New laboratory evidence for the association between endothelial dysfunction and COVID-19 disease progression

Abstract

There is growing evidence that angiotensin-converting enzyme 2 is highly expressed on endothelial cells, endothelial dysfunction plays a critical role in coronavirus disease 2019 (COVID-19) progression, but laboratory evidence is still lacking. This study established a multicenter retrospective cohort of 966 COVID-19 patients from three hospitals in Wuhan, China. We found that male (62.8% vs. 46.5%), old age [72 (17) vs. 60.5 (21)], and coexisting chronic diseases (88.5% vs. 60.0%) were associated with poor clinical prognosis in COVID-19. Furthermore, the deteriorated patients exhibited more severe multiorgan damage, coagulation dysfunction, and extensive inflammation. Additionally, a cross-sectional study including 41 non-COVID-19 controls and 39 COVID-19 patients assayed endothelial function parameters in plasma and showed that COVID-19 patients exhibited elevated vascular cell adhesion molecule-1 (VCAM-1) (median [IQR]: 0.32 [0.27] vs. 0.17 [0.11] μg/ml, p < 0.001), E-selectin (21.06 [12.60] vs. 11.01 [4.63] ng/ml, p < 0.001), tissue-type plasminogen activator (tPA) (0.22 [0.12] vs. 0.09 [0.04] ng/ml, p < 0.001), and decreased plasminogen activator inhibitor-1 (0.75 [1.31] vs 6.20 [5.34] ng/ml, p < 0.001), as compared to normal controls. Moreover, VCAM-1 was positively correlated with d-dimer (R = 0.544, p < 0.001); tPA was positively correlated with d-dimer (R = 0.800, p < 0.001) and blood urea nitrogen (R = 0.638, p < 0.001). Our findings further confirm the strong association between endothelial dysfunction and poor prognosis of COVID-19, which offers a rationale for targeting endothelial dysfunction as a therapeutic strategy for COVID-19.

Keywords: COVID-19; endothelial dysfunction; laboratory evidence; prognosis.

Figure 1

Study flow chart

Figure 2

Patients with COVID‐19 exhibit endothelial dysfunction. (A) The plasma concentration levels of VCAM‐1 in patients with COVID‐19 and non‐COVID‐19 control subjects. (B) The plasma concentration levels of E‐selectin in patients with COVID‐19 and non‐COVID‐19 control subjects. (C) The plasma concentration levels of endothelin‐1 in patients with COVID‐19 and non‐COVID‐19 control subjects. (D) The plasma concentration levels of tPA in patients with COVID‐19 and non‐COVID‐19 control subjects. (E) The plasma concentration levels of PAI‐1 in patients with COVID‐19 and non‐COVID‐19 control subjects. All data presented as the mean ± SEM. Differences were tested using unpaired two‐tailed Mann–Whitney test. COVID‐19, coronavirus disease 2019; PAI‐1, plasminogen activator inhibitor‐1; tPA, tissue‐type plasminogen activator; VCAM‐1, vascular cell adhesion molecule‐1

Figure 3

Positive correlations between indicators of endothelial function and clinical markers of disease severity. (A) Positive correlations between plasma concentrations of VCAM‐1 and clinical laboratory indices of d‐dimer. Positive correlations between plasma concentrations of tPA and clinical laboratory indices of (B) d‐dimer and (C) BUN. R for Pearson's correlation coefficient, *p < 0.001. BUN, blood urea nitrogen; tPA, tissue‐type plasminogen activator; VCAM‐1, vascular cell adhesion molecule‐1