Bending the Curve in Cardiovascular Disease Mortality: Bethesda + 40 and Beyond.

More than 40 years after the 1978 Bethesda Conference on the Declining Mortality from Coronary Heart Disease provided the scientific community with a blueprint for systematic analysis to understand declining rates of coronary heart disease, there are indications the decline has ended or even reversed despite advances in our knowledge about the condition and treatment. Recent data show a more complex situation, with mortality rates for overall cardiovascular disease, including coronary heart disease and stroke, decelerating, whereas those for heart failure are increasing. To mark the 40th anniversary of the Bethesda Conference, the National Heart, Lung, and Blood Institute and the American Heart Association cosponsored the "Bending the Curve in Cardiovascular Disease Mortality: Bethesda + 40" symposium. The objective was to examine the immediate and long-term outcomes of the 1978 conference and understand the current environment. Symposium themes included trends and future projections in cardiovascular disease (in the United States and internationally), the evolving obesity and diabetes epidemics, and harnessing emerging and innovative opportunities to preserve and promote cardiovascular health and prevent cardiovascular disease. In addition, participant-led discussion explored the challenges and barriers in promoting cardiovascular health across the lifespan and established a potential framework for observational research and interventions that would begin in early childhood (or ideally in utero). This report summarizes the relevant research, policy, and practice opportunities discussed at the symposium.

The impact of COVID-19 pandemic on AMI and stroke mortality in Lombardy: Evidence from the epicenter of the pandemic.

BACKGROUND: The first Covid-19 epidemic outbreak has enormously impacted the delivery of clinical healthcare and hospital management practices in most of the hospitals around the world. In this context, it is important to assess whether the clinical management of non-Covid patients has not been compromised. Among non-Covid cases, patients with Acute Myocardial Infarction (AMI) and stroke need non-deferrable emergency care and are the natural candidates to be studied. Preliminary evidence suggests that the time from onset of symptoms to emergency department (ED) presentation has significantly increased in Covid-19 times as well as the 30-day mortality and in-hospital mortality. METHODS: We check, in a causal inference framework, the causal effect of the hospital's stress generated by Covid-19 pandemic on in-hospital mortality rates (primary end-point of the study) of AMI and stroke over several time-windows of 15-days around the implementation date of the State of Emergency restrictions for COVID-19 (March, 9th 2020) using two quasi-experimental approaches, regression-discontinuity design (RDD) and difference-in-regression-discontinuity (DRD) designs. Data are drawn from Spedali Civili of Brescia, one of the most hit provinces in Italy by Covid-19 during March and May 2020. FINDINGS: Despite the potential adverse effects on expected mortality due to a longer time to hospitalization and staff extra-burden generated by the first wave of Covid-19, the AMI and stroke mortality rates are overall not statistically different during the first wave of Covid-19 than before the first peak. The obtained results provided by RDD models are robust also when we account for seasonality and unobserved factors with DRD models. INTERPRETATION: The non-statistically significant impact on mortality rates for AMI and stroke patients provides evidence of the hospital ability to manage -with the implementation of a dual track organization- the simultaneous delivery of high-quality cares to both Covid and non-Covid patients.

Recent advances in cell therapy for stroke.

The last 50 years have witnessed the translation of stem cell therapy from the laboratory to the clinic for treating brain disorders, in particular stroke. From the focal stereotaxic transplantation to the minimally invasive intravenous and intraarterial delivery, stem cells display the ability to replenish injured cells and to secrete therapeutic molecules, altogether promoting brain repair. The increased stroke incidence in COVID-19 survivors poses as a new disease indication for cell therapy, owing in part to the cells' robust anti-inflammatory properties. Optimization of the cell transplant regimen will ensure the safe and effective clinical application of cell therapy in stroke and relevant neurological disorders.

Gap junction-mediated cell-cell interaction between transplanted mesenchymal stem cells and vascular endothelium in stroke.

We have shown previously that transplanted bone marrow mononuclear cells (BM-MNC), which are a cell fraction rich in hematopoietic stem cells, can activate cerebral endothelial cells via gap junction-mediated cell-cell interaction. In the present study, we investigated such cell-cell interaction between mesenchymal stem cells (MSC) and cerebral endothelial cells. In contrast to BM-MNC, for MSC we observed suppression of vascular endothelial growth factor uptake into endothelial cells and transfer of glucose from endothelial cells to MSC in vitro. The transfer of such a small molecule from MSC to vascular endothelium was subsequently confirmed in vivo and was followed by suppressed activation of macrophage/microglia in stroke mice. The suppressive effect was absent by blockade of gap junction at MSC. Furthermore, gap junction-mediated cell-cell interaction was observed between circulating white blood cells and MSC. Our findings indicate that gap junction-mediated cell-cell interaction is one of the major pathways for MSC-mediated suppression of inflammation in the brain following stroke and provides a novel strategy to maintain the blood-brain barrier in injured brain. Furthermore, our current results have the potential to provide a novel insight for other ongoing clinical trials that make use of MSC transplantation aiming to suppress excess inflammation, as well as other diseases such as COVID-19 (coronavirus disease 2019).

Stroke in patients with COVID-19: Clinical and neuroimaging characteristics.

Acute cerebrovascular disease, particularly ischemic stroke, has emerged as a serious complication of infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of the Coronavirus disease-2019 (COVID-19). Accumulating data on patients with COVID-19-associated stroke have shed light on specificities concerning clinical presentation, neuroimaging findings, and outcome. Such specificities include a propensity towards large vessel occlusion, multi-territory stroke, and involvement of otherwise uncommonly affected vessels. Conversely, small-vessel brain disease, cerebral venous thrombosis, and intracerebral hemorrhage appear to be less frequent. Atypical neurovascular presentations were also described, ranging from bilateral carotid artery dissection to posterior reversible encephalopathy syndrome (PRES), and vasculitis. Cases presenting with encephalopathy or encephalitis with seizures heralding stroke were particularly challenging. The pathogenesis and optimal management of ischemic stroke associated with COVID-19 still remain uncertain, but emerging evidence suggest that cytokine storm-triggered coagulopathy and endotheliopathy represent possible targetable mechanisms. Some specific management issues in this population include the difficulty in identifying clinical signs of stroke in critically ill patients in the intensive care unit, as well as the need for a protected pathway for brain imaging, intravenous thrombolysis, and mechanical thrombectomy, keeping in mind that "time is brain" also for COVID-19 patients. In this review, we discuss the novel developments and challenges for the diagnosis and treatment of stroke in patients with COVID-19, and delineate the principles for a rational approach toward precision medicine in this emerging field.

Complete Clinicopathological Case Report of a Young Patient Dying of COVID-19-Related Stroke.

ABSTRACT: The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic has revealed diverse neurological manifestations of coronavirus disease 2019 (COVID-19). This case report begins with a background review of the neurological effects of COVID-19, focusing on stroke, neuroinflammation, and coagulopathy. It then describes the clinical course and autopsy findings of a young patient presenting with COVID-19-associated stroke. The formal neuropathological examination is presented, along with the systemic and brain histological features. Interesting aspects include multiterritory hemorrhagic infarctions, microinfarcts throughout the cortex and white matter, and prominent mixed inflammatory cell cuffing of intracerebral blood vessels distant from the infarcts.

Insights Into Immunothrombosis: The Interplay Among Neutrophil Extracellular Trap, von Willebrand Factor, and ADAMTS13.

Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.

COVID-19 presenting with agraphia and conduction aphasia in a patient with left-hemisphere ischemic stroke.

COVID-19 following infection by SARS-CoV-2 can affect the brain causing confusion, depression, and dementia-like signs. Nonetheless, the presence of more specific neuropsychological signs because of COVID-19 remains unexplored. We report on LA, a patient who was affected by a left-hemisphere ischemic stroke, probably because of SARS-CoV-2. The patient showed a highly specific neuropsychological profile characterized by severe agraphia and some signs of conduction aphasia. All other cognitive and sensorimotor functions remained intact. We sustain that specific neuropsychological signs can be observed in patients with COVID-19. Therefore, in-depth and comprehensive neuropsychological assessment should be included to better explore and qualify the neuropsychological consequences of COVID-19. This is a new challenge for diagnosis and rehabilitation, with important consequences for the involved neuropsychological services.

Immunothrombosis and thromboinflammation in host defense and disease.

Platelets are increasingly being recognized for playing roles beyond thrombosis and hemostasis. Today we know that they mediate inflammation by direct interactions with innate immune cells or secretion of cytokines/chemokines. Here we review their interactions with neutrophils and monocytes/macrophages in infection and sepsis, stroke, myocardial infarction and venous thromboembolism. We discuss new roles for platelet surface receptors like GPVI or GPIb and also look at platelet contributions to the formation of neutrophil extracellular traps (NETs) as well as to deep vein thrombosis during infection, e.g. in COVID-19 patients.

Neurological injuries in COVID-19 patients: direct viral invasion or a bystander injury after infection of epithelial/endothelial cells.

A subset of patients with coronavirus 2 disease (COVID-19) experience neurological complications. These complications include loss of sense of taste and smell, stroke, delirium, and neuromuscular signs and symptoms. The etiological agent of COVID-19 is SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), an RNA virus with a glycoprotein-studded viral envelope that uses ACE2 (angiotensin-converting enzyme 2) as a functional receptor for infecting the host cells. Thus, the interaction of the envelope spike proteins with ACE2 on host cells determines the tropism and virulence of SARS-CoV-2. Loss of sense of taste and smell is an initial symptom of COVID-19 because the virus enters the nasal and oral cavities first and the epithelial cells are the receptors for these senses. Stroke in COVID-19 patients is likely a consequence of coagulopathy and injury to cerebral vascular endothelial cells that cause thrombo-embolism and stroke. Delirium and encephalopathy in acute and post COVID-19 patients are likely multifactorial and secondary to hypoxia, metabolic abnormalities, and immunological abnormalities. Thus far, there is no clear evidence that coronaviruses cause inflammatory neuromuscular diseases via direct invasion of peripheral nerves or muscles or via molecular mimicry. It appears that most of neurologic complications in COVID-19 patients are indirect and as a result of a bystander injury to neurons.

Neurological manifestations of COVID-19: available evidences and a new paradigm.

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.

Vessel Wall Enhancement and Focal Cerebral Arteriopathy in a Pediatric Patient with Acute Infarct and COVID-19 Infection.

Herein, we report the findings of intracranial arterial wall enhancement, consistent with focal cerebral arteriopathy-inflammatory type, in a child presenting with acute infarct in the setting of coronavirus disease 2019 (COVID-19) infection. To our knowledge, this report provides the first description of vessel wall imaging findings in COVID-19-associated acute stroke.

Infarction of the Splenium of the Corpus Callosum in the Age of COVID-19: A Snapshot in Time.

BACKGROUND AND PURPOSE: Ischemic infarction of the corpus callosum is rare and infarction isolated to the corpus callosum alone rarer still, accounting for much <1% of ischemic stroke in most stroke registries. About half of callosal infarctions affect the splenium. METHODS: During a 2-week period, at the height of the coronavirus disease 2019 (COVID-19) pandemic in New York City, 4 patients at Montefiore Medical Center in the Bronx were found to have ischemic lesions of the splenium of the corpus callosum, 2 with infarction isolated to the corpus callosum. RESULTS: All patients tested positive for COVID-19 and 3 had prolonged periods of intubation. All had cardiovascular risk factors. Clinically, all presented with encephalopathy and had evidence of coagulopathy and raised inflammatory markers. CONCLUSIONS: Infarction of the splenium of the corpus callosum is exceedingly rare and a cluster of such cases suggests COVID-19 as an inciting agent, with the mechanisms to be elucidated.