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Drugs Modulating Renin-Angiotensin System in COVID-19 Treatment.

ABSTRACT: A massive worldwide vaccination campaign constitutes the main tool against the COVID-19 pandemic. However, drug treatments are also necessary. Antivirals are the most frequently considered treatments. However, strategies targeting mechanisms involved in disease aggravation may also be effective. A major role of the tissue renin-angiotensin system (RAS) in the pathophysiology and severity of COVID-19 has been suggested. The main link between RAS and COVID-19 is angiotensin-converting enzyme 2 (ACE2), a central RAS component and the primary binding site for SARS-CoV-2 that facilitates the virus entry into host cells. An initial suggestion that the susceptibility to infection and disease severity may be enhanced by angiotensin type-1 receptor blockers (ARBs) and ACE inhibitors (ACEIs) because they increase ACE2 levels, led to the consideration of discontinuing treatments in thousands of patients. More recent experimental and clinical data indicate that ACEIs and, particularly, ARBs can be beneficial for COVID-19 outcome, both by reducing inflammatory responses and by triggering mechanisms (such as ADAM17 inhibition) counteracting viral entry. Strategies directly activating RAS anti-inflammatory components such as soluble ACE2, Angiotensin 1-7 analogues, and Mas or AT2 receptor agonists may also be beneficial. However, while ACEIs and ARBs are cheap and widely used, the second type of strategies are currently under study.

SUBMITTER: Labandeira-Garcia JL

PROVIDER: S-EPMC8962306 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Drugs Modulating Renin-Angiotensin System in COVID-19 Treatment.

Labandeira-Garcia Jose L JL Labandeira Carmen M CM Valenzuela Rita R Pedrosa Maria A MA Quijano Aloia A Rodriguez-Perez Ana I AI

Biomedicines 20220221 2

A massive worldwide vaccination campaign constitutes the main tool against the COVID-19 pandemic. However, drug treatments are also necessary. Antivirals are the most frequently considered treatments. However, strategies targeting mechanisms involved in disease aggravation may also be effective. A major role of the tissue renin-angiotensin system (RAS) in the pathophysiology and severity of COVID-19 has been suggested. The main link between RAS and COVID-19 is angiotensin-converting enzyme 2 (AC ...[more]

PMID: 35203711

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Project description:SARS-CoV-2 gains cell entry via angiotensin-converting enzyme (ACE) 2, a membrane-bound enzyme of the "alternative" (alt) renin-angiotensin system (RAS). ACE2 counteracts angiotensin II by converting it to potentially protective angiotensin 1-7. Using mass spectrometry, we assessed key metabolites of the classical RAS (angiotensins I-II) and alt-RAS (angiotensins 1-7 and 1-5) pathways as well as ACE and ACE2 concentrations in 159 patients hospitalized with COVID-19, stratified by disease severity (severe, n = 76; non-severe: n = 83). Plasma renin activity (PRA-S) was calculated as the sum of RAS metabolites. We estimated ACE activity using the angiotensin II:I ratio (ACE-S) and estimated systemic alt-RAS activation using the ratio of alt-RAS axis metabolites to PRA-S (ALT-S). We applied mixed linear models to assess how PRA-S and ACE/ACE2 concentrations affected ALT-S, ACE-S, and angiotensins II and 1-7. Median angiotensin I and II levels were higher with severe versus non-severe COVID-19 (angiotensin I: 86 versus 30 pmol/L, p < 0.01; angiotensin II: 114 versus 58 pmol/L, p < 0.05), demonstrating activation of classical RAS. The difference disappeared with analysis limited to patients not taking a RAS inhibitor (angiotensin I: 40 versus 31 pmol/L, p = 0.251; angiotensin II: 76 versus 99 pmol/L, p = 0.833). ALT-S in severe COVID-19 increased with time (days 1-6: 0.12; days 11-16: 0.22) and correlated with ACE2 concentration (r = 0.831). ACE-S was lower in severe versus non-severe COVID-19 (1.6 versus 2.6; p < 0.001), but ACE concentrations were similar between groups and correlated weakly with ACE-S (r = 0.232). ACE2 and ACE-S trajectories in severe COVID-19, however, did not differ between survivors and non-survivors. Overall RAS alteration in severe COVID-19 resembled severity of disease-matched patients with influenza. In mixed linear models, renin activity most strongly predicted angiotensin II and 1-7 levels. ACE2 also predicted angiotensin 1-7 levels and ALT-S. No single factor or the combined model, however, could fully explain ACE-S. ACE2 and ACE-S trajectories in severe COVID-19 did not differ between survivors and non-survivors. In conclusion, angiotensin II was elevated in severe COVID-19 but was markedly influenced by RAS inhibitors and driven by overall RAS activation. ACE-S was significantly lower with severe COVID-19 and did not correlate with ACE concentrations. A shift to the alt-RAS axis because of increased ACE2 could partially explain the relative reduction in angiotensin II levels.

Project description:BackgroundDespite the availability of extensive literature on the effect of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-receptor blockers (ARBs) on COVID-19 outcomes, the evidence is still controversial. We aimed to provide a comprehensive assessment of the effect of ACEIs/ARBs on COVID-19-related outcomes by summarising the currently available evidence.MethodsAn umbrella review was conducted using Medline (OVID), Embase, Scopus, Cochrane library and medRxiv from inception to 1 February 2021. Systematic reviews with meta-analysis that evaluated the effect of ACEIs/ARBs on COVID-19-related clinical outcomes were eligible. Studies' quality was appraised using the AMSTAR 2 Critical Appraisal Tool. Data were analysed using the random-effects modelling including several subgroup analyses. Heterogenicity was assessed using I2 statistic. The study protocol was registered in PROSPERO (CRD42021233398) and reported using PRISMA guidelines.ResultsOverall, 47 reviews were eligible for inclusion. Out of the nine COVID-19 outcomes evaluated, there was significant associations between ACEIs/ARBs use and each of death (OR = 0.80, 95%CI = 0.75-0.86; I2 = 51.9%), death/ICU admission as composite outcome (OR = 0.86, 95%CI = 0.80-0.92; I2 = 43.9%), severe COVID-19 (OR = 0.86, 95%CI = 0.78-0.95; I2 = 68%) and hospitalisation (OR = 1.23, 95%CI = 1.04-1.46; I2 = 76.4%). The significant reduction in death/ICU admission, however, was higher among studies which presented adjusted measure of effects (OR = 0.63, 95%CI = 0.47-0.84) and were of moderate quality (OR = 0.74, 95%CI = 0.63-0.85).ConclusionsCollective evidence from observational studies indicate a good quality evidence on the significant association between ACEIs/ARBs use and reduction in death and death/ICU admission, but poor-quality evidence on both reducing severe COVID-19 and increasing hospitalisation. Our findings further support the current recommendations of not discontinuing ACEIs/ARBs therapy in patients with COVID-19.

Dataset Information

Drugs Modulating Renin-Angiotensin System in COVID-19 Treatment.

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Drugs Modulating Renin-Angiotensin System in COVID-19 Treatment.

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