Maximizing Brain Health After Hemorrhagic Stroke: Bugher Foundation Centers of Excellence.

Abstract

HomeStrokeVol. 53, No. 3Maximizing Brain Health After Hemorrhagic Stroke: Bugher Foundation Centers of Excellence Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBMaximizing Brain Health After Hemorrhagic Stroke: Bugher Foundation Centers of Excellence Kevin N. Sheth, MD, Christopher D. Anderson, MD, MMSc, Alessandro Biffi, MD, Nomazulu Dlamini, MD, PhD, Guido J. Falcone, MD, ScD, MPH, Christine K. Fox, MD, MAS, Heather J. Fullerton, MD, MAS, Steven M. Greenberg, MD, PhD, J. Claude Hemphill, MD, MAS, Anthony Kim, MD, MAS, Helen Kim, PhD, Nerissa U. Ko, MD, MAS, Jarod L. Roland, MD, Lauren H. Sansing, MD, MS, Susanne J. van Veluw, PhD and Jonathan Rosand, MD, MSc Kevin N. ShethKevin N. Sheth Correspondence to: Kevin N. Sheth, MD, Department of Neurology, Yale School of Medicine, 15 York St, PO Box 208018, New Haven, CT 06520. Email E-mail Address: [email protected] https://orcid.org/0000-0003-2003-5473 Department of Neurology, Yale School of Medicine, New Haven, CT (K.N.S., G.J.F., L.H.S.). Search for more papers by this author , Christopher D. AndersonChristopher D. Anderson https://orcid.org/0000-0002-0053-2002 Henry and Allison McCance Center for Brain Health (C.D.A., A.B., J.R.), Massachusetts General Hospital, Boston. Broad Institute, Cambridge, MA (C.D.A., J.R.). Division of Stroke and Cerebrovascular Diseases, Brigham and Women’s Hospital, Boston, MA (C.D.A.). Search for more papers by this author , Alessandro BiffiAlessandro Biffi https://orcid.org/0000-0001-7063-455X Henry and Allison McCance Center for Brain Health (C.D.A., A.B., J.R.), Massachusetts General Hospital, Boston. Division of Neuropsychiatry (A.B.), Massachusetts General Hospital, Boston. Department of Neurology (A.B., S.M.G., S.J.v.V., J.R.), Massachusetts General Hospital, Boston. Search for more papers by this author , Nomazulu DlaminiNomazulu Dlamini https://orcid.org/0000-0001-5927-3132 Division of Neurology, The Hospital for Sick Children, Toronto, Canada (N.D.). Search for more papers by this author , Guido J. FalconeGuido J. Falcone https://orcid.org/0000-0002-6407-0302 Department of Neurology, Yale School of Medicine, New Haven, CT (K.N.S., G.J.F., L.H.S.). Search for more papers by this author , Christine K. FoxChristine K. Fox https://orcid.org/0000-0001-6934-3624 Department of Neurology (C.K.F., H.J.F., J.C.H., A.K., N.U.K.), University of California at San Francisco. Search for more papers by this author , Heather J. FullertonHeather J. Fullerton https://orcid.org/0000-0002-4828-1687 Department of Neurology (C.K.F., H.J.F., J.C.H., A.K., N.U.K.), University of California at San Francisco. Search for more papers by this author , Steven M. GreenbergSteven M. Greenberg https://orcid.org/0000-0003-1792-8887 Department of Neurology (A.B., S.M.G., S.J.v.V., J.R.), Massachusetts General Hospital, Boston. Search for more papers by this author , J. Claude HemphillJ. Claude Hemphill https://orcid.org/0000-0003-4019-7525 Department of Neurology (C.K.F., H.J.F., J.C.H., A.K., N.U.K.), University of California at San Francisco. Search for more papers by this author , Anthony KimAnthony Kim https://orcid.org/0000-0002-8095-6517 Department of Neurology (C.K.F., H.J.F., J.C.H., A.K., N.U.K.), University of California at San Francisco. Search for more papers by this author , Helen KimHelen Kim https://orcid.org/0000-0002-1937-354X Department of Anesthesia (H.K.), University of California at San Francisco. Search for more papers by this author , Nerissa U. KoNerissa U. Ko Department of Neurology (C.K.F., H.J.F., J.C.H., A.K., N.U.K.), University of California at San Francisco. Search for more papers by this author , Jarod L. RolandJarod L. Roland https://orcid.org/0000-0002-1312-8826 Department of Neurological Surgery (J.L.R.), University of California at San Francisco. Search for more papers by this author , Lauren H. SansingLauren H. Sansing https://orcid.org/0000-0002-6898-1680 Department of Neurology, Yale School of Medicine, New Haven, CT (K.N.S., G.J.F., L.H.S.). Search for more papers by this author , Susanne J. van VeluwSusanne J. van Veluw https://orcid.org/0000-0002-7957-8643 Department of Neurology (A.B., S.M.G., S.J.v.V., J.R.), Massachusetts General Hospital, Boston. Search for more papers by this author and Jonathan RosandJonathan Rosand https://orcid.org/0000-0002-1014-9138 Henry and Allison McCance Center for Brain Health (C.D.A., A.B., J.R.), Massachusetts General Hospital, Boston. Department of Neurology (A.B., S.M.G., S.J.v.V., J.R.), Massachusetts General Hospital, Boston. Broad Institute, Cambridge, MA (C.D.A., J.R.). Search for more papers by this author Originally published3 Feb 2022https://doi.org/10.1161/STROKEAHA.121.036197Stroke. 2022;53:1020–1029Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: February 3, 2022: Ahead of Print In 2021, a $11.12M gift to scientific research from the Henrietta B. and Frederick H. Bugher Foundation supported the American Heart Association (AHA) creation of a Bugher Network in Hemorrhagic Stroke. Hemorrhagic stroke was chosen because it is the stroke subtype with the greatest morbidity and mortality. As a direct consequence, the Foundation determined that decreasing the burden of hemorrhagic stroke is central to the AHA mission to be a relentless force for a world of longer, healthier lives.In this article, we provide context for the Network’s scientific aims and overall strategy. We will also describe the training program for the next generation of hemorrhagic stroke researchers. As collaboration among scientists is one of the main goals of the AHA, we also highlight opportunities and resources available to external researchers interested in collaborating with any of these centers.The intent of the Bugher Network is to support research from different disciplines (basic, clinical, and population research) focusing on improving understanding of basic mechanistic pathways, diagnosis and risk assessment, comorbidities and disease progression, genetics and genomics, lifestyle behavior and prevention, social determinants, treatment, and quality of care in relation to stroke. For this first Bugher Network focused on hemorrhagic stroke, 3 centers with synergistic basic, population science and clinical projects were selected for the awards: Yale University, Mass General-Brigham, and the University of California, San Francisco Benioff Children’s Hospital (Table). Each of the 3 centers brings together a collaborative network on its own, expanding the full Bugher Foundation Network of Centers of Excellence in Hemorrhagic Stroke.Table 1. Overview of the Bugher Network in Hemorrhagic StrokeInstitutionBasicClinicalPopulationYale School of MedicineDr Sansing: Sympathetic activation, hypertension, and inflammation in experimental ICHDr Sheth: Novel Strategies Toward Improved Blood Pressure Management in Survivors of ICHDr Falcone: Polygenic Susceptibility to Hypertension in ICH: From Population Studies to Precision Medicine at the BedsideDr Sansing, MD, MS; Dr Sheth, MD, Center co-DirectorsMassachusetts General Hospital, Brigham and Women’s HospitalDr van Veluw: Mechanisms of Hemorrhagic Stroke After Superficial SiderosisDr Biffi, MD: Race and Ethnicity and Control of Hypertension After ICHDr Anderson: Precision Clinical and Genetic Tools for Brain Health in Hemorrhagic StrokeDr Rosand, MD, MSc, Center DirectorBenioff Children’s Hospital, University of California at San FranciscoDr Kim, PhD: Predictors of Growth, Recurrence, and High-Risk Features in Pediatric Brain Arteriovenous MalformationDr Roland, MD: Predicting Outcomes in Pediatric Hemorrhagic Stroke With Personalized ConnectomicsDr Fox, MD, MAS; Dr Dlamini, MD PhD: Epidemiology of Pediatric Hemorrhagic Stroke and Arteriovenous Malformations in a Multicenter, International CohortDr Fullerton, MD, MAS, Center DirectorICH indicates intracerebral hemorrhage.Hemorrhagic stroke affects people of all ages, including infants and children. Survivors must often live with substantial disability and can be, because of the progressive nature of the blood vessel conditions responsible for the majority of cases, at high risk for recurrent stroke and further clinical deterioration. Harnessing expertise across the entire translational spectrum, the goal of the Network is to identify effective preventive strategies to decrease the burden that intracerebral hemorrhage (ICH) poses to society and develop better acute and postacute treatments to improve the functional outcome of ICH survivors. Embedded in this concept is the notion that progress must be defined for all individuals, irrespective of their background; therefore, social determinants of health and health equity are a cornerstone. Because hypertension is the single most important determinant of ICH risk,1 outcome and recurrence in adults, the Network will directly tackle hypertension in ICH and then apply this approach to other determinants of adverse brain health. In children, structural causes of brain hemorrhage take center stage, and the University of California, San Francisco team incorporates local and global pediatric stroke consortia. The Network will leverage advances in personalized medicine and genomics, animal models, clinical trials, big data and artificial intelligence, expansive patient and social networks and all other capabilities towards the stated Aims. Collaboration is the defining principle of the Network.The Bugher Network establishes mechanisms for open science and training meant to sustain and multiply this effort beyond the award period. Each center receives a workspace in the AHA’s precision medicine platform where they are required to perform at least one of their projects and share published data from their Center Projects. Finally, each Center annually identifies and trains a postdoctoral research fellow who focuses on hemorrhagic stroke. Fellows are embedded in Center Projects and participate in Center and Network training activities, coordinated by a dedicated training hub.ICH Is a Problem Across the LifespanICH is the most severe form of stroke in adults. At least 30% of patients die in the first month after hospitalization, and among the 60% and 70% who survive, nearly 2/3 develop recurrent stroke or incident cognitive decline within 5 years (Figure 1). This rapid functional decline arises from progression of underlying cerebral small vessel disease (CSVD) responsible for the acute ICH. Common cardiometabolic risk factors such as hypertension drive neurological and systemic morbidity. Arresting this progression holds the promise of substantially improving brain health-span and quality of life for the >50 000 adults who survive ICH in the United States alone every year. Given that CSVD plays a pivotal role in other important cerebrovascular conditions, including small vessel ischemic stroke and asymptomatic white matter disease (see below), arresting this progression can also have significant multiplicative effects. Pediatric stroke is a major cause of lifelong neurological disability and one of the top 10 causes of death in childhood.2 Pediatric ICH (pICH) is associated with 10% to 20% mortality and 30% moderate to severe disability and accounts for half of all childhood strokes.3 Intracranial vascular malformations, particularly brain arteriovenous malformations (bAVM), are the most common cause of pICH.4 Cerebral cavernous malformations and intracranial aneurysms are also important causes. While the predisposing biology may differ in children and adults, preserving and supporting neurological health are common goals for both populations. In adults and children, treating persistent underlying risk factors and providing support to overcome social barriers to health, for patients and families, are opportunities to improve overall outcomes.Download figureDownload PowerPointFigure 1. Incident vascular contributions to cognitive impairment and dementia (VCID) or recurrent stroke in intracerebral hemorrhage (ICH) survivors and individuals with cerebral small vessel disease (CSVD) but without ICH. All individuals have been followed longitudinally at Mass General Hospital.ICH Research Is Fundamentally Brain Health ResearchBrain health, as articulated by the AHA/ASA Presidential Advisory in 2017,5 enables thought, planned action, and emotional connections that affect the daily lives and progress of individuals, families, and communities. Sustaining brain health over the course of a lifetime is important to allow one to maximize one’s overall ability and independence. Maintenance of brain health may also curtail the need for diversion of economic and health care resources for care and treatments that may have limited the allocation of resources to efforts aimed at maintaining and restoring one to a healthy brain state. Thus, the impact of maximizing and maintaining brain health has the potential to benefit individuals, family and friends, health care providers and systems, and society.Because it is a common, progressive condition of aging, CSVD is a major threat to brain health across the population. CSVD arises in 2 common forms, arteriolosclerosis/hypertensive arteriopathy and cerebral amyloid angiopathy. While ICH is the most severe CSVD manifestation, it is more frequently recognized through ischemic (lacunar) stroke, cognitive decline, late-life onset depression, gait deterioration, and white matter hyperintensities on magnetic resonance imaging (MRI). In children, ICH results from very different pathogenetic mechanisms—most commonly congenital vascular malformations—yet the impact on brain health is also severe and long-lasting. ICH sequelae, such as physical disability, epilepsy, and cognitive impairment, can persist for a lifetime. One-third of children with hemorrhagic stroke develop epilepsy during the first decade after pICH.6 Survivors of pICH and their caregivers report anxiety, depression, impaired self-esteem, and poorer quality of life for children with stroke compared with the general population.4 Impairment of academic progress, isolation, and parental and financial and emotional hardship may contribute further towards dependence and suffering. In both adults and children, understanding and testing strategies for improved outcomes must take place in the context in which patients live.Convergent Scientific Themes Across the Bugher CentersBasic Science: Discover Biological Mechanisms of Risk and InjuryThere is a paucity of experimental models for ICH risk (Figure 2). As an example, cortical superficial siderosis (cSS) has recently emerged as a clinically relevant harbinger of ICH. cSS is defined on T2*-weighted MRI as an area of hypointensity lining the cortical sulci over the convexities of the brain.7 Patients with disseminated cSS have an increased risk of developing recurrent or first-ever ICH.7 However, the underlying mechanisms that lead to bleeding are not well understood. Recent work, using ex vivo MRI-guided histopathologic investigation in autopsy cases with cerebral amyloid angiopathy, demonstrated that cSS is the result of severe cerebral amyloid angiopathy of particularly the leptomeningeal blood vessels.8 Subtle bleeding from those blood vessels leads to iron deposition in the underling cortex, which can trigger secondary tissue injury in the form of blood-brain barrier leakage and inflammation. This work will test the novel hypothesis that cSS-induced tissue injury predisposes these brain areas for future hemorrhagic stroke. We will characterize the degree of tissue injury in human autopsy samples and model cSS in mice with and without cerebral amyloid angiopathy to study the causes and consequences of secondary tissue injury in vivo in real-time with 2-photon microscopy.9 Developing an experimental model of cSS will inform the design of novel therapeutic strategies aimed at ICH prevention.Download figureDownload PowerPointFigure 2. Translational spectrum for investigation in intracerebral hemorrhage (ICH).In addition, experimental studies support a central role for inflammation in the development of ongoing brain injury and inflammatory responses, including phagocytosis of cellular debris. In murine models of ICH, monocyte-derived macrophages recruited to the perihematomal region are major effectors of early neurological disability.10 However, recent data have shown that the macrophages then transition phenotypes and are critical to the phagocytosis of erythrocytes and neurological recovery. Mice lacking monocytes have delayed hematoma clearance and worse functional outcomes at later time points after ICH. The transition in macrophage activation is induced by erythrophagocytosis of phosphatidylserine-expressing cells.11 This work highlights the importance of considering these transitions in macrophage phenotype and inflammatory processes in therapeutic strategies for ICH.Similarly, inflammation plays an important role in the pathogenesis of bAVMs, which are the leading cause of ICH.12 Both human studies and mouse models have shown greater expression of cytokines and chemokines in bAVM tissue13 and blood in ruptured compared with unruptured cases,14 as well as significant macrophage/microglia infiltration within and surrounding bAVMs.15 Polymorphisms in proinflammatory genes have also been shown to increase ICH risk by 2- to 4-fold in bAVM patients at presentation, during follow-up, or after treatment.16In addition to discovery science, the Bugher preclinical network will clarify the basic mechanisms of established clinical interventions. In adults, elevated admission blood pressure (BP) has been associated with increased mortality and disability among ICH patients. The optimal target BP remains elusive, and the most recent AHA guidelines state that acute lowering of systolic BP to 140 mm Hg is safe and can be effective for improving functional outcome based on results of 2 recent large clinical trials.17 However, use of specific antihypertensive medications relies on expediency, availability, and route of administration, without knowledge whether mechanisms of action impact the pathophysiology of ICH. Similar knowledge gaps persist for guiding medication selection for secondary prevention.The Bugher Network will leverage preclinical models of ICH that focus on BP treatments in the setting of acute murine experimental ICH. ICH patients often require antihypertensive treatment without understanding of secondary effects of different classes of medications on inflammatory responses and secondary brain injury. Leukocytes express high levels of adrenergic receptors and respond to catecholamines to inhibit or enhance inflammatory responses. We will determine how specific classes of antihypertensives may have direct impact on post-ICH neuroinflammatory responses (both injurious and reparative) and acute and longer-term outcomes. The central hypothesis is that commonly used antihypertensive approaches, including renin-angiotensin inhibition and β-adrenergic blockade, modulate acute neuroinflammation after ICH and impact neurological outcomes. The network will capitalize on the extensive characterization of inflammatory responses in murine models, informed by patient-derived RNAseq transcriptional data in myeloid cells, and complement studies with ex vivo human macrophage assays, to address this translationally relevant knowledge gap in acute ICH treatment.The Pediatric Bugher Center will focus on understanding the biological mechanism(s) of the most common ICH cause in children: bAVMs.18 Compared with adults, children with bAVM are more likely to present with ICH, and have different angiographic characteristics.19 Up to one-third of children may have recurrent bAVM after surgical resection and documented angiographic cure,20 suggesting that these are dynamic vascular lesions. The exact mechanisms leading to bAVM growth, recurrence or progression to ICH remain unknown, but abnormal angiogenesis and inflammation coupled with high flow and an abnormal response-to-injury are clearly involved.12,21 The higher prevalence of bAVM recurrence in children is likely related to intrinsic factors, such as a greater potential for cerebral blood vessel growth than adults, and is supported by increased expression of vascular endothelial growth factor in tissue from recurrent bAVMs.22 Importantly, several dynamic changes appear to increase risk of bAVM rupture, including the development of associated aneurysms, venous outflow stenosis, and silent microhemorrhages.23,24 We will investigate whether quantitative imaging flow parameters and molecular biomarkers correlate with bAVM biology and development of high-risk features in a prospectively followed cohort of pediatric bAVM cases with timed imaging, blood sample, and tissue sample collection. By discovering the mechanisms underlying dynamic changes in bAVMs—growth, recurrence, and the development of high-risk features—we hope to develop novel therapeutics that can ultimately prevent pICH from bAVM.Clinical Science: Novel Approaches to Established TargetsEstablished clinical and community level targets require new approaches in ICH management. For example, hypertension affects over 80% of patients who survive ICH and is the foremost modifiable risk factor for recurrent stroke, dementia, and future systemic vascular events, including stroke and myocardial infarction. However, fewer than 40% of ICH survivors achieve adequate BP control.25 While several factors may contribute, medication inadequacy and resistant hypertension have been shown to account for the majority of uncontrolled hypertension after ICH.26 Accelerating successful treatment approaches for hypertension in ICH survivors is an area of urgent need in this vulnerable population where there have been few to no treatment advances.Advances in the understanding of neurohormonal causes of hypertension have provided targeted therapeutic options. Aldosterone excess is an important contributor to hypertension. Our preliminary data suggest hyperaldosteronism is more common in hypertension patients with ICH than in those without ICH. A recent randomized trial found that spironolactone, an aldosterone-antagonist, was superior to other agents in patients with resistant hypertension on 3 other medications.27 In the Bugher clinical trial REDUCE (Regulating Blood Pressure During Recovery From Intracerebral Hemorrhage: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04760717), we will test the hypothesis that excess aldosterone and sympathetic hyperactivation are underrecognized and undertreated causes of hypertension after ICH and that direct inhibition of these pathways will improve BP control.REDUCE is a prospective, multicenter, randomized, open-label, blinded-end point clinical trial of spironolactone-containing versus standard hypertension regimens. The primary end point will compare the effect of spironolactone-containing versus standard hypertension treatment regimens on 3-month home systolic BP. The trial will enroll 100 white and 100 Black patients between 3 weeks and 3 months after ICH to a regimen including spironolactone 25 to 50 mg daily versus standard hypertension therapy for 1 year. The study will also examine whether plasma neurohormonal biomarkers and race modify the effect of spironolactone on BP reduction. These data will form the basis for future trials hypertension treatment in a broader population of patients with ICH.The Bugher Network embraces increasing recognition that social determinants of health (SDOH) play a significant role in ICH outcomes. SDOH, the conditions in which people are born, grow, work, live, and age, and the wider set of forces and systems shaping the conditions of daily life, contribute to rates of dementia and incident stroke28,29 in the United States as well as BP control.30 Crucially, they have also been associated with poor BP control after stroke.30 They contribute substantially to race and ethnic inequities and may underlie barriers to engagement identified in our prior clinical trials of BP management. Nonetheless, there have been no systematic studies of SDOH in ICH survivors. The joint Mass General-Boston University clinical project will investigate SDOH and social networks to comprehensively identify factors responsible for poor BP control—especially among minority ICH survivors that can be targeted for intervention. The study will enroll 200 ICH survivors (60 White, 70 Black, and 70 Hispanic), capturing detailed information on SDOH and social networks using dedicated tools. Recent studies suggest that Asians ICH survivors face significant rates of recurrent ICH.31 While the current network and sample will not have sufficient power to study this important subgroup, these data will inform future studies in broader populations. These data will be combined with individual genome-wide data (in collaboration with the population-based studies) and computed tomography/MRI neuroimaging to develop a prediction tool for hypertension control following ICH, to be deployed during the acute hemorrhagic stroke admission.The Pediatric Bugher Center aims to improve decision making around bAVM management. The primary goal of bAVM treatment in children is to prevent ICH with minimal treatment-related morbidity. There is currently no standard clinical care guidelines for children with bAVM—the only randomized controlled trial informing management of unruptured bAVM patients excluded children.Current bAVM management options include observation or treatment with either microsurgical resection, endovascular embolization, or stereotactic radiosurgery. Optimal timing and choice of modality remains controversial and is driven by lesion characteristics (size, deep venous drainage, and eloquent location), which comprise the widely used Spetzler-Martin surgical risk score. However, the original Spetzler-Martin score was derived and validated in adults with bAVM.32 In addition, traditional frameworks of eloquence are limiting because they often overlook the wide range of neuropsychiatric morbidity patients suffer after AVM rupture. The relationship of an AVM or hemorrhagic stroke with adjacent functional networks localized by advanced functional imaging has the potential to better inform risk to higher order cognitive processes. We define functional networks using resting state functional MRI and structural networks using diffusion tensor imaging tractography. We will define a connection map, or connectome, for individual children with ICH and bAVM based on their own personal data. The term connectome refers to connections defined by both structural and functional metrics (ie, a structural connectome and a functional connectome). We expect our personalized medicine approach will predict outcomes of hemorrhagic stroke and AVM treatment to a much greater precision than afforded by current clinical standards.Population Science: Developing New Approaches to Discovery and SolutionsGenomic information is emerging as a powerful precision medicine tool to identify persons at high risk of human disease. Consistent with other projects in the Bugher Network, hypertension is a natural target to tackle from population genetics standpoint. Importantly, BP is a highly heritable trait with numerous discovered genetic risk variants. These risk variants are present in 5% to 50% of the general population. While in isolation each of them has only a small effect, their aggregate contribution to BP can substantially modify an individual’s observed BP throughout life. The combined burden of these genetic risk variants determines a person’s polygenic susceptibility to hypertension (PSH), which explains up to 30% of observed BP levels. While PSH is a well-documented risk factor for first-ever ICH, its role in ICH survivors remains unknown. One of the goals of the Bugher network is, therefore, to study the role of PSH in ICH survivors.To accomplish this goal, we will evaluate the role of PSH in several different post-ICH scenarios. First, we will determine whether higher PSH increases the risk of stroke and uncontrolled hypertension in ICH survivors. To this end, we will harmonize existing clinical and genetic data from thousands of ICH survivors enrolled in 4 different genetic studies of this condition. The primary analysis will evaluate whether higher PSH increases the composite risk of recurrent ICH and post-ICH ischemic stroke. The study will also evaluate whether higher PSH increases the risk of uncontrolled and resistant hypertension.Second, we will evaluate whether PSH modifies the subtle risk/benefit balance of anticoagulation in ICH survivors with concomitant atrial fibrillation. Hypertension and uncontrolled BP are known contributors to the risk of bleeding in anticoagulated patients. The ongoing randomized clinical trials ASPIRE (Anticoagulation in ICH Survivors for Prevention and Recovery) and ENRICH-AF (Edoxaban for Intracranial Hemorrhage Survivors With Atrial Fibrillation) are currently evaluating anticoagulation in ICH survivors, providing a unique opportunity to study PSH in this specific clinical context. We will conduct a parallel genetic study to the ASPIRE and ENRICH-AF trials to determine whether PSH is an effect modifier of the effect of anticoagulation on the composite risk of ischemic and hemorrhagic stroke in this particular population. This study includes the completion of genome-wide genotyping in DNA samples from the study participants enrolled in these 2 clinical trials using Illumina’s Global Diversity Array, used by the newly established All of Us Research program. These genome-wide data will become a powerful too