WRITING GROUP MEMBERS Emelia J. Benjamin, MD, SCM, FAHA Michael J. Blaha, MD, MPH Stephanie E. Chiuve, ScD Mary Cushman, MD, MSc, FAHA Sandeep R. Das, MD, MPH, FAHA Rajat Deo, MD, MTR Sarah D. de Ferranti, MD, MPH James Floyd, MD, MS Myriam Fornage, PhD, FAHA Cathleen Gillespie, MS Carmen R. Isasi, MD, PhD, FAHA Monik C. Jiménez, ScD, SM Lori Chaffin Jordan, MD, PhD Suzanne E. Judd, PhD Daniel Lackland, DrPH, FAHA Judith H. Lichtman, PhD, MPH, FAHA Lynda Lisabeth, PhD, MPH, FAHA Simin Liu, MD, ScD, FAHA Chris T. Longenecker, MD Rachel H. Mackey, PhD, MPH, FAHA Kunihiro Matsushita, MD, PhD, FAHA Dariush Mozaffarian, MD, DrPH, FAHA Michael E. Mussolino, PhD, FAHA Khurram Nasir, MD, MPH, FAHA Robert W. Neumar, MD, PhD, FAHA Latha Palaniappan, MD, MS, FAHA Dilip K. Pandey, MBBS, MS, PhD, FAHA Ravi R. Thiagarajan, MD, MPH Mathew J. Reeves, PhD Matthew Ritchey, PT, DPT, OCS, MPH Carlos J. Rodriguez, MD, MPH, FAHA Gregory A. Roth, MD, MPH Wayne D. Rosamond, PhD, FAHA Comilla Sasson, MD, PhD, FAHA Amytis Towfighi, MD Connie W. Tsao, MD, MPH Melanie B. Turner, MPH Salim S. Virani, MD, PhD, FAHA Jenifer H. Voeks, PhD Joshua Z. Willey, MD, MS John T. Wilkins, MD Jason HY. Wu, MSc, PhD, FAHA Heather M. Alger, PhD Sally S. Wong, PhD, RD, CDN, FAHA Paul Muntner, PhD, MHSc On behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart Disease and Stroke Statistics—2017 Update

Heart Disease and Stroke Statistics—2017 Update: A Report From the American Heart Association

Author(s): Writing Group Members; Mozaffarian, Dariush; Benjamin, Emelia J; Go, Alan S; Arnett, Donna K; Blaha, Michael J; Cushman, Mary; Das, Sandeep R; de Ferranti, Sarah; Despres, Jean-Pierre; Fullerton, Heather J; Howard, Virginia J; Huffman, Mark D; Isasi, Carmen R; Jimenez, Monik C; Judd, Suzanne E; Kissela, Brett M; Lichtman, Judith H; Lisabeth, Lynda D; Liu, Simin; Mackey, Rachel H; Magid, David J; McGuire, Darren K; Mohler, Emile R; Moy, Claudia S; Muntner, Paul; Mussolino, Michael E; Nasir, Khurram; Neumar, Robert W; Nichol, Graham; Palaniappan, Latha; Pandey, Dilip K; Reeves, Mathew J; Rodriguez, Carlos J; Rosamond, Wayne; Sorlie, Paul D; Stein, Joel; Towfighi, Amytis; Turan, Tanya N; Virani, Salim S; Woo, Daniel; Yeh, Robert W; Turner, Melanie B; American Heart Association Statistics Committee; Stroke Statistics Subcommittee

Heart Disease and Stroke Statistics—2016 Update: A Report From the American Heart Association

For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

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The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

March 5, 2019 e1 WRITING GROUP MEMBERS Emelia J. Benjamin, MD, ScM, FAHA, Chair Paul Muntner, PhD, MHS, FAHA, Vice Chair Alvaro Alonso, MD, PhD, FAHA Marcio S. Bittencourt, MD, PhD, MPH Clifton W. Callaway, MD, FAHA April P. Carson, PhD, MSPH, FAHA Alanna M. Chamberlain, PhD Alexander R. Chang, MD, MS Susan Cheng, MD, MMSc, MPH, FAHA Sandeep R. Das, MD, MPH, MBA, FAHA Francesca N. Delling, MD, MPH Luc Djousse, MD, ScD, MPH Mitchell S.V. Elkind, MD, MS, FAHA Jane F. Ferguson, PhD, FAHA Myriam Fornage, PhD, FAHA Lori Chaffin Jordan, MD, PhD, FAHA Sadiya S. Khan, MD, MSc Brett M. Kissela, MD, MS Kristen L. Knutson, PhD Tak W. Kwan, MD, FAHA Daniel T. Lackland, DrPH, FAHA Tené T. Lewis, PhD Judith H. Lichtman, PhD, MPH, FAHA Chris T. Longenecker, MD Matthew Shane Loop, PhD Pamela L. Lutsey, PhD, MPH, FAHA Seth S. Martin, MD, MHS, FAHA Kunihiro Matsushita, MD, PhD, FAHA Andrew E. Moran, MD, MPH, FAHA Michael E. Mussolino, PhD, FAHA Martin O’Flaherty, MD, MSc, PhD Ambarish Pandey, MD, MSCS Amanda M. Perak, MD, MS Wayne D. Rosamond, PhD, MS, FAHA Gregory A. Roth, MD, MPH, FAHA Uchechukwu K.A. Sampson, MD, MBA, MPH, FAHA Gary M. Satou, MD, FAHA Emily B. Schroeder, MD, PhD, FAHA Svati H. Shah, MD, MHS, FAHA Nicole L. Spartano, PhD Andrew Stokes, PhD David L. Tirschwell, MD, MS, MSc, FAHA Connie W. Tsao, MD, MPH, Vice Chair Elect Mintu P. Turakhia, MD, MAS, FAHA Lisa B. VanWagner, MD, MSc, FAST John T. Wilkins, MD, MS, FAHA Sally S. Wong, PhD, RD, CDN, FAHA Salim S. Virani, MD, PhD, FAHA, Chair Elect On behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee

Heart Disease and Stroke Statistics—2019 Update: A Report From the American Heart Association

2018 ESC/ESH Guidelines for the management of arterial hypertension.

Using in vivo nonlinear microscopy, we found 2% of brain capillaries were occluded by an adhered leukocyte in Alzheimer’s disease mice. Blocking this adhesion eliminated these stalls, improved brain blood flow by 30%, and restored spatial memory.

Two-Photon Imaging Reveals Capillary Occlusions are Responsible for Reduced Brain Blood Flow and Cognitive Decline in Alzheimer’s Disease Mouse Models

Hypertension (HTN) disrupts vital neurovascular control mechanisms, thereby increasing the brain’s susceptibility to vascular insufficiency, white matter lesions, and cognitive impairment. Yet, the distinct vascular, neuronal, and glial cell types targeted by HTN, as well as the ensuing cellular network disruption driving the neurovascular and cognitive deficits remain undefined. Here we sought to uncover transcriptomic changes in neurons and vascular cells using unbiased, single-cell RNA sequencing on the neocortex of 10-week old C57BL/6 male mice with angiotensin II (AngII) HTN. Vehicle or AngII (600ng/kg/min s.c.) were administered for 3 days, when blood-brain barrier (BBB) permeability start to increase, or 42 days, when neurovascular and cognitive dysfunction are fully developed (n=3/group). We analyzed 39,451 single-cell transcriptomes comprising 26 cell types. Surprisingly, 3 days of AngII induced significantly greater transcriptional changes in venular ECs compared to arteriolar ECs (EdgeR; pval< 0.05, logFC> 2), supporting the notion that venular ECs are uniquely sensitive to the early effects of HTN (Hypertension 76:795, 2020). Gene ontology analysis of differentially expressed genes prominently implicated altered venular immune signaling, BBB dysfunction, and, notably, a secretory phenotype characteristic of senescence (pval <0.05). Moreover, unbiased ligand-receptor interaction analysis (CellChat) demonstrated that senescent venular ECs strongly communicate with oligodendrocyte precursors, and NPY-expressing interneurons, pointing to a previously unrecognized early disruption in the oligo-vascular niche, essential for maintaining white matter integrity, and neuronal network stability. Furthermore, at 42 days of AngII we observed an overrepresentation of aging and neurodegeneration-linked genes in oligos and NPY interneurons, relating to myelin disruption, synaptic dysfunction, and metabolic dysregulation. The data reveal a novel endothelial-oligo-interneuron crosstalk and transcriptomic alterations underlying the impact of HTN on the brain. Future studies will establish how these transcriptomic changes are linked to neurovascular dysfunction, white matter damage and cognitive impairment.

Abstract 007: Hypertension-induced Neurovascular Dysfunction At Single-cell Resolution

Background: Neutrophil-mediated inflammation in the acute phase of intracerebral hemorrhage (ICH) worsens outcome in preclinical studies. sICAM-1 (soluble intercellular adhesion molecule-1), an inducible ligand for integrins and cell-cell adhesion molecules, is critical for neutrophil extravasation. We aimed to determine whether serum levels of sICAM-1 are associated with worse outcomes after ICH. Methods: We conducted a post hoc secondary analysis of an observational cohort using data from the FAST trial (Factor-VII for Acute Hemorrhagic Stroke Treatment). The study exposure was the admission serum level of sICAM-1. The coprimary outcomes were mortality and poor outcome (modified Rankin Scale score 4–6) at 90 days. Secondary radiological outcomes were hematoma expansion at 24 hours and perihematomal edema expansion at 72 hours. We used multiple linear and logistic regression analyses to test for associations between sICAM-1 and outcomes, after adjustment for demographics, ICH severity characteristics, change in the systolic blood pressure in the first 24 hours, treatment randomization arm, and the time from symptom onset to study drug administration. Results: Of 841 patients, we included 507 (60%) with complete data. Hematoma expansion occurred in 169 (33%), while 242 (48%) had a poor outcome. In multivariable analyses, sICAM-1 was associated with mortality (odds ratio, 1.53 per SD increase [95% CI, 1.15–2.03]) and poor outcome (odds ratio, 1.34 per SD increase [CI, 1.06–1.69]). In multivariable analyses of secondary outcomes, sICAM-1 was associated with hematoma expansion (odds ratio, 1.35 per SD increase [CI, 1.11–1.66]), but was not associated with log-transformed perihematomal edema expansion at 72 hours. In additional analyses stratified by treatment assignment, similar results were noted in the recombinant activated factor-VII arm, but not in the placebo arm. Conclusions: Admission serum levels of sICAM-1 were associated with mortality, poor outcome, and hematoma expansion. Given the possibility of a biological interaction between recombinant activated factor-VII and sICAM-1, these findings highlight the need to further explore the role of sICAM-1 as a potential marker of poor ICH outcomes.

Association Between Soluble Intercellular Adhesion Molecule-1 and Intracerebral Hemorrhage Outcomes in the FAST Trial

Plasminogen activator inhibitor‐1 (PAI‐1), a secreted glycoprotein and member of the serine protease inhibitor family, has been implicated to have a role in Alzheimer’s disease (AD) pathogenesis by regulating amyloid‐beta (Aβ) accumulation (Neurobiol Aging 32:1079,2011; J Alzheimers Dis. 64:447,2018). A recent study found that plasma PAI‐1 was differentially expressed in subjects with Aβ pathology and neurodegeneration (A+TN+) compared to A‐TN‐ subjects, with decreased plasma PAI‐1 levels in clinical AD compared to cognitively normal controls (Alzheimers Dement 17:1452,2021). However, whether circulating PAI‐1 levels are altered during the preclinical stage of AD, where there is Aβ and tau pathology but no significant cognitive impairment, remains unclear.

Circulating plasminogen activator inhibitor‐1 (PAI‐1) levels in the preclinical stage of Alzheimer’s disease

Epidemiological studies implicate maternal immune activation (MIA) as a risk factor for a variety of neurodevelopmental disorders. Bacterial and viral infections including rubella, influenza, Toxoplasma gondii, and herpesvirus infections have been associated with autism spectrum disorder (ASD), schizophrenia, bipolar disorder, epilepsy, and cerebral palsy (1–4). The impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on the incidence of neurodevelopmental disorders in the offspring of infected mothers remains to be seen. MIA induces a maternal cytokine response, and exposure to these immunostimulants results in altered neural development in the fetus, a theory supported by several mouse and human studies (1–3). However, the underlying cause of lifetime cognitive defects in offspring due to MIA is unclear (Fig. 1). In PNAS, Zhao et al. (5) demonstrate that MIA is associated with increased blood–brain barrier (BBB) permeability and microglial activation in the offspring, leading to an inflammatory response in the fetal brain that persists into adulthood. MIA induces a maternal cytokine response, increasing the production of proinflammatory cytokines including interleukin (IL)-6, IL-17, tumor necrosis factor alpha (TNFα), and IL-1β (1, 2). It is thought that exposure to these factors causes an increase in cytokines in maternal serum, the placenta, amniotic fluid, and the fetal brain. While the link between MIA and neurodevelopmental disorder has been established, the mechanisms underlying neurodevelopmental defects and permanent neural disorder are unclear. During normal neurogenesis, the fetal brain expresses many different cytokine receptors in spatially and temporally distinct patterns. Mouse models have demonstrated that increased levels of IL-1β, IL-6, and IL-17a during fetal brain development result in behavioral traits associated with ASD and schizophrenia, neocortical malformations, enhancement of excitatory synapses, and hyperconnectivity in adult offspring (6–8). Thus, spatiotemporal changes in cytokine signaling can lead to developmental changes that cause long-lasting effects into adulthood, the mechanisms of which have remained elusive. MIA can also permanently affect fetal immune mechanisms (1, 2, 9). The predominant immune cells in the brain are microglia that perform canonical roles such as phagocytosis. In response to injury or infection, microglia become activated, adopt a rounder “amoeboid” shape, and undergo transcriptional changes to carry out inflammatory responses (10, 11). Microglia also carry out a number of noncanonical functions including regulating neural progenitor cell number, synaptic pruning, neuronal maturation, programmed neuronal cell death, and brain vasculogenesis (10–14). Microglia contribute to neurovascular organogenesis and function and play an important role in the development and maintenance of the BBB (15–17). Prenatal exposure to MIA leads to microglial activation; studies demonstrate that suppression of microglial activation in MIA mouse models can attenuate inflammatory response, rescue neuronal deficits, and restore locomotor activity (1, 18). In vitro studies have demonstrated that prolonged microglial activation impairs BBB permeability, contributing to the progression of neurodegenerative disease in animal models (15, 19–22). Disrupted BBB development in offspring of MIA mouse model Normal BBB development

Costantino Iadecola

Papers

Two-Photon Imaging Reveals Capillary Occlusions are Responsible for Reduced Brain Blood Flow and Cognitive Decline in Alzheimer’s Disease Mouse Models

Abstract 007: Hypertension-induced Neurovascular Dysfunction At Single-cell Resolution

Association Between Soluble Intercellular Adhesion Molecule-1 and Intracerebral Hemorrhage Outcomes in the FAST Trial

Circulating plasminogen activator inhibitor‐1 (PAI‐1) levels in the preclinical stage of Alzheimer’s disease

When the BBB goes MIA