Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19

Reinhold Kreutz, Engi Abd El-Hady Algharably, Michel Azizi, Piotr Dobrowolski, Tomasz Guzik, Andrzej Januszewicz, Alexandre Persu, Aleksander Prejbisz, Thomas Günther Riemer, Ji-Guang Wang, Michel Burnier, Reinhold Kreutz, Engi Abd El-Hady Algharably, Michel Azizi, Piotr Dobrowolski, Tomasz Guzik, Andrzej Januszewicz, Alexandre Persu, Aleksander Prejbisz, Thomas Günther Riemer, Ji-Guang Wang, Michel Burnier

Abstract

Systemic arterial hypertension (referred to as hypertension herein) is a major risk factor of mortality worldwide, and its importance is further emphasized in the context of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection referred to as COVID-19. Patients with severe COVID-19 infections commonly are older and have a history of hypertension. Almost 75% of patients who have died in the pandemic in Italy had hypertension. This raised multiple questions regarding a more severe course of COVID-19 in relation to hypertension itself as well as its treatment with renin-angiotensin system (RAS) blockers, e.g. angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). We provide a critical review on the relationship of hypertension, RAS, and risk of lung injury. We demonstrate lack of sound evidence that hypertension per se is an independent risk factor for COVID-19. Interestingly, ACEIs and ARBs may be associated with lower incidence and/or improved outcome in patients with lower respiratory tract infections. We also review in detail the molecular mechanisms linking the RAS to lung damage and the potential clinical impact of treatment with RAS blockers in patients with COVID-19 and a high cardiovascular and renal risk. This is related to the role of angiotensin-converting enzyme 2 (ACE2) for SARS-CoV-2 entry into cells, and expression of ACE2 in the lung, cardiovascular system, kidney, and other tissues. In summary, a critical review of available evidence does not support a deleterious effect of RAS blockers in COVID-19 infections. Therefore, there is currently no reason to discontinue RAS blockers in stable patients facing the COVID-19 pandemic.

Keywords: Angiotensin; COVID-19; Cardiovascular; Hypertension; Lung.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Risk of pneumonia with use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs): meta-analysis of 37 studies. The OR with the 95% CI in parentheses is shown.
Figure 2
Figure 2
(A) Schematic diagram of the RAS in the lung showing the role of ACE2 as a key element in the counter-regulatory axis of the RAS (elements in green; reviewed in Arendse et al.54). ACE2, a membrane-bound enzyme is cleaved (shedding) by ADAM17 into a soluble form released in the body fluids. ACE2 opposes the harmful effects on lung injury of the Ang II–AT1R axis (elements in red) by activating MasR and AT2R signalling. (B) ACE2 is expressed in airway epithelial cells including alveolar epithelial type II cells (AECII) in the lung. After infection, SARS-CoV-2 binds through its viral spike protein to host cell membrane-bound ACE2, thereby promoting viral cell entry and subsequent replication. SARS-CoV-2 requires in addition the cellular serine protease TMPRSS2, which will process SARS-CoV-2 by enzymatic cleavage of the spike protein and support cell entry. Importantly, binding of SARS-CoV-2 may lead to down-regulation of ACE2, and thus its own binding receptor required for cell entry. Impairment of ACE2 activity in the lung results in activation of the harmful Ang II–AT1R axis. This aggravates the viral pathogenicity of SARS-CoV-2, tipping the scale in favour of lung damage. A soluble form of human ACE2 (rhACE2) is currently considered as a therapeutic approach to act as a decoy halting the interaction between SARS-CoV-2 and ACE2 to lessen viral entry. In addition, an inhibitor for TMPRSS2, i.e. camostat mesylate, which is available and approved for other diseases, could be considered for treatment of SARS-CoV-2 by inhibiting cell entry. Pharmacological treatment with ARBs (C) or ACEIs (D) will modulate several components of the RAS either directly or by affecting feedback loops. Treatment with ARBs protects against lung injury by AT1R receptor blockade. The corresponding increase in Ang II and Ang I levels will at the same time activate the protective axis and thereby reduce viral pathogenicity. ARBs have been shown to increase ACE2 expression in various tissues, though current evidence for the lungs (particularly in human) is lacking (Table 1). Assuming that ARBs can also up-regulate ACE2 in the lung, this will contribute to their protective effect. Protective Ang 1-7, can be also generated by neutral endopeptidase (NEP) or neprilysin. Therefore, the protective effect mediated by Ang1-7 is expected to be lower in response to treatment with ARNIs containing sacubitril. (D) Treatment with ACEIs can primarily protect from lung injury by reducing Ang II levels due to the inhibition of Ang I to Ang II conversion. Additional indirect effects supporting the protective axis can contribute to their beneficial effects. An overall effect on lung tissue protection could additionally be promoted by modulation of ACE2, albeit the data supporting this mechanism are scant (Table 1). ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; ARNI, angiotensin receptor neprilysin inhibitor; AT1R, angiotensin II receptor type 1; AT2R, angiotensin II receptor type 2; MasR, Mas receptor; RAS, renin–-angiotensin system; rhACE2, recombinant human ACE2; TMPRSS2, type II transmembrane serine protease. Thicker arrows indicate a predominant pathway or an augmented activation; ↑↑ = up-regulation; ↑↓ = non-consistent effect.
Figure 3
Figure 3
The impact of RAS blockers on human ACE2 (hACE2) expression and SARS-CoV-2 viral cell entry is shown. Currently, no studies have reported on the effects of RAS blockers on tissue ACE2 activity in the upper or the lower respiratory tract. ACE2 is expressed in the oropharynx, ciliated upper airway epithelial cells. and in alveolar epithelial cells type II in the lung. Expression of ACE2 in the oropharynx may facilitate viral cell entry. ACE2 is also abundantly expressed in the gastrointestinal tract, particularly in the brush border membrane of human small intestine enterocytes. However, SARS-CoV-2 infectivity in the gastrointestinal tract is still poorly defined, while SARS-CoV-2 has been detected in rectal swabs or faeces of COVID-19 patients, but not yet in urine samples.

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