This editorial refers to ‘Cell type-specific expression of the putative SARS-CoV-2
receptor ACE2 in human hearts’
†
, by L. Nicin et al., on page 1804.
The current ongoing pandemic COVID-19 (coronavirus disease outbreak at the end of
2019) is based on a positive-sense single-stranded RNA virus associated with a nucleoprotein
within a capsid comprised of matrix proteins. Together with SARS-CoV and MERS-CoV,
SARS-CoV-2 belongs to human betacoronaviruses. Although those viruses show many similarities,
there are differences in their genomic and phenotypic structure resulting in huge
consequences for their pathogenesis. Whereas fatality rates with previous SARS-CoV
and MERS-CoV outbreaks were much higher, SARS-CoV-2 shows several unique features.
There is a much higher contagiosity with a high prevalence for asymptomatic disease
spreaders. The prolonged incubation period additionally helps the virus spreading
towards a worldwide pandemic.
In infected patients, a high rate of asymptomatic and mild courses have been reported,
with leading symptoms such as fatigue, coughing, shortness of breath, and fever.
1
However, in quite a number of cases, there is a rapid spread of the virus in various
organs including the lungs, neurological system, and most probably also the heart.
1
The notion that pre-existing cardiovascular diseases (CVDs) strongly increase COVID-19
fatality rates is important and is due to at least two causes. In general, underlying
diseases such as CVD, cancer, or immunocompromising diseases probably increase fatality
rates in many infectious diseases including general flu or SARS-CoV-2. A number of
pre-clinical studies have shown various organ systems to express the primary SARS-CoV-2
entry receptor, angiotensin-converting enzyme 2 (ACE2).
2
,
3
Importantly, pre-clinical studies in rats indicated increased expression of ACE2 after
renin–angiotensin–aldosterone system (RAAS) inhibitor medication.
4
While ACE inhibitor therapy increased cardiac ACE2 mRNA but not cardiac ACE2 activity
in rats, an angiotensin II type 1 receptor blocker (ARB) increased both cardiac ACE2
mRNA and activity.
4
A study published in the current issue of the European Heart Journal has now investigated
expression of ACE2 in human hearts.
5
Nicin et al. employed single nuclei RNA sequencing to analyse the expression of ACE
and ACE2 in the different cell types of the human heart in five patients with aortic
stenosis (AS), two patients with heart failure with reduced ejection fraction (HFrEF),
and two samples from one healthy donor heart. They found ACE2 to be expressed in cardiomyocytes
and pericytes, and at a lower level in fibroblasts, endothelial cells, and leucocytes.
ACE2 was elevated in cardiomyocytes of patients with heart disease compared with healthy
controls and also slightly, but not significantly, increased in endothelial cells
and to a lower extent in fibroblasts. Immunostainings suggest increased expression
of ACE2 in cardiomyocytes of patients with AS also at the protein level. In line with
previous pre-clinical data,
4
cardiomyocytes of patients who were treated with ACE inhibitors showed a significantly
higher ACE2 expression (Figure 1
). In contrast to pre-clinical data, they found less ACE2 activation in ARB-treated
patients. Although preliminary, these data provide novel insights into the cell type-specific
expression and regulation of ACE2 in the human heart.
Figure 1
Cell type-specific expression of the putative SARS-CoV2 receptor ACE2 in cardiovascular
cells and its infection consequences. Direct cardiac harm, fear of cardiac-diseased
patient to go to a physician/hospital and the suboptimal treatment in selected hospitals
with heavy COVID-19 overload may result in a post-pandemic wave of new cases of CVD
patients, especially those with heart failure. ACEi, angiotensin converting-enzyme
inhibitor; ARB, angiotensin II receptor blocker.
This is an important hypothesis-generating observation with profound implications
for basic and translational science, as well as another piece of the puzzle in the
ongoing discussion of the optimal pharmacotherapy of SARS-CoV-2-infected cardiovascular
patients.
6
There are several points I wish to discuss in light of those findings. In general,
and as mentioned also by the authors, this study is clearly underpowered and any conclusions
should be drawn very carefully. This especially includes the observation of less ACE2
activation in cardiomyocytes in patients treated with an ARB. Previous pre-clinical
studies in rats had shown partly different results.
4
However, there might be species differences as well as drug class-specific effects
that need to be investigated in more detail in future studies, e.g. by employing human
induced pluripotent stem cell (iPSC)-derived cardiomyocytes. Any clinical speculations
on the ‘optimal’ pharmacotherapy of cardiovascular diseases, especially for heart
failure patients, should at least currently not result in a change of guideline-directed
therapies. This also includes antihypertensive treatments that should not be discontinued
as doing so may be a greater risk factor for severe complications. In the future,
the effects of current and future SARS-CoV2 antiviral medications or of co-morbidities
such as diabetes on ACE2 expression should also be explored.
Although several organ systems seem to be affected, we currently do not exactly know
about the organ-specific invasiveness of SARS-CoV2 in humans. Interestingly, a previous
pathological study obtained from autopsies of fatal cases of SARS-CoV (not SARS-CoV2)
found that with the exception of the lungs and gut, there was no viral detection in
the heart, liver, spleen, kidney, lymph nodes, bone marrow, or muscles. The observations
of elevated markers of cardiac damage, inflammatory reactions, and higher rate of
rhythmological problems, however, may also suggest a direct cardiac infection by SARS-CoV-2.
1
,
7
,
8
Another important finding of the study by Nicin et al. is the observation of a cell
type-specific expression pattern of ACE2 in the human heart. This will also lead to
follow-up studies investigating the cell type-specific role of ACE2 and potential
functional implications. Importantly, another recent study also used single cell nuclei
RNA sequencing in 15 healthy donor hearts and 40 failing explanted hearts obtained
from the heart transplantation centre of Fuwai Hospital.
9
In contrast to the observation of Nicin et al., these investigators found only low
ACE2 expression in cardiomyocytes, but again high expression in pericytes. They conclude
that SARS-CoV-2 infection in the human heart might attack primarily pericytes, and
subsequently cause capillary endothelial cell dysfunction, thus inducing microcirculation
disorders, explaining the observed elevation in markers of cardiac damage. Mechanistic
follow-up studies in both cardiomyocytes and vascular cells, including pericytes and
endothelial cells, are clearly warranted. This may also lead to intriguing insights
and potential consequences for patients with heart failure of ischaemic vascular origin
as well as for heart failure patients with preserved ejection fraction and impaired
microvascular function.
Finally, we should not become ‘blinded’ by the COVID-19 pandemic for correct diagnosis
and therapy of our patients with CVD. Some of the COVID-19 symptoms such as shortness
of breath and coughing are typical problems of patients with heart failure, making
a fast and correct diagnosis extremely important with respect to future treatment.
Another impact of the COVID-19 pandemic leading to the heavy overload of hospitals
in several regions in the world is a potential increase in ‘event-to-balloon’ times
in patients with acute myocardial infarction.
10
Whether these initial findings can be extrapolated to European or US hospitals is
likely, but remains to be determined. Potentially, the COVID-19 outbreak will also
lead to an increase of long-term complications of patients with CVD such as heart
failure in both patients infected with SARS-CoV-2 and those that are not infected
but that were treated suboptimally during the ongoing pandemic (Figure 1
).
In conclusion, Nicin and co-workers report here an important observation with future
implications in both research and, potentially, treatment of SARS-CoV-2-infected cardiovascular
patients. These novel data at least suggest that it will be important to monitor SARS-CoV-2-infected
patients for cardiovascular complications and assess the impact of ARB/ACE inhibitor
therapy in more detail.