Distinct platelet crosstalk with adaptive and innate immune cells after adenoviral and mRNA vaccination against SARS-CoV-2

Background: Genetic-based COVID-19 vaccines have proved highly effective in reducing the risk of hospitalization and death. As they were first distributed on a large-scale population, adenoviral-based vaccines were linked to a very rare thrombosis with thrombocytopenia syndrome and the interplay between platelets and vaccinations increasingly gained attention. Objective: To study the crosstalk between platelets and the vaccine-induced immune response. Methods: We prospectively enrolled young healthy volunteers who received the mRNA-based vaccine, BNT162b2 (n=15), or the adenovirus-based vaccine, AZD1222 (n=25) and studied their short-term platelet and immune response before and after vaccine injections. In a separate cohort, we retrospectively analysed the effect of aspirin on the antibody response 1 and 5 months after BNT162b2 vaccination. Results: Here we show that a faster antibody response to either vaccine is associated to the formation of platelet aggregates with marginal zone-like B-cells, a subset geared to bridge the temporal gap between innate and adaptive immunity. However, while the mRNA-based vaccine is associated with a more gradual and tolerogenic response that fosters the crosstalk between platelets and adaptive immunity, the adenovirus-based vaccine, the less immunogenic of the two, evokes an antiviral-like response during which platelets are cleared and less likely to cooperate with B-cells. Moreover, subjects taking aspirin (n=56) display lower antibody levels after BNT162b2 vaccination compared to matched individuals. Conclusions: Platelets are a component of the innate immune pathways that promote the B-cell response after vaccination. Future studies on the platelet-immune crosstalk post-immunization will improve safety, efficacy, and strategic administration of next-generation vaccines

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound\u2010detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross\u2010sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, 120.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40\u2010ligand (P = 0.0238), soluble Nox2\u2010derived peptide (sNox2\u2010dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD40L (Spearman\u2019s rank correlation coefficient [rs], 120.33; P < 0.001), sNox2\u2010dp (rs, 120.57; P < 0.0001), and urinary excretion of isoprostanes (rs, 120.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2\u2010dp, and urinary 8\u2010iso prostaglandin F2\u3b1\u2010III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2\u2010dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Factors Associated with Progression of Atrial Fibrillation and Impact on All-Cause Mortality in a Cohort of European Patients

BackgroundParoxysmal atrial fibrillation (AF) may often progress towards more sustained forms of the arrhythmia, but further research is needed on the factors associated with this clinical course.MethodsWe analyzed patients enrolled in a prospective cohort study of AF patients. Patients with paroxysmal AF at baseline or first-detected AF (with successful cardioversion) were included. According to rhythm status at 1 year, patients were stratified into: (i) No AF progression and (ii) AF progression. All-cause death was the primary outcome.ResultsA total of 2688 patients were included (median age 67 years, interquartile range 60-75, females 44.7%). At 1-year of follow-up, 2094 (77.9%) patients showed no AF progression, while 594 (22.1%) developed persistent or permanent AF. On multivariable logistic regression analysis, no physical activity (odds ratio [OR] 1.35, 95% CI 1.02-1.78), valvular heart disease (OR 1.63, 95% CI 1.23-2.15), left atrial diameter (OR 1.03, 95% CI 1.01-1.05), or left ventricular ejection fraction (OR 0.98, 95% CI 0.97-1.00) were independently associated with AF progression at 1 year. After the assessment at 1 year, the patients were followed for an extended follow-up of 371 days, and those with AF progression were independently associated with a higher risk for all-cause death (adjusted hazard ratio 1.77, 95% CI 1.09-2.89) compared to no-AF-progression patients.ConclusionsIn a contemporary cohort of AF patients, a substantial proportion of patients presenting with paroxysmal or first-detected AF showed progression of the AF pattern within 1 year, and clinical factors related to cardiac remodeling were associated with progression. AF progression was associated with an increased risk of all-cause mortality

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

La sindrome metabolica: un modello clinico-terapeutico di endocrinologia di genere

Numerosi componenti contribuiscono all’insorgenza e alla progressione della sindrome metabolica e questi fattori differiscono significativamente fra i due sessi. È importante chiarire quali siano i meccanismi molecolari sottostanti a queste differenze correlate al sesso. È inoltre necessario condurre studi che includano anche variabili genere-specifiche (socioculturali, ambientali, ecc.), al fine di identificare criteri specifici per la gestione clinica e farmacologica del paziente

Gender-related determinants of adherence to the mediterranean diet in adults with ischemic heart disease

BACKGROUND:The reasons behind low adherence to the Mediterranean diet (Med-diet) are still not entirely known. We aimed to evaluate the effect of biological (i.e., sex-related) and psycho-socio-cultural (i.e., gender-related) factors on Med-diet adherence. METHODS:Baseline Med-diet adherence was measured using a self-administered questionnaire among adults with ischemic heart disease (IHD) from the EVA (Endocrine Vascular Disease Approach) study. A multivariable analysis was performed to estimate the effect of sex- and gender-related factors (i.e., identity, roles, relations, and institutionalized gender) on low adherence. RESULTS:Among 366 participants (66 ± 11 years, 31% women), 81 (22%) adults with low adherence demonstrated higher rates of diabetes, no smoking habit, lower male BSRI (Bem Sex Role Inventory) (median (IQR) 4.8 (4.1 to 5.5) vs. 5.1 (4.5 to 5.6) and p = 0.048), and higher Perceived Stress Scale 10 items (PSS-10) (median (IQR) 19 (11 to 23) vs. 15 (11 to 20) and p = 0.07) scores than those with medium-high adherence. In the multivariable analysis, only active smoking (odds ratio, OR = 2.10, 95% confidence interval, CI 1.14 to 3.85 and p = 0.017), PPS-10 (OR = 1.04, 95% CI 1.00 to 1.08, and p = 0.038) and male BSRI scores (OR = 0.70, 95% CI 0.52 to 0.95, and p = 0.021) were independently associated with low adherence. CONCLUSIONS:Male personality traits and perceived stress (i.e., gender identity) were associated with low Med-diet adherence regardless of the sex, age, and comorbidities. Therefore, gender-sensitive interventions should be explored to improve adherence in IHD

Female Sex Is Independently Associated To Coronary Microvascular Dysfunction And Worse Myocardial Reperfusion After Percutaneous Coronary Interventions

Introduction: Improvements in ischemic heart disease (IHD) management have been unbalanced between sexes. Coronary microvascular dysfunction (CMD) is a putative reason for worse outcomes in women. Hypothesis: To explore sex and gender-sensitive determinants of CMD in IHD patients. Methods: The Endocrine Vascular disease Approach (EVA) is an ongoing monocentric observational study, aimed to assess sex- and gender-specific interactions between coronary circulation, hormonal status, and platelet function. Consecutive IHD patients undergoing urgent or elective angiography with or without percutaneous coronary interventions (PCI) were enrolled. CMD was assessed using myocardial blush grade (MBG). Baseline clinical, pharmacological and sociocultural parameters were recorded. Results: One hundred and sixty-three patients (mean age 67±11 years; 39% women) were analyzed. The referral reason for angiography was acute coronary syndrome in half cases, regardless sex. A previous IHD diagnosis was reported more frequently in men, women were less smokers, more frequently retired and widow, less adherent to medication therapy (all, p<0.05). The Duke Activity Status Index identified a worse performance status in women compared to men (28.2±18 vs 38.3±17, p=0.0002). The median in-hospital stay was longer in women (9 [6-17.5] vs 7 [4-12.5] days, p=0.032). CMD (defined by MBG<2) was significantly more frequently detected in women compared to men (48% vs 31%, p=0.034). Ischemia with no obstructive coronary disease was prevalent in women (40% vs 25%, p= 0.017). In the subgroup of patients undergoing PCI (n=68, 41.7%) the no achievement of optimal microvascular reperfusion (MBG=3), despite optimal restoration of epicardial flow, was higher in women compared to men (86% vs 56%, p=0.015). In the multiple regression analysis, only female sex was independently associated to CMD (OR 2.02, 95% CI 1.05-3.88, p=0.034) and to a MBG<3 after PCI (OR 4.88, 95% CI 1.26-18.7, p=0.022). Conclusions: Female sex is significantly associated with both CMD and worst myocardial perfusion after PCI. The further exploration of hormonal balance and platelet reactivity, as well as availability of outcomes data in the EVA cohort, will provide deepen insights to analyze this phenomenon

High focused Evaluation of Atherosclerotic risk profile in Retinal Thrombosis: Vascular events Incidence, Sex involvement and Interventional outcomes assessed by Ophthalmologists and internists Network – HEART VISION study protocol

Background and objectives: Retinal vein occlusion (RVO), one of the most relevant causes of vision loss, still represents an open issue in ophthalmology and vascular medicine. Its epidemiology and management approach have not been clearly characterized yet, with several grey zones requiring investigation. Significance of RVO on cardiovascular prognosis is also unclear. “High focused Evaluation of Atherosclerotic risk profile in Retinal Thrombosis: Vascular events Incidence, Sex involvement and Interventional outcomes assessed by Ophthalmologists and internists Network” (HEART VISION) is a longitudinal, prospective, multi-center study which aims at determining the epidemiology, potentially modifiable risk factors and the determinants of RVO in an Italian-based cohort. Methods: Enrollment of all the eligible patients presenting to recruiting centers (i.e. ophthalmology emergency room and thrombosis centers) with suspect of RVO. At baseline, all patients will undergo an opthalmologic evaluation and further investigations about cardiovascular co-morbidities and risk factors. Recruited patients will be followed for a 2-year period. Outcome measures: Data about adverse cardiovascular events and eye-related outcomes will be recorded. Discussion: HEART VISION will present data on prevalence and will inform on the prognosis of RVO in an Italian-based cohort. Characterization and prospective evaluation of these patients will be useful in developing novel strategies for management of RVO and their cardiovascular-related risk factors. Ethics and dissemination: This study protocol (n. 1.0, 01.07.2014) was approved by the Sapienza-University of Rome, Ethics Board (Protocol No. 1076/14). This study will be performed in accordance with the Declaration of Helsinki. Dissemination plans include presentations at scientific conferences and publication in scientific journals. Trial registration: ClinicalTrials.gov Identifier: NCT02257333 on October 6, 2014

Asymptomatic vs. symptomatic atrial fibrillation: Clinical outcomes in heart failure patients

Background: The outcome implications of asymptomatic vs. symptomatic atrial fibrillation (AF) in specific groups of patients according to clinical heart failure (HF) and left ventricular ejection fraction (LVEF) need to be clarified. Methods: In a prospective observational study, patients were categorized according to overt HF with LVEF≤40 %, or with LVEF>40 %, or without overt HF with LVEF40 %≤ or > 40 %, as well as according to the presence of asymptomatic or symptomatic AF. Results: A total of 8096 patients, divided into 8 groups according to HF and LVEF, were included with similar proportions of asymptomatic AF (ranging from 43 to 48 %). After a median follow-up of 730 [699 -748] days, the composite outcome (all-cause death and MACE) was significantly worse for patients with asymptomatic AF associated with HF and reduced LVEF vs. symptomatic AF patients of the same group (p = 0.004). On adjusted Cox regression analysis, asymptomatic AF patients with HF and reduced LVEF were independently associated with a higher risk for the composite outcome (aHR 1.32, 95 % CI 1.04-1.69) and all-cause death (aHR 1.33, 95 % CI 1.02-1.73) compared to symptomatic AF patients with HF and reduced LVEF. Kaplan-Meier curves showed that HF-LVEF≤40 % asymptomatic patients had the highest cumulative incidence of all-cause death and MACE (p < 0.001 for both). Conclusions: In a large European cohort of AF patients, the risk of the composite outcome at 2 years was not different between asymptomatic and symptomatic AF in the whole cohort but adverse implications for poor outcomes were found for asymptomatic AF in HF with LVEF≤40 %

Platelet and immune signature associated with a rapid response to the BNT162b2 mRNA COVID-19 vaccine

none18noMinistero Italiano Istruzione Università e Ricerca, Grant/Award Number: 2017ATZ2YK and 2017WJBKKW_003Background: A rapid immune response is critical to ensure effective protection against COVID-19. Platelets are first-line sentinels of the vascular system able to rapidly alert and stimulate the immune system. However, their role in the immune response to vaccines is not known. Objective: To identify features of the platelet-immune crosstalk that would provide an early readout of vaccine efficacy in adults who received the mRNA-based COVID-19 vaccine (BNT162b2). Methods: We prospectively enrolled 11 young healthy volunteers (54% females, median age: 28 years) who received two doses of BNT162b2, 21 days apart, and we studied their platelet and immune response before and after each dose of the vaccine (3 and 10 ± 2 days post-injection), in relation to the kinetics of the humoral response. Results: Participants achieving an effective level of neutralizing antibodies before the second dose of the vaccine (fast responders) had a higher leukocyte count, mounted a rapid cytokine response that incremented further after the second dose, and an elevated platelet turnover that ensured platelet count stability. Their circulating platelets were not more reactive but expressed lower surface levels of the immunoreceptor tyrosine-based inhibitory motif (ITIM)-coupled receptor CD31 (PECAM-1) compared to slow responders, and formed specific platelet-leukocyte aggregates, with B cells, just 3 days after the first dose, and with non-classical monocytes and eosinophils. Conclusion: We identified features of the platelet-immune crosstalk that are associated with the development of a rapid humoral response to an mRNA-based vaccine (BNT162b2) and that could be exploited as early biomarkers of vaccine efficacy.openFlego, Davide; Cesaroni, Simone; Romiti, Giulio F; Corica, Bernadette; Marrapodi, Ramona; Scafa, Noemi; Maiorca, Francesca; Lombardi, Ludovica; Pallucci, Davide; Pulcinelli, Fabio; Raparelli, Valeria; Visentini, Marcella; Cangemi, Roberto; Piconese, Silvia; Alvaro, Domenico; Polimeni, Antonella; Basili, Stefania; Stefanini, LuciaFlego, Davide; Cesaroni, Simone; Romiti, Giulio F; Corica, Bernadette; Marrapodi, Ramona; Scafa, Noemi; Maiorca, Francesca; Lombardi, Ludovica; Pallucci, Davide; Pulcinelli, Fabio; Raparelli, Valeria; Visentini, Marcella; Cangemi, Roberto; Piconese, Silvia; Alvaro, Domenico; Polimeni, Antonella; Basili, Stefania; Stefanini, Luci