3.2 Cardiac Markers and Clinical Outcomes
To evaluate the relationship between the degree of cardiac abnormality and disease outcome in patients with COVID-19, serum cardiac markers were measured. Due to the 0% mortality and favorable prognosis of mild/moderate patients, we focused on the 1,515 patients with severe/critical COVID-19 in the follow-up period.
Of the 1,515 severe/critical cases, BNP, hs-TNI, α-HBDH, CK-MB, and LDH were detected in 835 patients, 660 patients, 1443 patients, 1442 patients, and 1443 patients, respectively. In total, 171 (20.5%), 79 (12.0%), 529 (36.7%), 124 (8.6%), and 447 (3.1%) patients showed abnormal serum levels of BNP, hs-TNI, α-HBDH, CK-MB, and LDH, respectively (Figure 2a ). Patients with an elevated level of a cardiac marker showed a significantly higher mortality than those with normal serum levels (Figure 2b ). The same trend was observed in the ICU admission rate (Figure 2c ). Figure 2d shows that the serum levels of BNP, hs-TNI, α-HBDH, CK-MB, and LDH were significantly higher during hospitalization in non-survivors than in survivors.
The scRNA-seq data of normal human heart tissue were analyzed and five cell types, namely, cardiomyocyte (CM), endothelial (EC), fibroblast (FB), macrophage (MP), and smooth muscle (SMC) cells, were identified (Figure 3a ). SARS-CoV-2 receptors ACE2, ANPEP, DPP4, and ENPEP were enriched in specific cell populations. ACE2 was mainly expressed in CM, EC, and FB cell types. ANPEP was enriched in CM, DPP4 was mainly expressed by CM and EC, and ENPEP was primarily expressed in CM and SMC (Figure 3b and Figure 3c ).
3.3 Heart Damage and Mortality Rate
The 1,515 severe/critical patients were further categorized into groups according to the presence or absence of pre-existing CAD (n=165 and n=1,350, respectively). Patients with pre-existing CAD had a significantly higher percent of elevated BNP than patients without CAD (Figure 4a ). To explore the underlying pathophysiological mechanism for the elevated levels of cardiac markers in COVID-19 patients with pre-existing CAD, RNA-seq data from 93 patients with CAD and 48 healthy people were analyzed and compared. The results showed that compared with healthy controls, SARS-CoV-2 receptors, including Transmembrane Serine Protease 2 (TMPRSS2) and Glutamyl Aminopeptidase (ENPEP), were significantly upregulated in CAD (Figure 4b ).
Compared to patients with normal levels of cardiac markers, those with abnormal levels of BNP, hs-TNI, α-HBDH, CK-MB, and LDH exhibited significantly higher mortality in both CAD and non-CAD groups (Figure 4c ). The same trend was observed for the ICU admission rate (Figure S1 ). The serum markers were then compared between non-survivors and survivors. The results showed that BNP, α-HBDH, CK-MB, and LDH were significantly higher in non-survivors than in survivors for patients with pre-existing CAD; however, the significant difference was not observed for hs-TNI (Figure 4d) . In patients without pre-existing CAD, all markers were significantly higher in non-survivors than in survivors during hospitalization (Figure 4e ).