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.