key: cord-0848525-k0u5das5 authors: Sanghavi, Devang K.; Titus, Anoop; Caulfield, Thomas R.; David Freeman, W. title: Endotheliitis, Endothelin, and Endothelin Receptor Blockers in COVID-19 date: 2021-03-23 journal: Med Hypotheses DOI: 10.1016/j.mehy.2021.110564 sha: 5ece36e96a9fde688c4168d30f98e648af97440d doc_id: 848525 cord_uid: k0u5das5 We summarize the role of endothelin as a potent vasoconstrictor, pro-inflammatory, pro-oxidative agent in the pathophysiologic effects and end-organ dysfunction of coronavirus disease 2019 (COVID-19). Endotheliitis is an under-recognized pathophysiologic process that causes various types of dysfunction in end organs, including heart, lung, kidney, and brain. Endothelin receptor blockers, such as bosentan and sitaxentan, can pave a path ahead in the realm of COVID-19 therapies. These agents have a potential role against COVID-19 and should be studied in research trials to determine their efficacy in treatment of this severe disease. From the beginning of the coronavirus disease 2019 (COVID- 19) pandemic, multiple studies had been underway to formulate a cure and treatment protocols. Initially, empirical ideologies were used, which eventually were disproved in clinical trials. Case fatality rates still range from 1% to 7%, but these numbers deserve scrutiny on the basis of data acquisition. 1 A gross limitation has been mentioned in identification of the exact causes of death in populations affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. 2 Although the infection may be present in a patient who is considered seropositive for the virus, the primary cause of the patient's death could be the worsening of a concurrent comorbidity, lack of hospital supplies and equipment, and/or a noninclusive cause regardless of the virus 2 . With careful introspection of the pathogenesis of SARS-CoV-2, we came across a wide variation in pathophysiologic mechanisms that show its virulence and mortality rate. Be it the Spanish flu of 1918 or COVID-19, the main cause of death was respiratory disease. 3 Initial findings showed that non-survivors had an early increased neutrophil to lymphocyte ratio, relatively low lymphocyte counts, and increased C-reactive protein and D- The entry mode of SARS-CoV-2 was identified to be through the angiotensin-converting enzyme (ACE) 2 receptor, expressed in such organs as heart, liver, kidney, lung, and gastrointestinal tract. All these organs have depicted symptoms among patients infected by the virus: carditis, pneumonitis, pneumonia, acute kidney injury, and multiorgan failure. The same receptor also is expressed on endothelial cells. 5 with an increase in endothelin, the hormone that regulates vascular tone and coagulative tendencies. 10 The hypothesis of endothelial dysfunction raises the question about whether endothelin is implicated in the pathogenesis of endothelial disruption and inflammation. Bottomline is that, the string that connects all these organs are endotheliitis and subsequent elevation of ET-1 in plasma. In the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial at the University of Oxford, investigators have shown that dexamethasone decreased the risk of death from 40% to 28%. 11 Earlier, dexamethasone had been shown to lessen the development of progressive pulmonary arterial hypertension in rats. 12 It also has been shown to block hypoxia-induced endothelial dysfunction. 13 Interestingly, the study of glucocorticoids (which also are involved in leukocyte endothelial adhesion), 14 vascular endothelial growth factor, 15 On comparison of patients with higher risks of death (eg, because of prior heart disease, coronary artery disease, diabetes mellitus, renal insufficiency, hypertension), 16 an observed common pathophysiologic thread to connect all these disease presentations is the prevalence of increased endothelin levels in blood and the ACE pathways. 17 Given a higher mortality risk among patients with elevated endothelin levels, it is prudent to investigate the association of endothelin receptor blockers as a potential therapy to reduce the severity and mortality rate of COVID-19. Endothelin is a potent vasoconstrictor, proinflammatory, Patients with heart failure have increased ET-1 levels. 18 Patients with essential hypertension have an elevated ET-1 level at the vasculature walls. Hyperglycemia of persons with diabetes is also an inducer for ET-1 production. Studies of heart failure, hypertension, and diabetes show evidence that upholds a reduction in morbidity and death with use of endothelin receptor antagonists. Endothelin receptor blockers such as bosentan and sitaxentan must be involved in clinical studies for combating the COVID-19 pandemic with this pathophysiologic foundation. 19 In addition, an area of cardiovascular overlap occurs where the ET-1 increase is reduced with use of ACE inhibitor drugs. 20 With more than 78.7 million confirmed COVID-19 cases globally and more than 1.73 million lives lost to COVID-19 thus far, scientists and physicians must combine efforts to fundamentally and continually decipher the pathophysiology behind the disease and the endothelial system and its interrelated molecular pathways, which are essential in the severe cases that require intensive care. Not applicable. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy Understanding pathways to death in patients with COVID-19 Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China Development and Validation of a Clinical Risk Score to Predict the Occurrence of Critical Illness in Hospitalized Patients With COVID-19 Effect of angiotensinconverting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2 COVID-19-Related Stroke Cardiovascular complications in COVID-19 Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2 Endothelial cell infection and endotheliitis in COVID-19 The vascular endothelium and human diseases Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats Dexamethasone blocks hypoxia-induced endothelial dysfunction in organ-cultured pulmonary arteries A mechanism for the antiinflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1 Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19 Prognostic impact of big endothelin-1 plasma concentrations compared with invasive hemodynamic evaluation in severe heart failure StatPearls [Internet Different effects of angiotensin converting enzyme inhibitors on endothelin-1 and nitric oxide balance in human vascular endothelial cells: evidence of an oxidant-sensitive pathway All authors have approved the contents of this paper for publication. Not applicable. The authors declare that they have no competing interests. None. D.K.S. and A.T. conceived the presented idea. D.K.S., A.T., T.R.C., and W.D.F. contributed to the manuscript writing equally.