The renin–angiotensin–aldosterone system (RAAS) is an elegant cascade of vasoactive
peptides that orchestrate key processes in human physiology. Severe acute respiratory
syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2, which have been responsible for
the SARS epidemic in 2002 to 2004 and for the more recent coronavirus disease 2019
(Covid-19) pandemic, respectively, interface with the RAAS through angiotensin-converting
enzyme 2 (ACE2), an enzyme that physiologically counters RAAS activation but also
functions as a receptor for both SARS viruses.
The interaction between the SARS viruses and ACE2 has been proposed as a potential
factor in their infectivity,
and there are concerns about the use of RAAS inhibitors that may alter ACE2 and whether
variation in ACE2 expression may be in part responsible for disease virulence in the
ongoing Covid-19 pandemic.
Indeed, some media sources and health systems have recently called for the discontinuation
of ACE inhibitors and angiotensin-receptor blockers (ARBs), both prophylactically
and in the context of suspected Covid-19.
Given the common use of ACE inhibitors and ARBs worldwide, guidance on the use of
these drugs in patients with Covid-19 is urgently needed. Here, we highlight that
the data in humans are too limited to support or refute these hypotheses and concerns.
Specifically, we discuss the uncertain effects of RAAS blockers on ACE2 levels and
activity in humans, and we propose an alternative hypothesis that ACE2 may be beneficial
rather than harmful in patients with lung injury. We also explicitly raise the concern
that withdrawal of RAAS inhibitors may be harmful in certain high-risk patients with
known or suspected Covid-19.
Covid-19 and Older Adults with Coexisting Conditions
have called attention to the potential overrepresentation of hypertension among patients
with Covid-19. In the largest of several case series from China that have been released
during the Covid-19 pandemic (Table S1 in the Supplementary Appendix, available with
the full text of this article at NEJM.org), hypertension was the most frequent coexisting
condition in 1099 patients, with an estimated prevalence of 15%
; however, this estimate appears to be lower than the estimated prevalence of hypertension
seen with other viral infections
and in the general population in China.
Coexisting conditions, including hypertension, have consistently been reported to
be more common among patients with Covid-19 who have had severe illness, been admitted
to the intensive care unit, received mechanical ventilation, or died than among patients
who have had mild illness. There are concerns that medical management of these coexisting
conditions, including the use of RAAS inhibitors, may have contributed to the adverse
health outcomes observed. However, these conditions appear to track closely with advancing
which is emerging as the strongest predictor of Covid-19–related death.
Unfortunately, reports to date have not rigorously accounted for age or other key
factors that contribute to health as potential confounders in risk prediction. With
other infective illnesses, coexisting conditions such as hypertension have been key
and this also appears to be the case with Covid-19.
It is important to note that, despite inferences about the use of background RAAS
inhibitors, specific details have been lacking in studies (Table S1). Population-based
studies have estimated that only 30 to 40% of patients in China who have hypertension
are treated with any antihypertensive therapy; RAAS inhibitors are used alone or in
combination in 25 to 30% of these treated patients.
Given such estimates, only a fraction of patients with Covid-19, at least in China,
are anticipated to have been previously treated with RAAS inhibitors. Data showing
patterns of use of RAAS inhibitors and associated health outcomes that rigorously
account for treatment indication and illness severity among patients with Covid-19
Uncertain Effects of RAAS Inhibitors on ACE2 in Humans
Tissue-specific and circulating components of the RAAS make up a complex intersecting
network of regulatory and counterregulatory peptides (Figure 1). ACE2 is a key counterregulatory
enzyme that degrades angiotensin II to angiotensin-(1–7), thereby attenuating its
effects on vasoconstriction, sodium retention, and fibrosis. Although angiotensin
II is the primary substrate of ACE2, that enzyme also cleaves angiotensin I to angiotensin-(1–9)
and participates in the hydrolysis of other peptides.
In studies in humans, tissue samples from 15 organs have shown that ACE2 is expressed
broadly, including in the heart and kidneys, as well as on the principal target cells
for SARS-CoV-2 (and the site of dominant injury), the lung alveolar epithelial cells.
Of interest, the circulating levels of soluble ACE2 are low and the functional role
of ACE2 in the lungs appears to be relatively minimal under normal conditions
but may be up-regulated in certain clinical states.
Because ACE inhibitors and ARBs have different effects on angiotensin II, the primary
substrate of ACE2, the effects of these agents on ACE2 levels and activity may be
anticipated to differ. Despite substantial structural homology between ACE and ACE2,
their enzyme active sites are distinct. As a result, ACE inhibitors in clinical use
do not directly affect ACE2 activity.
Experimental animal models have shown mixed findings with respect to the effects of
ACE inhibitors on ACE2 levels or activity in tissue.
Similarly, animal models have had inconsistent findings with respect to the effects
of ARBs on ACE2, with some showing that ARBs may increase messenger RNA expression
or protein levels of ACE2 in tissue
and others showing no effect.
In contrast to available animal models, there are few studies in humans regarding
the effects of RAAS inhibition on ACE2 expression. In one study, the intravenous administration
of ACE inhibitors in patients with coronary artery disease did not influence angiotensin-(1–7)
production, a finding that calls into question whether ACE inhibitors have any direct
effects on ACE2-directed angiotensin II metabolism.
Similarly, in another study, among patients with hypertension, angiotensin-(1–7) levels
appeared to be unaffected after initial treatment with the ACE inhibitor captopril;
however, with exposure to captopril monotherapy over a period of 6 months, angiotensin-(1–7)
Furthermore, few studies have examined plasma ACE2 activity or urinary ACE2 levels
in patients who have received long-term treatment with RAAS inhibitors. In cross-sectional
studies involving patients with heart failure,
and coronary artery disease,
plasma ACE2 activity was not higher among patients who were taking ACE inhibitors
or ARBs than among untreated patients. In a longitudinal cohort study involving Japanese
patients with hypertension, urinary ACE2 levels were higher among patients who received
long-term treatment with the ARB olmesartan than among untreated control patients,
but that association was not observed with the ACE inhibitor enalapril or with other
ARBs (losartan, candesartan, valsartan, and telmisartan).
Previous treatment with ACE inhibitors was associated with increased intestinal messenger
RNA levels of ACE2 in one study, but that association was not observed with ARBs
; data are lacking regarding the effects of RAAS inhibitors on lung-specific expression
These seemingly conflicting data indicate the complexity underlying RAAS responses
to pathway modulators and reinforce the concept that findings from preclinical models
may not readily translate to human physiology. Such data do suggest that effects on
ACE2 should not be assumed to be uniform across RAAS inhibitors or even in response
to therapies within a given drug class.
It is important to note that the plasma ACE2 level may not be a reliable indicator
of the activity of the full-length membrane-bound form, in part because ACE2 is shed
from the membrane, a process that appears to be separately regulated by an endogenous
In addition to the degree of expression, the biologic relevance of ACE2 may vary according
to tissue and clinical state. Unfortunately, data showing the effects of ACE inhibitors,
ARBs, and other RAAS inhibitors on lung-specific expression of ACE2 in experimental
animal models and in humans are lacking. Furthermore, even if RAAS inhibitors modify
ACE2 levels or activity (or both) in target tissue beds, clinical data are lacking
to indicate whether this would in turn facilitate greater engagement and entry of
SARS-CoV-2 spike protein. Further mechanistic studies in humans are needed to better
define the unique interplay between SARS-CoV-2 and the RAAS network.
Potential for Benefit Rather Than Harm of RAAS Blockers in Covid-19
SARS-CoV-2 appears not only to gain initial entry through ACE2 but also to subsequently
down-regulate ACE2 expression such that the enzyme is unable to exert protective effects
in organs. It has been postulated but unproven that unabated angiotensin II activity
may be in part responsible for organ injury in Covid-19.
After the initial engagement of SARS-CoV-2 spike protein, there is subsequent down-regulation
of ACE2 abundance on cell surfaces.
Continued viral infection and replication contribute to reduced membrane ACE2 expression,
at least in vitro in cultured cells.
Down-regulation of ACE2 activity in the lungs facilitates the initial neutrophil infiltration
in response to bacterial endotoxin
and may result in unopposed angiotensin II accumulation and local RAAS activation.
Indeed, in experimental mouse models, exposure to SARS-CoV-1 spike protein induced
acute lung injury, which is limited by RAAS blockade.
Other mouse models have suggested that dysregulation of ACE2 may mediate acute lung
injury that is secondary to virulent strains of influenza
and respiratory syncytial virus.
In a small study, patients with Covid-19 appeared to have elevated levels of plasma
angiotensin II, which were in turn correlated with total viral load and degree of
Restoration of ACE2 through the administration of recombinant ACE2 appeared to reverse
this devastating lung-injury process in preclinical models of other viral infections
and safely reduced angiotensin II levels in a phase 2 trial evaluating acute respiratory
distress syndrome in humans.
Dysregulated ACE2 may theoretically also attenuate cardioprotection in the context
of myocardial involvement and abnormal pulmonary hemodynamics
in Covid-19. Markers of myocardial injury have been shown to be elevated during the
disease course of Covid-19
and to increase rapidly with clinical deterioration and preceding death.
Many viruses are cardiotropic, and subclinical viral myocarditis is commonly seen
in viremia associated with a wide range of infectious agents. ACE2 has a well-recognized
role in myocardial recovery and injury response; in one study, ACE2 knockout in animal
models contributed to adverse left ventricular remodeling in response to acute injury
driven by angiotensin II.
In autopsies of patients who died from SARS, 35% of heart samples showed the presence
of viral RNA, which in turn was associated with reduced ACE2 protein expression.
Administration of recombinant ACE2 normalizes angiotensin II levels in human explanted
hearts with dilated cardiomyopathy.
These hypotheses have prompted trials to test whether the provision of recombinant
ACE2 protein may be beneficial in restoring balance to the RAAS network and potentially
preventing organ injury (ClinicalTrials.gov number, NCT04287686). In addition, paired
trials of losartan as a treatment for Covid-19 are being conducted among patients
who have not previously received treatment with a RAAS inhibitor and are either hospitalized
(NCT04312009) or not hospitalized (NCT04311177).
Maintenance of RAAS Inhibitors with Known or Suspected Covid-19
Despite these theoretical uncertainties regarding whether pharmacologic regulation
of ACE2 may influence the infectivity of SARS-CoV-2, there is clear potential for
harm related to the withdrawal of RAAS inhibitors in patients in otherwise stable
condition. Covid-19 is particularly severe in patients with underlying cardiovascular
and in many of these patients, active myocardial injury,
develop during the course of illness. RAAS inhibitors have established benefits in
protecting the kidney and myocardium, and their withdrawal may risk clinical decompensation
in high-risk patients.
Although rates of heart failure have been infrequently reported in epidemiologic reports
from China to date, the prevalence of heart failure among critically ill patients
with Covid-19 in the United States may be high (>40%).
In the Quinapril Heart Failure Trial, among patients with chronic symptomatic heart
failure, withdrawal of quinapril resulted in a progressive decline in clinical status.
In the TRED-HF trial, among asymptomatic patients with heart failure with recovered
left ventricular ejection fraction, the phased withdrawal of medical therapy (including
RAAS inhibitors) resulted in rapid relapse of dilated cardiomyopathy.
In addition, RAAS inhibitors are a cornerstone of therapy after myocardial infarction:
maintenance of therapy in the days to weeks after the index event has been shown to
reduce early mortality.
Among patients with unstable clinical status, myocardial injury associated with Covid-19
may pose even higher early risks after withdrawal of RAAS inhibitors.
Withdrawal of RAAS inhibitors that are being administered for the management of hypertension
may be less risky than withdrawal of RAAS inhibitors that are being administered for
conditions in which they are considered guideline-directed therapy but may be associated
with other challenges. Switching from a RAAS inhibitor to another antihypertensive
therapy in a stable ambulatory patient may require careful follow-up to avoid rebound
increases in blood pressure. In addition, selection of dose-equivalent antihypertensive
therapies may be challenging in practice and may be patient-dependent. Even small
and short-lived periods of blood pressure instability after a therapeutic change have
been associated with excess cardiovascular risk.
This may be an especially important consideration in patients with Covid-19, which
appears to result in a state of RAAS activation,
and in settings (e.g., China) where baseline blood-pressure control is infrequently
reached at the population level.
The effects of withdrawing RAAS inhibitors or switching treatments are uncertain among
patients with chronic kidney disease. Although reported rates of chronic kidney disease
appear to be low among hospitalized patients with Covid-19 in China (1 to 3%) (Table
S1), the prevalence may be higher among patients who are critically ill and among
those in other geographic regions.
Many patients have varying degrees of acute kidney injury during illness.
For these high-risk patients, individualized treatment decisions regarding the maintenance
of RAAS inhibitors that are guided by hemodynamic status, renal function, and clinical
stability are recommended.
On the basis of the available evidence, we think that, despite the theoretical concerns
and uncertainty regarding the effect of RAAS inhibitors on ACE2 and the way in which
these drugs might affect the propensity for or severity of Covid-19, RAAS inhibitors
should be continued in patients in otherwise stable condition who are at risk for,
are being evaluated for, or have Covid-19 (see text box), a position now supported
by multiple specialty societies (Table S2). Although additional data may further inform
the treatment of high-risk patients with Covid-19, clinicians need to be cognizant
of the unintended consequences of prematurely discontinuing proven therapies in response
to hypothetical concerns that may be based on incomplete experimental evidence.
Key Points Related to the Interplay between Covid-19 and the Renin–Angiotensin–Aldosterone
• ACE2, an enzyme that physiologically counters RAAS activation, is the functional
receptor to SARS-CoV-2, the virus responsible for the Covid-19 pandemic
• Select preclinical studies have suggested that RAAS inhibitors may increase ACE2
expression, raising concerns regarding their safety in patients with Covid-19
• Insufficient data are available to determine whether these observations readily
translate to humans, and no studies have evaluated the effects of RAAS inhibitors
• Clinical trials are under way to test the safety and efficacy of RAAS modulators,
including recombinant human ACE2 and the ARB losartan in Covid-19
• Abrupt withdrawal of RAAS inhibitors in high-risk patients, including those who
have heart failure or have had myocardial infarction, may result in clinical instability
and adverse health outcomes
• Until further data are available, we think that RAAS inhibitors should be continued
in patients in otherwise stable condition who are at risk for, being evaluated for,
or with Covid-19