versus IMT alone (n=1240), and carotid stenting and IMT versus IMT alone (n=1240) in asymptomatic patients with≥70% stenosis. Materials & Methods: CREST-2 consists of two parallel randomized clinical trials to be conducted at a target of ≈120 centers, including within NINDS StrokeNet. The composite primary outcome is stroke or death during the peri-procedural period or ipsilateral ischemic stroke thereafter up to 4 years. Blinded assessment of cognition will be done periodically. Centrally directed IMT includes tight control of blood pressure (systolic target <140 mm Hg) and cholesterol (LDL target <70 mg/dl) as well as lifestyle coaching. Results: As of June 12, 2015, 94 centers have been approved by the Site Selection Committee. Credentialing is ongoing, with 198 approved surgeons and 64 approved interventionists; 124 additional conditionally approved interventionists will be able to submit additional cases for review under the CREST-2 Registry. The Centers for Medicare and Medicaid will offer CAS reimbursement for Registry enrollees. As of June 12, 2015, there are 39 actively enrolling centers, and 37 patients have been randomized. Conclusion: CREST-2 is designed to identify the best approach for asymptomatic carotid stenosis. The first patient was randomized in December, 2014. An update will be provided regarding the numbers of patients randomized, centers certified, as well as surgeons and interventionists fully approved. Registration: ClinicalTrials.gov Identifier: NCT02089217

Background —The role of surgical closure of patent foramen ovale (PFO) for cerebral infarction (CI) or transient ischemic attack (TIA) resulting from paradoxical embolism is unclear, and its effect on recurrence is unknown. Our objective was to determine the outcome of surgical closure of PFO in patients with a prior ischemic neurological event, define the rate of CI or TIA recurrence after PFO closure, and identify risk factors for these recurrences. Methods and Results —We retrospectively analyzed 91 patients (58 men, 33 women) with ≥1 previous cerebrovascular ischemic events who underwent surgical PFO closure between April 1982 and March 1998. The presence of a PFO with a right-to-left shunt was confirmed with transesophageal echocardiography. Mean age was 44.2±12.2 years. The index event was a CI in 59 and a TIA in 32; a Valsalva-like episode preceded the event in 15 patients. Deep venous thrombosis was documented in 9 patients, and a hypercoagulable state was identified in 10. Surgical closure was performed with extracorporeal circulation by either direct suture (n=82) or patch closure (n=9). Limited incisions were used in 18.7% of patients. There was no operative mortality. Morbidity included transient atrial fibrillation (n=11), pericardial drainage for effusion (n=4), exploration for bleeding (n=3), and superficial wound infection (n=1). Follow-up totaled 176.3 patient-years, and mean follow-up was 2.0 years. No one had a CI, and 8 had a TIA during follow-up, with 1 caused by temporal arteritis. Transesophageal echocardiography demonstrated all closures to be intact in these patients. The overall freedom from TIA recurrence during follow-up was 92.5±3.2% at 1 year and 83.4±6.0% at 4 years. Having multiple neurological events before PFO closure was the only significant risk factor for TIA or CI recurrence after closure by univariate analysis ( P =0.05); the small number of post-PFO closure cerebral ischemic events precluded multivariate analysis. Conclusions —Surgical closure of PFO can be performed with minimal morbidity and mortality. PFO closure may decrease the risk of recurrent stroke or TIA and may avoid lifelong anticoagulation in the young adult if there is no other indication. Recurrent cerebrovascular ischemic events after surgery should prompt further evaluation to identify causes other than paradoxical embolism.

Background: Presence of atherosclerotic disease in more than one vascular bed (polyvascular disease) is associated with an increased risk of long-term vascular events. In the setting of asymptomatic carotid stenosis, the predictors of disease in other vascular beds is not well delineated. Objective: To identify the frequency and predictors of disease in other vascular beds the CREST 2 randomized trial population with hemodynamically significant stenosis. Methods: Recorded baseline characteristics among CREST 2 participants included: demographics, past medical history, lifestyle factors, and laboratory studies. Each variable was tested against three potential definitions of disease in other beds (cardiac, peripheral arterial disease (PAD) or disease in cardiac + PAD). Statistical analysis was done with Chi square and t tests as appropriate. Results: Data from 1447 patients were available for analysis. In these subjects with carotid disease, 51% also had cardiac disease, 24% also had PAD, and 16% had disease in in both cardiac and PAD. There was no relationship between age or race and presence of disease in other beds. Those with cardiac disease were more likely to be male. Diabetes, hypertension, hypercholesterolemia, and former history of smoking were all more common in those with either cardiac and PAD (TABLE). Elevated triglyceride and low HDL levels were also associated with all three definitions of disease in other beds. Those with either PAD or cardiac + PAD were more likely to be current smokers. Conclusions: Among CREST 2 participants, several medical conditions and lifestyle factors were associated with an increased frequency of disease in other vascular beds. Smoking, in particular, appears to be more common in those with PAD. Future analyses will address whether those with disease in other beds have higher rates of stroke or death.

Baseline Differences in Risk Factor Control and Medication Use Between 2 Trials Employing Intensive Medical Management (SAMMPRIS & CREST2) Background: The CREST2 trial Intensive Medical Management (IMM) protocol was adapted from the SAMMPRIS trial. However, since the 2011 publication of initial results of SAMMPRIS, there has been a greater appreciation for the importance of risk factor control in patients at risk of stroke associated with atherosclerosis. Therefore, we sought to determine differences in baseline risk factor control and medication use between SAMMPRIS and CREST2. Methods: Baseline risk factor and medication use data from 451 patients enrolled in SAMMPRIS (2008-2011) with severe symptomatic intracranial atherosclerosis and 1473 patients enrolled in CREST2 (2014-2019) with severe asymptomatic carotid stenosis were compared using the Chi-square test and t-test. Results: The Table shows baseline risk factor values and medications. SAMMPRIS patients were younger but had significantly worse risk factor control than CREST2 patients for all measures. There was no significant difference in statin use at baseline, but the mean SAMMPRIS subjects’ LDL was 16.1 mg/dL higher than in CREST2. CREST2 patients had higher rates of use of angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and thiazides, but lower rates of use of angiotensin converting enzyme (ACE) inhibitors. Conclusions: Despite being older, CREST2 patients have significantly better baseline risk factor profiles than SAMMPRIS patients. This could be due to greater appreciation of the importance of risk factor control and healthy lifestyle habits for stroke prevention or more aggressive treatment targets in guideline recommendations. Although risk factor control appears to be improving since SAMMPRIS, many CREST2 patients are still not meeting recommended risk factor goals at baseline and may benefit from IMM protocols.

Stroke subtype classification, applying standard criteria to clinical data, can reduce the heterogeneity of ischemic stroke for genetics studies. To date, most of the replicated genetic loci for ischemic stroke appear subtype-specific. Increasing homogeneity of phenotype comes with a trade-off in sample size, which influences the potential for successful identification of new loci. We estimated genetic associations using the union and intersection of two widely used stroke subtyping systems to assess the influence of sample size and homogeneity on test statistics. Methods: The Stroke Genetics Network (SiGN) study used both the Causative Classification of Stroke (CCS) and the Trial of ORG10172 Acute Stroke Trial (TOAST) classification systems. The CCS generates both a causal and a phenotypic subtype. Using all available data from case-control strata from the a previously performed GWAS, we focused on three main stroke subtypes: cardioembolic (CE), large artery atherosclerosis (LAA), and small artery occlusion (SAO). We estimated genetic associations with the union of the two CCS outputs and TOAST ( eg called CE by at least one method) and the intersection ( eg called CE by all three methods). Our modelling approach included a fixed-effects meta-analysis, i.e. pooling stratum specific estimates from logistic regression models using 10 principle components to account for genetic ancestry responsible for population stratification. Results: The majority of confirmatory findings from SiGN ( PITX2 and ZFHX3 for CE and HDAC9 for LAA) were evident in both models and in both the union and intersection of the subtyping systems. Some findings ( TSPAN2 in LAA) showed up best in the intersection with stronger corresponding p-values and odds ratios whereas other findings (12q24 for SAO) appear stronger in all of the union analyses, but were also evident in intersection analyses. We identify 16 potential novel loci, 6 of which appear in numerous analyses. Conclusion: Both expanding and refining stroke subtypes may help in the identification of additional stroke genetic risk variants and should be considered as complementary to a single classification system. We are pursuing replication of the novel findings.

Introduction: Cortical superficial siderosis (cSS) refers to deposition of blood breakdown products along the cerebral cortex, causing characteristic staining patterns seen with iron-sensitive MRI techniques. Cortical superficial siderosis is a relatively rare disorder, but has been linked to cerebral amyloid angiopathy and Alzheimer’s disease. The objective of this study was to determine the frequency and natural history of cSS in the general elderly population. Methods: MRI scans from the Mayo Clinic Study of Aging (MCSA), an ongoing population-based study of elderly residents in Olmsted County, Minnesota, were reviewed by neuroradiologists. Participants with cSS were identified based on linear pattern of hypointensity on gradient recalled echo imaging consistent with cSS. Exclusion criteria were: 1) MRI findings not consistent with cSS or 2) alternative explanation for MRI findings (such as aneurysmal subarachnoid hemorrhage, intracranial surgery, or trauma). Additional data abstracted included extent of cSS, presence of cerebral microbleeds, and clinical outcome. Results: Eleven out of 1,441 participants had MRI scans showing cSS (0.8%). When stratified by age, the frequency was 0.4% in those 50 to 70 years old and 1.1% in those over 70 years old. Six participants had only focal involvement of cSS (restricted to three or fewer sulci) and five had disseminated involvement (affecting more than three sulci). Microbleeds were seen in four of five (80%) participants with disseminated cSS, but none with focal cSS. Five participants (2 focal, 3 disseminated cSS) had follow up MRI scans, with an average follow up of 25 months. There was no further hemorrhage in those with focal cSS. However, all three participants with disseminated cSS experienced additional hemorrhage: one with new microbleeds, one with new microbleeds and lobar hemorrhage, and one with sulcal subarachnoid hemorrhage and lobar hemorrhage. Conclusion: Although rare, cSS may be encountered in the general elderly population. Extent of involvement of cSS and concomitant microbleeds may be important risk factors for progression of disease and intracerebral hemorrhage. The clinical significance of focal cSS occurring in the absence of microbleeds requires further investigation.

Introduction: Careful selection and timely activation of clinical sites in multicenter clinical trials is critical for successful enrollment, subject safety, and generalizability of results. Methods: In the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2), a multidisciplinary Site Selection Committee evaluated applicants referred via participation in CREST, CREST principal investigators (PIs) and other investigators, StrokeNet and industry partners. Data for consideration included performance metrics in CREST and other carotid trials and a site selection questionnaire containing information on the investigators as well as quantitative data on carotid procedures performed. Any FDA warning letters were reviewed. Results: The Committee met bi-weekly for 36 months (n=64 meetings). Applications from 176 sites between March 2014 and July 2016 were evaluated: 153 were approved, 7 are under Committee review, 5 were approved but withdrew, 5 were placed on a waiting list, and 6 were rejected. One-hundred-four sites have completed the regulatory and training requirements to randomize: 51 (49%) academic medical centers, 31 (30%) private hospital-based centers, 16 (15%) private office-based practices, and 6 (6%) Veterans Administration medical centers. The mean times from application-to- approval was 5.2 weeks (interquartile range, 1.9, 6.2), and from approval-to-randomization status was 46.7 weeks (interquartile range, 35.4, 51.7). Specialties of the 104 site PIs are vascular surgery for 35 (33.7%), cardiology for 30 (28.8%), neurology for 25 (24%), neurosurgery for 8 (7.7%), interventional radiology for 4 (3.8%), and interventional neuroradiology for 2 (1.9%). Conclusions: Careful site selection is time-consuming for prospective sites and for trial leadership. Times from application-to-site-approval were modest (mean = 5.2 weeks), in contrast to the times for completing regulatory and training requirements (mean = 46.7 weeks). However, subject enrollment by teams from a wide range of medical centers led by a multi-disciplinary cohort of PIs will promote the generalizability of trial results.

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.