to the editor: Emerging clinical reports from China, Italy, and the United States
reveal that SARS-CoV-2 is associated with a prominent incidence of cardiovascular
morbidities and complications (1, 36), including myocarditis, acute myocardial infarction,
and worsening heart failure. These cardiovascular manifestations have been encountered
in preceding epidemics of corona viruses, namely Severe Acute Respiratory Syndrome
(SARS) and Middle-East Respiratory Syndrome (MERS), as well as during H1N1 influenza
outbreaks (1, 36). Moreover, several preliminary reports indicate that a vast majority
of patients with comorbidities are prone to SARS-CoV-2 complications (50–86%). Congestive
heart failure (CHF), chronic kidney disease (CKD), diabetes, and pulmonary diseases
are the principal-identified clinical conditions predisposing to SARS-CoV-2-induced
morbidities and mortality (7). Although pneumonia, the principal alarming feature
of SARS-CoV-2 infection, could by itself evoke cardiovascular complications as a result
of hypoxemia, systemic inflammation and enhanced myocardial oxygen demand, a direct
cardiovascular injury, likely develops, initiated by binding of SARS-CoV-2 to angiotensin-converting
enzyme 2 (ACE2), widely expressed in myocardial and vascular endothelial cells, leading
to adverse cardiovascular consequences. The following short commentary outlines potential
mechanisms by which elimination of ACE2 by this virus may lead to deleterious cardiovascular
outcome.
ACE2 is a transcellular protein predominantly expressed in the heart, vasculature,
kidney, lung, brain, intestine, and testis and is usually located at the apical side
of cells attached to basal membrane (Fig. 1) (30). In the heart, ACE2 is widely expressed
in all cardiac cell types, including endothelial cells, smooth muscle cells in the
myocardial vasculature and in cardiac myocytes (2, 9). ACE2 has 400-fold affinity
to angiotensin II (ANG II), as compared with the classic ACE, and it converts ANG
II to angiotensin-(1–7) [Ang-(1–7)] (31). The latter short peptide exerts vasodilatory,
natriuretic/diuretic, anti-inflammatory, and antifibrotic effects via Mas receptor
(MasR). Noteworthy, both clinical (2, 3, 10, 13, 37) and experimental (2) heart failure
is characterized by upregulation of cardiac ACE2 and enhanced Ang-(1–7) generation,
which may represent a cardioprotective compensatory response aimed at reducing or
preventing cardiac remodeling (28) (Fig. 1). In agreement with this notion, targeted
overexpression of cardiac ACE2 by applying local injection of lenti-viral vector in
Sprague-Dawley normotensive rats significantly attenuated cardiac hypertrophy and
myocardial fibrosis induced by prolonged ANG II administration (15). Similarly, overexpression
of ACE2 in cardiac tissues of spontaneously hypertensive rats decreased cardiac remodeling
in as was evident by reduced left ventricular wall thickness and perivascular fibrosis
(6), probably via reduction of collagen production (11). Collectively, these animal
studies highlight a cardioprotective role for the ACE2–Ang-(1–7)–MasR axis.
Fig. 1.
The initial step after the invasion of Severe Acute Respiratory Syndrome (SARS)-CoV-2
is binding to membranal angiotensin-converting enzyme 2 (ACE2) widely expressed in
cardiac cells including endothelial cells, smooth muscle cells in the myocardial vasculature
and in cardiac myocytes. ACE2 is responsible for the conversion of ANG II to Ang-(1–7)
that exerts beneficial effects on the cardiac tissue such as vasodilation, antifibrosis,
and anti-inflammation via Mas receptor (MasR). The binding of SARS-CoV-2 to ACE2 is
preceded by furin-mediated exposure of the viral receptor binding protein (RBP) localized
to S-glycoprotein (S1 domain of the viral spike). Furin is abundant in the heart both
intracellulary and in the circulation as a free enzyme, making it a key factor in
the uncovering of RBP and eventually in SARS-CoV-2 transmission. In addition, furin
enhances the affinity of the virus to ACE2 by not only exposing the viral binding
site on S1 domain but also revealing the effusion site on the S2 domain in the viral
spike. Consequently, the virus undergoes endocytosis and massive replication accompanied
by profound activation by cathespsin L (CatL) and the abundant intracellular furin.
The activated intracellular SARS-CoV-2 undergoes exocytosis where it binds again to
ACE2 elsewhere, thus creating a vicious feed-forward devastating cycle. Importantly,
heart failure is characterized by enhanced expression of myocardial ACE2, which is
further upregulated by ACE-I, angiotensin receptor blockers (ARBs), and mineralocorticoid-receptor
(MR) antagonists, thus sensitizing ACE2 expressing target organs to SARS-CoV-2. ADAM
metallopeptidase domain 17 (ADAM 17) is responsible for shading of ACE2, a process
stimulated by ANG II type 1 receptors (AT1-R) and may explain why renin-angiotensin-aldosterone
system inhibitors augment ACE2 expression. ER, endoplasmic reticulum.
Binding of the SARS viral spike glycoprotein to ACE2 triggers its internalization
along with the virus (13). This might be of supreme importance for cardiomyocytes
of patients with heart failure, characterized by intense upregulation of ACE2 (9,
10, 37) (Fig. 1). Possibly, intracellular translocation of SARS-CoV-2 coupled with
ACE2 leads to its depletion in cell membranes. It is tempting to assume that consequent
ACE2 elimination might participate in many features of acute corona virus infection.
Among such clinical characteristics are decompensation of preexisting CHF, respiratory
distress irrespective to left-ventricular backward failure (due to impaired pulmonary
capillary endothelium and endothelial barrier function), acute kidney failure (reflecting
altered renal microcirculation and hypoxic injury), and diarrhea (caused by injured
gut microcirculation with hypoxic damage and injured mucosal barrier.
Indeed, corona virus has already been shown to induce myocardial inflammation and
dysfunction accompanied with adverse cardiac outcomes in patients with SARS, assumedly
due to downregulation/elimination of the myocardial ACE2 system (25). Support for
this concept emerges from previous experimental reports demonstrating cardiac contractility
defects in rats with reduced X chromosomal-derived ACE2 expression and heart failure
with pulmonary congestion in ACE2-knockout mice (ACE2-KO) (4, 34). These undesired
changes were prominent in males and progressed with age, coincidentally overlapping
the observations that elderly and men are more susceptible to SARS-CoV-2-induced serious
infection. Interestingly, the hearts of animals depleted of ACE2 exhibited similar
changes that occur after coronary artery disease or bypass surgery in humans (5).
Subsequent studies demonstrated extended infarct size, reduced contractility, altered
ventricular remodeling, and increased mortality following myocardial infarction (MI)
induced by ligation of the proximal LAD in mice with ACE2 deletion, as compared with
their wild-type controls (20). Moreover, these mice showed enhanced oxidative stress
and concomitant upregulation of proinflammatory cytokines, plausibly parallel to the
observed hypersensitive immunological response reported in patients with SARS-CoV-2
infection.
Furthermore, preliminary alarming data from SARS-CoV-2-infected patients suggested
that those treated with renin-angiotensin-aldosterone (RAAS) inhibitors such as angiotensin-converting
enzyme inhibitors (ACE-I) or angiotensin-receptor blockers (ARBs) experienced severe
symptoms with a higher mortality rate as compared with nonuser counterparts (7, 26).
Noteworthy, cardiac ACE2 expression is markedly enhanced in response to RAAS blockade
by ACEi (24), ARB (8, 18, 19), and even by mineralocorticoid receptor (MR) antagonist
(19, 21) (Fig. 1). Conceivably, this is translated into increased vulnerability of
patients with RAAS blockade during SARS-CoV-2 infection. Furthermore, several studies
have demonstrated that binding of ANG II to its AT1 receptors in target organs, including
the heart, activates ADAM 17, a sheddase affecting ACE2 (22) (Fig. 1). Conclusively,
blocking ANG II synthesis or its binding to AT1 receptors by RAAS inhibitors likely
leads to the upregulation of ACE2 and eventually hypersensitizing the heart to SARS-CoV-2
infection. Enhancement of myocardial invasion by the virus due to enhanced ACE2 likely
plays an important role.
An additional player that may contribute to the vulnerability of patients with heart
failure to SARS-CoV-2 is furin, also termed paired basic amino acid-cleaving enzyme
(PACE). Furin is essential for permeating viral functionality as it cleaves viral
envelope trimeric transmembrane glycoprotein (S) (12, 14, 29). This S-glycoprotein,
vital for the entry of the virus into the cell, contains two functional domains: an
ACE2-binding domain (also called receptor-binding domain (RBD) and a second domain
essential for fusion of the viral and cell membranes (23, 33, 35). Furin activity
exposes the binding and fusion domains essential for the entry of the virus into the
cell (32). Furin presents mainly intracellularly and to a lesser extent in the circulation
(16) (Fig. 1), where it converts ventricular proBNP to active BNP, an important physiological
process in heart failure subjects. Patients with heart failure are specifically characterized
by upregulation of cardiac furin, providing an additional potential explanation for
their vulnerability Covid-19 infection (17) (Fig. 1). Moreover, furin is detected
in circulating T cells that are activated during infections (27). This may form a
feed-forward loop of furin-facilitated coronavirus replication that may be responsible
for hypersensitive immunological response (cytokine storm) in some patients, leading
to fulminant myocarditis, devastating lung injury, and lethal multiorgan failure.
Collectively, evidently ACE2 exerts beneficial effects on cardiac function under normal
conditions and particularly in the presence of heart failure. Moreover, some of the
cardioprotective effects of ACE inhibitors, ARBs, and MR blockers are mediated by
their positive impact on ACE2 abundance in cardiac tissues. Nevertheless, in patients
infected with SARS-CoV-2, ACE2 may transform to a Trojan horse. Its binding with ACE2
neutralizes the advantageous cardiac effects of this enzyme, especially in patients
with heart failure. The susceptibility of these subjects to life-threatening SARS-CoV-2
infection could be attributed to the simultaneous upregulation of both ACE2 and furin
in the diseased myocardium and to the wide use of RAAS inhibitors in this population
(Fig. 1). Therefore, temporary blockade of the viral binding site on ACE2 or furin
by immunological or pharmacological means in patients infected with SARS-CoV-2 may
compose new therapeutic strategies in combating this unprecedented formidable viral
threat.
GRANTS
Z. Abassi acknowledges research support from the Israel Science Foundation Grant 544/18.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
Z.A.A. and E.E.K. prepared figure; Z.A.A., S.A., E.E.K., and S.N.H. drafted manuscript;
Z.A.A., S.A., E.E.K., and S.N.H. edited and revised manuscript; Z.A.A., S.A., E.E.K.,
and S.N.H. approved final version of manuscript.