Post-COVID-19 conditions alter a person's immune response. Iwanski J, Kazmouz SG, Li S, Stansfield B, Salem TT, Perez-Miller S, et al. Brain Pathol (Zur, Switz). Acute myocardial infarction in the Covid-19 era: Incidence, clinical characteristics and in-hospital outcomes-A multicenter registry. Biering SB, de Sousa FTG, Tjang LV, Pahmeier F, Ruan R, Blanc SF, et al. Tan R, Xiang X, Chen W, Yang Z, Hu W, Qu H, et al. 2021;107:2323. ISSN 1745-7254 (online) It is possible that these cytokines will disrupt the integrity of various types of junctional proteins, including VE-cadherin, ZO-1, -catenin and gap junction proteins. However, after SARS-CoV-2 infection, ECs are detached more quickly without efficient regeneration [20]. 2022;13:830061. Ma S, Sun S, Li J, Fan Y, Qu J, Sun L, et al. Clin Transl Immunol. The following is a summary of "Optimal positive end-expiratory pressure reduces right ventricular dysfunction in COVID-19 patients on venovenous extracorporeal membrane oxygenation: A retrospective single-center study," published in the February 2023 issue of Critical Care by Estoos et al. Cardiovasc Res. Effects of adding L-arginine orally to standard therapy in patients with COVID-19: A randomized, double-blind, placebo-controlled, parallel-group trial. Since atherosclerosis is an important cause for coronary artery disease, it might be of interest to investigate whether COVID-19 can accelerate the development of endothelial dysfunction and new onset atherosclerosis [26]. JAMA. N Engl J Med. SARS-CoV-2 targets the pulmonary system, as well as the extrapulmonary system [2]. Yamaoka-Tojo M. Vascular endothelial glycocalyx damage in COVID-19. In another translational study, treatment of human pluripotent stem cell-derived endothelial cells (hECs) with SARS-CoV-2 leads to enriched gene program involved in immunity, inflammation and viral response (such as TNF-, IFNs and NF-B signaling pathway). 2022;21:e13646. 3). It is appreciated that SARS-CoV-2 infection can trigger systemic vascular injury through binding to ACE2. Am J Physiol Lung Cell Mol Physiol. Markers of endothelial cell activation are associated with the severity of pulmonary disease in COVID-19. Physiological functions of the endothelium include fine control of vascular tone, tissue hemostasis, barrier integrity, inflammation, oxidative stress, vascular permeability, and structural and functional integrity [4]. Endothelin-1 is increased in the plasma of patients hospitalised with Covid-19. 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Online ahead of print. Since the outbreak of COVID-19 in early 2020, emerging evidence has demonstrated endothelial dysfunction as the unifying and central mechanism of COVID-19 [6]. Failure of neural thermoregulatory mechanisms or exposure to extreme or sustained temperatures that overwhelm the body's thermoregulatory capacity can also result in potentially life-threatening departures from normothermia. The https:// ensures that you are connecting to the Cellular senescence is a primary stress response in virus-infected endothelial cells. Consistent with this notion, elevated level of C3a in severe COVID-19 patients induced the activation of CD16+ cytotoxic T cells which promotes endothelial injury and the release of monocyte chemoattractant proteins as well as neutrophil activation [96]. Cholinergic dysfunction in COVID-19 is due to dysregulation of nAChR by SARS-CoV-2 promoting the central sympathetic drive with the development of the sympathetic storm. Meyer K, Patra T, Vijayamahantesh, Ray R. SARS-CoV-2 spike protein induces paracrine senescence and leukocyte adhesion in endothelial cells. 2021;276:119376. du Preez HN, Aldous C, Hayden MR, Kruger HG, Lin J. Pathogenesis of COVID-19 described through the lens of an undersulfated and degraded epithelial and endothelial glycocalyx. Therapeutic potential of megadose vitamin C to reverse organ dysfunction in sepsis and COVID-19. Sci Immunol. 2022;55:57. Thermoregulatory dysfunction is defined as significant loss of a person's capacity to control body temperature, and is associated with medical conditions that result in the person's health and bodily function being seriously affected when exposed to extremes of environmental temperatures. Rotoli BM, Barilli A, Visigalli R, Ferrari F, DallAsta V. Endothelial cell activation by SARS-CoV-2 Spike S1 protein: a crosstalk between endothelium and innate immune cells. SARS-CoV-2 causes ACE/ACE2 balance disruption and RAAS activation, which leads ultimately to COVID-19 progression, especially in patients with comorbidities, such as hypertension, diabetes mellitus, and cardiovascular disease. Acute brain dysfunction is highly prevalent in COVID-19 patients. PLoS One. 2020;11:70722. In addition, with the progress of aging, the expression of ACE2 was increased in the pulmonary vascular ECs with the possible involvement of interleukin 7 via an NF-B-dependent manner, which can be blocked by Vitamin C [49]. Nat Commun. This study highlights the crucial role of IL-6 trans-signaling in endothelial dysfunction/endotheliopathy in COVID-19 [137]. Keywords: 01 May 2023 01:18:34 Infection with various types of viruses, including SARS-CoV-2, can trigger endothelial senescence. Increased heparanase activity and heparan sulphate level have been observed in plasma derived from COVID-19 patients [113]. A recent study has shown that SARS-CoV-2-infection of human brain microvascular ECs showed augmented caspase 3 cleavage and apoptotic cell death of endothelial cells. 2021;128:13236. 2022;145:15035. Copyright 2016 The Author. 7). 2. 2022;10:812. de Rooij L, Becker LM, Carmeliet P. A role for the vascular endothelium in post-acute COVID-19? 4 and 5) [101]. SASP senescence-associated secretory phenotype. Endothelial dysfunction, inflammation, and oxidative stress in COVID-19-mechanisms and therapeutic targets. The endothelium, the widely-distributed organ of the human body, is essential for maintaining tissue homeostasis by producing a variety of vasoactive molecules. MeSH 2021;6:266. Am J Respiratory Cell Mol Biol. Interferon-alpha or -beta facilitates SARS-CoV-2 pulmonary vascular infection by inducing ACE2. Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, et al. 2022: e0095122. When endothelial dysfunction/endotheliopathy/endotheliitis occurs in COVID-19, several markers of endothelial cell activation are used for assessing endothelial dysfunction in COVID-19 (Figs. Life Sci. Protein Cell. Inflammatory cytokines, such as IL-6, promotes JAK and STATs phosphorylation [145]. Drost CC, Rovas A, Osiaevi I, Rauen M, van der Vlag J, Buijsers B, et al. Int J Obes (2005). Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. J Mol Cell Cardiol. 2021;22:4177. By doing so, anakinra significantly increased the survival rate of infected mice [140]. Front Endocrinol. 2021;20:66. Clin (Sao Paulo, Braz). Front Immunol. Circulatory exosomes from COVID-19 patients trigger NLRP3 inflammasome in endothelial cells. Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes. Treatment with a humanized anti-IL-6 receptor antibody-tocilizumab, decreased the PAI-1 level and alleviated critical illness in severe COVID-19 patients. Aging Cell. Zhang P, Zhu L, Cai J, Lei F, Qin JJ, Xie J, et al. Endothelial dysfunction in COVID-19: Current findings and therapeutic implications. Top manufacturers . It has been increasingly appreciated that COVID-19 is not only an infectious disease involving the lung; but also, a vascular disease affecting extrapulmonary organs [174]. A review of acute limb ischemia in COVID-positive patients. 2021;65:2226. SARS-CoV-2 and COVID-19: The most important research questions. Biomedicines. Emerging evidence has suggested that thinning of endothelial glycocalyx layer is associated with COVID-19, and thus the glycocalyx integrity was perceived as an important therapeutic target in COVID-19 [109, 110]. Viruses. Int J Infect Dis. Correspondence to 2021;15:70417. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. Published: April 28, 2023 at 7:55 a.m. J Virol. Stahl K, Gronski PA, Kiyan Y, Seeliger B, Bertram A, Pape T, et al. Theranostics. After that, STATs translocate into cell nucleus to orchestrate the expression of inflammatory cytokines, further instigating the cytokine storm feedback loop. The post-COVID-19 cardiovascular autonomic dysfunction can affect global circulatory control, producing not only a POTS-like pattern but also tachycardia at rest, blood pressure instability with . Pharmacopsychiatry. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. The evidence discussed below support both a direct mechanism (virus infection via ACE2, L-SIGN and other receptors) and indirect mechanisms (such as cytokine storm) are involved in SARS-CoV-2 infection associated endothelial dysfunction (Fig. 2021;75:64758. Mechanistically, fluvoxamine is a sigma-1 receptor (S1R) agonist which, on the one hand, reduces the expression of IL-6, while increasing that of eNOS. Aye YN, Mai AS, Zhang A, Lim OZH, Lin N, Ng CH, et al. Plasma level of resistin is increased in COVID-19 patients and associated with disease severity as well as the expression of inflammatory cytokines (IL-6, IL-8 and MCP-1) and adhesion molecules (ICAM1 and VCAM1) [80]. Treatment of virus-infected human lung microvascular endothelial cells (HMVECs) with diminazene aceturate (an ACE2 agonist) reverses SARS-CoV-2 infection-induced hyperpermeability, indicating the possibility that ACE2 agonism indeed stabilizes endothelial barrier integrity without affecting viral uptake into ECs [23]. Likewise, in a retrospective study involving ninety-nine patients with COVID-19, the degree of endothelial damage was correlated with disease severity in COVID-19, suggesting that number of CEC is a good predictor of disease severity [116]. However, pre-treatment of ECs with losartan (belonging to ARB) and lisinopril (belonging to ACEI), fail to affect the susceptibility of hEC to SARS-CoV-2 infection [131]. SARS-CoV-2 infection alters the balance of endothelial protective molecules and endothelial damaging molecules, leading to endothelial dysfunction. Hyperthermia, defined as a core temperature of >40.5C, may present with sweating, flushing, tachycardia, fatigue, lightheadedness, headache, and paresthesia, progressing to weakness, muscle cramps, oliguria, nausea, agitation, hypotension, syncope, confusion, delirium, seizures, and coma. The most common clinical presentation of severe COVID-19 is acute respiratory failure consistent with the acute respiratory distress syndrome. The infected cell releases danger signals leading to multiple aspects of endothelial dysfunction, which finally leads to impaired vascular activity and multi-organ injury. Employing mechanical ventilation techniques on venovenous extracorporeal membrane oxygenation (VV ECMO . Front Cardiovasc Med. This dual-function mechanisms suggest the important role of L-SIGN as the molecular bridge between ACE2 and SARS-CoV-2 spike protein to allow for virus infection in the patients. Front Pharmacol. 1). Potential role of statins in COVID-19. 2020;18:23919. eLife. COVID-19 can manifest with myocardial injury (ischemic heart disease, arrhythmias and cardiomyopathies), arterial stiffness, liver injury and kidney injury [3]. Moretta P, Maniscalco M, Papa A, Lanzillo A, Trojano L, Ambrosino P. Cognitive impairment and endothelial dysfunction in convalescent COVID-19 patients undergoing rehabilitation. The pleiotropic effects of metformin help to control hyperglycemia, inhibit viral entry, and reduce inflammation following SARS-CoV-2 infection. Lancet Glob Health. On the other hand, S1R agonism by fluvoxamine activates Akt-eNOS signaling in mouse aorta in a S1R-dependent manner. 2021. https://doi.org/10.1093/qjmed/hcab252. Google Scholar. Int J Mol Sci. Heparin prevents in vitro glycocalyx shedding induced by plasma from COVID-19 patients. May CN, Bellomo R, Lankadeva YR. Nat Med. Article 2020;159:105051. Analysis of ACE2 expression in autopsy tissues indicates that high expression of ACE2, transmembrane protease serine 2 (TMPRSS2) and associated endotheliitis in capillaries but less in arterioles/venules from COVID-19 patients, compared with COVID-19-free subjects. 2020;10:2045894020966547. The pathophysiology, impact, and outcomes of hyperpyrexia in patients with COVID-19 have not yet been studied. Theranostics. Thermoregulation is the biological mechanism responsible for maintaining a steady internal body temperature. 2022;79:361. However, blockade of TLR9 significantly mitigated SARS-CoV-2-induced IL-6 release and reversed SARS-CoV-2-induced eNOS downregulation. Han T, Ma S, Sun C, Zhang H, Qu G, Chen Y, et al. Hemil H, de Man AME. Mental status changes and core temperature distinguish potentially fatal heat stroke from heat exhaustion. Osburn WO, Smith K, Yanek L, Amat-Alcaron N, Thiemann DR, Cox AL, et al. Unauthorized use of these marks is strictly prohibited. Abstract. ACE2 angiotensin-converting enzyme-2, AXL AXL receptor tyrosine kinase, EndoMT endothelial-to-mesenchymal transition, NO nitric oxide, SASP senescence-associated secretory phenotype. NO also has an anti-thrombotic action, by preventing leukocyte and platelet adhesion to activated endothelium, thereby inhibiting immunothrombosis and atherosclerotic plaque development [15]. Circ Res. SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF- signaling. 6). Vasc Pharmacol. SARS-CoV-2 infection is associated with reduced krppel-like factor 2 in human lung autopsy. Furthermore, HIVC in combination with other drugs such as giammonium glycyrrhizinate, decreased the incidence rate of ARDS in COVID-19 patients [158]. QJM. 2020;26:101732. Unraveling the role of liver sinusoidal endothelial cells in COVID-19 liver injury. Medications to protect and/or restore the endothelial glycocalyx integrity hold great therapeutic potential for COVID-19 associated glycocalyx disruption. Semin Thrombosis Hemost. Kang X, Jin D, Jiang L, Zhang Y, Zhang Y, An X, et al. The authors declare no competing interests. Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, et al. Gladka MM, Maack C. The endothelium as Achilles heel in COVID-19 patients. 2021;137:106829. Effects of Shuanghuanglian oral liquids on patients with COVID-19: a randomized, open-label, parallel-controlled, multicenter clinical trial. J Virol. 2022;43:36776. In the meantime, to ensure continued support, we are displaying the site without styles Thermoregulatory physiology sustains health by keeping body core temperature within a degree or two of 37C, which enables normal cellular function. Among these physiological functions, nitric oxide (NO) represents the key mechanism for maintaining endothelial homeostasis [2, 15]. COVID-19-Associated lung microvascular endotheliopathy: a from the bench perspective. In a randomized clinical trial, L-arginine add-on therapy significantly reduces the length of hospitalization in severe COVID-19 patients and reduces the need of respiratory support, with no serious adverse events [147]. ICU admission levels of endothelial biomarkers as predictors of mortality in critically Ill COVID-19 patients. Large-scale clinical trials are warranted to evaluate whether the use of SGLT2 inhibitors can reduce the mortality and hospitalizations for heart failure in COVID-19 patients with or without T2DM. Fajgenbaum DC, June CH. Angpt-2 angiopoietin-2, CCL2 chemokine (C-C motif) ligand 2, ECs endothelial cells, FMD flow-mediated dilation, HMWM high-molecular-weight multimers, IL-1 interleukin-1, IL-6 interleukin 6, PDGF-BB platelet-derived growth factor BB, s-Flt soluble fms-like tyrosine kinase, sICAM1 soluble ICAM1, sVCAM1 soluble VCAM1, sVE-cadherin soluble vascular endothelial cadherin, TF tissue factor, TNF- tumor necrosis factor, VEGF-A vascular endothelial growth factor A, vWF von Willebrand factor. Google Scholar. 2020;40:24047. Samuel SM, Varghese E, Bsselberg D. Therapeutic potential of metformin in COVID-19: reasoning for its protective role. Employing mechanical ventilation techniques on venovenous extracorporeal membrane oxygenation (VV ECMO . In addition to mtROS, other sources of ROS can also be possible, such as ROS derived from NADPH oxidase activation as well as eNOS uncoupling [85]. SARS-CoV-2 or viral proteins can infect endothelial cells and other host cells via reported receptors and the vicious cycle was perpetuated. Based on these protective effects, statin may be used as an adjunctive therapy to mitigate endothelial dysfunction accompanying SARS-CoV-2 infection. Costa TJ, Potje SR, Fraga-Silva TFC, da Silva-Neto JA, Barros PR, Rodrigues D, et al. Six I, Guillaume N, Jacob V, Mentaverri R, Kamel S, Boullier A, et al. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Kang S, Tanaka T, Inoue H, Ono C, Hashimoto S, Kioi Y, et al. 2021;53:111623. This study provides additional clinical evidence supporting continuation of metformin use in COVID-19 patients with pre-existing T2DM by paying close attention to kidney function and acidosis [126]. Besides directly infected by SARS-CoV-2, the ECs also undergo injury by systemic inflammation caused by over-activation of innate immune response, referring to cytokine storm [91, 92]. Thermoregulation is a vital function of the autonomic nervous system in response to cold and heat stress. Maccio U, Zinkernagel AS, Shambat SM, Zeng X, Cathomas G, Ruschitzka F, et al. Virus-induced senescence is a pathogenic trigger of endothelial dysfunction. Endothelial integrity is essential for maintaining the pulmonary capillary-alveolar barrier and lung homoeostasis. ACE2 angiotensin-converting enzyme-2, TMPRSS2 transmembrane protease serine 2, ICAM-1 intercellular adhesion molecule 1, VCAM-1 vascular cell adhesion molecule 1, MCP1 monocyte chemoattractant protein-1, TGF- transforming growth factor , VEGF vascular endothelial growth factor, NO nitric oxide, IL-1 interleukin-1, IL-6 interleukin 6, TNF- tumor necrosis factor. Corrao S, Pinelli K, Vacca M, Raspanti M, Argano C. Type 2 diabetes mellitus and COVID-19: a narrative review. Ilonzo N, Judelson D, Al-Jundi W, Etkin Y, OBanion LA, Rivera A, et al. Heat exhaustion; Heat stroke; Hypohidrosis; Hypothermia; Rewarming; Small fiber neuropathy; Thermoregulation. Eur Heart J. COVID-19 and thermoregulation-related problems: Practical recommendations Description An international research team organized by the Global Heat Health Information Network prepared an inventory of the specific concerns about heat related illness and coronavirus transmission and began to address the issues. Circulating level of Angiopoietin-2 is associated with acute kidney injury in coronavirus disease 2019 (COVID-19). 2020;116:e195e7. Tomasa-Irriguible TM, Bielsa-Berrocal L. COVID-19: Up to 82% critically ill patients had low vitamin C values. Potje SR, Costa TJ, Fraga-Silva TFC, Martins RB, Benatti MN, Almado CEL, et al. Zhang X, Jiang M, Yang J. 2021;45:11639. Ma Z, Yang KY, Huang Y, Lui KO. Clinical and pathological investigation of patients with severe COVID-19. Mechanistically, L-SIGN interacted with high-mannose-type N-glycans on the receptor-binding domain of SARS-CoV-2 spike protein in a Ca2+-dependent manner [33]. An important question in endothelial dysfunction caused by SARS-Co-V2 is whether SARS-CoV-2 can infect and cause (passively or actively) endothelial dysfunction and long COVID [7]. Front Environ Sci Eng. Fardman A, Zahger D, Orvin K, Oren D, Kofman N, Mohsen J, et al. Biomedicines. 2017BT01S131), Hefei Comprehensive National Science Center (Grant No. It remains to be investigated whether other mechanisms that are more closely related to COVID-19, such as long non-coding RNA, circular RNA, RNA methylation, microbiota and metabolites, are involved in triggering endothelial dysfunction following SARS-COV-2 infection. 2021;12:18506. world J mens health. Keywords: COVID-19; heat plan; heat stress; pandemic; personal protective equipment; sars-CoV-2; thermometry. 2021;599:2839. 2022;119:31925. J Neuroinflammation. Bethesda, MD 20894, Web Policies COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. 2021;10:e69314. PubMed Central Heterogeneous ACE2 expression and endothelial damage was observed in COVID-19 autopsy tissues. Dexamethasone in hospitalized patients with Covid-19. 2020;24:422. Efficacy and mechanisms of traditional Chinese medicine for COVID-19: a systematic review. 2021;93:2506. Huang P, Zuo Q, Li Y, Oduro PK, Tan F, Wang Y, et al. 2021;58:457587. SARS-CoV-2 infection can also cause acute kidney injury (AKI). High-dose intravenous vitamin C decreases rates of mechanical ventilation and cardiac arrest in severe COVID-19. 2012;36:5715. Moreover, supernatant from virus-infected cells can trigger neutrophil extracellular trap formation and platelet activation [88]. Therefore, ACE2 expression may have paradoxical effects, aiding SARS-CoV-2 pathogenicity, yet conversely limiting viral infection [87, 130]. Mensah SA, Cheng MJ, Homayoni H, Plouffe BD, Coury AJ, Ebong EE. Libby P, Lscher T. COVID-19 is, in the end, an endothelial disease. Hussain M, Khurram Syed S, Fatima M, Shaukat S, Saadullah M, Alqahtani AM, et al. Beneficial effects of mineralocorticoid receptor pathway blockade against endothelial inflammation induced by SARS-CoV-2 spike protein. J Hepatol. Cecon E, Fernandois D, Renault N, Coelho CFF, Wenzel J, Bedart C, et al. Several clinical trials are ongoing to evaluate the safety and efficacy of JAK/STAT inhibitors [146]. PubMed Proc Natl Acad Sci USA. 2021;34:812. 2022;52:e13726. Article 2021;24:152233. Shao Y, Saredy J, Xu K, Sun Y, Saaoud F, Drummer CT, et al. Food Chem Toxicol. PubMed Intern Emerg Med. An official website of the United States government. Satarker S, Tom AA, Shaji RA, Alosious A, Luvis M, Nampoothiri M. JAK-STAT pathway inhibition and their implications in COVID-19 therapy. Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. The levels of biomarkers of endothelial cell activation/injury well correlate with the expression level of pro-inflammatory cytokines and chemokines [103]. ACE2 is a key regulator of RAAS by catalyzing the production of Ang-(17) from AngII, and the Ang-(17) can act on MAS receptor to combat the harmful effects caused by activation of RAAS[87, 130].
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