Role of Endothelium in Cardiovascular Sequelae of Long COVID.

The global action against coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 infection, shed light on endothelial dysfunction. Although SARS-CoV-2 primarily affects the pulmonary system, multiple studies have documented pan-vascular involvement in COVID-19. The virus is able to penetrate the endothelial barrier, damaging it directly or indirectly and causing endotheliitis and multi-organ injury. Several mechanisms cooperate to development of endothelial dysfunction, including endothelial cell injury and pyroptosis, hyperinflammation and cytokine storm syndrome, oxidative stress and reduced nitric oxide bioavailability, glycocalyx disruption, hypercoagulability, and thrombosis. After acute-phase infection, some patients reported signs and symptoms of a systemic disorder known as long COVID, in which a broad range of cardiovascular (CV) disorders emerged. To date, the exact pathophysiology of long COVID remains unclear: in addition to the persistence of acute-phase infection mechanisms, specific pathways of CV damage have been postulated, such as persistent viral reservoirs in the heart or an autoimmune response to cardiac antigens through molecular mimicry. The aim of this review is to provide an overview of the main molecular patterns of enduring endothelial activation following SARS-CoV-2 infection and to offer the latest summary of CV complications in long COVID.

Gut Microbiota and Cardiovascular Disease: Evidence on the Metabolic and Inflammatory Background of a Complex Relationship.

Several studies in recent years have demonstrated that gut microbiota-host interactions play an important role in human health and disease, including inflammatory and cardiovascular diseases. Dysbiosis has been linked to not only well-known inflammatory diseases, such as inflammatory bowel diseases, rheumatoid arthritis, and systemic lupus erythematous, but also to cardiovascular risk factors, such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. The ways the microbiota is involved in modulating cardiovascular risk are multiple and not only related to inflammatory mechanisms. Indeed, human and the gut microbiome cooperate as a metabolically active superorganism, and this affects host physiology through metabolic pathways. In turn, congestion of the splanchnic circulation associated with heart failure, edema of the intestinal wall, and altered function and permeability of the intestinal barrier result in the translocation of bacteria and their products into the systemic circulation, further enhancing the pro-inflammatory conditions underlying cardiovascular disorders. The aim of the present review is to describe the complex interplay between gut microbiota, its metabolites, and the development and evolution of cardiovascular diseases. We also discuss the possible interventions intended to modulate the gut microbiota to reduce cardiovascular risk.

High prevalence of lower limb atherosclerosis is linked with the gut-liver axis in patients with primary biliary cholangitis.

BACKGROUND AND AIMS: Hypercholesterolemia is frequent in people with primary biliary cholangitis (PBC); however, it does not seem to confer an increased risk of cardiovascular disease. We aimed to evaluate the prevalence of peripheral arterial disease in PBC women and its association with the gut-liver axis and systemic inflammation. METHODS: Thirty patients affected by PBC and hypercholesterolemia were enrolled, with equal-sized groups of women with non-alcoholic fatty liver disease (NAFLD) and healthy controls (CTRL). All patients underwent Doppler ultrasound examination of peripheral arteries, assessment of flow-mediated dilation, quantification of circulating cytokines and vasoactive mediators and characterization of the gut microbiota. RESULTS: PBC patients had a higher prevalence of lower extremity arterial disease (LEAD) defined as atherosclerotic plaques in any of femoral, popliteal and/or tibial arteries compared with both NAFLD and CTRL women (83.3% vs. 53.3% and 50%, respectively; p = .01). Factors associated with LEAD at univariate analysis were VCAM-1 (p = .002), ICAM-1 (p = .003), and TNF-alpha (p = .04) serum levels, but only VCAM-1 (OR 1.1, 95% CI 1.0-1.1; p = .04) and TNF-alpha (OR 1.12, 95% CI 0.99-1.26; p = .04) were confirmed as independent predictors in the multivariate model. Gut microbiota analysis revealed that Acidaminococcus (FDR = 0.0008), Bifidobacterium (FDR = 0.001) and Oscillospira (FDR = 0.03) were differentially expressed among groups. Acidaminococcus, which was increased in PBC, was positively correlated with TNF-alpha serum levels. Down-regulation of metabolic pathways linked to fatty acid and butyrate metabolism, glyoxylate metabolism and branched-chain amino acids degradation was found in the functional gut metagenome of PBC women. CONCLUSIONS: LEAD is common in patients affected by PBC and is associated with inflammatory markers and alterations in the gut-liver axis.

Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial.

Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis. A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g l-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence. Fifty participants were randomized to receive either l-arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 [65%] women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, l-arginine plus vitamin C increased the 6 min walk distance (+30 (40.5) m; placebo: +0 (75) m, p = 0.001) and induced a greater improvement in handgrip strength (+3.4 (7.5) kg) compared with the placebo (+1 (6.6) kg, p = 0.03). The flow-mediated dilation was greater in the active group than in the placebo (14.3% (7.3) vs. 9.4% (5.8), p = 0.03). At 28 days, fatigue was reported by two participants in the active group (8.7%) and 21 in the placebo group (80.1%; p < 0.0001). l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population.

Radial Peripapillary Capillary Plexus Perfusion and Endothelial Dysfunction in Early Post-SARS-CoV-2 Infection.

BACKGROUND: Endothelial cells damage and thromboinflammation are considered key elements in the generation of organ impairment in patients with COVID-19 disease. The endothelial function is evaluated by measuring flow-mediated dilation (FMD). We aimed to analyze the association between FMD impairment and retinal vascular parameters in early post-COVID-19 patients. 00118-00199Tomography (OCT), OCT Angiography (OCTA) and slit lamp examination were performed. FMD ≤ 7% was considered as pathological. Our primary outcome was to assess potential differences in the radial peripapillary capillary plexus flow index (RPCP-FI) and RPCP density (RPCP-D) values between post-COVID-19 patients with and without FMD impairment. The associations of other retinal vascular parameters with FMD impairment were assessed as secondary endpoints. RESULTS: FMD impairment was detected in 31 patients (37.8%). RPCP-FI (p = 0.047), age (p = 0.048) and prevalence of diabetes (p = 0.046) significantly differed in patients with FMD ≤ 7% in regression analysis. RPCP-FI was linearly correlated with FMD values (R = 0.244, p =0.027). SCT was found to be lower in patients with impaired FMD (p = 0.004), although this difference was only a trend in binary logistic regression output (p = 0.07). CONCLUSIONS: Early post-COVID-19 patients showed a higher prevalence of FMD impairment compared to the general population. Age, diabetes and RPCP-FI were independently correlated with the presence of endothelial impairment in the early post-infective period.

Impaired Endothelial Function in Convalescent Phase of COVID-19: A 3 Month Follow Up Observational Prospective Study.

Background: Endothelial dysfunction has a role in acute COVID-19, contributing to systemic inflammatory syndrome, acute respiratory distress syndrome, and vascular events. Evidence regarding COVID-19 middle- and long-term consequences on endothelium are still lacking. Our study aimed to evaluate if COVID-19 severity could significantly affect the endothelial function after three months from the acute phase. Methods: We assessed endothelial function in outpatients with previous COVID-19 three months after negative SARS-CoV-2 molecular test by measuring flow-mediated dilation (FMD) in patients categorized according to a four-variable COVID-19 severity scale ("home care"; "hospital, no oxygen"; "hospital, oxygen"; "hospital requiring high-flow nasal canula, non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation"). FMD difference among COVID-19 severity categories was assessed with analysis of variance; we further clarified the relationship between FMD and previous COVID-19 severity with multivariate logistic models. Results: Among 658 consecutive COVID-19 subjects, we observed a significant linear trend of FMD reduction with the increase of the COVID-19 category (p < 0.0001). The presence of endothelial dysfunction was more frequent among hospitalized patients (78.3%) with respect to home-care patients (21.7%; p < 0.0001). COVID-19 severity was associated with increased endothelial dysfunction risk (OR: 1.354; 95% CI: 1.06−1.71; p = 0.011) at multivariate binary logistic analysis. FMD showed a significant direct correlation with PaO2 (p = 0.004), P/F ratio (p = 0.004), FEV1 (p = 0.008), and 6MWT (p = 0.0001). Conclusions: Hospitalized COVID-19 subjects showed an impaired endothelial function three months after the acute phase that correlated with pulmonary function impairment. Further studies are needed to evaluate if these subjects are at higher risk of developing pulmonary disease or future cardiovascular events.

Distinctive Role of the Systemic Inflammatory Profile in Non-Small-Cell Lung Cancer Younger and Elderly Patients Treated with a PD-1 Immune Checkpoint Blockade: A Real-World Retrospective Multi-Institutional Analysis.

An immune checkpoint blockade with mAbs to PD-1 and PD-L1 is an expanding therapeutic option for mNSCLC patients. This treatment strategy is based on the use of mAbs able to restore the anti-tumor activity of intratumoral T cells inhibited by PD-1 binding to PD-L1/2 on tumor and inflammatory cells. It has been speculated that a chronic status of systemic inflammation as well as the immunosenescence physiologically occurring in elderly patients may affect the efficacy of the treatment and the occurrence of irAEs. We performed a multi-institutional retrospective study aimed at evaluating the effects of these mAbs (nivolumab or atezolizumab) in 117 mNSCLC patients younger (90 cases) and older (27 cases) than 75 years in correlation with multiple inflammatory parameters (NLR, CRP, ESR, LDH and PCT). No differences were observed when the cohorts were compared in terms of the frequency of PFS, OS, inflammatory markers and immune-related adverse events (irAEs). Similarly, the occurrence of irAEs was strictly correlated with a prolonged OS survival in both groups. On the contrary, a negative correlation between the high baseline levels of inflammatory markers and OS could be demonstrated in the younger cohort only. Overall, PD-1/PD-L1-blocking mAbs were equally effective in young and elderly mNSCLC patients; however, the detrimental influence of a systemic inflammation at the baseline was only observed in young patients, suggesting different aging-related inflammation immunoregulative effects.

Improved gut microbiota features after the resolution of SARS­CoV­2 infection.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) has a tropism for the gastrointestinal tract and several studies have shown an alteration of the gut microbiota in hospitalized infected patients. However, long-term data on microbiota changes after recovery are lacking. METHODS: We enrolled 30 patients hospitalized for SARS­CoV­2-related pneumonia. Their gut microbiota was analyzed within 48 h from the admission and compared with (1) that of other patients admitted for suspected bacterial pneumonia (control group) (2) that obtained from the same subject 6 months after nasopharyngeal swab negativization. RESULTS: Gut microbiota alpha-diversity increased 6 months after the resolution of SARS-CoV-2 infection. Bacteroidetes relative abundance was higher (≈ 36.8%) in patients with SARS-CoV-2, and declined to 18.7% when SARS-CoV-2 infection resolved (p = 0.004). Conversely, Firmicutes were prevalent (≈ 75%) in controls and in samples collected after SARS-CoV-2 infection resolution (p = 0.001). Ruminococcaceae, Lachnospiraceae and Blautia increased after SARS-CoV-2 infection resolution, rebalancing the gut microbiota composition. CONCLUSION: SARS-CoV-2 infection is associated with changes in the gut microbiome, which tend to be reversed in long-term period.

Depression and Endothelial Dysfunction in Psoriatic Arthritis: Is There Any Possible Relationship?

Background: Cardiovascular events (CVEs) are the first cause of death in patients with psoriatic arthritis (PsA). Depression is a recognized risk factor in cardiovascular events and is frequently associated with PsA. Flow-mediated dilatation (FMD) is a widely used method for assessing endothelial dysfunction, a parameter with strong prognostic implications for CVEs. The study aims to explore the relationship between FMD, depressive symptoms and serum cytokines in a cohort of patients with PsA. Patients and Methods: FMD was assessed in 50 consecutive PsA patients aged between 30 and 75 years without known cerebrovascular and coronary heart disease or diabetes. Depressive symptoms were reported using the related subscale of the Hospital Anxiety and Depression Scale (HDS). Disease features, activity indexes, and adjusted Framingham risk score (aFRS) were calculated. Serum level of IL-6, TNF-α, and IL-17A were also assessed. Results: In PsA patients (age 50.7 ± 10.2 years, male 42%, disease duration 5.9 ± 3.3 years, Disease Activity in PSoriatic Arthritis (DAPSA) score 14.0 ± 9.4) FMD inversely correlated with the severity of depressive symptoms according to HDS (ρ = -0.339, p = 0.016), age (ρ = -0.507, p = 0.001), aFRS (rs = -0.453, p < 0.001), duration of PsA (ρ = -0.507, p = 0.001), intensity of pain (ρ = -0.507, p = 0.001), and DAPSA (ρ = -0.507, p = 0.001). No statistically significant correlation was found between FMD or HDS and serum cytokines concentrations. HDS predicted FMD in a model adjusted for age, aFRS, PsA duration, and pain intensity (ß = -0.271, p = 0.008), with depressive symptoms contributing directly to 6.4% of the variance. Conclusions: Depressive symptoms correlate with endothelial dysfunction with an exposure-response pattern in our cohort of PsA patients.

Liver involvement is not associated with mortality: results from a large cohort of SARS-CoV-2-positive patients.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is frequently associated with liver test abnormalities. AIMS: To describe the evolution of liver involvement during SARS-CoV-2 infection and its effect on clinical course and mortality. METHODS: Data of 515 SARS-CoV-2-positive patients were collected at baseline and during follow-up, last evaluation or death. Stratification based on need for hospitalisation, severe disease and admission to intensive care unit (ICU) was performed. The association between liver test abnormalities (baseline and peak values) and ICU admission or death was also explored. RESULTS: Liver test abnormalities were found in 161 (31.3%) patients. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) were increased in 20.4%, 19% and 13.6% of patients, respectively. Baseline liver test abnormalities were associated with increased risk of ICU admission (OR 2.19 [95% CI 1.24-3.89], P = 0.007) but not with mortality (OR 0.84 [95% CI 0.49-1.41], P = 0.51). Alkaline phosphatase (ALP) peak values were correlated with risk of death (OR 1.007 [95% CI 1.002-1.01], P = 0.005) along with age, multiple comorbidities, acute respiratory distress syndrome, ICU admission and C-reactive protein. Alterations of liver tests worsened within 15 days of hospitalisation; however, in patients with the longest median follow-up, the prevalence of liver test alterations decreased over time, returning to around baseline levels. CONCLUSIONS: In SARS-CoV-2-positive patients without pre-existing severe chronic liver disease, baseline liver test abnormalities are associated with the risk of ICU admission and tend to normalise over time. The ALP peak value may be predictive of a worse prognosis.

Incidence of deep vein thrombosis among non-ICU patients hospitalized for COVID-19 despite pharmacological thromboprophylaxis.

BACKGROUND: A remarkably high incidence of venous thromboembolism (VTE) has been reported among critically ill patients with COVID-19 assisted in the intensive care unit (ICU). However, VTE burden among non-ICU patients hospitalized for COVID-19 that receive guideline-recommended thromboprophylaxis is unknown. OBJECTIVES: To determine the incidence of VTE among non-ICU patients hospitalized for COVID-19 that receive pharmacological thromboprophylaxis. METHODS: We performed a systematic screening for the diagnosis of deep vein thrombosis (DVT) by lower limb vein compression ultrasonography (CUS) in consecutive non-ICU patients hospitalized for COVID-19, independent of the presence of signs or symptoms of DVT. All patients were receiving pharmacological thromboprophylaxis with either enoxaparin or fondaparinux. RESULTS: The population that we screened consisted of 84 consecutive patients, with a mean age of 67.6 ± 13.5 years and a mean Padua Prediction Score of 5.1 ± 1.6. Seventy-two patients (85.7%) had respiratory insufficiency, required oxygen supplementation, and had reduced mobility or were bedridden. In this cohort, we found 10 cases of DVT, with an incidence of 11.9% (95% confidence interval [CI] 4.98-18.82). Of these, 2 were proximal DVT (incidence rate 2.4%, 95% CI -0.87-5.67) and 8 were distal DVT (incidence rate 9.5%, 95% CI 3.23-5.77). Significant differences between subjects with and without DVT were D-dimer > 3000 µg/L (P < .05), current or previous cancer (P < .05), and need of high flow nasal oxygen therapy and/or non-invasive ventilation (P < .01). CONCLUSIONS: DVT may occur among non-ICU patients hospitalized for COVID-19, despite guideline-recommended thromboprophylaxis.

Minimal Hepatic Encephalopathy is Associated with Increased Cerebral Vascular Resistance. A Transcranial Doppler Ultrasound Study.

Minimal hepatic encephalopathy (MHE) is a subclinical complication of liver cirrhosis with a relevant social impact. Thus, there is urgent need to implement easy to use diagnostic tools for the early identification of affected patients. The aim of this study was to investigate cerebral blood flow, systemic hemodynamics as well as endothelial function of cirrhotic patients with MHE, and to verify their change after treatment with rifaximin. Fifty cirrhotic patients with or without MHE and an equal number of healthy controls underwent transcranial Doppler ultrasound (TCD), abdominal Doppler ultrasound (US), and measurement of flow mediated dilation (FMD). In cirrhotic patients diagnosed with MHE receiving rifaximin, the tests were repeated at the end of treatment. Middle (MCA) and posterior (PCA) cerebral artery resistive (RI) and pulsatility (PI) indices were higher in cirrhotic patients than controls, as well as renal and splenic artery RI. Conversely, FMD was reduced. MCA-RI and PI were even higher in cirrhotic patients with MHE compared to those without; a MCA-RI cut-off of 0.65 showed an accuracy of 74% in discriminating the presence of MHE, with 65% sensitivity and 76% specificity. Rifaximin treatment showed no efficacy in the modulation of cerebral vascular flow. In conclusion, cirrhotic patients with MHE have significantly increased cerebral vascular resistances that are not improved by rifaximin treatment. MCA-RI measurement has a good accuracy for the diagnosis of MHE and can be useful for the early identification of this harmful complication of liver cirrhosis.

Effects of a New Combination of Medical Food on Endothelial Function and Lipid Profile in Dyslipidemic Subjects: A Pilot Randomized Trial.

Nutritional approaches to improve dyslipidemias have been recently developed, but evidences on different medical foods are often incomplete. The main aim of our study was to evaluate the effects on endothelial function, lipid profile, and glucose metabolism of two different combinations of nutraceuticals, first one containing Bergavit (200 mg Citrus bergamia), Omega-3 (400 mg), Crominex 3+ (10 mcg trivalent chromium), and red yeast rice (100 mg; 5 mg monacolin K) and second one containing red yeast rice (200 mg; 3 mg monacolin K), Berberine (500 mg), Astaxanthin (0.5 mg), folic acid (200 mcg), Coenzyme Q10 (2 mg), and Policosanol (10 mg). Fifty subjects affected by dyslipidemia not requiring statin treatment were enrolled in this randomized, blind, controlled trial and submitted to blood sampling for lipid and glucose profiles and instrumental evaluation of endothelial function before and after 6 weeks of treatment with nutraceuticals. Both nutraceutical combinations improved the lipid profile; the nutraceutical containing 5 mg of monacolin K, 200 mg of the extract Citrus bergamia, 400 mg of Omega-3, and 10 mcg of trivalent chromium entailed a significant improvement of endothelial function with enhanced cholesterol lowering effect. In conclusion, this study confirms the positive effect of functional food on lipid profile and endothelial function in absence of major undesirable effects.

Exercise and Protein Intake: A Synergistic Approach against Sarcopenia.

Sarcopenia, the age-dependent loss of muscle mass and function/strength, is increasingly recognized as a major risk factor for adverse outcomes in frail older people. As such, the skeletal muscle is a relevant target for interventions aimed at preventing or postponing the occurrence of negative health-related events in late life. The association among physical inactivity, insufficient intake of energy and protein, and poor muscle health in older adults suggests that physical exercise and targeted nutritional supplementation may offer substantial therapeutic gain against sarcopenia and its negative correlates. This view is supported by observational studies as well as by small-scale clinical trials. In this review, we summarize the available evidence on the beneficial effects of behavioral interventions on sarcopenia. We also briefly describe how the knowledge gathered so far has been used to design the "Sarcopenia and Physical fRailty IN older people: multicomponenT Treatment strategies" (SPRINTT) project. The randomized clinical trial conducted within SPRINTT will provide robust evidence on the effectiveness of exercise and nutrition at preventing negative outcomes associated with sarcopenia and physical frailty.

New semiquantitative ultrasonographic score for peripheral arterial disease assessment and its association with cardiovascular risk factors.

The data concerning the distribution, extent and progression of peripheral arterial disease (PAD), as well as its association with traditional cardiovascular (CV) risk factors, have generally been obtained from studies of patients in advanced stages of the disease undergoing surgical or endovascular treatment. In this study, we have introduced a new semiquantitative ultrasonographic score (ultrasonographic lower limb atherosclerosis (ULLA) score) that is able to categorize lower limb atherosclerotic lesions at all stages of PAD. We then associated these ultrasonographic categories with a CV risk profile. We enrolled 320 consecutive subjects with symptoms suggestive of PAD or with known CV risk factors referring to our angiology unit between 1 July 2014 and 30 June 2015 for ultrasonographic evaluation of the lower limb arteries. Femoropopliteal and run-off segments were categorized together and separately based on their ultrasonographic characteristics. In univariate and multivariate analyses, the ULLA scores were significantly associated with the main CV risk factors, that is, age, male gender, cigarette smoking, arterial hypertension, diabetes, dyslipidemia, sedentary lifestyle, previous CV events and family history of CV disease, and also confirming the specific association of single risk factors with different segments of lower limb arteries. The proposed ULLA score enables a complete evaluation of the entire lower limb atherosclerotic burden, extending the results concerning the association of PAD with CV risk factors to all stages of the disease, including the early stages. It can be feasible that this new score will facilitate better evaluation of the progression of PAD and its prospective role in CV risk stratification.