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Background Cardiovascular diseases are the leading cause of mortality, morbidity, and disability in the world, especially in the older adults. A relevant proportion of patients admitted to Cardiac Rehabilitation (CR) may suffer from frailty, a complex geriatric syndrome with multifactorial aetiology. Aims The hypothesis underlying the study is that frailty complicates the management of older patients undergoing CR. The main objective is, therefore, to determine the relationship between frailty and CR outcomes in hospitalized older adults. Methods The participants have been recruited among patients aged ≥ 65 years admitted at the hospital for CR. A Comprehensive Geriatric Assessment (CGA)-based Frailty Index (FI) was created following a standard procedure. The outcome was measured as the ratio between 6-min walk test (6MWT) distance at the end of CR and normal predicted values for a healthy adult of same age and gender, according to reference equations. Results The study population consisted of 559 elderly patients, 387 males (69.2%), with age of 72 (69–76) years. The most frequent diagnosis at admission was ischaemic heart disease (231, 41.5%) and overall 6MWT ratio was 0.62 ± 0.21. At the multivariable regression analysis, gender, diagnosis and FI were significantly and independently associated with 6MWT ratio (p ≤ 0.0001, p ≤ 0.001 and p ≤ 0.0001, respectively), while no significant association emerged for age. Conclusion FI resulted independently correlated to 6MWT ratio in a population of older patients undergoing in-hospital CR programs. Frailty is a multifactorial geriatric syndrome whose assessment is essential for prognostic evaluation of older patients, also in CR clinical setting.

Introduction: The subcutaneous implantable cardioverter defibrillator (S-ICD) represents a major advancement in ICD technology. Inappropriate shocks (IAS) occur in more than 3.1% of the population with S-ICD each year and are usually followed by admission to the emergency department (ED). In this setting, the disabling of IAS is mandatory during a pseudo-electrical storm (ES). This report describes the strategies that can be followed in order to temporarily inhibit IAS in critical care settings with the use of magnets. Case presentation: An S-ICD was implanted more than 6 weeks prior to presentation in a 68-year-old man with hypertrophic cardiomyopathy. In the ED, the patient experienced 3 IAS in the last hour. A Medtronic magnet was applied to stop IAS, as the specific programmer was not available. The maneuver interrupted the IAS. In order to verify the universal magnetic response of the S-ICD, six different magnets and one smartphone with MagSafe technology were tested. All magnet models suspended arrhythmia detection and IAS, while the smartphone did not cause magnet interferences. Conclusions: This report demonstrates the safety and efficacy of all clinical magnet models in inhibiting IAS. In case of pseudo-ES, any type of magnet allows ED providers to easily and rapidly disable the functionality of the devices when appropriate.

Space Rider is the European program proposed to develop an affordable and sustainable reusable space transportation system to enable access to and return from space. To procure a safe and accurate ...

Aims Elevated maternal cholesterol during pregnancy (MCP) enhances atherogenesis in childhood, but its possible impact on acute myocardial infarction (AMI) in adults is unknown. Methods and results We retrospectively evaluated 310 patients who were admitted to hospital and whose MCP data were retrievable. Eighty-nine AMI patients with typical chest pain, transmural infarction Q-waves, elevated creatinine kinase, and 221 controls hospitalized for other reasons were identified. The AMI cohort was classified by MI severity (severe = involving three arteries, left ventricle ejection fraction ≤35, CK-peak >1200 mg/dL, or CK-MB >200 mg/dL). The association of MCP with AMI severity was tested by linear and multiple regression analysis that included conventional cardiovascular risk factors, gender, age, and treatment. Associations of MCP with body mass index (BMI) in patients were assessed by linear correlation. In the AMI cohort, MCP correlated with four measures of AMI severity: number of vessels (β = 0.382, P = 0.001), ejection fraction (β = −0.315, P = 0.003), CK (β = 0.260, P = 0.014), and CK-MB (β = 0.334, P = 0.001), as well as survival time (β = −0.252, P = 0.031). In multivariate analysis of patients stratified by AMI severity, MCP predicted AMI severity independently of age, gender, BMI, and CHD risk factors (odds ratio = 1.382, 95% confidence interval 1.046–1.825; P = 0.023). Survival was affected mainly by AMI severity. Conclusions Maternal cholesterol during pregnancy is associated with adult BMI, atherosclerosis-related risk, and severity of AMI.

This article presents a study on the Italian stay-behind network ‘Gladio’ based on documentary evidence from the Italian secret services made available in recent years. The aim is to re-contextuali...

In heart failure (HF), prognostic risk scores focus on all-cause mortality prediction. However, in advanced HF (AdHF) ambulatory patients awaiting heart transplantation (HTx), hospitalizations for acutely decompensated/worsening HF are relevant to clinical decision-making, but unpredicted by common risk functions.Among consecutive ambulatory patients added to the waitlist for HTx, event discriminators within 2 years from recruitment were assessed prospectively by area under the curve from receiver-operating characteristic curves, and by Cox proportional hazards models. Primary composite end points included the first between all-cause mortality and acutely decompensated/worsening HF requiring hospitalization and specific treatments.In 89 patients, 36 primary composite events were recorded in a 2-year follow-up (40% of the study sample), and associated with nonischemic etiology and nonsinus rhythm, with lower systolic blood pressure (BP), lower plasma sodium and hemoglobin concentrations, and with higher N-terminal pro-brain natriuretic peptide (NT-proBNP), larger left ventricular (LV) dimensions and lower LV ejection fraction, greater proportion of significant mitral regurgitation, lower tricuspid annulus peak systolic excursion (TAPSE), lower percentage of predicted distance at 6-minute walking test (%p6MWT) and lower global symptoms burden by the Kansas City Cardiomyopathy Questionnaire, lower peak oxygen uptake by cardiopulmonary exercise, and higher wedge pressure by right heart catheterization, as compared with those with no events (P 0.05). Only Metabolic Exercise Cardiac Kidney Index (MECKI) at recruitment was higher with patients reporting events, which predicted composite end points in addition to and independently of NT-proBNP, and lower systolic BP (all P 0.05). In an alternative risk model, severe mitral regurgitation and lower TAPSE replaced MECKI and BP but not NT-proBNP (all P 0.01).Higher NT-pro-BNP, lower systolic BP and higher MECKI may contribute to predicting all-cause death and acutely decompensated/worsening HF among ambulatory patients awaiting HTx, with lower TAPSE and severe mitral regurgitation representing further alternative independent prognosticators.

Data from the "Trattamento Ormonale nello Scompenso CArdiaco" (T.O.S.CA) registry showed that heart failure (HF) represents a complex clinical syndrome with different hormonal alterations. Renal failure represents a frequent complication in HF. We evaluated the relationship between renal function and insuline-like growth factor-1 (IGF-1) deficiency and its impact on cardiovascular mortality (CVM) in patients enrolled in the T.O.S.CA. registry.At the enrolment, all subjects underwent chemistry examinations, including circulating hormones and cardiovascular functional tests. COX regression analysis was used to evaluate factors related to CVM during the follow-up period in all populations, in high-risk patients and in the young-adult population. Also, we evaluate the effects of renal function on the CVM.337 patients (41 deceased) were analyzed. CVM was related to severe renal dysfunction (HR stages IV-V = 4.86), high-risk conditions (HR 2.25), serum IGF-1 (HR 0.42), and HF etiology (HR 5.85 and HR 1.63 for valvular and ischemic etiology, respectively). In high-risk patients, CVM was related to IGF-1 levels, severe renal dysfunction and valvular etiology, whereas in young patients CMV was related to the high-risk pattern and serum IGF-1 levels.Our study showed the clinical and prognostic utility of the IGF-1 assay in patients with HF.

Aims: The study assesses the reliability of fr-AGILE, a validated rapid tool used for the evaluation of multidimensional frailty in older adults hospitalized with COVID-19. Methods: Two different staff members independently assessed the presence of frailty in 144 patients aged ≥ 65 years affected by COVID-19 using the fr-AGILE tool. The internal consistency of fr-AGILE was evaluated by examining the item-total correlations and the Kuder–Richardson (KR) formula. The inter-rater reliability was evaluated using linear weighted kappa. Results: Multidimensional frailty severity increases with age and is associated to higher use of non-invasive ventilation (p = 0.025), total severity score on chest tomography (p = 0.001) and in-hospital mortality (p = 0.032). Fr-AGILE showed good internal consistency (KR-20 = 0.742) and excellent inter-rater reliability (weighted kappa = 0.752 and 0.878 for frailty score and frailty degree, respectively). Conclusions: fr-AGILE tool can quickly identify and quantify multidimensional frailty in hospital settings for older patient affected by COVID-19.

The aim of this study was to characterize both by flow cytometry analysis and immunohistochemistry cervix uteri cells of nulliparous women screened for cervical intraepithelial neoplasia (CIN) in comparison to a group without CIN by using mesenchymal stem cell-like and hematopoietic lineage markers. A significant expression for CD29, CD38, HLA-I, and HLA-II was correlated positively to the CIN degree and it was more relevant in patients positive for human papilloma virus (HPV). Thus, identification and detailed characterization of pluripotent resident in uteri cells could be a promising therapeutic target.

Background: Early pathogenesis of diabetic cardiomyopathy (DMCM) may involve lipotoxicity of cardiomyocytes in the context of hyperglycemia. There are many preclinical studies of DMCM pathogenesis, but the human evidence is still poorly understood. Objectives: By using a nondiabetic mellitus (non-DM) heart transplanted (HTX) in diabetes mellitus (DM) recipients, this study conducted a serial study of human heart transplant recipients evaluating cardiac effects of diabetic milieu (hyperglycemia and insulin resistance) on lipotoxic-mediated injury. We evaluated cardiomyocyte morpho-pathology by seriated biopsies of healthy implanted hearts in DM recipients during 12-month follow-up from HTX. Because metformin reduces ectopic lipid accumulation, we evaluated the effects of the drug in a nonrandomized subgroup. Methods: The DMCM-AHEAD (Diabetes and Lipid Accumulation and Heart Transplant) prospective ongoing study (NCT03546062) evaluated 158 first HTX recipients (82 non-DM, 76 DM of whom 35 [46%] were receiving metformin). HTX recipients were undergoing clinical standard evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsies). Biopsies evaluated immune response, Oil Red-O staining, ceramide, and triacylglycerol levels. Lipotoxic factors and insulin resistance were evaluated by reverse transcriptase–polymerase chain reaction. Results: There was a significant early and progressive cardiomyocyte lipid accumulation in DM but not in non-DM recipients (p = 0.019). In the subgroup receiving metformin, independently from immunosuppressive therapy that was similar among groups, lipid accumulation was reduced in comparison with DM recipients not receiving the drug (hazard ratio: 6.597; 95% confidence interval: 2.516 to 17.296; p < 0.001). Accordingly, lipotoxic factors were increased in DM versus non-DM recipients, and, relevantly, metformin use was associated with fewer lipotoxic factors. Conclusions: Early pathogenesis of human DMCM started with cardiomyocyte lipid accumulation following HTX in DM recipients. Metformin use was associated with reduced lipid accumulation independently of immunosuppressive therapy. This may constitute a novel target for therapy of DMCM.

Aims The aim of this study was to investigate prospectively the effect of sacubitril/valsartan in advanced heart failure (HF) patients in waiting list for heart transplantation (HT) and the effect on physical frailty (PF). Methods and results We treated 37 consecutive patients with advanced HF with sacubitril/valsartan. Patients were followed up until HT, device implant, or last follow‐up visit after 2 years of follow‐up. At baseline, mean New York Heart Association (NYHA) class was 3.1 ± 0.4, with 64.9% in NYHA III and 35.1% NYHA IIIB. Left ventricular ejection fraction was 23.5 ± 5.8%, VO2 max was 10.3 ± 2.3 mL/kg/min, cardiac index was 2.3 ± 0.5 L/min/m2, and N‐terminal pro‐brain natriuretic peptide (NT‐pro‐BNP) was 4943.0 ± 5326.8 pg/mL. After a mean follow‐up of 17.1 ± 4.4 months, no deaths were observed, but NYHA class improved significantly with 56.8% in NYHA II, 40.5% in NYHA III, and 2.7% in NYHA IIIB (P < 0.001). VO2 max and 6 min walk test (6MWT) increased, whereas pulmonary systolic blood pressure, E/E′, VE/VCO2 slope, and NT‐pro‐BNP decreased. At right heart catheterization performed after 1 year of follow‐up, cardiac index and pulmonary vascular resistance remained stable, while a decrease in systolic pulmonary artery pressure and pulmonary capillary wedge pressure is observed. Furosemide dosage decrease from 102.7 ± 69.4 to 78.7 ± 66.3 mg (P = 0.040). PF decreased from 3.35 ± 1.0 at baseline to 1.57 ± 1.3 at the end of follow‐up (P < 0.001), with a reduction in all PF domains. Conclusions Our study showed a rapid improvement in PF in HT waiting list patients treated with sacubitril/valsartan. The improvement in all PF domains was paralleled by VO2 and 6MWT increase and together with an NT‐pro‐BNP reduction constant over the follow‐up.

The meeting of the European Innovation Partnership on Active and Healthy Ageing (EIPonAHA) action group A3 together with members of the Reference site collaborative network (RSCN) in December 2019 in Rome focused on integration of evidence-based approaches on health and care delivery for older citizens at different levels of needs with expertise coming from stakeholder across Europe. It was the final aim of the group to co-create culturally sensitive pathways and facilitate co-ownership for further implementation of the pathways in different care systems across Europe. The study design is a mixed method approach. Based on data analysis from a cohort of community-dwelling over-65 citizens in the framework of a longitudinal observational study in Rome, which included health, social and functional capacity data, three personas profiles were developed: the pre-frail, the frail and the very frail personas. Based on these data, experts were asked to co-create care pathways due to evidence and eminence during a workshop and included into a final report. All working groups agreed on a common understanding that integration of care means person-centered integration of health and social care, longitudinally provided across primary and secondary health care including citizens' individual social, economic and human resources. Elements for consideration during care for pre-frail people are loneliness and social isolation, which, lead to limitation of physical autonomy in the light of reduced access to social support. Frail people need adaption of environmental structures and, again, social resource allocation to maintain at home. Very frail are generally vulnerable patients with complex needs. Most of them remain at home because of a strong individual social support and integrated health care delivery. The approach described in this publication may represent a first approach to scaling-up care delivery in a person-centered approach.

This article describes how innovations are exploited in Campania (Italy) to improve health outcomes, quality of life, and sustainability of social and healthcare services. Campania's strategy for digitalization of health and care and for healthy aging is based on a person-centered, life-course, “One Health” approach, where demographic change is considered capable of stimulating a growth dynamic linked to the opportunities of combining the “Silver Economy” with local assets and the specific health needs of the population. The end-users (citizens, patients, and professionals) contribute to the co-creation of products and services, being involved in the identification of unmet needs and test-bed activity. The Campania Reference Site of the European Innovation Partnership on Active and Healthy Aging is a flexible regional ecosystem to address the challenge of an aging population with a life-course approach. The good practices, developed in the context of research and innovation projects and innovative procurements by local stakeholders and collaborations with international networks, have been allowing the transfer of innovative solutions, knowledge, and skills to the stakeholders of such a multi-sectoral ecosystem for health.

BACKGROUND AND AIM: Permanent Atrial Fibrillation (pAF) is associated with increased risk of embolic complications. The relationship between pAF and pulmonary embolism (PE) has not been extensively investigated in elderly patients. Here, we aim at verifying whether pAF is associated to an increased risk of PE in a cohort of elderly patients with and without Deep Vein Thrombosis (DVT). METHODS: 235 patients older than 65 years with PE with or without pAF were retrospectively enrolled and stratified by the absence or presence of DVT. The diagnosis of PE was performed by computed tomography angiography (CTA). Right echocardiographic parameters were monitored. The severity of PE was evaluated by CTA quantization (PE score = 1, involvement of main branches of pulmonary artery) and by dimer-D (> 3000 µg/L). RESULTS: DVT was identified only in 51 cases of PE (21.7%). pAF prevalence was higher in PE without than in those with DVT (64.9% vs. 35.1%, p 3000 µg/L). CONCLUSIONS: We conclude that in elderly patients with PE, the prevalence of pFA was doubled, in the absence of DVT, and it is associated with a more severe PE in the absence than in the presence of DVT. Thus, in the absence of DVT, pFA should be considered as cause of PE.

Introduction A hypercoagulable condition was described in patients with coronavirus disease 2019 (COVID-19) and proposed as a possible pathogenic mechanism contributing to disease progression and lethality. Aim We evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients. Methods In a retrospective observational study, 2,574 unselected patients hospitalized in 30 clinical centers in Italy from February 19, 2020 to June 5, 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection were analyzed. The primary endpoint in a time-to event analysis was in-hospital death, comparing patients who received heparin (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores. Results Out of 2,574 COVID-19 patients, 70.1% received heparin. LMWH was largely the most used formulation (99.5%). Death rates for patients receiving heparin or not were 7.4 and 14.0 per 1,000 person-days, respectively. After adjustment for propensity scores, we found a 40% lower risk of death in patients receiving heparin (hazard ratio = 0.60; 95% confidence interval: 0.49–0.74; E-value = 2.04). This association was particularly evident in patients with a higher severity of disease or strong coagulation activation. Conclusion In-hospital heparin treatment was associated with a lower mortality, particularly in severely ill COVID-19 patients and in those with strong coagulation activation. The results from randomized clinical trials are eagerly awaited to provide clear-cut recommendations.

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February–May 2020). Patients’ characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction ( p < 0.001 ). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment.

Heart failure (HF) is a clinical syndrome characterized by typicalsymptoms and signscaused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. Due to increasing incidence, prevalence and, most importantly mortality, HF is a healthcare burden worldwide, despite the improvement of treatment options and effectiveness. Acute and chronic cardiac injuries trigger the activation of neurohormonal, inflammatory, and mechanical pathways ultimately leading tofibrosis, which plays a key role in the development of cardiac dysfunction and HF. The use ofnanoparticlesfortargeted drug deliverywould greatly improve therapeutic options to identify, prevent and treatcardiac fibrosis. In this review we will highlight the mechanisms of cardiac fibrosis development to depict the pathophysiological features for passive and active targeting of acute and chronic cardiac fibrosis with nanoparticles. Then we will discuss how cardiomyocytes, immune and inflammatory cells, fibroblasts and extracellular matrix can be targeted with nanoparticles to prevent or restore cardiac dysfunction and to improve themolecular imagingof cardiac fibrosis.

The utilization of hybridized INS/GNSS systems for space launcher applications presents big advantages with respect to the conventional navigators (as INS alone) used in such applications. However, for its integration it is necessary to cope with some challenging facts when using a GNSS receiver in a space launcher: the extreme dynamics as accelerations and jerks caused by the own launcher propulsion and the separation of the different stages, the environmental conditions caused by engines vibration, the rapidly changing environment caused by fast altitude increments, the launcher continuously rotating in roll and its effects on satellite visibility, the changing elevation angles, etcetera. In the frame of the project NAVIGA-VNE, SENER Aeroespacial (as project prime and Data Fusion design authority - DF), Deimos Space (as GNSS receiver design authority), and AVIO as the final integrator, are jointly working on the development of the Vega-C Navigation Equipment (VNE), an INS/GNSS navigation system aimed for the precise estimation of the PVT trajectory and attitude of AVIO’s VEGA-C space launcher. The objective of this paper is the description of the tools developed to support the VNE GNSS and Data Fusion and verification. It is overviewed the elements of the environment that have been modelled. Then a description of the GNSS performance model integrated in the Data Fusion Functional Engineering Simulator (DF-FES) tool is performed, focusing on the geometrical and signal propagation, the way the receiver logic has been simulated and the error models that have been included for the generation of the simulated GNSS raw observations. It is also explained how the GNSS model has been validated using a semi-analytical GNSS simulator that has also been developed in the frame of this project from tools already available at Deimos Space. After that, the integration of the performance model with other elements of the DF-FES is described; focusing on the iteration of the GNSS model with the integrated GNSS PVT estimator also developed by Deimos Space (also known as Navigation Processor or NAVPRO), which among other features integrates a velocity estimator based on Time Difference Carrier Phase (TDCP) algorithm. Finally, some relevant results of the GNSS performance model, with NAVPRO PVT output and DF PVT output will be included.

Background and aims There is poor knowledge on characteristics, comorbidities and laboratory measures associated with risk for adverse outcomes and in-hospital mortality in European Countries. We aimed at identifying baseline characteristics predisposing COVID-19 patients to in-hospital death. Methods and results Retrospective observational study on 3894 patients with SARS-CoV-2 infection hospitalized from February 19th to May 23rd, 2020 and recruited in 30 clinical centres distributed throughout Italy. Machine learning (random forest)-based and Cox survival analysis. 61.7% of participants were men (median age 67 years), followed up for a median of 13 days. In-hospital mortality exhibited a geographical gradient, Northern Italian regions featuring more than twofold higher death rates as compared to Central/Southern areas (15.6% vs 6.4%, respectively). Machine learning analysis revealed that the most important features in death classification were impaired renal function, elevated C reactive protein and advanced age. These findings were confirmed by multivariable Cox survival analysis (hazard ratio (HR): 8.2; 95% confidence interval (CI) 4.6–14.7 for age ≥85 vs 18–44 y); HR = 4.7; 2.9–7.7 for estimated glomerular filtration rate levels, Highlights • Impaired renal function, elevated C-reactive protein and advanced age were major indicators of death in COVID-19 patients. • These associations were substantially homogenous across all sub-groups analysed. • No relation was found with obesity, tobacco use, cardiovascular disease and related-comorbidities. • Death rates were higher in the Northern as opposed to Central-Southern Italian regions.

Background Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19. Objective We set-up a multicenter Italian collaboration to investigate the relationship between HCQ therapy and COVID-19 in-hospital mortality. Methods In a retrospective observational study, 3,451 unselected patients hospitalized in 33 clinical centers in Italy, from February 19, 2020 to May 23, 2020, with laboratory-confirmed SARS-CoV-2 infection, were analyzed. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received HCQ with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores, with the addition of subgroup analyses. Results Out of 3,451 COVID-19 patients, 76.3% received HCQ. Death rates (per 1,000 person-days) for patients receiving or not HCQ were 8.9 and 15.7, respectively. After adjustment for propensity scores, we found 30% lower risk of death in patients receiving HCQ (HR=0.70; 95%CI: 0.59 to 0.84; E-value=1.67). Secondary analyses yielded similar results. The inverse association of HCQ with inpatient mortality was particularly evident in patients having elevated C-reactive protein at entry. Conclusions HCQ use was associated with a 30% lower risk of death in COVID-19 hospitalized patients. Within the limits of an observational study and awaiting results from randomized controlled trials, these data do not discourage the use of HCQ in inpatients with COVID-19.

Objective The hypothesis that been set forward that use of Renin Angiotensin Aldosterone System (RAAS) inhibitors is associated with COVID−19 severity. We set-up a multicenter Italian collaboration (CORIST Project, ClinicalTrials.gov ID: NCT04318418 ) to retrospectively investigate the relationship between RAAS inhibitors and COVID−19 in-hospital mortality. We also carried out an updated meta-analysis on the relevant studies. Methods We analyzed 4069 unselected patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in 34 clinical centers in Italy from February 19, 2020 to May 23, 2020. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received angiotensin-converting–enzyme inhibitors (ACE I) or angiotensin-receptor blockers (ARB) with patients who did not. Articles for the meta-analysis were retrieved until July 13th, 2020 by searching in web-based libraries, and data were combined using the general variance-based method. Results Out of 4069 COVID−19 patients, 13.5% and 13.3% received ACE-I or ARB, respectively. Use of neither ACE-I nor ARB was associated with mortality (multivariable hazard ratio (HR) adjusted also for COVID−19 treatments: 0.96, 95% confidence interval 0.77–1.20 and HR = 0.89, 0.67–1.19 for ACE-I and ARB, respectively). Findings were similar restricting the analysis to hypertensive (N = 2057) patients (HR = 1.00, 0.78–1.26 and HR = 0.88, 0.65–1.20) or when ACE-I or ARB were considered as a single group. Results from the meta-analysis (19 studies, 29,057 COVID−19 adult patients, 9700 with hypertension) confirmed the absence of association. Conclusions In this observational study and meta-analysis of the literature, ACE-I or ARB use was not associated with severity or in-hospital mortality in COVID−19 patients.

Background: The subcutaneous implantable cardioverter defibrillator (S-ICD) is an established treatment for the prevention of sudden cardiac death. In the S-ICD studies, inappropriate shocks (IAS) rate were reported to renge between 5% to 25% and to be mainly due to cardiac and noncardiac oversensing. Objective: This review highlights data on IAS complications of the S-ICD and is aimed to help in identifying the causes of extracardiac oversensing to facilitate safe and effective emergency management and to reduce the incidence of adverse outcomes. Methods: Literature between January 2010 and March 2020 on IAS and S-ICD was identified by database search. We included studies assessing IAS rates due to extracardiac oversensing. We identified 12 eligible articles including meta-analysis and 28 selected case reports. Results: The total population included 2654 reported patients. Of these, 84 patients received extracardiac IAS. The malfunction of S-ICD due to extracardiac oversensing was related, in particular, to myopotentials (34%) and electromagnetic interferences (29%). The meta-analysis demonstrates an overall high prevalence of extracardiac IAS of 22% (95% CI 8% - 50%); the prevalence was 6% (95% CI 3% - 12%) in patients without the SP (SMART-Pass) filter and 46% (95% CI 12% - 84%) in patients with the SP filter (P=0.047). Conclusion: Our findings show the high prevalence of extracardiac IAS in patients with S-ICD and demonstrated that the SP is unable to prevent the IAS due to extracardiac reasons. It is important in the Emergency Department for the appropriate management of IAS to identify the various causes.

Aims The assessment of frailty in older adults with heart failure (HF) is still debated. Here, we compare the predictive role and the diagnostic accuracy of physical vs. multidimensional frailty assessment on mortality, disability, and hospitalization in older adults with and without HF. Methods and results A total of 1077 elderly (≥65 years) outpatients were evaluated with the physical (phy‐Fi) and multidimensional (m‐Fi) frailty scores and according to the presence or the absence of HF. Mortality, disability, and hospitalizations were assessed at baseline and after a 24 month follow‐up. Cox regression analysis demonstrated that, compared with phy‐Fi score, m‐Fi score was more predictive of mortality [hazard ratio (HR) = 1.05 vs. 0.66], disability (HR = 1.02 vs. 0.89), and hospitalization (HR = 1.03 vs. 0.96) in the absence and even more in the presence of HF (HR = 1.11 vs. 0.63, 1.06 vs. 0.98, and 1.14 vs. 1.03, respectively). The area under the curve indicated a better diagnostic accuracy with m‐Fi score than with phy‐Fi score for mortality, disability, and hospitalizations, both in absence (0.782 vs. 0.649, 0.763 vs. 0.695, and 0.732 vs. 0.666, respectively) and in presence of HF (0.824 vs. 0.625, 0.886 vs. 0.793, and 0.812 vs. 0.688, respectively). Conclusions The m‐Fi score is able to predict mortality, disability, and hospitalizations better than the phy‐Fi score, not only in absence but also in presence of HF. Our data also demonstrate that the m‐Fi score has better diagnostic accuracy than the phy‐Fi score. Thus, the use of the m‐FI score should be considered for the assessment of frailty in older HF adults.

Modifications of lean mass are a frequent critical determinant in the pathophysiology and progression of heart failure (HF). Sarcopenia may be considered one of the most important causes of low physical performance and reduced cardiorespiratory fitness in older patients with HF. Sarcopenia is frequently misdiagnosed as cachexia. However, muscle wasting in HF has different pathogenetic features in sarcopenic and cachectic conditions. HF may induce sarcopenia through common pathogenetic pathways such as hormonal changes, malnutrition, and physical inactivity; mechanisms that influence each other. In the opposite way, sarcopenia may favor HF development by different mechanisms, including pathological ergoreflex. Paradoxically, sarcopenia is not associated with a sarcopenic cardiac muscle, but the cardiac muscle shows a hypertrophy which seems to be “not-functional.” First-line agents for the treatment of HF, physical activity and nutritional interventions, may offer a therapeutic advantage in sarcopenic patients irrespective of HF. Thus, sarcopenia is highly prevalent in patients with HF, contributing to its poor prognosis, and both conditions could benefit from common treatment strategies based on pharmacological, physical activity, and nutritional approaches.

Background Several tools have been proposed and validated to operationally define frailty. Recently, the Italian Frailty index (IFi), an Italian modified version of Frailty index, has been validated but its use in clinical practice is limited by long time of administration. Therefore, the aim of this study was to create and validate a quick version of the IFi (AGILE). Methods Validation study was performed by administering IFi and AGILE, after a Comprehensive Geriatric Assessment (CGA) in 401 subjects aged 65 or over (77 ± 7 years). AGILE was a 10-items tool created starting from the more predictive items of the four domains of frailty investigated by IFi (mental, physical, socioeconomic and nutritional). AGILE scores were stratified in light, moderate and severe frailty. At 24 months of follow-up, death, disability (taking into account an increase in ADL lost ≥1 from the baseline) and hospitalization were considered. Area under curve (AUC) was evaluated for both IFi and AGILE. Results Administration time was 9.5 ± 3.8 min for IFi administered after a CGA, and 2.4 ± 1.2 min for AGILE, regardless of CGA (p p = NS). Relative Risk for each unit of increase in AGILE was 56, 44 and 24% for mortality, disability and hospitalization, respectively and was lower for IFi (8, 7 and 4% for mortality, disability and hospitalization, respectively). The AUC was higher in AGILE vs. IFi for mortality (0.729 vs. 0.698), disability (0.715 vs. 0.682) and hospitalization (0.645 vs. 0.630). Conclusions Our study shows that AGILE is a rapid and effective tool for screening multidimensional frailty, able to predict mortality, disability and hospitalization, especially useful in care settings that require reliable assessment instruments with short administration time.

Purpose Human leukocyte antigen (HLA)-G is a non-classic major histocompatibility complex HLA class I molecule. HLA-G may have tolerogenic properties which are linked to epigenetic-sensitive pathways. There is a correlation of sHLA-G levels and graft acceptance in transplantation studies. There are previous data on correlation of sHLA-G with graft rejection as well as with viral infections such as hepatitis C virus (HCV) in kidney transplanted patients. Here, we report the sHLA-G expression in patients on the waiting list for kidney transplantation, with and without anti-HCV compared to a control group. Methods Serum of 67 patients on the waiting list for kidney transplantation (n = 43 with anti-HCV and n = 24 without anti-HCV) was analyzed. Among these patients, n = 39 were on the waiting list for the first transplantation, while n = 28 were patients who returned in the list. The control group included n = 23 blood donors with anti-HCV (n = 13) and without anti-HCV (n = 10). Results The expression of sHLA-G was significantly lower in the control group (39.6 ± 34.1 U/ml) compared to both - patients on the waiting list for the first transplantation (62.5 ± 42.4 U/ml, p=0.031) and patients who returned in the list (76.7 ± 53.9 U/ml, p=0.006). No significant differences were observed in all anti-HCV positive groups. A positive linear correlation between sHLA-G and TNF-α, and patient age was observed. Conclusions Serum sHLA-G values were significantly increased in both - patients on the waiting list for the first transplantation and patients who returned in the list, as compared to control group. Our findings confirm the key tolerogenic role of sHLA-G levels as epigenetic-related marker for measuring the state of kidney allograft acceptance.

BACKGROUND: Depression is highly prevalent in Heart Failure (HF). Treatment with sacubitril/valsartan improved quality of life and survival in HF patients. Aim of the study was to investigate prospectively the effect of sacubitril/valsartan on depression in advanced HF patients in waiting list for heart transplant (HT). METHODS: 37 consecutive patients with advanced HF in waiting list for HT were treated with sacubitril/valsartan. We analyzed data derived from the assessment performed the year before the beginning of sacubitril/valsartan, at study entry, and at one year of follow-up. Depression was assessed with Beck Depression Inventory II (BDI) scale. Cognitive function were assessed with Mini-Mental State Examination (MMSE). Functioning was evaluated measuring meters at 6 Minute Walking Test (6MWT) and maximum rate of oxygen consumption (VO2 max). RESULTS: At baseline, 64.9% of HF patients were in NYHA III and 35.1% NYHA IIIB, BDI was 15.2 ± 5.2 with 59.5% of patients with a score > 13. MMSE was 27.8 ± 2.6. After one year of follow-up NYHA class improved significantly, with 56.8% in NYHA II, 40.5% in NYHA III and 2.7% NYHA in IIIB (p 13. MMSE remain stable (28.2 ± 2.1) (p = 0.104). No statistical differences are observed between data collected in the evaluation 1-year before and soon before treatment with sacubitril/valsartan. Multivariate regression analysis demonstrate a relationship between reduction in BDI-II score and improvement in six-minute walking test independently by the effect of sex, age, selective serotonin reuptake inhibitors, VO2 max, NT-proBNP, PAPs, NYHA class differences evaluated at follow-up versus baseline. CONCLUSIONS: Our study showed a reduction in depressive symptomatology in heart transplant waiting list patients treated with sacubitril/valsartan. The improvement in depressive symptomatology was paralleled by 6MWT increase in the follow-up.

In the last years, guidelines for the treatment of hypertension recommended individualized blood pressure goals for geriatric population because of elderly susceptibility to adverse outcomes and higher mortality rate deriving from the excessive blood pressure lowering, especially in "frail" elderly. Recent findings from the SPRINT study, which demonstrated that intensive blood pressure lowering was associated with lower rates of cardiovascular events and mortality in both hypertensive fit and frail elderly subjects compared to standard treatment, heavily influenced the recent US guidelines. In SPRINT sub-study analysis of adults aged ≥75 years, the most controversial issue appears the method of blood pressure measurement, the selection of patients and related-frailty degree that appears to be very light. Accordingly, it has been described that light frailty is related to good outcomes in older adults. SPRINT findings in "frail elderly patients" cannot be applied to the clinical practice because this condition has been clearly under-estimated. Thus, frailty status should be routinely and correctly quantified in order to identify the frailty degree and to find the best harms-benefits balance of antihypertensive drug treatment in frail older adults.

Background How metabolic impairment leads to cardiac dysfunction in diabetics is unknown. A recent theory, derived mainly from rodent models, involves lipid over-storage to cardiomyocytes. Previous human study demonstrated cardiac steatosis on explanted hearts of diabetics with heart failure. However, this study did not provide any evidence about the effects of diabetes milieu on implanted non-diabetic heart. Purpose We evaluated intramyocyte lipid infiltration in explanted heart of type 2 diabetics with end-stage heart failure. Moreover, we studied the effects of diabetic milieu on myocyte lipid infiltration and cardiac function of non-diabetic implanted hearts in type 2 diabetics one year after heart transplantation (HTx). Methods We conducted a prospective study with a follow-up of 12 months on 88 patients over 18 years of age underwent first HTX. Patients with pre-HTx diabetes duration for at least 6 months were included in the study. Patients with endomyocardial biopsy (EMB) considered positive for rejection, according to International Society for Heart Lung Transplantation (ISHLT), and with post-HTx diabetes were excluded from the study. All patients underwent immunosuppression induction according ISHLT indications. All patients were followed applying internationally accepted patient evaluations (echocardiography and metabolic control) and EMB schedules. EBM from patients without rejection evidences were evaluated for intramyocyte lipid infiltration with oil red-O staining (Or-O). Results The patients were divided in diabetics (44%, age 51.6±7.2 y, diabetes duration 11±3 y) and no-diabetics (56%, 52.1±10.9 y). The patients were matched on the basis of eligibility for a HTx. Seven patients (3 diabetics and 4 no-diabetics) died in hospital. 5 (11%) patients developed post- HTx diabetes. No differences were seen in rejection (12% vs. 10%), infection (9% vs. 10%), renal dysfunction (9% vs. 8%) or mortality (7% vs. 8%). Therefore, the study population included 23 no-diabetics and 22 diabetics. After 1 year, we evidenced an impairment of both sx and dx ventricular function as showed by a significantly reduction of ejection fraction and TAPSE in diabetic patients (Figure-A). Although diastolic function not show significant differences among groups, the E/e' ratio showed lower reduction in diabetics. Or-O evidenced that 91% of diabetic and only 2 of no-diabetic explanted hearts (9%) showed intramyocyte lipid infiltration (Figure-B). Moreover, Or-O of EMB, for monitoring heart transplant during 1 year, evidenced a progressive intramyocyte lipid infiltration in 18 diabetics (81%), whereas none of no-diabetics showed intramyocyte lipid infiltration. Conclusions Our data show that almost all of the explanted diabetic hearts had intramyocyte lipid infiltration. More interesting, we observed that healthy heart transplanted in recipients with pretransplant diabetes were affected early by metabolic disorders leading to intramyocyte lipid infiltration.

Background Treatment with valsartan/sacubitril was found to be associated both with reduction in mortality risk for HF. Purpose To investigate the effect of sacubitril/valsartan on physical frailty (PF) in advanced HF patients in waiting list for heart transplantion (HT) in a two years follow-up study. Methods We enrolled 45 consecutive patients (status 2B UNOs). Patients tolerant to ACE-inhibitor and/or ARBs were treated with valsartan/sacubitril. Patients were required to have left ventricular ejection fraction (LVEF) of ≤35% and to be taking a stable dose of a β-blocker and an ACE inhibitor or an ARB for at least 4 weeks before enrollment. The dosage of sacubitril/valsartan was increased if tolerance was good. Frailty was assessed using an adapted version of Fried's Frailty Phenotype used in advanced HF patients in waiting list for transplantation. Patients were followed up until HT, device (TAH/LVAD) implant, or last follow-up visit. Results Mean NYHA class was 3.1±0.4, with 5.7% NYHA 2, 62.9% NYHA 3 and 31.4% NYHA 3B. LVEF was 25.1±6.4, VO2 max (ml/kg/min) was 10.3±2.3, cardiac index (L/min/m2) was 2.3±0.6, and NT-proBNP (pg/ml) was 4054.8±3977. At 3 months, 31.5% of patients received the target dose of 97/103 mg/BID, 31.6% the half dose (49/51mg BID) and 26.3% the low dose (24/26 mg BID) and 10.5% the half low dose (24/26 mg daily). The baseline mean value of physical frailty was 3.86±0.8, specifically 94.3% showed exhaustion, 91.4% physical inactivity, 88.6% weakness, 85.7% slowness and 28.6% loss of appetite. All patients had a frailty score ≥3. During follow-up there were no deaths. After treatment, NYHA class improved significantly (2.4±0.6 vs 3.1±0.4; p=0.002), with 5.7% NYHA 1, 48.6% NYHA 2, 42.9% NYHA 3 and 2.9% NYHA 3B (p Conclusions Our study shows an improvement in PH in patients with advanced HF in waiting list for HT after therapy with sacubitril/valsartan. These changes seem to appear very early after introduction of the treatment and to be maintained over time. The improvement in all physical domain was paralleled by VO2 max and 6-minute walking test increase. The pro-BNP-NT reduction was significant in the first month of treatment and remain quite stable in the follow-up.