Renin-angiotensin system blockade in the COVID-19 pandemic

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 counterregulatory 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.

Keywords: COVID-19; SARS-CoV-2; angiotensin II receptor blocker; angiotensin-converting enzyme 2; angiotensin-converting enzyme inhibitor; coronavirus; hypertension; renin–angiotensin system.

FIGURE 1

Three proposed mechanisms of ACEI and ARB effect in COVID-19. ACE, angiotensin-converting enzyme; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ACE2, angiotensin-converting enzyme 2; Ang I, angiotensin I; Ang II, angiotensin II; Ang-(1–7), angiotensin-(1–7); MasR, mas receptor; AT₁R, angiotensin II type 1 receptor; DABK, [des-Arg⁹]-bradykinin; B1, G-protein-coupled receptor for DABK; B2, G-protein-coupled receptor for bradykinin. Red dashed lines: harmful effects of ACEI/ARB; blue dashed lines: beneficial effects of ACEI/ARB; black dashed lines: effects of SARS-CoV-2; black solid lines: normal pathways; red Xs: downstream detrimental effects of ACEI on normal pathways; purple Xs: downstream detrimental effects of SARS-CoV-2 on normal pathways. This three-panel figure shows proposed mechanisms of ACEIs and ARBs in COVID-19 infection. Mechanism 1: ACEIs and ARBs are harmful. ACEIs and ARBs upregulate ACE2 expression on respiratory epithelial cells, thus increasing available receptors to bind SARS-CoV-2 and facilitate cell entry. Mechanism 2: ACEIs and ARBs are beneficial. ACEIs inhibit conversion of Ang I into Ang II, while ARBs inhibit Ang II binding to AT₁R, thereby both ACEIs and ARBs block Ang II-AT₁R–mediated deleterious effects in the lungs. Also shown are SARS-CoV-2-mediated ACE2 downregulation and subsequent Ang II cleavage into Ang-1–7 and Ang-1–7-MasR–mediated anti-inflammatory and anti-fibrotic effects. In the presence of SARS-CoV-2, there is less ACE2 available to cleave Ang II and hence more Ang II is available to bind to AT₁R. Additionally, less Ang-1–7 is available to bind to MasR, leading to increased inflammation and fibrosis. Mechanism 3: ACEIs are harmful and ARBs are neutral. ACEIs inhibit bradykinin breakdown into harmless products, thus increased bradykinin either binds to the B2 receptor or is converted to DABK that binds to the B1 receptor, leading to increased lung inflammation. ARBs play no role in the bradykinin cascade and are not pictured. Additionally, SARS-CoV-2 downregulates ACE2, which normally breaks down DABK. More DABK is then available to bind to the B1 receptor, further promoting lung inflammation.