The Identikit of Patient at Risk for Severe COVID-19 and Death: The Dysregulation of Renin-Angiotensin System as the Common Theme

Since the first months of the coronavirus disease 2019 (COVID-19) pandemic, several specific physiologic traits, such as male sex and older age, or health conditions, such as overweight/obesity, arterial hypertension, metabolic syndrome, and type 2 diabetes mellitus, have been found to be highly prevalent and associated with increased risk of adverse outcomes in hospitalized patients. All these cardiovascular morbidities are widespread in the population and often coexist, thus identifying a common patient phenotype, characterized by a hyper-activation of the “classic” renin-angiotensin system (RAS) and mediated by the binding of angiotensin II (Ang II) to the type 1-receptor. At the same time, the RAS imbalance was proved to be crucial in the genesis of lung injury after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, where angiotensin-converting-enzyme-2 (ACE2) is not only the receptor for SARS-CoV-2, but its down-regulation through internalization and shedding, caused by the virus binding, leads to a further dysregulation of RAS by reducing angiotensin 1-7 (Ang 1-7) production. This focused narrative review will discuss the main available evidence on the role played by cardiovascular and metabolic conditions in severe COVID-19, providing a possible pathophysiological link based on the disequilibrium between the two opposite arms of RAS.

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Renin–angiotensin system blocker discontinuation and adverse outcomes in chronic kidney disease

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa300 ◽

2020 ◽

Author(s):

Carl P Walther ◽

Wolfgang C Winkelmayer ◽

Peter A Richardson ◽

Salim S Virani ◽

Sankar D Navaneethan

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Renin Angiotensin System ◽

Cox Proportional Hazards ◽

Adverse Outcomes ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Renin Angiotensin ◽

Risk Of Death ◽

Increased Risk

Abstract Background Treatment with renin–angiotensin system inhibitors (RASIs), angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) is the standard of care for those with chronic kidney disease (CKD) and albuminuria. However, ACEI/ARB treatment is often discontinued for various reasons. We investigated the association of ACEI/ARB discontinuation with outcomes among US veterans with non-dialysis-dependent CKD. Methods We performed a retrospective cohort study of patients in the Veterans Affairs healthcare system with non-dialysis-dependent CKD who subsequently were started on ACEI/ARB therapy (new user design). Discontinuation events were defined as a gap in ACEI/ARB therapy of ≥14 days and were classified further based on duration (14–30, 31–60, 61–90, 91–180 and >180 days). This was treated as a time-varying risk factor in adjusted Cox proportional hazards models for the outcomes of death and incident end-stage kidney disease (ESKD), which also adjusted for relevant confounders. Results We identified 141 252 people with CKD and incident ACEI/ARB use who met the inclusion criteria; these were followed for a mean 4.87 years. There were 135 356 discontinuation events, 68 699 deaths and 6152 incident ESKD events. Discontinuation of ACEI/ARB was associated with a higher risk of death [hazard ratio (HR) 2.3, 2.0, 1.99, 1.92 and 1.74 for those discontinued for 14–30, 31–60, 61–90, 91–180 and >180 days, respectively]. Similar associations were noted between ACEI and ARB discontinuation and ESKD (HR 1.64, 1.47, 1.54, 1.65 and 1.59 for those discontinued for 14–30, 31–60, 61–90, 91–180 and >180 days, respectively). Conclusions In a cohort of predominantly male veterans with CKD Stages 3 and 4, ACEI/ARB discontinuation was independently associated with an increased risk of subsequent death and ESKD. This may be due to the severity of illness factors that drive the decision to discontinue therapy. Further investigations to determine the causes of discontinuations and to provide an evidence base for discontinuation decisions are needed.

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Covid-19: the renin–angiotensin system imbalance hypothesis

Clinical Science ◽

10.1042/cs20200492 ◽

2020 ◽

Vol 134 (11) ◽

pp. 1259-1264 ◽

Cited By ~ 15

Author(s):

Katharina Lanza ◽

Lucas G. Perez ◽

Larissa B. Costa ◽

Thiago M. Cordeiro ◽

Vitria A. Palmeira ◽

...

Keyword(s):

Clinical Laboratory ◽

Renin Angiotensin System ◽

Disease Course ◽

Ang Ii ◽

Cellular Mechanisms ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Mas Receptor

Abstract The emergency of SARS-CoV-2 in China started a novel challenge to the scientific community. As the virus turns pandemic, scientists try to map the cellular mechanisms and pathways of SARS-CoV-2 related to the pathogenesis of Coronavirus Disease 2019 (Covid-19). After transmembrane angiotensin-converting enzyme 2 (ACE2) has been found to be SARS-CoV-2 receptor, we hypothesized an immune-hematological mechanism for Covid-19 based on renin–angiotensin system (RAS) imbalance to explain clinical, laboratory and imaging findings on disease course. We believe that exaggerated activation of ACE/Angiotensin II (Ang II)/Angiotensin Type 1 (AT1) receptor RAS axis in line with reduction of ACE2/Angiotensin-(1-7)/Mas receptor may exert a pivotal role in the pathogenesis of Covid-19. In this perspective, we discuss potential mechanisms and evidence on this hypothesis.

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Epochs in the depressor/pressor balance of the renin–angiotensin system

Clinical Science ◽

10.1042/cs20150939 ◽

2016 ◽

Vol 130 (10) ◽

pp. 761-771 ◽

Cited By ~ 14

Author(s):

Katrina M. Mirabito Colafella ◽

Lucinda M. Hilliard ◽

Kate M. Denton

Keyword(s):

Extracellular Fluid ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Mas Receptor ◽

Angiotensin Type 2 Receptor ◽

Angiotensin Type

The renin–angiotensin system (RAS) plays a commanding role in the regulation of extracellular fluid homoeostasis. Tigerstadt and Bergman first identified the RAS more than two centuries ago. By the 1980s a voyage of research and discovery into the mechanisms and actions of this system led to the development of drugs that block the RAS, which have become the mainstay for the treatment of cardiovascular and renal disease. In the last 25 years new components of the RAS have come to light, including the angiotensin type 2 receptor (AT2R) and the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1–7) [Ang(1–7)]/Mas receptor (MasR) axis. These have been shown to counter the classical actions of angiotensin II (AngII) at the predominant angiotensin type 1 receptor (AT1R). Our studies, and those of others, have demonstrated that targeting these depressor RAS pathways may be therapeutically beneficial. It is apparent that the evolution of both the pressor and depressor RAS pathways is distinct throughout life and that the depressor/pressor balance of the RAS vary between the sexes. These temporal patterns of expression suggest that therapies targeting the RAS could be optimized for discrete epochs in life.

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Renin-Angiotensin System Blockade In The Coronavirus Disease 2019 Pandemic

Clinical Kidney Journal ◽

10.1093/ckj/sfab026 ◽

2021 ◽

Author(s):

Jordana B Cohen ◽

Andrew M South ◽

Hossam A Shaltout ◽

Matthew R Sinclair ◽

Matthew A Sparks

Keyword(s):

Viral Entry ◽

Renin Angiotensin System ◽

Adverse Outcomes ◽

Host Cells ◽

Protective Effects ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Epidemiologic Evidence

ABSTRACT In the early months of the coronavirus disease 2019 (COVID-19) pandemic, a hypothesis emerged suggesting that pharmacologic inhibitors of the renin-angiotensin system (RAS) may increase COVID-19 severity. This hypothesis was based on the role of angiotensin-converting enzyme 2 (ACE2), a counter-regulatory component of the RAS, as the binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing viral entry into host cells. Extrapolations from prior evidence led to speculation that upregulation of ACE2 by RAS blockade may increase the risk of adverse outcomes from COVID-19. However, counterarguments pointed to evidence of potential protective effects of ACE2 and RAS blockade with regard to acute lung injury, as well as substantial risks from discontinuing these commonly used and important medications. Here we provide an overview of classic RAS physiology and the crucial role of ACE2 in systemic pathways affected by COVID-19. Additionally, we critically review the physiologic and epidemiologic evidence surrounding the interactions between RAS blockade and COVID-19. We review recently published trial evidence and propose important future directions to improve upon our understanding of these relationships.

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Berberine Reshapes the Balance of the Local Renin-Angiotensin System by Modulating Autophagy under Metabolic Stress in Pancreatic Islets

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1155/2021/9928986 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Chenghu Huang ◽

Pan Lei ◽

Caibi Peng ◽

Min Li ◽

Yifei Guo ◽

...

Keyword(s):

Prolonged Exposure ◽

Metabolic Stress ◽

Renin Angiotensin System ◽

Islet Function ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Low Fat Diet ◽

Transmission Electron

Hypothesis/Introduction. Berberine, a natural compound, has multiple pharmacological activities to promote islet function. We hypothesized that berberine could reshape the local renin-angiotensin system (RAS) balance to ameliorate the development of obesity via the modulation of autophagy. Materials and methods. After 8 weeks of administration of intragastric berberine to ob/ob mice, metabolic parameters, islet structure, and the angiotensin-converting enzyme 2 (ACE2) expression were detected. Additionally, ACE2 knockout (ACE2KO) mice were fed a low-fat diet for 16 weeks. Furthermore, we measured changes in the islet ultrastructure by transmission electron microscope (TEM) and protein expression of LC3 and SQSTM1/p62 by immunohistochemistry in ob/ob and ACE2KO mice. Results. Prolonged exposure to palmitate increased the expression of ACE and AngII type 1 receptor (ATR1) and decreased the ACE2 expression, which was partly offset by berberine. In ob/ob mice, berberine increased in tolerance to glucose, improved abnormal β-cell and α-cell distributions, upregulated ACE2 expression, and decreased autophagosomes and the expression of LC3 and SQSTM1/p62. Autophagosomes and expression of LC3 and SQSTM1/p62 were increased in ACE2KO mice. Conclusions. We demonstrated that berberine may improve the pancreatic islet function by regulating local RAS-mediated autophagy under metabolic stress.

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Outcomes of COVID-19 Hospitalized Patients Previously Treated with Renin-Angiotensin System Inhibitors

Journal of Clinical Medicine ◽

10.3390/jcm9113472 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3472 ◽

Cited By ~ 1

Author(s):

Elena-Mihaela Cordeanu ◽

Lucas Jambert ◽

Francois Severac ◽

Hélène Lambach ◽

Jonathan Tousch ◽

...

Keyword(s):

Renin Angiotensin System ◽

Severe Pneumonia ◽

University Hospital ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Previously Treated ◽

The Impact ◽

Harmful Effects ◽

Observation Period

(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) penetrates respiratory epithelium through angiotensin-converting enzyme-2 binding, raising concerns about the potentially harmful effects of renin–angiotensin system inhibitors (RASi) on Human Coronavirus Disease 2019 (COVID-19) evolution. This study aimed to provide insight into the impact of RASi on SARS-CoV-2 outcomes in patients hospitalized for COVID-19. (2) Methods: This was a retrospective analysis of hospitalized adult patients with SARS-CoV-2 infection admitted to a university hospital in France. The observation period ended at hospital discharge. (3) Results: During the study period, 943 COVID-19 patients were admitted to our institution, of whom 772 were included in this analysis. Among them, 431 (55.8%) had previously known hypertension. The median age was 68 (56–79) years. Overall, 220 (28.5%) patients were placed under mechanical ventilation and 173 (22.4%) died. According to previous exposure to RASi, we defined two groups, namely, “RASi” (n = 282) and “RASi-free” (n = 490). Severe pneumonia (defined as leading to death and/or requiring intubation, high-flow nasal oxygen, noninvasive ventilation, and/or oxygen flow at a rate of ≥5 L/min) and death occurred more frequently in RASi-treated patients (64% versus 53% and 29% versus 19%, respectively). However, in a propensity score-matched cohort derived from the overall population, neither death (hazard ratio (HR) 0.93 (95% confidence interval (CI) 0.57–1.50), p = 0.76) nor severe pneumonia (HR 1.03 (95%CI 0.73–1.44), p = 0.85) were associated with RASi therapy. (4) Conclusion: Our study showed no correlation between previous RASi treatment and death or severe COVID-19 pneumonia after adjustment for confounders.

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Pathological Role of Angiotensin II in Severe COVID-19

TH Open ◽

10.1055/s-0040-1713678 ◽

2020 ◽

Vol 04 (02) ◽

pp. e138-e144 ◽

Cited By ~ 5

Author(s):

Wolfgang Miesbach

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Treatment Options ◽

Renin Angiotensin System ◽

Target Cells ◽

Converting Enzyme ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Novel Coronavirus

AbstractThe activated renin–angiotensin system induces a prothrombotic state resulting from the imbalance between coagulation and fibrinolysis. Angiotensin II is the central effector molecule of the activated renin–angiotensin system and is degraded by the angiotensin-converting enzyme 2 to angiotensin (1–7). The novel coronavirus infection (classified as COVID-19) is caused by the new coronavirus SARS-CoV-2 and is characterized by an exaggerated inflammatory response that can lead to severe manifestations such as acute respiratory distress syndrome, sepsis, and death in a proportion of patients, mostly elderly patients with preexisting comorbidities. SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor to enter the target cells, resulting in activation of the renin–angiotensin system. After downregulating the angiotensin-converting enzyme 2, the vasoconstrictor angiotensin II is increasingly produced and its counterregulating molecules angiotensin (1–7) reduced. Angiotensin II increases thrombin formation and impairs fibrinolysis. Elevated levels were strongly associated with viral load and lung injury in patients with severe COVID-19. Therefore, the complex clinical picture of patients with severe complications of COVID-19 is triggered by the various effects of highly expressed angiotensin II on vasculopathy, coagulopathy, and inflammation. Future treatment options should focus on blocking the thrombogenic and inflammatory properties of angiotensin II in COVID-19 patients.

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