Controversy over renin–angiotensin–aldosterone system (RAAS) inhibitors treatment in nephrology and cardiovascular diseases

Abstract It has been established SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2), a membrane-bound regulatory peptide, for host cell entry. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been reported to increase ACE2 in type 2 pneumocytes pulmonary tissue. Controversy exists for the continuation of ACE inhibitors, angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs) in the current pandemic. ACE2 serves as regulatory enzyme in maintaining homeostasis between proinflammatory Angiotensin II and anti-inflammatory Angiotensin 1,7 peptides. Derangements in these peptides are associated with cardiovascular disease and are implicated in the progression of acute respiratory distress syndrome (ARDS). Augmentation of the ACE2/Ang1,7 axis represent a critical target in the supportive management of COVID-19 associated lung disease. Observational data describing the use of RAAS inhibitors in the setting of SARS-CoV-2 have not borne signals of harm to date. However, equipoise persists requiring an analysis of novel agents including recombinant human-ACE2 and existing RAAS inhibitors while balancing ongoing controversies associated with increased coronavirus infectivity and virulence.

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Tactics of antihypertensive therapy during COVID-19 pandemic

Terapevticheskii arkhiv ◽

10.26442/00403660.2021.09.201015 ◽

2021 ◽

Vol 93 (9) ◽

pp. 1125-1131

Author(s):

Valery I. Podzolkov ◽

Anna Е. Bragina ◽

Yulia N. Rodionova ◽

Galina I. Bragina ◽

Ekaterina E. Bykova

Keyword(s):

Blood Pressure ◽

Cardiovascular Diseases ◽

Arterial Hypertension ◽

Ace Inhibitor ◽

Fixed Combination ◽

Significant Risk ◽

Effective Control ◽

Combination Drug ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin

Results of foreign and Russian studies indicate a higher mortality rate of patients with concomitant cardiovascular diseases (CVD) due to the new coronavirus infection COVID-19. It has been proven that arterial hypertension, as one of the significant risk factors for the development of concomitant cardiovascular diseases, is associated with a more severe prognosis of COVID-19. This article presents the results of modern studies and large meta-analyzes of necessity and safety of the use of blockers of the renin-angiotensin-aldosterone system in patients with arterial hypertension and COVID-19. The data of studies show that an angiotensin-converting enzyme inhibitor (ACE inhibitor) and a thiazide-like diuretic is a pathogenetically rational combination. It realizes various ways of lowering blood pressure by reducing the activity of the renin-angiotensin-aldosterone system, which is achieved by using an ACE inhibitor, and natriuresis due to diuretics. As an example, a highly effective fixed combination of drugs is considered, characterized by good tolerance, which consists of an ACE inhibitor lisinopril and a thiazide-like diuretic indapamide of prolonged action. The authors expressed the opinion that the appointment of the fixed combination drug Diroton Plus (Gedeon Richter) will contribute to effective control of blood pressure and organoprotection in conditions of increased thrombogenic and prooxidative potential, characteristic of COVID-19 both in the acute stage and within the post-COVID Syndrome.

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Renin-angiotensin-aldosterone system inhibitors – a realm of confusion in COVID-19

Journal of Ideas in Health ◽

10.47108/jidhealth.vol4.issspecial2.125 ◽

2021 ◽

Vol 4 (Special2) ◽

pp. 389-394

Author(s):

Angela Madalina Lazar

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Current Knowledge ◽

Angiotensin Receptor Blockers ◽

Protective Effects ◽

Converting Enzyme ◽

Angiotensin I ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

Raas Inhibitors

Currently, there is a persisting dispute regarding the renin-angiotensin-aldosterone-system (RAAS) inhibitors' safety of use in COVID-19 pandemics. On one side, RAAS inhibitors appear to determine an overexpression of ACE2, the receptor of SARS-CoV-2. Therefore, they could increase the risk of SARS-CoV-2 infection and its degree of severity. On the other side, the discontinuation of RAAS leads to cardiovascular decompensation and has been discouraged by the major medical societies. Also, large-cohort studies report beneficial or at least neutral effects for the RAAS inhibitors in COVID-19 patients. Worldwide, millions of patients receive RAAS inhibitors for the treatment of hypertension and other important comorbidities. In this context, knowledge of the exact effect of these medications becomes of crucial significance. This paper aims to fill in a gap in the current knowledge and presents a putative mechanism by which RAAS inhibitor administration's beneficial results can be explained better. RAAS inhibitors can be beneficial, as they counteract the excessive detrimental activation of the classical angiotensin-converting enzyme (ACE) axis, decreasing the angiotensin II levels. The angiotensin receptor blockers (ARBs) increase the angiotensin II levels, while the angiotensin-converting enzyme inhibitors (ACEI) increase the angiotensin I levels; these substrates will compete with the SARS-CoV-2 for the ACE2 binding, decreasing the viral infectivity. In addition, following the RAAS inhibitors treatment, the up-regulated ACE2 will cleave these substrates (angiotensin I and II), particularly to angiotensin 1-7 that possesses vasodilator, protective effects.

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Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status

British Journal of Pharmacology ◽

10.1111/j.1476-5381.2010.00750.x ◽

2010 ◽

Vol 160 (6) ◽

pp. 1273-1292 ◽

Cited By ~ 183

Author(s):

Terry KW Ma ◽

Kevin KH Kam ◽

Bryan P Yan ◽

Yat-Yin Lam

Keyword(s):

Cardiovascular Diseases ◽

Current Status ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin

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Review of polymorphisms, associated with cardiovascular diseases

Russian Journal of Geriatric Medicine ◽

10.37586/2686-8636-4-2020-333-338 ◽

2021 ◽

pp. 333-338

Author(s):

A. A. Akopyan ◽

I. D. Strazhesko ◽

O. N. Tkacheva ◽

A. P. Yesakova ◽

I. A. Orlova

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Cardiovascular Diseases ◽

Chronic Inflammation ◽

Gene Polymorphisms ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

System Activation ◽

And Oxidative Stress

In this research we examined studies of gene polymorphisms, associated with cardiovascular diseases through renin-angiotensin-aldosterone system activation (AGT с.521С>Т, AСE Ins>Del), nitric oxide decline (NOS3 с.894G>T), chronic inflammation (TNF -238G>A, MMP9 -1562С>T) and oxidative stress (CYBA c.214Т>С).

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Renin-Angiotensin-Aldosterone System peptide profiles in patients with COVID-19

Acta Endocrinologica ◽

10.1530/eje-20-1445 ◽

2021 ◽

Author(s):

Alexander Kutz ◽

Anna Conen ◽

Claudia Gregoriano ◽

Sebastian Haubitz ◽

Daniel Koch ◽

...

Keyword(s):

Respiratory Infections ◽

Tertiary Care ◽

Plasma Renin ◽

Adverse Outcomes ◽

Care Hospital ◽

Renin Angiotensin Aldosterone System ◽

Peptide Profile ◽

Renin Angiotensin ◽

Subgroup Analyses ◽

Raas Inhibitors

Objective While evidence on the interface between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and the renin-angiotensin-aldosterone-system (RAAS) is accumulating, clinical data on RAAS peptide alteration among coronavirus disease-19 (COVID-19) patients is missing. Design and Methods In this exploratory study, we prospectively included adult patients (aged ≥18 years) admitted between February 26 and April 30, 2020 to a tertiary care hospital in Switzerland. We assessed the association of an underlying SARS-CoV-2 infection and equilibrium serum levels of RAAS peptides in hospitalized COVID-19 patients 1:1 propensity-score matched with patients suffering from SARS-CoV-2-negative respiratory infections. Subgroup analyses involved stratification for taking RAAS inhibitors. Results COVID-19 patients had about 50% lower equilibrium serum RAAS peptide levels as compared with matched controls (angiotensin I: 31.6 vs. 66.8pmol/l, -52.7% [95%CI -68.5% to -36.9%]; angiotensin II: 37.7 vs. 92.5pmol/l, -59.2% [95%CI -72.1% to -46.3%]; angiotensin (1-5): 3.3 vs. 6.6pmol/l, -49.7% [95%CI -59.2% to -40.2%]; angiotensin (1-7): 4.8 vs. 7.6pmol/l, -64.9% [95%CI -84.5% to -45.3%]). While the plasma renin activity (PRA-S) was lower in COVID-19 patients (88.6 vs. 207.9pmol/l, -58.5% [95%CI -71.4% to -45.6%]), there was no difference of angiotensin-converting enzyme (ACE) and ACE2 plasma activity between the groups. Subgroup analyses revealed a pronounced RAAS peptide profile depression in COVID-19 patients among those not on RAAS inhibitors. Conclusions As compared with SARS-CoV-2-negative patients, we found a downregulated RAAS in presence of a SARS-CoV-2 infection. Whether the lower levels of the protective angiotensin (1-5) and (1-7) are linked to adverse outcomes in COVID-19 warrants further investigation.

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Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Short-Term Mortality After Sepsis

Hypertension ◽

10.1161/hypertensionaha.119.13197 ◽

2020 ◽

Vol 75 (2) ◽

pp. 483-491 ◽

Cited By ~ 9

Author(s):

Wan-Ting Hsu ◽

Brandon Patrick Galm ◽

Gregory Schrank ◽

Tzu-Chun Hsu ◽

Shih-Hao Lee ◽

...

Keyword(s):

Propensity Score ◽

Meta Analysis ◽

Hazard Ratio ◽

Short Term ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

Mortality Hazard ◽

Short Term Mortality ◽

Raas Inhibitors ◽

Mortality Hazard Ratio

Antagonists of the renin-angiotensin-aldosterone system (RAAS), including ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers), may prevent organ failure. We, therefore, investigated whether specific RAAS inhibitors are associated with reduced mortality in patients with sepsis.We conducted a population-based retrospective cohort study using multivariable propensity score–based regression to control for differences among patients using different RAAS inhibitors. A multivariable-adjusted Cox proportional-hazards regression model was used to determine the association between RAAS inhibitors and sepsis outcomes. To directly compare ACEI users, ARB users, and nonusers, a 3-way propensity score matching approach was performed. Results were pooled with previous evidence via a random-effects meta-analysis. A total of 52 727 patients were hospitalized with sepsis, of whom 7642 were prescribed an ACEI and 4237 were prescribed an ARB. Using propensity score–matched analyses, prior ACEI use was associated with decreased 30-day mortality (hazard ratio, 0.84 [95% CI, 0.75–0.94]) and 90-day mortality (hazard ratio, 0.83 [95% CI, 0.75–0.92]) compared with nonuse. Prior ARB use was associated with an improved 90-day survival (hazard ratio, 0.88 [95% CI, 0.83–0.94]). These results persisted in sensitivity analyses focusing on patients without cancer and patients with hypertension. By contrast, no beneficial effect was found for antecedent β-blockers exposure (hazard ratio, 0.99 [95% CI, 0.94–1.05]). The pooled estimates obtained from the meta-analysis was 0.71 (95% CI, 0.58–0.87) for prior use of ACEI/ARB.The short-term mortality after sepsis was substantially lower among those who were already established on RAAS inhibitor treatment when sepsis occurred.

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Recent Advances in the Knowledge of Naturally-derived Bioactive Compounds as Modulating Agents of the Renin-angiotensin-aldosterone System: Therapeutic Benefits in Cardiovascular Diseases

Current Pharmaceutical Design ◽

10.2174/1381612825666190329122443 ◽

2019 ◽

Vol 25 (6) ◽

pp. 670-684 ◽

Cited By ~ 1

Author(s):

Priscila de Souza ◽

Luisa M. da Silva ◽

Sérgio F. de Andrade ◽

Arquimedes Gasparotto Junior

Keyword(s):

Cardiovascular Diseases ◽

Bioactive Compounds ◽

Current Therapy ◽

Renal Diseases ◽

Attractive Alternative ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

Raas Blockade ◽

Therapeutic Benefits ◽

Cardiovascular Morbidity And Mortality

Background: One of the biggest challenges to public health worldwide is to reduce the number of events and deaths related to the cardiovascular diseases. Numerous approaches have been applied to reach this goal, and drug treatment intervention has been indispensable along with an effective strategy for reducing both cardiovascular morbidity and mortality. Renin-angiotensin-aldosterone system (RAAS) blockade is currently one of the most important targets of cardiovascular drug therapy. Many studies have proven the valuable properties of naturally-derived bioactive compounds to treat cardiovascular diseases. Methods: The goal of this review, therefore, is to discuss the recent developments related to medicinal properties about natural compounds as modulating agents of the RAAS, which have made them an attractive alternative to be available to supplement the current therapy options. Results: Data has shown that bioactive compounds isolated from several natural products act either by inhibiting the angiotensin-converting enzyme or directly by modulating the AT1 receptors of angiotensin II, which consequently changes the entire classical axis of this system. Conclusion: While there are a few evidence about the positive actions of different classes of secondary metabolites for the treatment of cardiovascular and renal diseases, data is scarce about the clinical assays established to demonstrate their value in humans.

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Clinical Features of COVID-19 in Patients With Essential Hypertension and the Impacts of Renin-angiotensin-aldosterone System Inhibitors on the Prognosis of COVID-19 Patients

Hypertension ◽

10.1161/hypertensionaha.120.15289 ◽

2020 ◽

Vol 76 (3) ◽

pp. 732-741 ◽

Cited By ~ 12

Author(s):

Wei Pan ◽

Jishou Zhang ◽

Menglong Wang ◽

Jing Ye ◽

Yao Xu ◽

...

Keyword(s):

Cox Regression ◽

Medication History ◽

Renin Angiotensin Aldosterone System ◽

Cox Regression Analysis ◽

Renin Angiotensin ◽

Reactive Protein ◽

All Cause Mortality ◽

History Of ◽

Raas Inhibitors ◽

The Impact

Hypertension is one of the most common comorbidities in patients with coronavirus disease 2019 (COVID-19). This study aimed to clarify the impact of hypertension on COVID-19 and investigate whether the prior use of renin-angiotensin-aldosterone system (RAAS) inhibitors affects the prognosis of COVID-19. A total of 996 patients with COVID-19 were enrolled, including 282 patients with hypertension and 714 patients without hypertension. Propensity score-matched analysis (1:1 matching) was used to adjust the imbalanced baseline variables between the 2 groups. Patients with hypertension were further divided into the RAAS inhibitor group (n=41) and non-RAAS inhibitor group (n=241) according to their medication history. The results showed that COVID-19 patients with hypertension had more severe secondary infections, cardiac and renal dysfunction, and depletion of CD8 + cells on admission. Patients with hypertension were more likely to have comorbidities and complications and were more likely to be classified as critically ill than those without hypertension. Cox regression analysis revealed that hypertension (hazard ratio, 95% CI, unmatched cohort [1.80, 1.20–2.70]; matched cohort [2.24, 1.36–3.70]) was independently associated with all-cause mortality in patients with COVID-19. In addition, hypertensive patients with a history of RAAS inhibitor treatment had lower levels of C-reactive protein and higher levels of CD4 + cells. The mortality of patients in the RAAS inhibitor group (9.8% versus 26.1%) was significantly lower than that of patients in the non-RAAS inhibitor group. In conclusion, hypertension may be an independent risk factor for all-cause mortality in patients with COVID-19. Patients who previously used RAAS inhibitors may have a better prognosis.

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RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM INHIBITORS AND COVID-19 COMPLICATIONS

10.51162/health2021-0001 ◽

2021 ◽

Author(s):

ARTHUR FIOROTTO DE MATTOS ◽

NATHALIA SILVEIRA BARSOTTI ◽

RAFAEL RIBEIRO ALMEIDA

Keyword(s):

Rna Virus ◽

Host Cells ◽

Converting Enzyme ◽

Respiratory Complications ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

The World ◽

Raas Inhibitors ◽

The Impact ◽

Different Tissues

The world faces today a pandemic of unquestionable importance, caused by an infection with a new enveloped RNA virus that belongs to the Coronaviridae family. The new coronavirus (SARS-CoV 2) uses a glycoprotein present on its surface to bind to and infect host cells that express the angiotensin converting enzyme II (ACE-2). Although different tissues may be targeted by the virus, respiratory complications remain as the main cause of death. It has been demonstrated that Renin-Angiotensin-Aldosterone System (RAAS) inhibitors increase ACE-2 expression in animal models, raising the concern that patients under treatment with these drugs could become more susceptible to COVID-19 complications. Here, we discuss the impact of RAAS inhibitors on COVID-19 outcomes and show that no evidence so far supports that the use of these drugs could pose a risk to SARS-CoV 2-infected patients. In fact, clinical data suggest that RAAS inhibitors may even act in a protective way against COVID-19 complications and should not be discontinued.,

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