The Lung, the Heart, the Novel Coronavirus, and the Renin-Angiotensin System; The Need for Clinical Trials

Lumbers, Eugenie R.; Delforce, Sarah J.; Pringle, Kirsty G.; Smith, Gary R.

doi:10.3389/fmed.2020.00248

Cited by 39 publications

(34 citation statements)

References 52 publications

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“… *The threshold for clinically significant effect (harm) was arbitrarily established as an increase of 25% in the odds of the outcome (a measure suggested by GRADE [43] ). CI: Confidence interval; OR: Odds ratio.…”

Section: Resultsmentioning

confidence: 99%

“…The potential role of ACE2 in the case of SARS-CoV-2 infection is still ambiguous. While its increase may supply pathways for SARS-CoV-2 entrance into the cells [2] , it is known that cleaved and shedded ACE2 leads to the breakdown of Angiotensin II to Angiotensin 1-7 (directly or indirectly increased with ARB or ACEi, respectively) have anti-inflammatory and anti-fibrotic effect through Mas receptors [41] , [43] . The SARS-CoV-2 infection also leads to a downregulation of ACE2, that was associated with increased lung injury in animal models [44] , [45] .…”

Section: Discussionmentioning

confidence: 99%

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Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and the risk of COVID-19 infection or severe disease: Systematic review and meta-analysis

Caldeira¹,

Alves²,

Melo³

et al. 2020

IJC Heart & Vasculature

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Objective Animal studies suggested that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) facilitate the inoculation of potentially leading to a higher risk of infection and/or disease severity. We aimed to systematically evaluate the risk of COVID-19 infection and the risk of severe COVID-19 disease associated with previous exposure to (ACEi) and/or ARB). Methods MEDLINE, CENTRAL, PsycINFO, Web of Science Core Collection were searched in June 2020 for controlled studies. Eligible studies were included and random-effects meta-analyses were performed. The estimates were expressed as odds ratios (OR) and 95% confidence intervals (95%CI). Heterogeneity was assessed with I 2 test. The confidence in the pooled evidence was appraised using the GRADE framework. Results Twenty-seven studies were included in the review. ACEi/ARB exposure did not increase the risk of having a positive test for COVID-19 infection (OR 0.99, 95%CI 0.89–1.11; I 2 = 36%; 5 studies, GRADE confidence moderate). The exposure to ACEi/ARB did not increase the risk of all-cause mortality among patients with COVID-19 (OR 0.91, 95%CI 0.74–1.11; I 2 = 20%; 17 studies; GRADE confidence low) nor severe/critical COVID-19 disease (OR 0.90, 95%CI 0.74–1.11; I 2 = 55%; 17 studies; GRADE confidence very low). Exploratory analyses in studies enrolling hypertensive patients showed a association of ACEi/ARB with a significant decrease of mortality risk. Conclusions ACEi/ARB exposure does not seem to increase the risk of having the SARS-CoV-2 infection or developing severe stages of the disease including mortality. The potential benefits observed in mortality of hypertensive patients reassure safety, but robust studies are required to increase the confidence in the results.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and the risk of COVID-19 infection or severe disease: Systematic review and meta-analysis

Caldeira¹,

Alves²,

Melo³

et al. 2020

IJC Heart & Vasculature

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“…This score, in essence, quantifies the stability of the docked complex by optimizing global minimum energy conformation of the complex [44, 45]. On the other side, while it is probable that a better stability of S-R complex could lead to an increased viral load and maybe an increased infectivity, previous works showed that the spike protein – hACE2 complex is crucial for viral pathogenesis by causing acute lung damage [46, 47], which suggests a direct link between S-R complex stability and fatality rate. However, the robustness of the potential of S-R complex stability index for the spike protein variants as a tracker of fatality rate or disease severity needs to be studied in greater depths with more structured region-specific patient data (that are primarily available to selected government/non-government agencies) in connection with larger population-level sequence datasets for the given locations.…”

Section: Discussionmentioning

confidence: 99%

Spike protein mutational landscape in India: Could Muller’s ratchet be a future game-changer for COVID-19?

Banerjee¹,

Basak²,

Ghosh

et al. 2020

Preprint

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The dire need of effective preventive measures and treatment approaches against SARS CoV 2 virus, causing COVID 19 pandemic, calls for an in-depth understanding of its evolutionary dynamics with attention to specific geographic locations, since lockdown and social distancing to prevent the virus spread could lead to distinct localized dynamics of virus evolution within and between countries owing to different environmental and host specific selection pressures. To decipher any correlation between SARS CoV 2 evolution and its epidemiology in India, we studied the mutational diversity of spike glycoprotein, the key player for the attachment, fusion and entry of virus to the host cell. For this, we analyzed the sequences of 630 Indian isolates as available in GISAID database till June 07, 2020, and detected the spike protein variants to emerge from two major ancestors, Wuhan-Hu-1/2019 and its D614G variant. Average stability of the docked spike protein host receptor (SR) complexes for these variants correlated strongly (R2=0.96) with the fatality rates across Indian states. However, while more than half of the variants were found unique to India, 67% of all variants showed lower stability of SR complex than the respective ancestral variants, indicating a possible fitness loss in recently emerged variants, despite a continuous increase in mutation rate. These results conform to the sharply declining fatality rate countrywide (>7 fold during April 11 and June 28, 2020). Altogether, while we propose the potential of SR complex stability to track disease severity, we urge an immediate need to explore if SARS CoV 2 is approaching mutational meltdown in India.

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“…80 However, binding of SARS-CoV-2 to ACE2 alters functionality of the enzyme, which is discussed later. 80 Viral entry requires priming of the S protein by cellular proteases, which cleave the S protein at the S1/S2 and S2 site, allowing fusion of viral and cellular membranes. 77 SARS-CoV-1 and SARS CoV-2 both utilize the cellular serine protease TMPRSS2 and cathepsins B/L for S protein priming.…”

Section: Introductionmentioning

confidence: 99%

SARS‐CoV‐2 infection, COVID‐19 pathogenesis, and exposure to air pollution: What is the connection?

Woodby

Arnold

Valacchi

2020

Annals of the New York Academy of Sciences

131

113

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Exposure to air pollutants has been previously associated with respiratory viral infections, including influenza, measles, mumps, rhinovirus, and respiratory syncytial virus. Epidemiological studies have also suggested that air pollution exposure is associated with increased cases of SARS-CoV-2 infection and COVID-19-associated mortality, although the molecular mechanisms by which pollutant exposure affects viral infection and pathogenesis of COVID-19 remain unknown. In this review, we suggest potential molecular mechanisms that could account for this association. We have focused on the potential effect of exposure to nitrogen dioxide (NO 2), ozone (O 3), and particulate matter (PM) since there are studies investigating how exposure to these pollutants affects the life cycle of other viruses. We have concluded that pollutant exposure may affect different stages of the viral life cycle, including inhibition of mucociliary clearance, alteration of viral receptors and proteases required for entry, changes to antiviral interferon production and viral replication, changes in viral assembly mediated by autophagy, prevention of uptake by macrophages, and promotion of viral spread by increasing epithelial permeability. We believe that exposure to pollutants skews adaptive immune responses toward bacterial/allergic immune responses, as opposed to antiviral responses. Exposure to air pollutants could also predispose exposed populations toward developing COIVD-19associated immunopathology, enhancing virus-induced tissue inflammation and damage.

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The Lung, the Heart, the Novel Coronavirus, and the Renin-Angiotensin System; The Need for Clinical Trials

Cited by 39 publications

References 52 publications

Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and the risk of COVID-19 infection or severe disease: Systematic review and meta-analysis

Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and the risk of COVID-19 infection or severe disease: Systematic review and meta-analysis

Spike protein mutational landscape in India: Could Muller’s ratchet be a future game-changer for COVID-19?

SARS‐CoV‐2 infection, COVID‐19 pathogenesis, and exposure to air pollution: What is the connection?

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