Well-Known and Novel Players in Endothelial Dysfunction: Updates on a Notch(ed) Landscape.

Endothelial dysfunction characterizes every aspect of the so-called cardiovascular continuum, a series of events ranging from hypertension to the development of atherosclerosis and, finally, to coronary heart disease, thrombus formation, myocardial infarction, and heart failure. Endothelial dysfunction is the main prognostic factor for the progression of vascular disorders, which responds to drug intervention and lifestyle changes. Virtually all of the drugs used to prevent cardiovascular disorders, such as long-used and new antilipidemic agents and inhibitors of angiotensin enzyme (ACEi), exert an important effect on the endothelium. Endothelial dysfunction is a central feature of coronavirus disease -19 (COVID-19), and it is now clear that life-risk complications of the disease are prompted by alterations of the endothelium induced by viral infection. As a consequence, the progression of COVID-19 is worse in the subjects in whom endothelial dysfunction is already present, such as elderly, diabetic, obese, and hypertensive patients. Importantly, circulating biomarkers of endothelial activation and injury predict the severity and mortality of the disease and can be used to evaluate the efficacy of treatments. The purpose of this review is to provide updates on endothelial function by discussing its clinical relevance in the cardiovascular continuum, the latest insights from molecular and cellular biology, and their implications for clinical practice, with a focus on new actors, such as the Notch signaling and emerging therapies for cardiovascular disease.

A serum proteome signature to predict mortality in severe COVID-19 patients.

Here, we recorded serum proteome profiles of 33 severe COVID-19 patients admitted to respiratory and intensive care units because of respiratory failure. We received, for most patients, blood samples just after admission and at two more later time points. With the aim to predict treatment outcome, we focused on serum proteins different in abundance between the group of survivors and non-survivors. We observed that a small panel of about a dozen proteins were significantly different in abundance between these two groups. The four structurally and functionally related type-3 cystatins AHSG, FETUB, histidine-rich glycoprotein, and KNG1 were all more abundant in the survivors. The family of inter-α-trypsin inhibitors, ITIH1, ITIH2, ITIH3, and ITIH4, were all found to be differentially abundant in between survivors and non-survivors, whereby ITIH1 and ITIH2 were more abundant in the survivor group and ITIH3 and ITIH4 more abundant in the non-survivors. ITIH1/ITIH2 and ITIH3/ITIH4 also showed opposite trends in protein abundance during disease progression. We defined an optimal panel of nine proteins for mortality risk assessment. The prediction power of this mortality risk panel was evaluated against two recent COVID-19 serum proteomics studies on independent cohorts measured in other laboratories in different countries and observed to perform very well in predicting mortality also in these cohorts. This panel may not be unique for COVID-19 as some of the proteins in the panel have previously been annotated as mortality markers in aging and in other diseases caused by different pathogens, including bacteria.

Blood Interferon-α Levels and Severity, Outcomes, and Inflammatory Profiles in Hospitalized COVID-19 Patients.

Background: Deficient interferon responses have been proposed as one of the relevant mechanisms prompting severe manifestations of COVID-19. Objective: To evaluate the interferon (IFN)-α levels in a cohort of COVID-19 patients in relation to severity, evolution of the clinical manifestations and immune/inflammatory profile. Methods: This is prospective study recruiting consecutive hospitalized patients with respiratory failure associated with SARS-COV-2 infection and matched controls. After enrollment, patients were assessed every 7 ± 2 days for additional 2 consecutive visits, for a total of 21 days. The severity of the clinical condition was ranked based on the level of respiratory support required. At each time-point blood samples were obtained to assess immune cells and mediators by multiplex immunoassay. Results: Fifty-four COVD-19 and 11 control patients matched for severity were enrolled. At recruitment, lower levels of blood IFN-α were found in COVID-19 patients compared to controls (3.8-fold difference, p < 0.01). Improvements in COVID-19 severity were paralleled by a significant increase of blood IFN-α levels. A significant increase in blood IFN-α was found over the study period in survivors (70% of the study population). A similar trend was found for blood IFN-ß with IFN-ß levels below the threshold of detectability in a substantial proportion of subjects. Significantly higher values of blood lymphocytes and lower levels of IL-10 were found at each time point in patients who survived compared to patients who died. In patients who clinically improved and survived during the study, we found an inverse association between IL-10 and IFN-α levels. Conclusion: The study identifies a blood immune profile defined by deficient IFN-α levels associated with increased IL-10 expression in patients progressing to severe/life threatening COVID-19 conditions, suggesting the involvement of immunological pathways that could be target of pharmacological intervention. Clinical Trial Registration: ClinicalTrials.gov identifier NCT04343053.

Markers of endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients.

BACKGROUND: Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. METHODS: This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. RESULTS: In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001). CONCLUSIONS: COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053 , Date of registration: April 13, 2020.

Over time relationship between platelet reactivity, myocardial injury and mortality in patients with SARS-CoV-2-associated respiratory failure.

The aim of this study (NCT04343053) is to investigate the relationship between platelet activation, myocardial injury, and mortality in patients affected by Coronavirus disease 2019 (COVID-19). Fifty-four patients with respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were enrolled as cases. Eleven patients with the same clinical presentation, but negative for SARS-CoV-2 infection, were included as controls. Blood samples were collected at three different time points (inclusion [T1], after 7 ± 2 days [T2] and 14 ± 2 days [T3]). Platelet aggregation by light transmittance aggregometry and the circulating levels of soluble CD40 ligand (sCD40L) and P-selectin were measured. Platelet biomarkers did not differ between cases and controls, except for sCD40L which was higher in COVID-19 patients (p = .003). In COVID-19 patients, P-selectin and sCD40L levels decreased from T1 to T3 and were higher in cases requiring admission to intensive care unit (p = .004 and p = .008, respectively). Patients with myocardial injury (37%), as well as those who died (30%), had higher values of all biomarkers of platelet activation (p < .05 for all). Myocardial injury was an independent predictor of mortality. In COVID-19 patients admitted to hospital for respiratory failure, heightened platelet activation is associated with severity of illness, myocardial injury, and mortality.ClinicalTrials.gov number: NCT04343053.

COVID-19 in the heart and the lungs: could we "Notch" the inflammatory storm?

From January 2020, coronavirus disease (COVID-19) originated in China has spread around the world. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The presence of myocarditis, cardiac arrest, and acute heart failure in COVID-19 patients suggests the existence of a relationship between SARS-CoV-2 infection and cardiac disease. The Notch signalling is a major regulator of cardiovascular function and it is also implicated in several biological processes mediating viral infections. In this report we discuss the possibility to target Notch signalling to prevent SARS-CoV-2 infection and interfere with the progression of COVID-19- associated heart and lungs disease.