Debra L. Beck and Eugene Braunwald, MD

Published: March 31, 2020

The novel coronavirus SARS-CoV-2 interfaces with the renin-angiotensin-aldosterone system (RAAS) through angiotensin-converting enzyme 2 (ACE2). ACE2 is the functional receptor to SARS-CoV-2. It has been suggested that the commonly used angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which increase ACE2 expression, may increase both the risk of infection and the severity of COVID-19.

At this time (late March 2020), most of the experts on this topic disagree with this hypothesis1  and the major professional societies (The American Heart Association, American College of Cardiology, and European Society of Cardiology) have advised against routinely discontinuing ACE inhibitors in individuals suffering from COVID-19, the disease caused by SARS-CoV-2. In this Special Report, Vaduganathan and colleagues review the data in humans on this topic and propose a hypothesis on the impact of ACE2 in patients with COVID-19-induced lung injury.2

Observational data from China indicates overrepresentation of hypertension among patients hospitalized with COVID-19. However, since hypertension tracks closely with advancing age, which is at this time considered the strongest predictor of COVID-19-related death, the impact of concurrent ACE inhibition cannot be determined. After reviewing the current data, Vaduganathan et al concluded that there is insufficient evidence available to determine whether RAAS inhibitors exacerbate COVID-19.

The authors also express concern over the abrupt withdrawal of RAAS inhibitors in high-risk patients, including those with heart failure or a history of myocardial infarction.

An alternative hypothesis proposed by the authors suggests that ACE2 may, in fact, be beneficial rather than harmful in patients with lung injury. SARS-CoV-2 gains initial entry through ACE2 but also appears to subsequently down-regulate expression of ACE2, limiting the enzymes ability to exert protective effects in organs. In a small study, COVID-19 patients appeared to have elevated levels of plasma angiotensin II, which were in turn correlated with total viral load and degree of lung injury. Vaduganathan et al suggest that administration of recombinant ACE2 may restore balance to the RAAS network and potentially prevent organ injury. This is being tested. As well, there are two ongoing trials of losartan as a treatment for COVID-19 in patients who have not previously been treated with an RAAS inhibitor and are either hospitalized or not hospitalized.

References

1. https://www.ncbi.nlm.nih.gov/pubmed/32196087

2. Vaduganathan M, Verdeny O, Michel R, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone inhibitors in patients with COVID-19. N Engl J Med. 2020; published online March

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