The global coronavirus disease 2019 (COVID-19) pandemic has highlighted inherent susceptibility
to specific age–group and cardiovascular co-morbidities. While individuals of any
age can be infected, and viral load is important, those who are 70 years or older
have a notably increased risk. In addition, patients with obesity, heart failure,
coronary artery disease, diabetes mellitus and hypertension are also at increased
risk and more likely to deteriorate to serious or critical condition when infected.
It is not yet clear why these diseases predispose patients to a more severe response
to infection. In this letter, we lend insight and perspective to these observations.
Many have raised the potential issue that use of angiotensin converting enzyme (ACE)
inhibitors (ACEi) and angiotensin receptor blockers (ARBs) may lead to higher susceptibility
to COVID-19 infection due to their ability to increase angiotensin converting enzyme
2 (ACE2) mRNA expression; however, others have suggested that ACEi and ARB use may
be protective against COVID-19. To understand why there are conflicting theories,
it is important to recognize that ACE2 plays multiple roles in the context of COVID-19.
ACE2 is a principal receptor for virus entry into cells and is highly expressed in
vascular tissue, as well as the heart and lungs [1]. SARS-CoV-2 uses the SARS-CoV
receptor ACE2 for entry, and the serine protease TMPRSS2 for S protein priming [2].
Of interest, TMPRSS2 is the drug target of Camostat [Foipan®], and it is starting
to attract some interest for COVID-19, though rigorous evaluation for that use remains
to be done. Because we do not fully know all of the mechanisms involved in viral entry
or virus concentrations across tissue and cell types, distribution of viral infection
within the cardiovascular system remains speculative.
In addition, ACE2 negatively regulates angiotensin II by cleaving it to Ang1–7. Animal
model studies in genetically modified mice showed that angiotensin and its type 1a
receptor levels play a role in the pathogenesis of acute respiratory distress syndrome
(ARDS), with ACE2 serving a protective effect [3]. For these reasons, the consequences
of inhibiting ACE (e.g. with ACEi/ARB) within the context of COVID-19 are mechanistically
convoluted. The use of ACEi or ARB increased gene expression of ACE2 in cardiac cells
in a rat model by 5-fold and 3-fold respectively [4]. At the same time, a human study
showed no significant change in plasma activity of ACE2 with these medications [5].
The presence or type of heart disease mattered more than whether or not someone was
taking an ACEi/ ARB when determining angiotensin II levels or plasma activity of ACE2
[5]. Additional studies are needed to determine if the variation in findings is related
to differences in medications or cells used in these experiments. If ACE2 expression
is increased by these drugs, it raises the question of increased infectivity and rapid
clinical progression of COVID-19 in patients on ACEi/ARB. Currently, there is a paucity
of clinical data to support the hypothesis of increased susceptibility to infection
in these patients.
ACEi and ARBs may actually confer a benefit later in the immunologic response to infection.
The mechanism of action proposed is to limit the excess angiotensin II binding to
its receptors during fulminant viral inflammation. Excess angiotensin II binding to
its receptor results in increased vascular permeability in the lungs which is a proposed
mechanism for ARDS, which has similar presentations to COVID-19 induced lung injury
[3,6]. This is important when one considers that the binding of COVID-19 to its receptor
ACE2 results in inactivation and downregulation of ACE2 to further increase levels
of angiotensin [3]. This could promote cellular injury in the lungs, leading to pulmonary
edema and ARDS. In support of this hypothesis, recombinant human ACE2 insertion in
mice deficient in ACE2 led to a lower risk of developing ARDS when these animals were
exposed to acid-induced lung injury [3]. Thus, in a patient, administration of an
agent which is specific for blocking virus binding to ACE2 yet does not affect ACE2
functionality, could neutralize the virus and might have the net effect of decreasing
infectivity while maintaining angiotensin II conversion to Ang1–7, potentially mitigating
lung inflammation and damage.
Myocardial injury associated with the SARS-CoV-2 was a common condition in patients
diagnosed with COVID-19 in Wuhan and associated with a higher risk of in-hospital
mortality [7].
In the US there have been early unpublished reports about elevated troponin, bradycardia
and sudden cardiac death in these patients. There are also early verbal reports of
secondary septic-like cardiomyopathy and cardiogenic shock that develops rather late,
usually during the pre-terminal phases of the disease. Unpublished observations also
suggest troponin positive patients have vascular inflammation, microthrombosis, microvascular
hypo-perfusion, and resultant myocardial damage. These mechanisms may also be participating
in pulmonary complications and other non-cardiac systemic vascular manifestations
of COVID-19. The predisposing biology of acute viral, thrombotic and inflammatory
mechanisms that underpin these cardiovascular observations are novel presentations
of this infection and need to be further elucidated.
While there might be a hypothetical argument for discontinuing ACEi and ARBs prior
to COVID-19 infection to avoid early excessive ACE2 gene upregulation (i.e. increase
potential for viral susceptibility), the administration of ACEi or ARBs could mitigate
the impact of cellular injury and ARDS in COVID-19 infection and increased pulmonary
vascular permeability due to an excessive impact of angiotensin II. While a dual strategy
of stopping ACEi/ARB early and then restarting later in COVID-19 patients may appear
reasonable, no data to support such a strategy has been established. This dual role
in pathogenicity is expected to confound the impact of data interpretation of these
medications on clinical outcomes. Furthermore, if patients were to be guided to discontinue
these medications during the pandemic, this would likely put them at risk of decompensated
heart failure and uncontrolled hypertension. It is imperative that such decisions
be made between clinicians and patients to ensure that risks of discontinuing the
drugs are understood and weighed against the uncertain benefit. If patients are cardio-dependent
on these medications, the prevailing approach is that the benefit of continuation
outweighs the risk, and the focus should be on all possible precautions to reduce
exposure to COVID-19.
Another issue with this pathogen is that generally, the immune response appears to
be inappropriate in some cases leading to severe immunopathology [8]. Most notably,
coronaviruses initiate a robust innate immune response, which causes generalized inflammation
with little specificity to the virus. As such, the inflammatory response is predominantly
mediated through cytokines and the strategy to dampen this response is challenging
due to the lack of specific inhibitors of the adaptive immune response to the virus.
At this time, it is understood that there is a very specific and robust T helper (CD4+)
cell response, but a less than impressive antibody response to those with asymptomatic
to mild disease. Indeed, in a limited serological study of COVID-19 it was reported
that one patient showed peak specific IgM at day 9 after disease onset and switching
to IgG by week 2. In addition, combined sera from a few patients were able to neutralize
COVID-19 in an in vitro plaque assay, suggesting they are possibly mounting a neutralizing
antibody response [9]. Whether the kinetics and titer of specific antibody correlates
with disease severity remains to be investigated.
Since little is known about the pathogenesis of COVID-19, there is an urgent need
for prospective data to address questions expeditiously. As summarized in Table 1
, there are a number of gaps that remain to be filled. Timely initiation of high-quality
COVID-19 and cardiovascular research is warranted, given clear scientific aims and
readily available research infrastructure [10]. Moving forward, widespread use of
these important drug classes for hypertension, cardiac, and renal disease management
may confound interpretation of their impact in the setting of COVID-19 in population
studies. These data must therefore be evaluated and interpreted carefully. Ultimately,
answering these questions will promote our ability to mitigate the global impact of
this pandemic and improve individual COVID-19 patient outcomes. This will be critical,
as there are currently no therapies for COVID-19 that have been shown effective to
date [11].
Table 1
Gaps in our understanding of the connections between COVID-19 and cardiovascular implications.
Table 1
1. Exploration of the effects of TMPRSS2 inhibition on infectivity2. Explanation for
variation in response to different ACEi/ARBs in ACE2 expression3. Elucidation of whether
patients on ACEi/ARB are at greater risk for higher infectivity4. Clarification of
whether ACEi/ARB has a dual role: Is detrimental early (increasing infectivity) and
beneficial later (mitigating pulmonary complications)5. Understanding of how infection
induces myocardial damage6. Determination of whether other components of the renin-angiotensin-aldosterone
system are in play7. Identification of how immune response variation translates to
differences in pathology
Disclosures
None.