Introduction
The World Health Organization has declared the severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) outbreak a pandemic disease, given its spreading in more than 100 countries
worldwide, infecting over 185,000 people and killing more than 7000. Now, the epicentre
of the infection has moved from China to Europe. In Italy, the number of infected
patients closely follows an exponential trend, with the risk of reaching the saturation
of intensive care units soon.
Cardiovascular diseases (CVDs) and cardiovascular (CV) risk factors, such as hypertension,
are the most common cause of death worldwide. It is not surprising that hypertension
is very common among patients who died as a consequence (or co-cause) of SARS-CoV-2
disease (coronavirus disease 2019 (COVID-19)). Data from the China epidemic and the
COVID-19 deaths show that most of those patients were old and commonly affected by
CVD. A retrospective cohort study on clinical course and risk factors for mortality
of adult inpatients with COVID-19 in Wuhan, China, found that non-survivors had a
mean age of 69 years and hypertension was the most common comorbidity (48%), followed
by diabetes mellitus (31%) and coronary heart disease (24%).
1
In Italy, the Italian Health Institute (Istituto Superiore di Sanità-ISS) on 17 March
2020 reported 2003 patients who died with COVID-19. They had a mean age of 79.5 years
and a mean of 2.7 comorbidities. Similarly to what was observed in Chinese population,
the more prevalent comorbidities were arterial hypertension (76.1%), ischaemic heart
disease (33.0%) and diabetes mellitus (35.5%) (www.iss.it). A high prevalence of hypertension
is also present in patients who died after Middle East respiratory syndrome (MERS)-coronavirus
(CoV) and influenza virus infections, indicating that this comorbidity is not specific
for COVID-19 patients, but most likely represents a confounder related to the high
prevalence of hypertension and CVD among older adults. It is not known if a specific
link between these CV conditions and SARS-CoV-2 infection does exist.
On the other hand, after the confirmation of the key role played by angiotensin-converting
enzyme 2 (ACE2) in SARS-CoV-2 cell entry,
2
some authors have drawn attention to the possible risks associated with the administration
of ACE inhibitors (ACE-Is) and angiotensin II type 1 receptor blockers (ARBs), also
suggesting a change in anti-hypertensive therapies, given their capacity to increase
ACE2 levels in some tissues such as the myocardium, with a consequent hypothetical
greater susceptibility to SARS-CoV-2 infection and higher risk for severe disease.
3,4
However, as some scientific societies promptly stated (European Society of Cardiology
(ESC) Council on Hypertension
5
and Heart Failure Society of America/American College of Cardiology/American Heart
Association),
6
it is crucial not to draw hasty conclusions from simple deductions not supported by
experimental data, as in the published comments cited above.3,4 Here, we briefly discuss
about the role of ACE2 in the CV system and in acute respiratory syndromes, in order
to deepen understanding of this controversial situation.
Pathophysiology of renin–angiotensin–aldosterone system and ACE2 in CV homeostasis
The renin–angiotensin–aldosterone system (RAAS) plays a central role in the homeostatic
control of the CV and renal systems and in regulating fluid volume and blood pressure.
The RAAS blockade represents a cornerstone of the therapy of arterial hypertension
and its related CV sequelae, such as ischaemic heart disease and heart failure (HF).
The RAAS consists of a cascade of both systemic and tissue enzymatic reactions, resulting
in generation of angiotensin (Ang) II. In the first place, renin, a proteinase released
by the kidneys, cleaves angiotensinogen to produce Ang I, both locally and in the
circulation, which is then hydrolysed by the widespread endothelial angiotensin-converting
enzyme (ACE), producing the octapeptide Ang II. This biologically active peptide binds
Ang II type 1 and type 2 receptors (AT1R and AT2R). After binding the AT1R, Ang II
stimulates aldosterone secretion and promotes salt and water reabsorption, vasoconstriction,
inflammation and oxidative stress. This picture had been further enriched by the discovery
of ACE2 in 2000.
7
This is a type I transmembrane metallocarboxypeptidase, with homology to ACE, that
cleaves Ang I into a nonapeptide (Ang 1-9), that binds AT2R, and Ang II into a heptapeptide
(Ang 1-7), that binds an endogenous orphan Mas receptor (MasR), thus playing a central
role in counterbalancing RAAS activation, resulting in CV protection. Ang 1-9 can
also be rapidly changed into Ang 1-7 by the classical ACE activity. In conclusion,
decreased ACE2 activity leads to activation of the Ang II-AT1R axis, contributing
to progression of CV disease, while increased ACE2 activity leads to activation of
ACE2-Ang 1-9-AT2R but mostly ACE2-Ang 1-7-MasR axes, contributing to protection against
CV disease (Figure 1(a)). ACE2-Ang 1-7 pathway has also a key protective role against
HF.
Figure 1.
(a) Schematic of the renin-angiotensin system counterbalanced by the angiotensin-converting
enzyme 2 (ACE2)-angiotensin (Ang) 1-7-Mas axis. Note the role of angiotensin-converting
enzyme (ACE) also in the conversion of Ang 1-9 to Ang 1-7. (b) Evidence-based hypothesis
of the protective role of Ang II type 1 receptor blockers (ARBs) in pulmonary conditions
potentially leading to acute respiratory distress syndrome (ARDS). ACE inhibitors
(ACE-Is) are also likely to exert protective effects by reducing Ang II synthesis,
but since ACE-Is also reduce the conversion of Ang 1-9 to Ang 1-7, they might hypothetically
lessen the protective effects of a more intense Mas stimulation by higher concentrations
of Ang 1-7.
AT1R: angiotensin II type 1 receptor; AT2R: angiotensin II type 2 receptor; MasR:
Mas receptor; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.
Initially thought to be expressed only in limited organs (mainly heart and kidney),
ACE2 was later found to be expressed in several other tissues, including lungs,
8
exerting its key roles in maintaining homeostasis of the body, counterbalancing excessive
RAAS activity.
Role of ACE2 in acute respiratory syndromes
While ACE is detectable in the entire capillary network of the alveoli in human lungs,
ACE2 is produced mainly in Clara cells and type II alveolar epithelial cells,
8
and epithelial injury is crucial for the development of acute respiratory distress
syndrome (ARDS) in humans. Very consistent experimental data has been reproduced in
different animal models which showed that an imbalance between classical RAAS and
ACE2 activity is likely to promote and accelerate lung injury. The ACE-Ang II-AT1R
axis induces pulmonary vasoconstriction and increase vascular permeability resulting
in pulmonary ‘leaky’ vessels with secondary production of inflammatory cytokines,
acceleration of apoptosis in alveolar epithelial cells and promotion of extracellular
matrix synthesis with human lung fibrosis.
9
On the contrary, Ang 1-7 was found to improve oxygenation, reduce inflammation and
attenuate lung fibrosis in acute lung injury, a noteworthy factor in protecting against
ARDS-related poor prognosis.
10
Indeed, the use of an ARB or ACE-I, through reduction of Ang II-AT1R stimulation and
the induced increase of ACE2, has been effective in decreasing lung injury in animal
models of ARDS,
11
and the use of human recombinant ACE2 could also be promising, although the interaction
between RAAS and ARDS needs to be further elucidated. In 2003, ACE2 returned to the
limelight following the discovery that it serves as a receptor for the binding of
the SARS coronavirus. Now, it has just been confirmed that is also used as a receptor
by the SARS-CoV-2 virus.
2
However, it is not just the gateway for the virus. In fact, previous studies found
that ACE2 can protect lungs from severe acute injury in mice, while the Ang II-AT1R
axis promotes lung disease, leading to leaky pulmonary blood vessels, and impairs
lung function.
12
Furthermore, previous studies on SARS and MERS showed that the binding of the viral
surface-spike protein to ACE2 leads to its downregulation, through its internalization
and, perhaps, its shedding.
12
The downregulation of ACE2 results in a hyper-effective Ang II-AT1R axis that increases
pulmonary vascular damage and leakage, promoting the development of ARDS. Indeed,
experimental SARS-CoV infections of wild-type mice in vivo lead to reduced ACE2 expression
in the lungs, suggesting that reduced ACE2 expression might have a role in SARS-CoV-mediated
severe acute lung pathologies. Importantly, after the AT1R blockade up-regulating
ACE2, the acute severe lung injury in spike-Fc-treated mice was attenuated. Furthermore,
AT1R blockade also led to attenuated pulmonary oedema. Therefore, SARS-CoV infections
are likely to exaggerate acute lung failure through dysregulation of the RAAS and
this process can be attenuated by the AT1R blockade
12
(Figure 1(b)). However, whether SARS-CoV-2 also induces ACE2 downregulation is yet
to be determined. Meanwhile, a controversy has arisen on the role of the ACE-I and
ARB in SARS-CoV-2 entry and the consequent susceptibility and severity of COVID-19,
due to their property of ACE2 overexpression. But no data have been published on this
topic, whereas the evidence for the protective role of ARB at least is well-founded.
Conclusion
Hasty speculation on a negative relationship between COVID-19 and RAAS blockers could
be dangerous
3,4
and is not justified by our knowledge. To date, no data from randomised clinical trials
or even large observational studies are available to support the discontinuation of
ACE-I or ARB in COVID-19 patients and there is no evidence that these drugs can improve
or worsen SARS-CoV-2 lung invasion and COVID-19 course. Therefore, hypertensive patients,
especially if having CVD and high CV risk, should continue to take their drugs with
high adherence to the prescribed therapies. At the same time, the administration of
ACE-Is or ARBs aiming at preventing COVID-19 or lowering the disease severity is not
supported by conclusive data. However, some authors have hypothesised a protective
role of ARBs, especially losartan and telmisartan that strongly bind to the AT1R,
against the spread and mortality from SARS-CoV-2 infection,
13
given the mechanisms described above.
What is certain is that the use of an ACE-I/ARB in patients affected by hypertension,
diabetes mellitus and the most prevalent CV diseases, such as ischaemic heart disease
and HF, is associated with lower risk of death, even in the oldest patients hospitalised
for acute medical conditions.
14
Therefore, their discontinuation due to speculative observations could be harmful
and lead to higher rates of CV deaths, especially in older COVID-19 patients, in which
CV comorbidities are likely to strongly affect mortality. Several scientific societies
have just made appropriate statements regarding the importance of taking ACE-I/ARB
medication as per indications, in order not to put millions of patients affected by
hypertension and related CVD at further risk
5,6
Furthermore, at present, given the lack of data it is not recommended to discontinue
these drugs because of the COVID-19. On the contrary, several experimental animal
models suggest exactly the opposite, with ARBs found to limit lung damage in ARDS.
11
At the same time, we feel there is urgency to provide solid evidence on the therapeutic
and prognostic role of anti-hypertensive therapy in COVID-19 patients because both
positive and negative effects would have important pragmatic implications, given the
rapid spread of the infection globally.