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1.
Vascul Pharmacol ; 144: 106975, 2022 06.
Article in English | MEDLINE | ID: covidwho-2184357

ABSTRACT

BACKGROUND: Coronavirus disease-19 (COVID-19) is implicated by active endotheliitis, and cardiovascular morbidity. The long-COVID-19 syndrome implications in atherosclerosis have not been elucidated yet. We assessed the immediate, intermediate, and long-term effects of COVID-19 on endothelial function. METHODS: In this prospective cohort study, patients hospitalized for COVID-19 at the medical ward or Intensive Care Unit (ICU) were enrolled and followed up to 6 months post-hospital discharge. Medical history and laboratory examinations were performed while the endothelial function was assessed by brachial artery flow-mediated dilation (FMD). Comparison with propensity score-matched cohort (control group) was performed at the acute (upon hospital admission) and follow-up (1 and 6 months) stages. RESULTS: Seventy-three patients diagnosed with COVID-19 (37% admitted in ICU) were recruited. FMD was significantly (p < 0.001) impaired in the COVID-19 group (1.65 ± 2.31%) compared to the control (6.51 ± 2.91%). ICU-treated subjects presented significantly impaired (p = 0.001) FMD (0.48 ± 1.01%) compared to those treated in the medical ward (2.33 ± 2.57%). During hospitalization, FMD was inversely associated with Interleukin-6 and Troponin I (p < 0.05 for all). Although, a significant improvement in FMD was noted during the follow-up (acute: 1.75 ± 2.19% vs. 1 month: 4.23 ± 2.02%, vs. 6 months: 5.24 ± 1.62%; p = 0.001), FMD remained impaired compared to control (6.48 ± 3.08%) at 1 month (p < 0.001) and 6 months (p = 0.01) post-hospital discharge. CONCLUSION: COVID-19 patients develop a notable endothelial dysfunction, which is progressively improved over a 6-month follow-up but remains impaired compared to healthy controls subjects. Whether chronic dysregulation of endothelial function following COVID-19 could be accompanied by a residual risk for cardiovascular and thrombotic events merits further research.


Subject(s)
COVID-19 , COVID-19/complications , Cohort Studies , Endothelium, Vascular , Humans , Prospective Studies , Vasodilation/physiology
2.
Molecules ; 27(22)2022 Nov 16.
Article in English | MEDLINE | ID: covidwho-2115975

ABSTRACT

Nitric oxide (NO) is implicated in numerous physiological processes, including vascular homeostasis. Reduced NO bioavailability is a hallmark of endothelial dysfunction, a prequel to many cardiovascular diseases. Biomarkers of an early NO-dependent endothelial dysfunction obtained from routine venous blood sampling would be of great interest but are currently lacking. The direct measurement of circulating NO remains a challenge due by its high reactivity and short half-life. The current techniques measure stable products from the NO signaling pathway or metabolic end products of NO that do not accurately represent its bioavailability and, therefore, endothelial function per se. In this review, we will concentrate on an original technique of low temperature electron paramagnetic resonance spectroscopy capable to directly measure the 5-α-coordinated heme nitrosyl-hemoglobin in the T (tense) state (5-α-nitrosyl-hemoglobin or HbNO) obtained from fresh venous human erythrocytes. In humans, HbNO reflects the bioavailability of NO formed in the vasculature from vascular endothelial NOS or exogenous NO donors with minor contribution from erythrocyte NOS. The HbNO signal is directly correlated with the vascular endothelial function and inversely correlated with vascular oxidative stress. Pilot studies support the validity of HbNO measurements both for the detection of endothelial dysfunction in asymptomatic subjects and for the monitoring of such dysfunction in patients with known cardiovascular disease. The impact of therapies or the severity of diseases such as COVID-19 infection involving the endothelium could also be monitored and their incumbent risk of complications better predicted through serial measurements of HbNO.


Subject(s)
COVID-19 , Nitric Oxide , Humans , Nitric Oxide/metabolism , Hemoglobins/metabolism , Endothelium, Vascular/metabolism
5.
J Physiol Pharmacol ; 73(2)2022 Apr.
Article in English | MEDLINE | ID: covidwho-2002832

ABSTRACT

Since the beginning of the COVID-19 pandemic, there has been an urgent need to find effective treatment. It is widely known that virus attacks and damages mostly the lungs, but also infect vascular endothelial cells. Therefore, the protection of the endothelium is a promising target in the therapy of COVID-19 and its complications. In this review article, we focused on several groups of drugs with potential to protect the endothelium. The most promising ones are angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, drugs targeting angiotensin-converting enzyme 2, heparins, sulodexide, acetylsalicylic acid, statins, tocilizumab, baricitinib, and defibrotide. Although the short period of trials and the lack of data necessitate further research, endothelial protection remains a promising target for COVID-19 therapy.


Subject(s)
COVID-19 , COVID-19/drug therapy , Endothelial Cells , Endothelium, Vascular , Humans , Pandemics , SARS-CoV-2
6.
Eur J Clin Invest ; 52(11): e13859, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2001632

ABSTRACT

BACKGROUND: Accumulating evidence suggests that endothelial dysfunction is implicated in the pathogenesis and severity of coronavirus disease 2019 (COVID-19). In this context, vascular impairment in COVID-19 might be associated with clinical manifestations and could refine risk stratification in these patients. METHODS: This systematic review aims to synthesize current evidence on the frequency and the prognostic value of vascular dysfunction during acute and post-recovery COVID-19. After systematically searching the MEDLINE, clinicaltrials.gov and the Cochrane Library from 1 December 2019 until 05 March 2022, we identified 24 eligible studies with laboratory confirmed COVID-19 and a thorough examination of vascular function. Flow-mediated dilation (FMD) was assessed in 5 and 12 studies in acute and post-recovery phase respectively; pulse wave velocity (PWV) was the marker of interest in three studies in the acute and four studies in the post-recovery phase. RESULTS: All studies except for one in the acute and in the post-recovery phase showed positive association between vascular dysfunction and COVID-19 infection. Endothelial dysfunction in two studies and increased arterial stiffness in three studies were related to inferior survival in COVID-19. DISCUSSION: Overall, a detrimental effect of COVID-19 on markers of endothelial function and arterial stiffness that could persist even for months after the resolution of the infection and provide prognostic value was congruent across published studies. Further research is warranted to elucidate clinical implications of this association.


Subject(s)
COVID-19 , Vascular Stiffness , Brachial Artery , COVID-19/complications , Endothelium , Endothelium, Vascular , Humans , Pulse Wave Analysis
7.
Medicine (Baltimore) ; 101(33): e30001, 2022 Aug 19.
Article in English | MEDLINE | ID: covidwho-2001502

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 is a highly infectious pathogenic coronavirus, which has appeared toward the end of 2019. The virus seen all over the world caused a pandemic of an acute respiratory disease named coronavirus disease 2019 (Covid-19). It has been shown that the virus that uses angiotensin-converting enzyme 2 receptors is causing endothelial dysfunction resulting in vascular inflammation and coagulopathy. It is possible to assess endothelial dysfunction by the flow-mediated dilatation (FMD) technique. Our study aimed to demonstrate the effect of endothelial dysfunction assessed using the FMD on prognosis and mortality in the patients hospitalized with the diagnosis of Covid-19. In this prospective observational study, endothelial functions of 94 patients hospitalized due to the Covid-19 in the ward or intensive care unit (ICU) were evaluated by FMD. The relationship among endothelial dysfunction and prognosis of disease, biochemical parameters, lung involvement, and mortality was investigated. We found that the FMD% values of the Covid-19 ICU patients compared to those followed up in the ward (2.66 ± 0.62 vs. 5.23 ± 1.46/P < .001) and those who died due to Covid-19 compared to those who were discharged alive (2.57 ± 0.22 vs. 4.66 ± 1.7/P < .001) were significantly lower. There were moderate negative correlation between FMD% and peak values of D-dimer (r = -0.52, P < .001), troponin (r = -0.45, P < .001), ferritin (r = -0.47, P < .001), lactate dehydrogenase (r = -0.49, P < .001), and white blood cells count (r = -0.23, P = .024). Lower FMD% was associated with higher lung parenchymal involvement (P < .001). The optimum cutoff point of FMD in predicting mortality was found to be 3.135% (sensitivity: 1, selectivity: 0.70). According to our results, lower FMD% was associated with higher lung parenchyma involvement, ICU admission, and mortality rate in Covid-19 patients. The best cutoff point for predicting mortality of FMD was 3.135%. Nevertheless, largescale, multicenter studies are needed to evaluate lower FMD values as a risk factor for mortality in Covid-19.


Subject(s)
Brachial Artery , COVID-19 , Dilatation , Endothelium, Vascular , Humans , Lung/diagnostic imaging , Prognosis , Vasodilation/physiology
8.
Int J Mol Sci ; 23(15)2022 Jul 27.
Article in English | MEDLINE | ID: covidwho-1994078

ABSTRACT

The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin.


Subject(s)
Factor V/metabolism , Thrombophilia , von Willebrand Factor , Anticoagulants , Endothelium, Vascular/metabolism , Factor VIII/genetics , Factor VIII/therapeutic use , Homeostasis , Humans , Protein C/therapeutic use , Thrombophilia/genetics , von Willebrand Factor/metabolism
9.
Nat Rev Immunol ; 22(10): 639-649, 2022 10.
Article in English | MEDLINE | ID: covidwho-1984398

ABSTRACT

COVID-19-associated coagulopathy (CAC) is a life-threatening complication of SARS-CoV-2 infection. However, the underlying cellular and molecular mechanisms driving this condition are unclear. Evidence supports the concept that CAC involves complex interactions between the innate immune response, the coagulation and fibrinolytic pathways, and the vascular endothelium, resulting in a procoagulant condition. Understanding of the pathogenesis of this condition at the genomic, molecular and cellular levels is needed in order to mitigate thrombosis formation in at-risk patients. In this Perspective, we categorize our current understanding of CAC into three main pathological mechanisms: first, vascular endothelial cell dysfunction; second, a hyper-inflammatory immune response; and last, hypercoagulability. Furthermore, we pose key questions and identify research gaps that need to be addressed to better understand CAC, facilitate improved diagnostics and aid in therapeutic development. Finally, we consider the suitability of different animal models to study CAC.


Subject(s)
Blood Coagulation Disorders , COVID-19 , Thrombosis , Animals , Blood Coagulation Disorders/etiology , COVID-19/complications , Endothelium, Vascular , SARS-CoV-2 , Thrombosis/etiology
13.
Am J Respir Crit Care Med ; 206(8): 926-928, 2022 Oct 15.
Article in English | MEDLINE | ID: covidwho-1932888
14.
Int J Mol Sci ; 23(14)2022 Jul 07.
Article in English | MEDLINE | ID: covidwho-1928573

ABSTRACT

The endothelium has multiple functions, ranging from maintaining vascular homeostasis and providing nutrition and oxygen to tissues to evocating inflammation under adverse conditions and determining endothelial barrier disruption, resulting in dysfunction. Endothelial dysfunction represents a common condition associated with the pathogenesis of all diseases of the cardiovascular system, as well as of diseases of all of the other systems of the human body, including sepsis, acute respiratory distress syndrome, and COVID-19 respiratory distress. Such evidence is leading to the identification of potential biomarkers and therapeutic targets for preserving, reverting, or restoring endothelium integrity and functionality by promptly treating its dysfunction. Here, some strategies for achieving these goals are explored, despite the diverse challenges that exist, necessitating significant bench work associated with an increased number of clinical studies.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Adult , Biomarkers , Endothelium, Vascular/pathology , Humans , Liquid Biopsy
15.
PLoS One ; 17(5): e0268296, 2022.
Article in English | MEDLINE | ID: covidwho-1910641

ABSTRACT

Severe coronavirus disease-19 (COVID-19) is characterized by vascular inflammation and thrombosis. We and others have proposed that the inflammatory response to coronavirus infection activates endothelial cells, leading to endothelial release of pro-thrombotic proteins. These mediators can trigger obstruction of the pulmonary microvasculature, leading to worsening oxygenation, acute respiratory distress syndrome, and death. In the current study, we tested the hypothesis that higher levels of biomarkers released from endothelial cells are associated with worse oxygenation in patients with COVID-19. We studied 83 participants aged 18-84 years with COVID-19 admitted to a single center. The severity of pulmonary disease was classified by oxygen requirement, including no oxygen requirement, low-flow oxygen, high-flow nasal cannula oxygen, mechanical ventilation, and death. We measured plasma levels of two proteins released by activated endothelial cells, von Willebrand Factor (VWF) antigen and soluble P-Selectin (sP-Sel), and a biomarker of systemic thrombosis, D-dimer. Additionally, we explored the association of endothelial biomarker levels with the levels of pro-inflammatory cytokine and chemokines, and vascular inflammation biomarkers. We found that levels of VWF, sP-sel, and D-dimer were increased in individuals with more severe COVID-19 pulmonary disease. Biomarkers of endothelial cell activation were also correlated with proinflammatory cytokines and chemokines. Taken together, our data demonstrate increased levels of VWF and sP-selectin are linked to the severity of lung disease in COVID-19 and correlated with biomarkers of inflammation and vascular inflammation. Our data support the concept that COVID-19 is a vascular disease which involves endothelial injury in the context of an inflammatory state.


Subject(s)
COVID-19 , Thrombosis , Biomarkers , Chemokines/metabolism , Endothelial Cells/metabolism , Endothelium, Vascular/metabolism , Humans , Inflammation/metabolism , Oxygen/metabolism , Thrombosis/metabolism , von Willebrand Factor/metabolism
16.
Arq Bras Cardiol ; 119(2): 319-325, 2022 08.
Article in English, Portuguese | MEDLINE | ID: covidwho-1893709

ABSTRACT

BACKGROUND: Inflammation is known to play a crucial role in many diseases, including COVID-19. OBJECTIVE: Using flow-mediated dilatation (FMD), we aimed to assess the effects of inflammation on endothelial function in COVID-19 patients. METHODS: This study was conducted with a total of 161 subjects, of whom 80 were diagnosed with COVID-19 within the last six months (comprising 48 women and 32 men with a mean age of 32.10 ± 5.87 years) and 81 were healthy controls (comprising 45 women and 36 men with a mean age of 30.51 ± 7.33 years). We analyzed the findings of transthoracic echocardiography and FMD in all subjects. All results were considered statistically significant at the level of p < 0.05. RESULTS: The echocardiography and FMD of the COVID-19 group were performed 35 days (range: 25-178) after diagnosis. There was no statistically significant difference in echocardiographic parameters. Differently, FMD (%) was significantly higher in the control group (9.52 ± 5.98 vs. 12.01 ± 6.18, p=0.01). In multivariate analysis with the forward stepwise model, FMD was significantly different in the control group compared to the COVID-19 group (1.086 (1.026 - 1.149), p=0.04). A Spearman's correlation test indicated that FMD (r=0.27, p=0.006) had a weak positive correlation with the presence of COVID-19. CONCLUSION: Our findings point to COVID-19-induced endothelial dysfunction, as assessed by FMD, in the early recovery phase.


FUNDAMENTO: Sabe-se que a inflamação desempenha um papel crucial em muitas doenças, incluindo a COVID-19. OBJETIVO: Utilizando a dilatação fluxo-mediada (DFM), objetivou-se avaliar os efeitos da inflamação na função endotelial de pacientes com COVID-19. MÉTODOS: Este estudo foi realizado com um total de 161 indivíduos, dos quais 80 foram diagnosticados com COVID-19 nos últimos seis meses (48 mulheres e 32 homens com idade média de 32,10±5,87 anos) e 81 eram controles saudáveis (45 mulheres e 36 homens com idade média de 30,51±7,33 anos). Os achados do ecocardiograma transtorácico e da DFM foram analisados em todos os indivíduos. Resultados com p<0,05 foram considerados estatisticamente significantes. RESULTADOS: O ecocardiograma e a DFM do grupo COVID-19 foram realizados 35 dias (intervalo: 25­178) após o diagnóstico. Não houve diferença estatisticamente significativa nos parâmetros ecocardiográficos. Em contraste, a DFM (%) foi significativamente maior no grupo controle (9,52±5,98 versus 12,01±6,18; p=0,01). Na análise multivariada com o modelo stepwise progressivo, a DFM foi significativamente diferente no grupo controle em relação ao grupo COVID-19 (1,086 (1,026­1,149), p=0,04). O teste de correlação de Spearman indicou que a DFM (r=0,27; p=0,006) apresentou correlação positiva fraca com a presença de COVID-19. CONCLUSÃO: Os achados deste estudo apontam para disfunção endotelial induzida por COVID-19, avaliada por DFM, na fase inicial de recuperação.


Subject(s)
COVID-19 , Vascular Diseases , Adult , Brachial Artery/diagnostic imaging , Dilatation , Dilatation, Pathologic/diagnostic imaging , Endothelium, Vascular , Female , Humans , Inflammation , Male , Vasodilation , Young Adult
18.
Int J Mol Sci ; 23(11)2022 May 31.
Article in English | MEDLINE | ID: covidwho-1869643

ABSTRACT

The endothelium has a fundamental role in the cardiovascular complications of coronavirus disease 2019 (COVID-19). Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) particularly affects endothelial cells. The virus binds to the angiotensin-converting enzyme 2 (ACE-2) receptor (present on type 2 alveolar cells, bronchial epithelial cells, and endothelial cells), and induces a cytokine storm. The cytokines tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 have particular effects on endothelial cells-leading to endothelial dysfunction, endothelial cell death, changes in tight junctions, and vascular hyperpermeability. Under normal conditions, apoptotic endothelial cells are removed into the bloodstream. During COVID-19, however, endothelial cells are detached more rapidly, and do not regenerate as effectively as usual. The loss of the endothelium on the luminal surface abolishes all of the vascular responses mediated by the endothelium and nitric oxide production in particular, which results in greater contractility. Moreover, circulating endothelial cells infected with SARS-CoV-2 act as vectors for viral dissemination by forming clusters that migrate into the circulation and reach distant organs. The cell clusters and the endothelial dysfunction might contribute to the various thromboembolic pathologies observed in COVID-19 by inducing the formation of intravascular microthrombi, as well as by triggering disseminated intravascular coagulation. Here, we review the contributions of endotheliopathy and endothelial-cell-derived extracellular vesicles to the pathogenesis of COVID-19, and discuss therapeutic strategies that target the endothelium in patients with COVID-19.


Subject(s)
COVID-19 , Vascular Diseases , COVID-19/complications , Cytokines/metabolism , Endothelial Cells/metabolism , Endothelium, Vascular/metabolism , Humans , SARS-CoV-2 , Vascular Diseases/metabolism
19.
20.
Am J Physiol Renal Physiol ; 322(3): F309-F321, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1799210

ABSTRACT

Substantial evidence has supported the role of endothelial cell (EC) activation and dysfunction in the development of hypertension, chronic kidney disease (CKD), and lupus nephritis (LN). In both humans and experimental models of hypertension, CKD, and LN, ECs become activated and release potent mediators of inflammation including cytokines, chemokines, and reactive oxygen species that cause EC dysfunction, tissue damage, and fibrosis. Factors that activate the endothelium include inflammatory cytokines, mechanical stretch, and pathological shear stress. These signals can activate the endothelium to promote upregulation of adhesion molecules, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which promote leukocyte adhesion and migration to the activated endothelium. More importantly, it is now recognized that some of these signals may in turn promote endothelial antigen presentation through major histocompatibility complex II. In this review, we will consider in-depth mechanisms of endothelial activation and the novel mechanism of endothelial antigen presentation. Moreover, we will discuss these proinflammatory events in renal pathologies and consider possible new therapeutic approaches to limit the untoward effects of endothelial inflammation in hypertension, CKD, and LN.


Subject(s)
Hypertension , Lupus Nephritis , Renal Insufficiency, Chronic , Cytokines/metabolism , Endothelial Cells/metabolism , Endothelium, Vascular/metabolism , Female , Humans , Hypertension/metabolism , Inflammation/metabolism , Intercellular Adhesion Molecule-1/metabolism , Lupus Nephritis/metabolism , Male , Renal Insufficiency, Chronic/metabolism , Vascular Cell Adhesion Molecule-1/metabolism
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