Endothelin-1 is Increased in the Plasma of Patients Hospitalized with Covid-19

ABSTRACT

ImportanceThe coronavirus disease 2019 (Covid-19) pandemic continues to place a devastating strain on healthcare services worldwide and there remains an ongoing requirement for new treatments. A key mechanism recognised in progressive severe disease is virus-induced endothelial dysregulation. Endothelin-1 (ET-1), being the most highly expressed peptide in endothelial cells and potent vasoconstrictor of human blood vessels, represents a potential therapeutic target through the use of Endothelin receptor antagonists. ObjectiveTo investigate the association of plasma ET-1 with Covid-19 disease severity DesignRetrospective longitudinal cohort study of Covid-19 patients divided into Group A (asymptomatic or symptoms not requiring hospitalisation), Group B (symptoms requiring hospitalisation) and Group C (symptoms requiring supplemental oxygen therapy or assisted ventilation) recruited between March and July 2020 (the first wave of the Covid-19 pandemic in the UK). Data were compared with a contemporaneous cross-section of non-infected volunteers (Controls). SettingSingle Tertiary National Health Service Hospital. ParticipantsTissue banked plasma samples were obtained from 194 patients. ExposuresQuantitation of ET-1 in plasma by specific enzyme linked immunosorbent assay. Main outcome and measuresPairwise comparison of ET-1 levels (median [IQR]) between patient categories, and subgroups defined by clinical outcomes. ResultsBaseline ET-1 plasma levels (pg/ml) were elevated in patients requiring hospitalisation compared with controls and patients with asymptomatic or mild infection (Group B 1.59 [1.13-1.98], and Group C 1.65 [1.02-2.32] versus controls 0.68 [0.47-0.87], p=<0.001 and Group A 0.72 [0.57-1.10], p=<0.001). ET-1 levels were also elevated in patients that died (2.09 [1.66-3.15]), developed acute kidney (1.70 [1.07-2.36]) or myocardial injury (1.50 [0.92-2.28]) compared with patients with an uncomplicated infection (1.00 [0.61-1.57], p=<0.01). Amongst surviving hospitalised patients, ET-1 concentrations decreased when measured at 28 days (Group B 0.86 [0.60-1.61] and Group C 1.17 [0.66-1.62] versus baseline, p=<0.05) and 90 days (Group B 0.69 [0.59-1.38] and Group C 1.01 [0.64-1.21] versus baseline, p=<0.05). Conclusions and relevanceHospitalised Covid-19 patients demonstrate elevated ET-1 levels during the acute phase of infection and this is associated with increasing clinical severity of the disease. The results support the hypothesis that endothelin receptor antagonists may be beneficial for certain Covid-19 patients. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the association of the endothelial peptide and potent vasoconstrictor endothelin-1 with disease severity in Covid-19 infection? FindingsHospitalised Covid-19 patients (especially those requiring supplemental oxygen and assisted ventilation, dying patients, and those who developed acute myocardial or kidney injury) have higher circulating endothelin-1 levels during the acute phase of their infection, compared with patients with asymptomatic or only mildly symptomatic Covid-19 infection. MeaningEndothelial dysregulation is a well-recognised mechanism for progressive severe Covid-19 infection and these results suggest targeting endothelin-1 activity through the use of Endothelin receptor antagonists may be of benefit.