Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors—lessons from available evidence and insights into COVID-19

Kai, Hisashi; Kai, Masaya

doi:10.1038/s41440-020-0455-8

Cited by 390 publications

(380 citation statements)

References 42 publications

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“…Another study has reported lower risk of all‐cause mortality among COVID‐19‐hospitalized patients receiving RAAS inhibitors 21 . Other studies have concluded that there is no clinical or experimental evidence supporting that ARBs and ACEIs either augment the susceptibility to SARS‐CoV‐2or aggravate the severity and outcomes of COVID‐19 at present 22 . Indeed, a recent review has concluded that ACEIs and ARBs may be associated with lower incidence and/or improved outcome in patients with lower respiratory tract infections 20 .…”

Section: Discussionmentioning

confidence: 99%

Use of distinct anti‐hypertensive drugs and risk for COVID‐19 among hypertensive people: A population‐based cohort study in Southern Catalonia, Spain

Vila-Córcoles

Satué-Gracia

Ochoa-Gondar

et al. 2020

J of Clinical Hypertension

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The use of some anti‐hypertensive drugs in the current COVID‐19 pandemic has become controversial. This study investigated possible relationships between anti‐hypertensive medications use and COVID‐19 infection risk in the ambulatory hypertensive population. This is a population‐based retrospective cohort study involving 34 936 hypertensive adults >50 years in Tarragona (Southern Catalonia, Spain) who were retrospectively followed through pandemic period (from 01/03/2020 to 30/04/2020). Two data sets including demographic/clinical characteristics (comorbidities and cardiovascular medications use) and laboratory PCR codes for COVID‐19 were linked to construct an anonymized research database. Cox regression was used to calculate multivariable hazard ratios (HRs) and estimate the risk of suffering COVID‐19 infection. Across study period, 205 PCR‐confirmed COVID‐19 cases were observed, which means an overall incidence of 586.8 cases per 100 000 persons‐period. In multivariable analyses, only age (HR: 1.03; 95% CI: 1.02‐1.05; P < .001) and nursing home residence (HR: 19.60; 95% CI: 13.80‐27.84; P < .001) appeared significantly associated with increased risk of COVID‐19. Considering anti‐hypertensive drugs, receiving diuretics (HR: 1.22; 95% CI: 0.90‐1.67; P = .205), calcium channel blockers (HR: 1.29; 95%CI: 0.91‐1.82; P = .148), beta‐blockers (HR: 0.97; 95% CI: 0.68‐1.37; P = .844), and angiotensin‐converting enzyme inhibitors (HR: 0.83; 95% CI: 0.61‐1.13; P = .238) did not significantly alter the risk of PCR‐confirmed COVID‐19, whereas receiving angiotensin II receptor blockers was associated with an almost statistically significant reduction risk (HR: 0.67; 95% CI: 0.44‐1.01; P = .054). In conclusion, our data support that receiving renin‐angiotensin‐aldosterone system inhibitors does not predispose for suffering COVID‐19 infection in ambulatory hypertensive people. Conversely, receiving angiotensin II receptor blockers could be related with a reduced risk.

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Section: Discussionmentioning

confidence: 99%

Use of distinct anti‐hypertensive drugs and risk for COVID‐19 among hypertensive people: A population‐based cohort study in Southern Catalonia, Spain

Vila-Córcoles

Satué-Gracia

Ochoa-Gondar

et al. 2020

J of Clinical Hypertension

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“…It has been reported that the Spike (S) protein of SARS-CoV-2 binds with high a nity to human ACE2, and before SARS-CoV-2's entry into the cells [16][17][18], the S protein is subjected to a priming process via serine protease TMPRSS2 in order to permit the attachment of viral particles to ACE2 and thus on cell surface [19,20]. Therefore, SARS-CoV-2 can directly attack cardiac muscle cells through this pathway [21][22][23]. This entry mechanism is con rmed by the fact that TMPRSS2 inhibition or TMPRSS2-KO mice show both decreased, though not abolished, S protein priming, and reduced viral entry, spread, as well as, in ammatory chemokine and cytokine release [19].…”

Section: Discussionmentioning

confidence: 99%

A nomogramic model based on clinical and laboratory parameters at admission for predicting the survival of COVID-19 patients

Wang

Huang

et al. 2020

Preprint

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Background and AimCOVID-19 has become a major global threat. The present study aimed to develop a nomogram model to predict the survival of COVID-19 patients based on their clinical and laboratory data at admission.Methods COVID-19 patients who were admitted at Hankou Hospital and Huoshenshan Hospital in Wuhan, China from January 12, 2020 to March 20, 2020, whose outcome during the hospitalization was known, were retrospectively reviewed. The categorical variables were compared using Pearson’s χ2-test or Fisher’s exact test, and continuous variables were analyzed using Student’s t-test or Mann Whitney U-test, as appropriate. Then, variables with a P-value of ≤0.1 were included in the log-binomial model, and merely these independent risk factors were used to establish the nomogram model. The discrimination of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUC), and internally verified using the Bootstrap method.Results A total of 262 patients (134 surviving and 128 non-surviving patients) were included in the analysis. Seven variables, which included age (relative risk [RR]: 0.905, 95% confidence interval [CI]: 0.868-0.944; P<0.001), chronic heart disease (CHD, RR: 0.045, 95% CI: 0.0097-0.205; P<0.001, the percentage of lymphocytes (Lym%, RR: 1.125, 95% CI: 1.041-1.216; P=0.0029), platelets (RR: 1.008, 95% CI: 1.003-1.012; P=0.001), C-reaction protein (RR: 0.982, 95% CI: 0.973-0.991; P<0.001), lactate dehydrogenase (LDH, RR: 0.993, 95% CI: 0.990-0.997; P<0.001) and D-dimer (RR: 0.734, 95% CI: 0.617-0.879; P<0.001), were identified as the independent risk factors. The nomogram model based on these factors exhibited a good discrimination, with an AUC of 0.948 (95% CI: 0.923-0.973). ConclusionA nomogram based on age, CHD, Lym%, platelets, C-reaction protein, LDH and D-dimer was established to accurately predict the prognosis of COVID-19 patients. This can be used as an alerting tool for clinicians to take early intervention measures, when necessary.

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“…With so many pieces of data missing, the need for vigorous clinical studies guided by physiology-based questions and hypotheses are most urgent. Such a question includes the continuation or even introduction, rather than cessation of RAS inhibitors in patients infected by SARS-CoV-2 ( Kai and Kai, 2020 ), or can we inhibit binding of SARS spike proteins to ACE2, for instance by antibodies, without hampering its catalytic capacities to generate Ang 1-7? Is there a role for the application of Ang 1-7 or MasR agonists or for the administration of intravenous sACE2, with an available proof of concept for such postulated approaches ( Yang et al, 2014 ; Hemnes et al, 2018 )?…”

Section: Knowledge Gaps: the Missing Pieces In The Puzzlementioning

confidence: 99%

ACE2, COVID-19 Infection, Inflammation, and Coagulopathy: Missing Pieces in the Puzzle

et al. 2020

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Engulfed by the grave consequences of the coronavirus disease 2019 (COVID-19) pandemic, a better understanding of the unique pattern of viral invasion and virulence is of utmost importance. Angiotensin (Ang)-converting enzyme (ACE) 2 is a key component in COVID-19 infection. Expressed on cell membranes in target pulmonary and intestinal host cells, ACE2 serves as an anchor for initial viral homing, binding to COVID-19 spike-protein domains to enable viral entry into cells and subsequent replication. Viral attachment is facilitated by a multiplicity of membranal and circulating proteases that further uncover attachment loci. Inherent or acquired enhancement of membrane ACE2 expression, likely leads to a higher degree of infection and may explain the predisposition to severe disease among males, diabetics, or patients with respiratory or cardiac diseases. Additionally, once attached, viral intracellular translocation and replication leads to depletion of membranal ACE2 through degradation and shedding. ACE2 generates Ang 1-7, which serves a critical role in counterbalancing the vasoconstrictive, pro-inflammatory, and pro-coagulant effects of ACE-induced Ang II. Therefore, Ang 1-7 may decline in tissues infected by COVID-19, leading to unopposed deleterious outcomes of Ang II. This likely leads to microcirculatory derangement with endothelial damage, profound inflammation, and coagulopathy that characterize the more severe clinical manifestations of COVID-19 infection. Our understanding of COVID-ACE2 associations is incomplete, and some conceptual formulations are currently speculative, leading to controversies over issues such as the usage of ACE inhibitors or Ang-receptor blockers (ARBs). This highlights the importance of focusing on ACE2 physiology in the evaluation and management of COVID-19 disease.

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Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors—lessons from available evidence and insights into COVID-19

Abstract: The rapid spread of a novel coronavirus,

Cited by 390 publications

References 42 publications

Use of distinct anti‐hypertensive drugs and risk for COVID‐19 among hypertensive people: A population‐based cohort study in Southern Catalonia, Spain

Use of distinct anti‐hypertensive drugs and risk for COVID‐19 among hypertensive people: A population‐based cohort study in Southern Catalonia, Spain

A nomogramic model based on clinical and laboratory parameters at admission for predicting the survival of COVID-19 patients

ACE2, COVID-19 Infection, Inflammation, and Coagulopathy: Missing Pieces in the Puzzle

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