Endothelial dysfunction, oxidative stress and low-grade endotoxemia in COVID-19 patients hospitalised in medical wards.

BACKGROUND: Endothelial dysfunction, assessed by flow-mediated dilation (FMD), is related to poor prognosis in patients with COVID-19 pneumonia (CP). In this study, we explored the interplay among FMD, NADPH oxidase type 2 (NOX-2) and lipopolysaccharides (LPS) in hospitalised patients with CP, community acquired pneumonia (CAP) and controls (CT). METHODS: We enrolled 20 consecutive patients with CP, 20 hospitalised patients with CAP and 20 CT matched for sex, age, and main cardiovascular risk factors. In all subjects we performed FMD and collected blood samples to analyse markers of oxidative stress (soluble Nox2-derived peptide (sNOX2-dp), hydrogen peroxide breakdown activity (HBA), nitric oxide (NO), hydrogen peroxide (H2O2)), inflammation (TNF-α and IL-6), LPS and zonulin levels. RESULTS: Compared with controls, CP had significant higher values of LPS, sNOX-2-dp, H2O2,TNF-α, IL-6 and zonulin; conversely FMD, HBA and NO bioavailability were significantly lower in CP. Compared to CAP patients, CP had significantly higher levels of sNOX2-dp, H2O2, TNF-α, IL-6, LPS, zonulin and lower HBA. Simple linear regression analysis showed that FMD inversely correlated with sNOX2-dp, H2O2, TNF-α, IL-6, LPS and zonulin; conversely FMD was directly correlated with NO bioavailability and HBA. Multiple linear regression analysis highlighted LPS as the only predictor of FMD. CONCLUSION: This study shows that patients with COVID-19 have low-grade endotoxemia that could activate NOX-2, generating increased oxidative stress and endothelial dysfunction.

Asymptomatic and symptomatic deep venous thrombosis in hospitalized acutely ill medical patients: risk factors and therapeutic implications.

BACKGROUND: Acutely ill medical patients experience deep venous thrombosis (DVT) during the hospitalization, however the time course of DVT is still unclear. OBJECTIVES: To evaluate risk factors in acutely ill hospitalized medical patients for proximal asymptomatic DVT (ADVT) and symptomatic DVT (SDVT) at admission and discharge. PATIENTS/METHODS: In this prospective observational study, consecutive acutely ill medical patients (hospitalized mainly for acute medical disease as infections, neoplasm, anemia, heart failure) underwent compression ultrasonography (CUS) of proximal lower limb veins within 48 h from admission and at discharge to diagnose ADVT and SDVT. Covid-19 patients, anticoagulant therapy, surgical procedures, acute SDVT, and acute pulmonary embolism, were exclusion criteria. Biographical characteristics at hospitalization, D-Dimer (assessed by ELISA)) and DD-improve score. RESULTS: Of 2,100 patients (1002 females, 998 males, age 71 ± 16 years) 58 (2.7%) had proximal ADVT at admission. Logistic regression analysis showed that age, and active cancer were independently associated with ADVT at admission. The median length of hospitalization was 10 days [interquartile range: 6-15]. During the hospital stay, 6 patients (0.3%) with a negative CUS at admission experienced DVT (2 SDVT and 4 ADVT). In the subgroup of patients (n = 1118), in whom D-dimer was measured at admission, D-Dimer and IMPROVE-DD score were associated with ADVT at admission (n = 37) and with all DVT (n = 42) at discharge. ROC curve defined an IMPROVE-DD score of 2.5 as the optimal cut-off for discriminating patients with and without thrombotic events. CONCLUSIONS: We provide evidence of early development of ADVT in unselected acutely ill medical patients suggesting the need of investigating patients by CUS immediately after hospital admission (within 48 h). Advanced age, active cancer, known thrombophilia and increased IMPROVE-DD score may identify patients at risk. The benefit of anticoagulation needs to be investigated in patients with these specific risk factors and negative CUS at admission. TRIAL REGISTRATION: NCT03157843.

A case of transient constrictive pericarditis after COVID-19.

Cardiovascular disorders have been associated with coronavirus disease 2019 (COVID-19). Here, we describe a case of transient constrictive pericarditis after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A few days following SARS-CoV-2 pneumonia, a 55-year-old man developed fever and chest pain exacerbated by movement and breathing, and acute pericarditis was diagnosed. After two weeks, he progressively developed fatigue, dyspnea, peripheral edema, ascites, and bilateral pleural effusion. The patient's clinical condition, as well as imaging findings, were consistent with a diagnosis of constrictive pericarditis. Therefore, medical therapy was optimized with a progressive clinical improvement. Follow-up echocardiography showed full recovery of pericardial constriction. Transient constrictive pericarditis, defined as a reversible pericardial constriction followed by resolution, can be spontaneous or treatment-related, and represents an uncommon complication of acute pericarditis. Although a broad spectrum of COVID-19-related cardiac diseases (including pericarditis) have already been reported, transient pericardial constriction after SARS-CoV-2 infection has not previously been described. Learning objective: Transient constrictive pericarditis is an uncommon complication of acute pericarditis that can occur sporadically after viral acute pericarditis. We hereby describe a case of coronavirus disease 2019-related transient pericardial constriction. This case confirms that pericardial constriction after viral acute pericarditis often resolves with medical therapy.

Low-grade endotoxemia and NOX2 in patients with coronary microvascular angina.

BACKGROUND: Endothelial dysfunction and oxidative stress were hypothesized to be involved in the pathogenesis of coronary microvascular angina (MVA). NADPH oxidase-2 (NOX2) activation could provoke increased oxidative stress and endothelial dysfunction, but data on MVA have not been provided yet. AIMS: This study aimed to evaluate the interaction among NOX2 activation, serum lipopolysaccharide (LPS) levels, as well as oxidative stress production as potential causes of endothelial dysfunction in MVA patients. METHODS: In this study, we wanted to compare serum levels of soluble NOX2-dp (sNOX2-dp), H2O2 production, hydrogen peroxide breakdown activity (HBA), nitric oxide (NO) bioavailability, endothelin 1 (ET-1), serum zonulin (as intestinal permeability assay), and LPS in 80 consecutive subjects, including 40 MVA patients and 40 controls (CT), matched for age and sex. RESULTS: Compared with CT, MVA patients had significantly higher values of sNOX2-dp, H2O2, ET-1, LPS, and zonulin. Conversely HBA and NO bioavailability were significantly lower in MVA patients. Simple linear regression analysis showed that sNOX2 was associated with serum LPS, serum zonulin, H2O2, and ET-1. Furthermore, an inverse correlation between sNOX2, HBA, and nitric oxide bioavailability was observed. Multiple linear regression analysis showed that LPS and zonulin emerged as the only independent predictive variables associated with sNOX2. CONCLUSIONS: This study provides the first report attesting that patients with MVA have high LPS levels, NOX2 activation, and an imbalance between pro-oxidant and antioxidant systems, in favor of the oxidizing molecules that could be potentially implicated in the endothelial dysfunction and vasoconstriction of this disease.

Chocolate enriched by extra virgin olive oil improves endothelial function and oxidative stress in patients with diabetes.

OBJECTIVE: Endothelial dysfunction and oxidative stress are among the most relevant mechanisms underlying the atherosclerotic process in patients with type 2 diabetes mellitus (T2 DM). Extra virgin olive oil (EVOO) reduces postprandial glycemia with a mechanism counteracting oxidative stress-mediated incretin down-regulation in healthy subjects and in patients with impaired fasting glucose. The aim of this study was to evaluate if the intake of chocolate enriched by EVOO had positive effects on endothelial function and oxidative stress in patients with T2 DM. METHODS: In this study we enrolled and randomly assigned 25 consecutive patients with T2 DM to receive 40 g of EVOO-enriched chocolate or 40 g of control chocolate spread. Participants were assessed at baseline and 2 h after chocolate intake. Endothelial function was assessed by arterial brachial flow-mediated dilation (FMD); oxidative stress was evaluated by the measurement of serum nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (Nox2) levels, nitric oxide availability, and serum hydrogen peroxide breakdown activity (HBA). RESULTS: We observed a significant increase of FMD, nitric oxide (NO) availability, and HBA in the EVOO-enriched chocolate group (P < 0.001). Conversely, soluble Nox2-derived peptide (sNox2-dp) levels significantly decreased (P < 0.001). No significant change was observed in the control chocolate group. To assess the relation of EVOO-enriched chocolate to endothelial function and oxidative stress, a general linear model (GLM) analysis was performed; a significant difference for treatments was found with respect to FMD, NO availability, HBA, and sNox-dp. CONCLUSIONS: Administration of 40 g of EVOO-enriched chocolate is associated with increased endothelial function and reduction of oxidative stress in patients with T2 DM. Future studies are needed to analyze the effect of chronic assumption of EVOO-enriched chocolate on vascular function, oxidative stress, and cardiovascular complications in patients with T2 DM.

Oxidative stress and gut-derived lipopolysaccharides in children affected by paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.

BACKGROUND: Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections syndrome (PANDAS) identifies patients with acute onset of obsessive-compulsive and tic disorders. The objective of this study was to evaluate serum NOX2 levels, as well as 8-iso-prostaglandin F2α (8-iso-PGF2α) and lipopolysaccharide (LPS) of PANDAS patients. METHODS: In this study we wanted to compare serum levels of soluble NOX2-dp (sNOX-2-dp), iso-PGF2α and LPS in 60 consecutive subjects, including 30 children affected by PANDAS and 30 controls (CT) matched for age and gender. Serum zonulin was used as intestinal permeability assay. RESULTS: Compared with CT, PANDAS children had increased serum levels of sNOX-2-dp, 8-iso-PGF2α and LPS. Bivariate analysis showed that serum sNOX2-dp was significantly correlated with LPS (Rs = 0.359; p = 0.005), zonulin (Rs = 0.444; p < 0.001) and 8-iso-PGF2α (Rs = 0.704; p < 0.001). Serum LPS significantly correlated with zonulin (Rs = 0.610; p < 0.001), and 8-iso-PGF2α (Rs = 0.591; p = 0.001). Finally, a multiple linear regression analysis showed that serum 8-iso-PGF2α and zonulin were the only independent variables associated with sNOX2-dp (R2 = 68%). CONCLUSION: This study shows that children affected by PANDAS have high circulating levels of sNOX2-dp, isoprostanes and of LPS that could be involved in the process of neuroinflammation.

Digoxin treatment is associated with increased total and cardiovascular mortality in anticoagulated patients with atrial fibrillation.

BACKGROUND: Some evidences suggest that the use of digoxin may be harmful inatrial fibrillation (AF) patients. The aim of the study was to investigate in a "real world" of AF patients receiving vitamin K antagonists (VKAs), the relationship between digoxin use and mortality. METHODS: Prospective single-center observational study including 815 consecutive non-valvular AF patients treated with VKAs. Total mortality was the primary outcome of the study. We also performed a sub-analysis considering only cardiovascular (CV) deaths. Time in therapeutic range (TTR) was used for anticoagulation quality. RESULTS: Median follow-up was 33.2months (2460 person-years); 171 (21.0%) patients were taking digoxin. Compared to those without, patients on digoxin were older (p=0.007), with a clinical history of HF (p<0.001) and at higher risk of thromboembolic events (p<0.001). No difference in TTR between the two groups was registered (p=0.598). During the follow-up, 85 deaths occurred: 47 CV and 38 non-CV deaths; 35 deaths occurred in digoxin users (20.6%). A significant increased rate of total mortality was observed in digoxin-treated patients (p<0.001). Multivariable analysis showed that digoxin was associated with total mortality (hazard ratio [HR]: 2.224, p<0.001) and CV death (HR: 4.686, p<0.001). A propensity score-matched analysis confirmed that digoxin was associated with total mortality (HR: 2.073, p=0.0263) and CV death (HR: 4.043, p=0.004). CONCLUSIONS: In AF patients on good anticoagulation control with VKAs, digoxin use was associated with a higher rate of total and CV mortality.