Intended for healthcare professionals

Rapid response to:

Editorials

Preventing a covid-19 pandemic

BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m810 (Published 28 February 2020) Cite this as: BMJ 2020;368:m810

Read our latest coverage of the Coronavirus outbreak

Rapid Response:

Relationship between COVID-19 and renin-angiotensin-aldosterone-system blockers: Hasty speculation could be dangerous

Dear Editor,

Older age and cardiovascular (CV) diseases are very common among patients admitted to intensive care units or dying from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (COVID-19). Many of these patients are treated with angiotensin-converting-enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB), very effective in reducing blood pressure and CV events. The ACE2, a metallocarboxypeptidase with homology to ACE, is the receptor for SARS-CoV-2 [1] and, thus, ACE-I and ARB, given their capacity to increase ACE2 levels, have been accused to possibly increase the likelihood of lung infection.

Indeed, some authors [2] speculated that the increased ACE2 expression, linked to ACE-I and ARB treatment, could promote the spread and severity of COVID-19 and they even hypothesized to replace such drugs with other anti-hypertensive agents. We think that this simple deduction is not supported by experimental data and could even be dangerous, leading to higher rates of CV deaths, especially in older COVID-19 patients with acute medical conditions, in which CV comorbidities are likely to strongly affect mortality [3].

On the contrary, a protective role of ACE-I and ARB against the aggressiveness and mortality from SARS-CoV-2 infection might be hypothesized, given the peculiar protective action of the ACE2-Angiotensin (Ang) 1-7-Mas axis on the lung. ACE2 cleaves Ang I into a nonapeptide (Ang 1–9), that binds Ang II type 2 receptor (AT2R), and Ang II into Ang 1–7, that binds an endogenous orphan receptor (MasR), thus playing a central role in counterbalancing renin-angiotensin-aldosterone-system (RAAS) activation. While the activation of ACE-Ang II-Ang II type 1 receptor (AT1R) axis induces vascular permeability, inflammation and lung fibrosis, previous studies found that ACE2-Ang 1-7-MasR axis can protect lungs from the development of acute respiratory distress syndrome (ARDS) in several animal models, through opposite mechanisms [4]. The binding of the viral surface-spike protein to ACE2 leads to its downregulation with a consequent hyperactivation of RAAS, which contributes to lung injury.

This process is attenuated by RAAS blockers, especially ARB, through reduction of Ang II-AT1R stimulation, increase in Ang II substrate, and increase in ACE2, leading to a larger increase in Ang 1-7 [5]. Therefore, CV patients should safely continue to take these drugs also in the context of the pandemic COVID-19 outbreak, as also recently stated by several Scientific Societies (ESC council on Hypertension and HFSA/ACC/AHA).

REFERENCES
1. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020 doi: 10.1016/j.cell.2020.02.052
2. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? The Lancet Respiratory medicine 2020 doi: 10.1016/S2213-2600(20)30116-8
3. Spannella F, Giulietti F, Balietti P, et al. Renin-Angiotensin System Blockers and Statins Are Associated With Lower In-Hospital Mortality in Very Elderly Hypertensives. Journal of the American Medical Directors Association 2018;19(4):342-47. doi: 10.1016/j.jamda.2017.09.023
4. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005;436(7047):112-6. doi: 10.1038/nature03712
5. Shen L, Mo H, Cai L, et al. Losartan prevents sepsis-induced acute lung injury and decreases activation of nuclear factor kappaB and mitogen-activated protein kinases. Shock 2009;31(5):500-6. doi: 10.1097/SHK.0b013e318189017a

Competing interests: No competing interests

24 March 2020
Riccardo Sarzani
Prof. Dr.
Federico Giulietti, Chiara Di Pentima, Piero Giordano, Francesco Spannella
Internal Medicine and Geriatrics, IRCCS INRCA, Department of Clinical and Molecular Sciences, University “Politecnica delle Marche”
Ancona, Italy