4. DISSCUSSION
Our study provides detailed information about the association between
cardiac markers and clinical outcomes of COVID-19 patients with or
without pre-existing CAD. Patients with abnormal serum levels of cardiac
markers, namely, BNP, hs-TNI, α-HBDH, CK-MB, and LDH, had a
significantly higher mortality rate than patients with normal serum
marker levels. In COVID-19 non-survivors with or without pre-existing
CAD, the BNP level measured within one week after admission was a
sensitive and reliable indicator of heart damage, showing a 5.8-fold and
1.4-fold significant increase from the upper reference limit,
respectively. Moreover, our results demonstrated that BNP is an
independent risk factor for in-hospital mortality. Additionally, the
present study indicates that the BNP level is not only correlated with
cardiac damage but also with the clinical parameters of other organ
systems.
SARS-CoV-2 uses the ACE2 receptor to facilitate viral entry into target
cells, causing multiorgan dysfunction (Zou, Chen, Zou, Han, Hao & Han,
2020). It has been reported that the mechanism of acute myocardial
injury caused by SARS-CoV-2 infection might be related to ACE2 (South,
Diz & Chappell, 2020). The scRNA-seq analysis in the present study
showed that ACE2 was mainly expressed in CM, EC, and FB cell types,
suggesting that SARS-CoV-2 receptor-related signaling pathways in
myocardial injury may be mainly related to these cell populations.
Hoffman et al. (Zhang, Penninger, Li, Zhong & Slutsky, 2020) recently
demonstrated that the initial spike in protein priming by TMPRSS2 is
essential for the entry and viral spread of SARS-CoV-2 through
interaction with the ACE2 receptor (Stopsack, Mucci, Antonarakis, Nelson
& Kantoff, 2020). Our results showed that there was a significantly
high expression of TMPRSS2 in CAD patients compared with healthy
controls. This implies that upregulated TMPRSS2 may be the reason that
patients with CAD represented a higher percentage of individuals with
abnormal levels of cardiac markers after SARS-CoV-2 infection. The
serine protease inhibitor camostat mesylate, approved in Japan to treat
diseases, has been shown to block TMPRSS2 activity and is thus an
interesting candidate to treat COVID-19 patients with pre-existing CAD
(Kawase, Shirato, van der Hoek, Taguchi & Matsuyama, 2012; Zhou et al.,
2015).
Previous studies have investigated the association between myocardial
injury markers and prognosis (Dong, Li, Yu, Lv & Chen, 2020; Lippi,
Lavie & Sanchis-Gomar, 2020). However, evidence on markers that are
appropriate for monitoring heart damage in a timely manner is lacking.
Because of limited space in ICUs, the triage rules for access to
intensive care are becoming tougher and tougher. In this study, an
extensive investigation of various clinical indices revealed that BNP is
a sensitive and reliable biomarker for prognosis in COVID-19 patients.
Particularly, compared with survivors, the median value of BNP was
strikingly higher in non-survivors with or without CAD. Remarkably,
abnormal elevation of serum BNP can accurately predict the risk of
mortality on the day of admission through the first week after
admission, which provides an early and wide window for clinical
monitoring to strengthen cardio-protective treatment. α-HBDH and LDH
could also be used as indicators in risk stratification management;
however, they are not specific indicators of heart damage and had a less
drastic change in levels compared to BNP.
As a classic serum indicator for cardiac dysfunction, the detection of
BNP is widely used in clinical practice and is, therefore, easy to
implement in hospitals at all levels. Our results showed BNP is a
powerful biomarker to predict the outcomes of COVID-19 patients and it
should be detected on admission to guide therapy. Monitoring serum BNP
status will improve the risk-stratified management and prognosis of
COVID-19 patients with or without CAD on admission.
Some limitations exist in the present study. First, data from larger
populations and multiple centers are needed to further verify the
results. Second, some data regarding heart damage, such as
echocardiography, magnetic resonance, and electrocardiography, were
incomplete due to the limited conditions in the isolation ward. Third,
causes of death may involve multiple organ dysfunctions in most cases,
and it is difficult to differentiate the heart damage as the main and
direct cause in an individual case.
In conclusion, COVID-19 patients with pre-existing CAD represented a
higher abnormal percentage of cardiac markers, accompanied by high
mortality and ICU admission rate. Of note, COVID-19 patients without
pre-existing CAD who represented abnormal levels of cardiac markers also
had high mortality. BNP is a sensitive and reliable biomarker for early
warning of high mortality risk at the time of admission and through the
first week. Monitoring BNP status as early as possible and providing
cardioprotective combination therapy will improve the risk-stratified
management and prognosis of patients.