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

Importance The 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. Objective To investigate the association of plasma ET-1 with Covid-19 disease severity Design Retrospective 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). Setting Single Tertiary National Health Service Hospital. Participants Tissue banked plasma samples were obtained from 194 patients. Exposures Quantitation of ET-1 in plasma by specific enzyme linked immunosorbent assay. Main outcome and measures Pairwise comparison of ET-1 levels (median [IQR]) between patient categories, and subgroups defined by clinical outcomes. Results Baseline 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 relevance Hospitalised 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.

Light-dependent induction of Edn2 expression and attenuation of retinal pathology by endothelin receptor antagonists in Prominin-1- deficient mice

Retinitis pigmentosa (RP) and macular dystrophy (MD) are prevalent retinal degenerative diseases associated with gradual photoreceptor death. These diseases are often caused by genetic mutations that result in degeneration of the retina postnatally after it has fully developed. The Prominin-1 gene (Prom1) is a causative gene for RP and MD, and Prom1- knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and stenosis of retinal blood vessels. The mechanisms underlying progression of such degeneration have remained unknown, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. High-throughput analysis revealed that expression of the endothelin-2 gene (Edn2) was markedly up-regulated in the Prom1-deficient retina during this period. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice that had been reared in the dark. Finally, treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis, and retinal vessel stenosis in Prom1-KO mice. Our findings suggest that inhibitors of endothelin signalling may delay the progression of RP and MD and therefore warrant further study as potential therapeutic agents for these diseases.

Comparative effectiveness of endothelin receptor antagonists on mortality in patients with pulmonary arterial hypertension in a US Medicare population: a retrospective database analysis

Limited evidence is available on outcomes associated with currently available medications from the endothelin receptor antagonist drug class (bosentan, ambrisentan, and macitentan) in elderly patients with pulmonary arterial hypertension. We evaluated mortality in predominantly elderly patients with pulmonary arterial hypertension in the US taking endothelin receptor antagonists. A retrospective administrative claims study was conducted using the Centers for Medicare and Medicaid Services national Medicare database. Patients with pulmonary arterial hypertension were identified using diagnostic codes. Cohort inclusion required age ≥18 years; ≥1 claim for macitentan, ambrisentan, or bosentan between 1 January 2014 and 31 December 2015 (index date and index endothelin receptor antagonist defined by first such claim); continuous enrollment for ≥12 months before and after the index date; and ≥80% of days covered for the index endothelin receptor antagonist. Follow-up was from index date until the earliest of Medicare disenrollment, death, or 31 December 2016. Multivariable Cox proportional hazards regression models were used to estimate mortality hazard ratios with 95% confidence intervals for macitentan vs. ambrisentan or bosentan, adjusting for potential confounders. The study cohort included 1628 patients on index macitentan, 2852 on ambrisentan, and 1972 on bosentan. Overall, 69% of patients were aged ≥65 years and most were females (76%). Macitentan was associated with an 18% lower risk for mortality than ambrisentan (hazard ratio: 0.82, 95% confidence interval: 0.72–0.93; P = 0.0026) and a 39% lower risk than bosentan (hazard ratio: 0.61, 95% confidence interval: 0.53–0.71; P < 0.0001). Variables that independently increased the risk of mortality included higher comorbidity index, increasing age, and inpatient hospitalizations at baseline.