Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is involved in a global outbreak affecting millions of people who manifest a variety of symptoms. Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is increasingly associated with cardiovascular complications requiring hospitalizations; however, the mechanisms underlying these complications remain unknown. Nitric oxide (NO) and hydrogen sulfide (H
2
S) are gasotransmitters that regulate key cardiovascular functions.
Methods
Blood samples were obtained from 68 COVID-19 patients and 33 controls and NO and H
2
S metabolites were assessed. H
2
S and NO levels were compared between cases and controls in the entire study population and subgroups based on race. The availability of gasotransmitters was examined based on severity and outcome of COVID-19 infection. The performance of H
2
S and NO levels in predicting COVID-19 infection was also analyzed. Multivariable regression analysis was performed to identify the effects of traditional determinants of gasotransmitters on NO and H
2
S levels in the patients with COVID-19 infection.
Results
Significantly reduced NO and H
2
S levels were observed in both Caucasian and African American COVID-19 patients compared to healthy controls. COVID-19 patients who died had significantly higher NO and H
2
S levels compared to COVID-19 patients who survived. Receiver-operating characteristic analysis of NO and H
2
S metabolites in the study population showed free sulfide levels to be highly predictive of COVID-19 infection based on reduced availability. Traditional determinants of gasotransmitters, namely age, race, sex, diabetes, and hypertension had no effect on NO and H
2
S levels in COVID-19 patients.
Conclusion
These observations provide the first insight into the role of NO and H
2
S in COVID-19 infection, where their low availability may be a result of reduced synthesis secondary to endotheliitis, or increased consumption from scavenging of reactive oxygen species.
Background:
Inflammation has been implicated in the pathogenesis, severity, and outcomes of COVID-19. Extracellular newly identified receptor for advanced glycation end-product (EN-RAGE), a soluble EF-hand calcium-binding protein, causes integrin activation, activates inflammation, and upregulates the synthesis of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1. While it is positively associated with atherosclerosis, high EN-RAGE levels have been shown to predict remission of auto-immune diseases. The role of EN-RAGE as a biomarker in COVID-19 is unknown.
Methods:
Serum EN-RAGE levels were measured from blood samples of 146 COVID-19 in-patients using Myriad® Cytokine MAP and compared between the subgroups based on race and outcomes. T-test, Chi-square, and multivariable regression analysis were performed to identify the correlation of EN-RAGE with race and outcomes.
Results:
Of 146 patients (mean age=59 years), 60% were female, 35% were White, and 60% were African Americans. 21 of the 146 (14%) patients died. Mortality was higher in Whites compared to African Americans (21% vs 10%) consistent with CDC data showing higher mortality in Whites compared to non-Whites. Surprisingly, African Americans had significantly higher EN-RAGE levels compared to Whites. (574.6 vs 360.9 respectively, p=0.002). Congruently, EN-RAGE levels were significantly higher in the patients who survived compared to the patients who died. (514.82 vs 336.29, p=0.039) suggesting that increased serum EN-RAGE levels may be associated with improved outcomes in hospitalized COVID-19 patients.
Conclusion:
Our study reveals a negative association of EN-RAGE levels with in-patient mortality associated with COVID-19 and could possibly be used as a biomarker of survival in hospitalized COVID-19 patients. EN-RAGE levels could partly explain mortality differences based on race. Further studies are required to confirm this association.
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