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1.
J Stroke Cerebrovasc Dis ; 30(12): 106118, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1415616

ABSTRACT

BACKGROUND AND OBJECTIVES: RCVS (Reversible Cerebral Vasoconstrictive Syndrome) is a condition associated with vasoactive agents that alter endothelial function. There is growing evidence that endothelial inflammation contributes to cerebrovascular disease in patients with coronavirus disease 2019 (COVID-19). In our study, we describe the clinical features, risk factors, and outcomes of RCVS in a multicenter case series of patients with COVID-19. MATERIALS AND METHODS: Multicenter retrospective case series. We collected clinical characteristics, imaging, and outcomes of patients with RCVS and COVID-19 identified at each participating site. RESULTS: Ten patients were identified, 7 women, ages 21 - 62 years. Risk factors included use of vasoconstrictive agents in 7 and history of migraine in 2. Presenting symptoms included thunderclap headache in 5 patients with recurrent headaches in 4. Eight were hypertensive on arrival to the hospital. Symptoms of COVID-19 included fever in 2, respiratory symptoms in 8, and gastrointestinal symptoms in 1. One patient did not have systemic COVID-19 symptoms. MRI showed subarachnoid hemorrhage in 3 cases, intraparenchymal hemorrhage in 2, acute ischemic stroke in 4, FLAIR hyperintensities in 2, and no abnormalities in 1 case. Neurovascular imaging showed focal segment irregularity and narrowing concerning for vasospasm of the left MCA in 4 cases and diffuse, multifocal narrowing of the intracranial vasculature in 6 cases. Outcomes varied, with 2 deaths, 2 remaining in the ICU, and 6 surviving to discharge with modified Rankin scale (mRS) scores of 0 (n=3), 2 (n=2), and 3 (n=1). CONCLUSIONS: Our series suggests that patients with COVID-19 may be at risk for RCVS, particularly in the setting of additional risk factors such as exposure to vasoactive agents. There was variability in the symptoms and severity of COVID-19, clinical characteristics, abnormalities on imaging, and mRS scores. However, a larger study is needed to validate a causal relationship between RCVS and COVID-19.


Subject(s)
COVID-19/complications , Cerebral Arteries/physiopathology , Cerebrovascular Circulation , Vasoconstriction , Vasospasm, Intracranial/etiology , Adult , COVID-19/diagnosis , COVID-19/therapy , Cerebral Arteries/diagnostic imaging , Female , Humans , Male , Middle Aged , Neuroimaging , Retrospective Studies , Risk Factors , Severity of Illness Index , Syndrome , Time Factors , Treatment Outcome , United States , Vasospasm, Intracranial/diagnostic imaging , Vasospasm, Intracranial/physiopathology , Vasospasm, Intracranial/therapy , Young Adult
2.
Eur Respir Rev ; 30(161)2021 Sep 30.
Article in English | MEDLINE | ID: covidwho-1412449

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a serious complication of severe systemic or local pulmonary inflammation, such as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ARDS is characterised by diffuse alveolar damage that leads to protein-rich pulmonary oedema, local alveolar hypoventilation and atelectasis. Inadequate perfusion of these areas is the main cause of hypoxaemia in ARDS. High perfusion in relation to ventilation (V/Q<1) and shunting (V/Q=0) is not only caused by impaired hypoxic pulmonary vasoconstriction but also redistribution of perfusion from obstructed lung vessels. Rebalancing the pulmonary vascular tone is a therapeutic challenge. Previous clinical trials on inhaled vasodilators (nitric oxide and prostacyclin) to enhance perfusion to high V/Q areas showed beneficial effects on hypoxaemia but not on mortality. However, specific patient populations with pulmonary hypertension may profit from treatment with inhaled vasodilators. Novel treatment targets to decrease perfusion in low V/Q areas include epoxyeicosatrienoic acids and specific leukotriene receptors. Still, lung protective ventilation and prone positioning are the best available standard of care. This review focuses on disturbed perfusion in ARDS and aims to provide basic scientists and clinicians with an overview of the vascular alterations and mechanisms of V/Q mismatch, current therapeutic strategies, and experimental approaches.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , COVID-19/complications , Humans , Hypoxia , Lung/physiopathology , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , Vasoconstriction
5.
Biomolecules ; 11(7)2021 07 03.
Article in English | MEDLINE | ID: covidwho-1295754

ABSTRACT

Angiotensin II (Ang II) may contain a charge relay system (CRS) involving Tyr/His/carboxylate, which creates a tyrosinate anion for receptor activation. Energy calculations were carried out to determine the preferred geometry for the CRS in the presence and absence of the Arg guanidino group occupying position 2 of Ang II. These findings suggest that Tyr is preferred over His for bearing the negative charge and that the CRS is stabilized by the guanidino group. Recent crystallography studies provided details of the binding of nonpeptide angiotensin receptor blockers (ARBs) to the Ang II type 1 (AT1) receptor, and these insights were applied to Ang II. A model of binding and receptor activation that explains the surmountable and insurmountable effects of Ang II analogues sarmesin and sarilesin, respectively, was developed and enabled the discovery of a new generation of ARBs called bisartans. Finally, we determined the ability of the bisartan BV6(TFA) to act as a potential ARB, demonstrating similar effects to candesartan, by reducing vasoconstriction of rabbit iliac arteries in response to cumulative doses of Ang II. Recent clinical studies have shown that Ang II receptor blockers have protective effects in hypertensive patients infected with SARS-CoV-2. Therefore, the usage of ARBS to block the AT1 receptor preventing the binding of toxic angiotensin implicated in the storm of cytokines in SARS-CoV-2 is a target treatment and opens new avenues for disease therapy.


Subject(s)
Angiotensin II/metabolism , Angiotensin Receptor Antagonists/chemistry , Angiotensin Receptor Antagonists/pharmacology , COVID-19/drug therapy , Drug Discovery , Receptor, Angiotensin, Type 1/metabolism , Angiotensin II/analogs & derivatives , Animals , COVID-19/metabolism , Crystallography, X-Ray , Humans , Hypertension/drug therapy , Hypertension/metabolism , Male , Models, Molecular , Rabbits , Receptor, Angiotensin, Type 1/chemistry , Vasoconstriction/drug effects
6.
J Physiol ; 599(11): 2791-2792, 2021 06.
Article in English | MEDLINE | ID: covidwho-1263885
7.
J Stroke Cerebrovasc Dis ; 30(7): 105822, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1179851

ABSTRACT

There have been limited cases linking SARS-CoV-2 infection with the development of reversible cerebral vasoconstriction syndrome (RCVS). We hereby report a rare case of RCVS in the setting of mild SARS-CoV-2 respiratory infection successfully treated with nimodipine and aspirin. SARS-CoV-2 attacks the ACE2-receptors, which are expressed in various body organs including the lungs, kidneys, and blood vessels. Vasoconstriction can result from down-regulation of the ACE2-receptors that can lead to sympathetic hypertonia of the cerebral blood vessel walls and/or over-activation of the renin-angiotensin axis.


Subject(s)
Aspirin/therapeutic use , COVID-19/complications , Cerebral Arteries/drug effects , Nimodipine/therapeutic use , Vasoconstriction/drug effects , Vasodilator Agents/therapeutic use , Vasospasm, Intracranial/drug therapy , Adult , COVID-19/diagnosis , Cerebral Arteries/diagnostic imaging , Cerebral Arteries/physiopathology , Female , Humans , Syndrome , Treatment Outcome , Vasospasm, Intracranial/diagnostic imaging , Vasospasm, Intracranial/etiology , Vasospasm, Intracranial/physiopathology
9.
Mayo Clin Proc ; 96(4): 989-1005, 2021 04.
Article in English | MEDLINE | ID: covidwho-1039483

ABSTRACT

Pernio or chilblains is characterized by erythema and swelling at acral sites (eg, toes and fingers), typically triggered by cold exposure. Clinical and histopathologic features of pernio are well described, but the pathogenesis is not entirely understood; vasospasm and a type I interferon (IFN-I) immune response are likely involved. During the coronavirus disease 2019 (COVID-19) pandemic, dermatologists have observed an increase in pernio-like acral eruptions. Direct causality of pernio due to COVID-19 has not been established in many cases because of inconsistent testing methods (often negative results) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a form of COVID-19‒associated pernio (also called COVID toes) is probable because of increased occurrence, frequently in young patients with no cold exposure or a history of pernio, and reports of skin biopsies with positive SARS-CoV-2 immunohistochemistry. PubMed was searched between January 1, 2020, and December 31, 2020 for publications using the following keywords: pernio, chilblain, and acral COVID-19. On the basis of our review of the published literature, we speculate that several unifying cutaneous and systemic mechanisms may explain COVID-19‒associated pernio: (1) SARS-CoV-2 cell infection occurs through the cellular receptor angiotensin-converting enzyme 2 mediated by transmembrane protease serine 2, subsequently affecting the renin-angiotensin-aldosterone system with an increase in the vasoconstricting, pro-inflammatory, and prothrombotic angiotensin II pathway. (2) Severe acute respiratory syndrome coronavirus 2 cell infection triggers an immune response with robust IFN-I release in patients predisposed to COVID-19‒associated pernio. (3) Age and sex discrepancies correlated with COVID-19 severity and manifestations, including pernio as a sign of mild disease, are likely explained by age-related immune and vascular differences influenced by sex hormones and genetics, which affect susceptibility to viral cellular infection, the renin-angiotensin-aldosterone system balance, and the IFN-I response.


Subject(s)
COVID-19 , Chilblains , SARS-CoV-2/pathogenicity , Vasoconstriction , COVID-19/immunology , COVID-19/physiopathology , Chilblains/immunology , Chilblains/physiopathology , Chilblains/virology , Disease Susceptibility , Fingers/blood supply , Humans , Renin-Angiotensin System/physiology , Toes/blood supply
10.
Eur J Heart Fail ; 22(12): 2228-2237, 2020 12.
Article in English | MEDLINE | ID: covidwho-965861

ABSTRACT

AIMS: Interstitial pneumonia due to coronavirus disease 2019 (COVID-19) is often complicated by severe respiratory failure. In addition to reduced lung compliance and ventilation/perfusion mismatch, a blunted hypoxic pulmonary vasoconstriction has been hypothesized, that could explain part of the peculiar pathophysiology of the COVID-19 cardiorespiratory syndrome. However, no invasive haemodynamic characterization of COVID-19 patients has been reported so far. METHODS AND RESULTS: Twenty-one mechanically-ventilated COVID-19 patients underwent right heart catheterization. Their data were compared both with those obtained from non-mechanically ventilated paired control subjects matched for age, sex and body mass index, and with pooled data of 1937 patients with 'typical' acute respiratory distress syndrome (ARDS) from a systematic literature review. Cardiac index was higher in COVID-19 patients than in controls [3.8 (2.7-4.5) vs. 2.4 (2.1-2.8) L/min/m2 , P < 0.001], but slightly lower than in ARDS patients (P = 0.024). Intrapulmonary shunt and lung compliance were inversely related in COVID-19 patients (r = -0.57, P = 0.011) and did not differ from ARDS patients. Despite this, pulmonary vascular resistance of COVID-19 patients was normal, similar to that of control subjects [1.6 (1.1-2.5) vs. 1.6 (0.9-2.0) WU, P = 0.343], and lower than reported in ARDS patients (P < 0.01). Pulmonary hypertension was present in 76% of COVID-19 patients and in 19% of control subjects (P < 0.001), and it was always post-capillary. Pulmonary artery wedge pressure was higher in COVID-19 than in ARDS patients, and inversely related to lung compliance (r = -0.46, P = 0.038). CONCLUSIONS: The haemodynamic profile of COVID-19 patients needing mechanical ventilation is characterized by combined cardiopulmonary alterations. Low pulmonary vascular resistance, coherent with a blunted hypoxic vasoconstriction, is associated with high cardiac output and post-capillary pulmonary hypertension, that could eventually contribute to lung stiffness and promote a vicious circle between the lung and the heart.


Subject(s)
COVID-19/physiopathology , Hemodynamics/physiology , Hypertension, Pulmonary/physiopathology , Hypoxia/physiopathology , Respiratory Distress Syndrome/physiopathology , Vascular Resistance/physiology , Vasoconstriction/physiology , Aged , COVID-19/therapy , Cardiac Catheterization , Cardiac Output/physiology , Case-Control Studies , Echocardiography , Female , Humans , Hypoxia/therapy , Lung Compliance/physiology , Male , Middle Aged , Respiration, Artificial , Respiratory Distress Syndrome/therapy , Retrospective Studies , SARS-CoV-2 , Ventilation-Perfusion Ratio
11.
Int J Mol Sci ; 21(21)2020 Oct 29.
Article in English | MEDLINE | ID: covidwho-902541

ABSTRACT

The 1918 influenza killed approximately 50 million people in a few short years, and now, the world is facing another pandemic. In December 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of a respiratory illness termed coronavirus disease 2019 (COVID-19) and rapidly spread to cause the worst pandemic since 1918. Recent clinical reports highlight an atypical presentation of acute respiratory distress syndrome (ARDS) in COVID-19 patients characterized by severe hypoxemia, an imbalance of the renin-angiotensin system, an increase in thrombogenic processes, and a cytokine release storm. These processes not only exacerbate lung injury but can also promote pulmonary vascular remodeling and vasoconstriction, which are hallmarks of pulmonary hypertension (PH). PH is a complication of ARDS that has received little attention; thus, we hypothesize that PH in COVID-19-induced ARDS represents an important target for disease amelioration. The mechanisms that can promote PH following SARS-CoV-2 infection are described. In this review article, we outline emerging mechanisms of pulmonary vascular dysfunction and outline potential treatment options that have been clinically tested.


Subject(s)
Acute Lung Injury/pathology , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Severe Acute Respiratory Syndrome/pathology , Vasoconstriction/physiology , Betacoronavirus , COVID-19 , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/pathology , Kallikrein-Kinin System/physiology , Pandemics , Renin-Angiotensin System/physiology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/drug therapy , Vasoconstriction/drug effects
12.
Nat Commun ; 11(1): 4883, 2020 09 28.
Article in English | MEDLINE | ID: covidwho-801570

ABSTRACT

Early stages of the novel coronavirus disease (COVID-19) are associated with silent hypoxia and poor oxygenation despite relatively minor parenchymal involvement. Although speculated that such paradoxical findings may be explained by impaired hypoxic pulmonary vasoconstriction in infected lung regions, no studies have determined whether such extreme degrees of perfusion redistribution are physiologically plausible, and increasing attention is directed towards thrombotic microembolism as the underlying cause of hypoxemia. Herein, a mathematical model demonstrates that the large amount of pulmonary venous admixture observed in patients with early COVID-19 can be reasonably explained by a combination of pulmonary embolism, ventilation-perfusion mismatching in the noninjured lung, and normal perfusion of the relatively small fraction of injured lung. Although underlying perfusion heterogeneity exacerbates existing shunt and ventilation-perfusion mismatch in the model, the reported hypoxemia severity in early COVID-19 patients is not replicated without either extensive perfusion defects, severe ventilation-perfusion mismatch, or hyperperfusion of nonoxygenated regions.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Coronavirus Infections/physiopathology , Hypoxia/etiology , Hypoxia/physiopathology , Lung Diseases/etiology , Lung Diseases/physiopathology , Lung/blood supply , Lung/physiopathology , Models, Biological , Pneumonia, Viral/complications , Pneumonia, Viral/physiopathology , Pulmonary Circulation/physiology , COVID-19 , Computer Simulation , Coronavirus Infections/epidemiology , Humans , Hypoxia/therapy , Lung Diseases/therapy , Mathematical Concepts , Models, Cardiovascular , Oxygen Inhalation Therapy , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Time Factors , Vasoconstriction/physiology , Vasodilation/physiology , Ventilation-Perfusion Ratio/physiology
13.
Med Hypotheses ; 143: 110125, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-665482

ABSTRACT

The novel coronavirus (SARS-CoV-2) is primarily a respiratory pathogen and its clinical manifestations are dominated by respiratory symptoms, the most severe of which is acute respiratory distress syndrome (ARDS). However, COVID-19 is increasingly recognized to cause an overwhelming inflammatory response and cytokine storm leading to end organ damage. End organ damage to heart is one of the most severe complications of COVID-19 that increases the risk of death. We proposed a two-fold mechanism responsible for causing acute coronary events in patients with COVID-19 infection: Cytokine storm leading to rapid onset formation of new coronary plaques along with destabilization of pre-existing plaques and direct myocardial injury secondary to acute systemic viral infection. A well-coordinated immune response is the first line innate immunity against a viral infection. However, an uncoordinated response and hypersecretion of cytokines and chemokines lead to immune related damage to the human body. Human Coronavirus (HCoV) infection causes infiltration of inflammatory cells that cause excessive production of cytokines, proteases, coagulation factors, oxygen radicals and vasoactive molecules causing endothelial damage, disruption of fibrous cap and initiation of formation of thrombus. Systemic viral infections also cause vasoconstriction leading to narrowing of vascular lumen and stimulation of platelet activation via shear stress. The resultant cytokine storm causes secretion of hypercoagulable tissue factor without consequential increase in counter-regulatory pathways such as AT-III, activated protein C and plasminogen activator type 1. Lastly, influx of CD4+ T-cells in cardiac vasculature results in an increased production of cytokines that stimulate smooth muscle cells to migrate into the intima and generate collagen and other fibrous products leading to advancement of fatty streaks to advanced atherosclerotic lesions. Direct myocardial damage and cytokine storm leading to destabilization of pre-existing plaques and accelerated formation of new plaques are the two instigating mechanisms for acute coronary syndromes in COVID-19.


Subject(s)
Acute Coronary Syndrome/etiology , Betacoronavirus , Coronavirus Infections/complications , Models, Cardiovascular , Pandemics , Pneumonia, Viral/complications , Acute Coronary Syndrome/physiopathology , CD4-Positive T-Lymphocytes/immunology , COVID-19 , Chemokines/physiology , Coronary Artery Disease/etiology , Coronary Artery Disease/physiopathology , Coronary Vessels/metabolism , Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/physiopathology , Cytokines/physiology , Humans , Immunity, Innate , Plaque, Atherosclerotic/etiology , Plaque, Atherosclerotic/physiopathology , Platelet Activation , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , SARS-CoV-2 , Vasoconstriction , Virus Diseases/complications , Virus Diseases/immunology
14.
ACS Chem Neurosci ; 11(14): 2048-2050, 2020 07 15.
Article in English | MEDLINE | ID: covidwho-627315

ABSTRACT

In COVID-19, lung manifestations present as a slowly evolving pneumonia with insidious early onset interstitial pulmonary edema that undergoes acute exacerbation in the late stages and microvascular thrombosis. Currently, these manifestations are considered to be only consequences of pulmonary SARS-CoV-2 virus infection. We are proposing a new hypothesis that neurogenic insult may also play a major role in the pathogenesis of these manifestations. SARS-CoV-2 mediated inflammation of the nucleus tractus solitarius (NTS) may play a role in the acute exacerbation of pulmonary edema and microvascular clotting in COVID-19 patients.


Subject(s)
Coronavirus Infections/physiopathology , Hypotension/physiopathology , Lung/blood supply , Microvessels/physiopathology , Pneumonia, Viral/physiopathology , Pulmonary Edema/physiopathology , Solitary Nucleus/physiopathology , Thrombosis/physiopathology , Betacoronavirus , COVID-19 , Capillary Permeability/physiology , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/physiopathology , Facial Nerve , Glossopharyngeal Nerve , Humans , Inflammation , Lung/immunology , Microvessels/immunology , Pandemics , Parasympathetic Nervous System/physiopathology , Pneumonia, Viral/immunology , Pulmonary Edema/immunology , SARS-CoV-2 , Solitary Nucleus/immunology , Vagus Nerve , Vasoconstriction
15.
J Stroke Cerebrovasc Dis ; 29(9): 105011, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-548355

ABSTRACT

The current COVID-19 pandemic has recently brought to attention the myriad of neuro- logic sequelae associated with Coronavirus infection including the predilection for stroke, particularly in young patients. Reversible cerebral vasoconstriction syndrome (RCVS) is a well-described clinical syndrome leading to vasoconstriction in the intracra- nial vessels, and has been associated with convexity subarachnoid hemorrhage and oc- casionally cervical artery dissection. It is usually reported in the context of a trigger such as medications, recreational drugs, or the postpartum state; however, it has not been described in COVID-19 infection. We report a case of both cervical vertebral ar- tery dissection as well as convexity subarachnoid hemorrhage due to RCVS, in a pa- tient with COVID-19 infection and no other triggers.


Subject(s)
Betacoronavirus/pathogenicity , Cerebral Arteries/physiopathology , Coronavirus Infections/complications , Pneumonia, Viral/complications , Subarachnoid Hemorrhage/complications , Vasoconstriction , Vertebral Artery Dissection/complications , Adult , COVID-19 , Cerebral Arteries/diagnostic imaging , Cerebral Arteries/drug effects , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Female , Headache Disorders, Primary/etiology , Headache Disorders, Primary/physiopathology , Host-Pathogen Interactions , Humans , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Risk Factors , SARS-CoV-2 , Subarachnoid Hemorrhage/diagnostic imaging , Subarachnoid Hemorrhage/drug therapy , Subarachnoid Hemorrhage/physiopathology , Syndrome , Vasoconstriction/drug effects , Vasodilation , Vertebral Artery Dissection/diagnostic imaging , Vertebral Artery Dissection/drug therapy , Vertebral Artery Dissection/physiopathology
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