| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T34 |
0-67 |
Sentence |
denotes |
Potential for Benefit Rather Than Harm of RAAS Blockers in Covid-19 |
| T35 |
68-255 |
Sentence |
denotes |
SARS-CoV-2 appears not only to gain initial entry through ACE2 but also to subsequently down-regulate ACE2 expression such that the enzyme is unable to exert protective effects in organs. |
| T36 |
256-866 |
Sentence |
denotes |
It has been postulated but unproven that unabated angiotensin II activity may be in part responsible for organ injury in Covid-19.43,44 After the initial engagement of SARS-CoV-2 spike protein, there is subsequent down-regulation of ACE2 abundance on cell surfaces.45 Continued viral infection and replication contribute to reduced membrane ACE2 expression, at least in vitro in cultured cells.46 Down-regulation of ACE2 activity in the lungs facilitates the initial neutrophil infiltration in response to bacterial endotoxin47 and may result in unopposed angiotensin II accumulation and local RAAS activation. |
| T37 |
867-1665 |
Sentence |
denotes |
Indeed, in experimental mouse models, exposure to SARS-CoV-1 spike protein induced acute lung injury, which is limited by RAAS blockade.45 Other mouse models have suggested that dysregulation of ACE2 may mediate acute lung injury that is secondary to virulent strains of influenza48,49 and respiratory syncytial virus.50 In a small study, patients with Covid-19 appeared to have elevated levels of plasma angiotensin II, which were in turn correlated with total viral load and degree of lung injury.44 Restoration of ACE2 through the administration of recombinant ACE2 appeared to reverse this devastating lung-injury process in preclinical models of other viral infections49,50 and safely reduced angiotensin II levels in a phase 2 trial evaluating acute respiratory distress syndrome in humans.51 |
| T38 |
1666-1828 |
Sentence |
denotes |
Dysregulated ACE2 may theoretically also attenuate cardioprotection in the context of myocardial involvement and abnormal pulmonary hemodynamics52,53 in Covid-19. |
| T39 |
1829-2147 |
Sentence |
denotes |
Markers of myocardial injury have been shown to be elevated during the disease course of Covid-1954 and to increase rapidly with clinical deterioration and preceding death.14 Many viruses are cardiotropic, and subclinical viral myocarditis is commonly seen in viremia associated with a wide range of infectious agents. |
| T40 |
2148-2906 |
Sentence |
denotes |
ACE2 has a well-recognized role in myocardial recovery and injury response; in one study, ACE2 knockout in animal models contributed to adverse left ventricular remodeling in response to acute injury driven by angiotensin II.55 In autopsies of patients who died from SARS, 35% of heart samples showed the presence of viral RNA, which in turn was associated with reduced ACE2 protein expression.56 Administration of recombinant ACE2 normalizes angiotensin II levels in human explanted hearts with dilated cardiomyopathy.57 These hypotheses have prompted trials to test whether the provision of recombinant ACE2 protein may be beneficial in restoring balance to the RAAS network and potentially preventing organ injury (ClinicalTrials.gov number, NCT04287686). |
| T41 |
2907-3150 |
Sentence |
denotes |
In addition, paired trials of losartan as a treatment for Covid-19 are being conducted among patients who have not previously received treatment with a RAAS inhibitor and are either hospitalized (NCT04312009) or not hospitalized (NCT04311177). |
