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1.
Molecules ; 26(20)2021 Oct 11.
Article in English | MEDLINE | ID: covidwho-1480881

ABSTRACT

We performed an in silico, in vitro, and in vivo assessment of a potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (compound 1) as a potential prodrug for cognitive function improvement in ischemic brain injury. Using in silico methods, we predicted the pharmacological efficacy and possible safety in rat models. In addition, in silico data showed neuroprotective features of compound 1, which were further supported by in vitro experiments in a glutamate excitotoxicity-induced model in newborn rat cortical neuron cultures. Next, we checked whether compound 1 is capable of crossing the blood-brain barrier in intact and ischemic animals. Compound 1 improved animal behavior both in intact and ischemic rats and, even though the concentration in intact brains was low, we still observed a significant anxiety reduction and activity escalation. We used molecular docking and molecular dynamics to support our hypothesis that compound 1 could affect the AMPA receptor function. In a rat model of acute focal cerebral ischemia, we studied the effects of compound 1 on the behavior and neurological deficit. An in vivo experiment demonstrated that compound 1 significantly reduced the neurological deficit and improved neurological symptom regression, exploratory behavior, and anxiety. Thus, here, for the first time, we show that compound 1 can be considered as an agent for restoring cognitive functions.


Subject(s)
Ischemic Stroke/drug therapy , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Animals , Behavior, Animal/drug effects , Brain Ischemia , Cognition/drug effects , Cognition/physiology , Disease Models, Animal , Glutamic Acid/pharmacology , Infarction, Middle Cerebral Artery , Ischemic Stroke/physiopathology , Male , Molecular Docking Simulation , Neurons/drug effects , Neuroprotective Agents/pharmacology , Primary Cell Culture , Pyrrolidines/chemical synthesis , Rats , Rats, Wistar , Stroke
2.
Stroke ; 52(7): 2422-2426, 2021 07.
Article in English | MEDLINE | ID: covidwho-1195875

ABSTRACT

BACKGROUND AND PURPOSE: Stroke may complicate coronavirus disease 2019 (COVID-19) infection based on clinical hypercoagulability. We investigated whether transcranial Doppler ultrasound has utility for identifying microemboli and clinically relevant cerebral blood flow velocities (CBFVs) in COVID-19. METHODS: We performed transcranial Doppler for a consecutive series of patients with confirmed or suspected COVID-19 infection admitted to 2 intensive care units at a large academic center including evaluation for microembolic signals. Variables specific to hypercoagulability and blood flow including transthoracic echocardiography were analyzed as a part of routine care. RESULTS: Twenty-six patients were included in this analysis, 16 with confirmed COVID-19 infection. Of those, 2 had acute ischemic stroke secondary to large vessel occlusion. Ten non-COVID stroke patients were included for comparison. Two COVID-negative patients had severe acute respiratory distress syndrome and stroke due to large vessel occlusion. In patients with COVID-19, relatively low CBFVs were observed diffusely at median hospital day 4 (interquartile range, 3-9) despite low hematocrit (29.5% [25.7%-31.6%]); CBFVs in comparable COVID-negative stroke patients were significantly higher compared with COVID-positive stroke patients. Microembolic signals were not detected in any patient. Median left ventricular ejection fraction was 60% (interquartile range, 60%-65%). CBFVs were correlated with arterial oxygen content, and C-reactive protein (Spearman ρ=0.28 [P=0.04]; 0.58 [P<0.001], respectively) but not with left ventricular ejection fraction (ρ=-0.18; P=0.42). CONCLUSIONS: In this cohort of critically ill patients with COVID-19 infection, we observed lower than expected CBFVs in setting of low arterial oxygen content and low hematocrit but not associated with suppression of cardiac output.


Subject(s)
Blood Flow Velocity , Brain/diagnostic imaging , COVID-19/diagnostic imaging , Cerebrovascular Circulation , Ischemic Stroke/diagnostic imaging , Adult , Aged , Blood Gas Analysis , Brain/blood supply , C-Reactive Protein/metabolism , COVID-19/physiopathology , Case-Control Studies , Critical Illness , Female , Humans , Ischemic Stroke/physiopathology , Male , Middle Aged , Oxygen/blood , Respiratory Distress Syndrome/diagnostic imaging , Respiratory Distress Syndrome/physiopathology , SARS-CoV-2 , Stroke Volume/physiology , Ultrasonography, Doppler, Transcranial
3.
Stroke ; 52(5): 1895-1904, 2021 05.
Article in English | MEDLINE | ID: covidwho-1166638

ABSTRACT

The Coronavirus disease 2019 (COVID)-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications. The increasing incidence of large vessel ischemic strokes as well as intracranial hemorrhages, frequently in younger individuals, and associated with increased morbidity and mortality, has raised questions as to why the brain is a major target of the disease. COVID-19 is characterized by hypercoagulability with alterations in hemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.


Subject(s)
Brain Ischemia/complications , Brain/physiopathology , COVID-19/complications , Endothelial Cells/cytology , Ischemic Stroke/complications , Angiotensin-Converting Enzyme 2/metabolism , Blood Coagulation , Brain Ischemia/physiopathology , COVID-19/physiopathology , Cytokines/metabolism , Fibrin/chemistry , Fibrin Fibrinogen Degradation Products/chemistry , Hemostasis , Humans , Hypoxia , Incidence , Inflammation , Ischemic Stroke/physiopathology , Myocardial Infarction/physiopathology , Pandemics , Prognosis
4.
Stroke ; 52(5): 1885-1894, 2021 05.
Article in English | MEDLINE | ID: covidwho-1166635

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 or coronavirus disease 2019 (COVID-19) pandemic has raised concerns about the correlation with this viral illness and increased risk of stroke. Although it is too early in the pandemic to know the strength of the association between COVID-19 and stroke, it is an opportune time to review the relationship between acute viral illnesses and stroke. Here, we summarize pathophysiological principles and available literature to guide understanding of how viruses may contribute to ischemic stroke. After a review of inflammatory mechanisms, we summarize relevant pathophysiological principles of vasculopathy, hypercoagulability, and hemodynamic instability. We will end by discussing mechanisms by which several well-known viruses may cause stroke in an effort to inform our understanding of the relationship between COVID-19 and stroke.


Subject(s)
Brain Ischemia/complications , Brain Ischemia/physiopathology , COVID-19/complications , COVID-19/epidemiology , Ischemic Stroke/complications , Ischemic Stroke/physiopathology , Acute Disease , Blood Coagulation , Brain Ischemia/virology , Hemodynamics , Herpesvirus 3, Human , Humans , Inflammation/physiopathology , Ischemic Stroke/virology , Pandemics , Plaque, Atherosclerotic/physiopathology , Risk , Thrombophilia/physiopathology , Thrombosis/physiopathology , Vascular Diseases/physiopathology , Virus Diseases/physiopathology
5.
Cerebrovasc Dis ; 50(4): 412-419, 2021.
Article in English | MEDLINE | ID: covidwho-1158151

ABSTRACT

INTRODUCTION: Acute ischemic stroke (AIS) and thrombotic events (TEs) were reported in patients with COVID-19. Clinical outcome of AIS in the course of COVID-19 remains unknown. We compared early clinical outcome and mortality of COVID-positive (+) patients admitted for AIS with COVID-negative (-) ones. We hypothesized that COVID+ patients would have poorer clinical outcomes and present a higher rate of TEs and mortality compared with COVID- ones. METHODS: In this multicentric observational retrospective study, we enrolled patients over 18 years old admitted for AIS in 3 stroke units of the Parisian region during lockdown from March 17, 2020, to May 2, 2020. COVID-19 status as well as demographic, clinical, biological, and imaging data was collected retrospectively from medical records. Poor outcome was defined as modified Rankin score (mRS) 3-6 (3-6) at discharge. We also compared TE frequency and mortality rate through a composite criterion in both groups. RESULTS: Two hundred and sixteen patients were enrolled; mean age was 68 years old, and 63% were male. Forty patients were CO-VID+ (18.5%) and 176 were COVID-. Obesity was statistically more frequent in the COVID+ group (36 vs. 13% p < 0.01). The percentage of patients with mRS (3-6) at discharge was higher in the COVID+ group compared with the COVID- group (60 vs. 41%, p = 0.034). The main predictor of presenting a mRS (3-6) at discharge was high NIHSS score at admission (OR, CI 95%: 1.325, 1.22-1.43). Mortality rate was higher in the COVID+ group (12 vs. 3.4%, p = 0.033) as well as TE frequency (15 vs. 2.8%, p < 0.01). CONCLUSION: In this study, patients with AIS infected by SARS-CoV-2 showed a poorer early outcome than COVID- ones. However, when compared to other factors, COVID-19 was not a significant predictor of poor outcome. Vascular morbidity and mortality rates were significantly higher in the COVID+ group compared with the COVID- group.


Subject(s)
COVID-19/physiopathology , Ischemic Stroke/physiopathology , Aged , Aged, 80 and over , COVID-19/epidemiology , Case-Control Studies , Diabetes Mellitus/epidemiology , Female , France/epidemiology , Functional Status , Hospital Mortality , Humans , Ischemic Stroke/epidemiology , Male , Middle Aged , Obesity/epidemiology , Prognosis , Retrospective Studies , Risk Factors , SARS-CoV-2
6.
Cardiol Rev ; 29(3): 143-149, 2021.
Article in English | MEDLINE | ID: covidwho-1148006

ABSTRACT

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 has affected the health of people across the globe. Cardiovascular diseases (CVDs) have a significant relationship with COVID-19, both as a risk factor and prognostic indicator, and as a complication of the disease itself. In addition to predisposing to CVD complications, the ongoing pandemic has severely affected the delivery of timely and appropriate care for cardiovascular conditions resulting in increased mortality. The etiology behind the cardiac injury associated with severe acute respiratory syndrome coronavirus-2 is likely varied, including coronary artery disease, microvascular thrombosis, myocarditis, and stress cardiomyopathy. Further large-scale investigations are needed to better determine the underlying mechanism of myocardial infarction and other cardiac injury in COVID-19 patients and to determine the incidence of each type of cardiac injury in this patient population. Telemedicine and remote monitoring technologies can play an important role in optimizing outcomes in patients with established CVD. In this article, we summarize the various impacts that COVID-19 has on the cardiovascular system, including myocardial infarction, myocarditis, stress cardiomyopathy, thrombosis, and stroke.


Subject(s)
COVID-19/physiopathology , Cardiovascular Diseases/physiopathology , COVID-19/complications , COVID-19/epidemiology , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Comorbidity , Coronary Artery Disease/epidemiology , Coronary Artery Disease/etiology , Coronary Artery Disease/physiopathology , Coronary Thrombosis/etiology , Coronary Thrombosis/physiopathology , Heart Disease Risk Factors , Humans , Ischemic Stroke/epidemiology , Ischemic Stroke/etiology , Ischemic Stroke/physiopathology , Microvessels , Myocardial Infarction/epidemiology , Myocardial Infarction/etiology , Myocardial Infarction/physiopathology , Myocarditis/etiology , Myocarditis/physiopathology , SARS-CoV-2 , Stroke/epidemiology , Stroke/etiology , Stroke/physiopathology , Takotsubo Cardiomyopathy/etiology , Takotsubo Cardiomyopathy/physiopathology , Thrombosis/etiology , Thrombosis/physiopathology
7.
BMJ Case Rep ; 14(3)2021 Mar 02.
Article in English | MEDLINE | ID: covidwho-1115107

ABSTRACT

The COVID-19 pandemic has dealt a devastating blow to healthcare systems globally. Approximately 3.2% of patients infected with COVID-19 require invasive ventilation during the course of the illness. Within this population, 25% of patients are affected with neurological manifestations. Among those who are affected by severe neurological manifestations, some may have acute cerebrovascular complications (5%), impaired consciousness (15%) or exhibit skeletal muscle hypokinesis (20%). The cause of the severe cognitive impairment and hypokinesis is unknown at this time. Potential causes include COVID-19 viral encephalopathy, toxic metabolic encephalopathy, post-intensive care unit syndrome and cerebrovascular pathology. We present a case of a 60 year old patient who sustained a prolonged hospitalization with COVID-19, had a cerebrovascular event and developed a persistent unexplained encephalopathy along with a hypokinetic state. He was treated successfully with modafinil and carbidopa/levodopa showing clinical improvement within 3-7 days and ultimately was able to successfully discharge home.


Subject(s)
Brain Diseases , COVID-19 , Carbidopa/administration & dosage , Hypokinesia , Ischemic Stroke , Levodopa/administration & dosage , Modafinil/administration & dosage , Rehabilitation/methods , SARS-CoV-2/isolation & purification , Blood Coagulation , Brain Diseases/physiopathology , Brain Diseases/virology , COVID-19/blood , COVID-19/complications , COVID-19/physiopathology , COVID-19/therapy , Central Nervous System Stimulants/administration & dosage , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/etiology , Critical Care/methods , Drug Combinations , Humans , Hypokinesia/diagnosis , Hypokinesia/etiology , Hypokinesia/therapy , Ischemic Stroke/diagnostic imaging , Ischemic Stroke/etiology , Ischemic Stroke/physiopathology , Ischemic Stroke/therapy , Magnetic Resonance Imaging/methods , Male , Middle Aged , Respiration, Artificial/methods , Severity of Illness Index , Treatment Outcome , Ventilator Weaning/methods
9.
J Thromb Thrombolysis ; 51(4): 985-988, 2021 May.
Article in English | MEDLINE | ID: covidwho-1053058

ABSTRACT

OBJECTIVES: Infection with the SARS-COV2 virus (COVID-19) may be complicated by thrombotic diathesis. This complication often involves the pulmonary microcirculation. While macrovascular thrombotic complications of the lung may include pulmonary artery embolism, pulmonary artery thrombus in situ has also been hypothesized. Pulmonary vein thrombosis has not been described in this context. METHODS/RESULTS: Herein, we provide a case of an otherwise healthy male who developed an ischemic stroke with left internal carotid thrombus. Further imaging revealed pulmonary emboli with propagation through the pulmonary veins into the left atrium. This left atrial thrombus provides a source of atypical "paradoxic arterial embolism". CONCLUSIONS: Thrombotic outcomes in the setting of severe COVID 19 pneumonia may include macrovascular venous thromboembolism, microvascular pulmonary vascular thrombosis and arterial thromboembolism. Pulmonary vein, herein described, provides further mechanistic pathway for potential arterial embolic phenomenon.


Subject(s)
COVID-19 , Carotid Artery Thrombosis , Ischemic Stroke , Pulmonary Embolism , Pulmonary Veno-Occlusive Disease , Brain/diagnostic imaging , COVID-19/blood , COVID-19/complications , COVID-19/physiopathology , Carotid Artery Thrombosis/complications , Carotid Artery Thrombosis/diagnosis , Diagnosis, Differential , Heart Atria/diagnostic imaging , Heart Atria/pathology , Hemiplegia/diagnosis , Hemiplegia/etiology , Humans , Ischemic Stroke/diagnosis , Ischemic Stroke/etiology , Ischemic Stroke/physiopathology , Lung/diagnostic imaging , Male , Middle Aged , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/etiology , Pulmonary Veno-Occlusive Disease/complications , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/physiopathology , SARS-CoV-2/pathogenicity , Tomography, X-Ray Computed/methods
10.
J Thromb Thrombolysis ; 51(1): 237-242, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-636047

ABSTRACT

Coronavirus disease 2019 (COVID-19) could predispose to both venous and arterial thromboembolism, in an exaggerated immune response to the virus, especially in severe patients. Even though aortic clots are a rare entity, the pro-coagulant nature of COVID-19 is associated with thrombosis in atypical locations and should be considered in patients with severe abnormalities in coagulation parameters. We describe a series of three cases of aortic thrombi diagnosed by computerized tomography (CT) angiography in patients with confirmed SARS-CoV-2 infection.


Subject(s)
Anticoagulants/administration & dosage , Aorta/diagnostic imaging , Aortic Diseases , COVID-19 , Thrombosis , Aged , Anticoagulants/classification , Aortic Diseases/diagnosis , Aortic Diseases/etiology , Aortic Diseases/physiopathology , COVID-19/blood , COVID-19/complications , COVID-19/diagnosis , COVID-19/therapy , Computed Tomography Angiography/methods , Diagnosis, Differential , Fibrin Fibrinogen Degradation Products/analysis , Humans , Ischemic Stroke/diagnosis , Ischemic Stroke/etiology , Ischemic Stroke/physiopathology , Male , Middle Aged , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/etiology , Pulmonary Embolism/therapy , SARS-CoV-2/isolation & purification , Severity of Illness Index , Thrombosis/blood , Thrombosis/diagnosis , Thrombosis/drug therapy , Thrombosis/etiology , Tomography, X-Ray Computed/methods , Treatment Outcome
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