Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19

Abstract

Introduction Endothelial damage and thrombosis caused by COVID-19 may imperil cardiovascular health. More than a year since the WHO declared COVID-19 pandemic, information on its effects beyond the acute phase is lacking. We investigate endothelial dysfunction, coagulation and inflammation, 3 months post-COVID-19. Materials and methods A cohort study was conducted including 203 patients with prior COVID-19. Macrovascular dysfunction was assessed by measuring the carotid artery diameter in response to hand immersion in ice-water. A historic cohort of 312 subjects served as controls. Propensity score matching corrected for baseline differences. Plasma concentrations of endothelin-1 were measured in patients post-COVID-19, during the acute phase, and in matched controls. Coagulation enzyme:inhibitor complexes and inflammatory cytokines were studied. Results and conclusions The prevalence of macrovascular dysfunction did not differ between the COVID-19 (18.6%) and the historic cohort (22.5%, RD −4%, 95%CI: −15–7, p = 0.49). Endothelin-1 levels were significantly higher in acute COVID-19 (1.67 ± 0.64 pg/mL) as compared to controls (1.24 ± 0.37, p < 0.001), and further elevated 3 months post-COVID-19 (2.74 ± 1.81, p < 0.001). Thrombin:antithrombin(AT) was high in 48.3%. Markers of contact activation were increased in 16–30%. FVIIa:AT (35%) and Von Willebrand Factor:antigen (80.8%) were elevated. Inflammatory cytokine levels were high in a majority: interleukin(IL)-18 (73.9%), IL-6 (47.7%), and IL-1ra (48.9%). At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction; there was evidence, however, of sustained endothelial cell involvement, coagulation activity and inflammation. Our data highlight the importance of further studies on SARS-CoV-2 related vascular inflammation and thrombosis, as well as longer follow-up in recovered patients.

Endothelin-1 is increased in the plasma of patients hospitalised with Covid-19

“…Our results are replicated by Willems et al who reported an elevation in ET-1 levels for a subset of 36 Covid-19 infected patients during the acute illness compared with a historic non-infected control group [12]. Gregoriano et al had earlier reported on the lack of prognostic utility of C-terminal proendothelin-1 (proET-1) to predict mortality in Covid-19 [14].…”

“…Willems et al have recently reported elevated ET-1 levels in patients 3 months post Covid-19 infection [12]; however the association of ET-1 with clinical outcomes likely to impact the provision of healthcare resources, such as hospitalisation, has not been investigated. In the present study, we tested the hypothesis that elevated levels of plasma ET-1 in the acute phase of Covid-19 infection would be associated with more severe disease.…”

Metabolic dyshomeostasis induced by SARS-CoV-2 structural proteins reveals immunological insights into viral olfactory interactions

“…EDN1 (Endothelin-1) has been considered a neuroprotective factor that participates in the olfactory response modulation through the uncoupling of gap junctions ( 87 , 88 ). Interestingly, elevated EDN1 levels together with a sustained inflammation has been observed 3 months after recovery from acute COVID-19 symptoms ( 89 ). SPP1 (osteopontin) participates in the OB synaptic plasticity ( 90 ) and acts as a molecular brake regulating neuroinflammatory response to chronic viral infections ( 91 ).…”

Metabolic dyshomeostasis induced by SARS-CoV-2 structural proteins reveals immunological insights into viral olfactory interactions

“…EDN1 (Endothelin-1) has been considered a neuroprotective factor that participates in the olfactory response modulation through the uncoupling of gap junctions (Le Bourhis et al, 2014;Bryche et al, 2019). Interestingly, elevated EDN1 levels together with a sustained inflammation has been observed 3 months after recovery from acute COVID-19 symptoms (Willems et al, 2021). SPP1 (osteopontin) participates in the OB synaptic plasticity (Powell et al, 2019) and acts as a molecular brake regulating neuroinflammatory response to chronic viral infections (Mahmud et al, 2020).…”