Sacubitril/valsartan: potential impact of ARNi “beyond the
Wall” of ACE2 on treatment and prognosis of heart failure patients with
COVID-19
Speranza Rubattu 1,2, Giovanna Gallo1, Massimo Volpe 1,2
1 Cardiology Unit, Department of Clinical and Molecular Medicine,
Sapienza University of Rome, Sant’Andrea Hospital, Rome, Italy.
2 IRCCS Neuromed, Pozzilli (IS), Italy
Running title: ARNi and COVID-19 in HFrEF
Total word count (excluding references): 835
Corresponding address:
Speranza Rubattu, M.D.
Department of Clinical and Molecular Medicine,
School of Medicine and Psychology,
Sapienza University of Rome;
IRCCS Neuromed, Pozzilli (Isernia), Italy
e-mail: speranzadonatella.rubattu@uniroma1.it
From the beginning of the SARS-CoV-2 pandemic and of its related
COVID-19 outbreak, the angiotensin-converting enzyme 2 (ACE2), probably
the most “unloved and neglected” member of the
renin-angiotensin-aldosterone system (RAAS) family, has attracted
increasing attention since it has been shown as the cell receptor
through which the virus enters into the cells (Iaccarino, Grassi et al.,
2020).
The physiological action of ACE2 consists in degrading angiotensin II
(Ang II) to angiotensin (1-7), a heptapeptide with a potent vasodilator
function through the Mas receptor able to counterbalance the Ang II
effects on vasoconstriction, sodium retention, and fibrosis (Gallagher,
Ferrario et al., 2014).
Previous studies have shown that angiotensin type 1 receptor (AT1R)
blockers (ARBs), ACE inhibitors (ACEI) and mineralocorticoid receptor
antagonists (MRA) may up-regulate the expression of ACE2 both in acute
and chronic settings of cardiovascular diseases (CVDs) such as
hypertension, heart failure (HF) and myocardial infarction (MI)
(Gallagher, Ferrario et al., 2014).
These data have generated concern during the early phases of the
pandemic, since it has been speculated that the increase in ACE2 level
may have contributed to disease virulence and to adverse outcomes
particularly in those subjects affected by chronic coexisting CVDs who
commonly received treatment with RAAS inhibitors and who were
characterized by a worse clinical course (Iaccarino, Grassi et al.,
2020).
On the other hand, it has been observed that the binding between
coronavirus and ACE2 leads to
ACE2 downregulation, resulting in an unopposed production of angiotensin
II by ACE, contributing to lung damage as a consequence of AT1R mediated
inflammation, fibrosis, thrombosis, vasoconstriction and increased
vascular permeability. According to these findings, RAAS inhibitors and
in particular ARBs may even protect against COVID-19 acute lung injury
(Iaccarino, Grassi et al., 2020). As a matter of fact, epidemiological
studies conducted in large populations of COVID-19 patients demonstrated
that ARBs or ACEI had no association with a severe or fatal course of
the disease (Iaccarino, Grassi et al., 2020).
In such a context, natriuretic peptides (NPs), which include atrial
natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type
natriuretic peptide (CNP), along with their N-terminal counterparts, may
play an important protective role in COVID-19 disease. NPs are released
as a consequence of increased volume overload and myocytes stress and,
through their vasorelaxant, diuretic and natriuretic effects, are able
to counterbalance RAAS and sympathetic nervous system actions,
ultimately regulating blood pressure, electrolytes and water homeostasis
(Volpe, Rubattu et al, 2014). At the vascular level, NPs reduce cellular
growth and proliferation, preserving endothelial function and integrity
as well as vascular tone, and they oppose blood clotting, inflammation,
angiogenesis and atherosclerosis progression (Volpe, Rubattu et al,
2014). Besides their well-described systemic haemodynamic and
autocrine/paracrine functions within the cardiovascular system, NPs play
an important protective role in the lungs. It fact, ANP is able to
reduce lung endothelial permeability caused by inflammation and
oxidative stress, avoiding the development of acute respiratory distress
syndrome and improving arterial oxygenation during mechanical
ventilation. According to these evidences, it has been proposed that
COVID-19 patients with deficiencies in the NP system, mainly obese and
black subjects, may have an increased risk of developing severe lung
complications.
A bidirectional interaction between ANP and ACE2 has been demonstrated
in experimental models. ANP, through cyclic guanosine monophosphate
(cGMP) production, inhibited the Ang II-mediated decrease of ACE2 mRNA
synthesis. On the other hand, Ang-(1-7), the product of ACE2 activity,
stimulated ANP secretion (Gallagher, Ferrario et al., 2014).
In such a context, a field of great interest is represented by the
potential impact on the clinical course of the COVID-19 disease and on
its outcome of a treatment with sacubitril/valsartan (S/V), a member of
the new pharmacological class of AT1R/neprilysin inhibitors (ARNi) and
currently recognized as a cornerstone of the therapeutic management of
HF with reduced ejection fraction (HFrEF). With regard to the trend of
different NPs levels after the initiation of S/V, NT-proBNP level
decreases as a consequence of the improvement of cardiac function; BNP
level slightly increases due to its relatively low affinity to
neprilysin, whereas ANP level consistently and substantially increases,
mediating most of the benefits of neprilysin inhibition (Ibrahim,
McCarthy et al., 2019).
According to these evidences, an approach based on early administration
of S/V has been proposed in the therapeutic management of COVID-19
hospitalized patients (Acanfora, Ciccone at al., 2020). This intriguing
hypothesis appears devoid of any practical value in non CVD patients,
due to the undesirable haemodynamic effects of this drug and to the lack
of indication for S/V administration in the absence of HFrEF.
In our opinion, a more specific and rational approach to test the
expected beneficial role of S/V would be to retrospectively investigate
in existing registries of hospitalized COVID-19 patients whether, among
subjects affected by HFrEF, those who were treated with S/V presented a
lower disease incidence, a better prognosis and clinical course,
compared to patients who received other medications, including
ACEI/ARBs. A call to action is required to test the potential benefits
of S/V in HFrEF patients affected by COVID-19 through new prospective
randomized clinical trials.