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Aims: To determine the clinical and economic implications of first-line or drug-naïve catheter ablation compared to antiarrhythmic drugs (AADs), or shorter AADs-to-Ablation time (AAT) in atrial fibrillation (AF) patients in France and Italy, using a patient level-simulation model., Materials and Methods: A patient-level simulation model was used to simulate clinical pathways for AF patients using published data and expert opinion. The probabilities of adverse events (AEs) were dependent on treatment and/or disease status. Analysis 1 compared scenarios of treating 0%, 25%, 50%, 75% or 100% of patients with first-line ablation and the remainder with AADs. In Analysis 2, scenarios compared the impact of delaying transition to second-line ablation by 1 or 2 years., Results: Over 10 years, increasing first-line ablation from 0% to 100% (versus AAD treatment) decreased stroke by 12%, HF hospitalization by 29%, and cardioversions by 45% in both countries. As the rate of first-line ablation increased from 0% to 100%, the overall 10-year per-patient costs increased from €13,034 to €14,450 in Italy and from €11,944 to €16,942 in France. For both countries, the scenario with no delay in second-line ablation had fewer AEs compared to the scenarios where ablation was delayed after AAD failure. Increasing rates of first-line or drug-naïve catheter ablation, and shorter AAT, resulted in higher cumulative controlled patient years on rhythm control therapy., Limitations: The model includes assumptions based on the best available clinical data, which may differ from real-world results, however, sensitivity analyses were included to combat parameter ambiguity. Additionally, the model represents a payer perspective and does not include societal costs, providing a conservative approach., Conclusion: Increased first-line or drug-naïve catheter ablation, and shorter AAT, could increase the proportion of patients with controlled AF and reduce AEs, offsetting the small investment required in total AF costs over 10 years in Italy and France.

Background: A systematic analysis of concomitant arterial hypertension in COVID-19 patients and the impact of angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) have not been studied in a large multicentre cohort yet. We conducted a subanalysis from the international HOPE Registry (https://hopeprojectmd.com, NCT04334291) comparing COVID-19 in presence and absence of arterial hypertension., Materials and Methods: Out of 5837 COVID-19 patients, 2850 (48.8%) patients had the diagnosis arterial hypertension. 1978/2813 (70.3%) patients were already treated with ACEI or ARBs. The clinical outcome of the present subanalysis included all-cause mortality over 40 days of follow-up., Results: Patients with arterial hypertension suffered significantly more from different complications including respiratory insufficiency (60.8% vs 39.5%), heart failure (9.9% vs 3.1%), acute kidney injury (25.3% vs 7.3%), pneumonia (90.6% vs 86%), sepsis (14.7% vs 7.5%), and bleeding events (3.6% vs 1.6%). The mortality rate was 29.6% in patients with concomitant arterial hypertension and 11.3% without arterial hypertension (P < .001). Invasive and non-invasive respiratory supports were significantly more required in presence of arterial hypertension as compared without it. In the multivariate cox regression analysis, while age≥65, benzodiazepine, antidepressant at admission, elevated LDH or creatinine, respiratory insufficiency and sepsis might be a positive independent predictors of mortality, antiviral drugs, interferon treatment, ACEI or ARBs at discharge or oral anticoagulation at discharge might be an independent negative predictor of the mortality., Conclusions: The mortality rate and in-hospital complications might be increased in COVID-19 patients with a concomitant history of arterial hypertension. The history of ACEI or ARBs treatments does not seem to impact the outcome of these patients., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: The use of Renin-Angiotensin system inhibitors (RASi) in patients with coronavirus disease 2019 (COVID-19) has been questioned because both share a target receptor site., Methods: HOPE-COVID-19 (NCT04334291) is an international investigator-initiated registry. Patients are eligible when discharged after an in-hospital stay with COVID-19, dead or alive. Here, we analyze the impact of previous and continued in-hospital treatment with RASi in all-cause mortality and the development of in-stay complications., Results: We included 6503 patients, over 18 years, from Spain and Italy with data on their RASi status. Of those, 36.8% were receiving any RASi before admission. RASi patients were older, more frequently male, with more comorbidities and frailer. Their probability of death and ICU admission was higher. However, after adjustment, these differences disappeared. Regarding RASi in-hospital use, those who continued the treatment were younger, with balanced comorbidities but with less severe COVID19. Raw mortality and secondary events were less frequent in RASi. After adjustment, patients receiving RASi still presented significantly better outcomes, with less mortality, ICU admissions, respiratory insufficiency, need for mechanical ventilation or prone, sepsis, SIRS and renal failure (p<0.05 for all). However, we did not find differences regarding the hospital use of RASi and the development of heart failure., Conclusion: RASi historic use, at admission, is not related to an adjusted worse prognosis in hospitalized COVID-19 patients, although it points out a high-risk population. In this setting, the in-hospital prescription of RASi is associated with improved survival and fewer short-term complications., Competing Interests: Conflict of interest None declared., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Recently the coronavirus disease (COVID-19) outbreak has been declared a pandemic. Despite its aggressive extension and significant morbidity and mortality, risk factors are poorly characterized outside China. We designed a registry, HOPE COVID-19 (NCT04334291), assessing data of 1021 patients discharged (dead or alive) after COVID-19, from 23 hospitals in 4 countries, between 8 February and 1 April. The primary end-point was all-cause mortality aiming to produce a mortality risk score calculator. The median age was 68 years (IQR 52-79), and 59.5% were male. Most frequent comorbidities were hypertension (46.8%) and dyslipidemia (35.8%). A relevant heart or lung disease were depicted in 20%. And renal, neurological, or oncological disease, respectively, were detected in nearly 10%. Most common symptoms were fever, cough, and dyspnea at admission. 311 patients died and 710 were discharged alive. In the death-multivariate analysis, raised as most relevant: age, hypertension, obesity, renal insufficiency, any immunosuppressive disease, 02 saturation < 92% and an elevated C reactive protein (AUC = 0.87; Hosmer-Lemeshow test, p > 0.999; bootstrap-optimist: 0.0018). We provide a simple clinical score to estimate probability of death, dividing patients in four grades (I-IV) of increasing probability. Hydroxychloroquine (79.2%) and antivirals (67.6%) were the specific drugs most commonly used. After a propensity score adjustment, the results suggested a slight improvement in mortality rates (adjusted-OR hydroxychloroquine 0.88; 95% CI 0.81-0.91, p = 0.005; adjusted-OR antiviral 0.94; 95% CI 0.87-1.01; p = 0.115). COVID-19 produces important mortality, mostly in patients with comorbidities with respiratory symptoms. Hydroxychloroquine could be associated with survival benefit, but this data need to be confirmed with further trials. Trial Registration: NCT04334291/EUPAS34399.

Aims: The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups., Methods and Results: We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping., Conclusion: The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: Initial data on COVID-19 infection has pointed out a special vulnerability of older adults., Design: We performed a meta-analysis with available national reports on May 7, 2020 from China, Italy, Spain, United Kingdom, and New York State. Analyses were performed by a random effects model, and sensitivity analyses were performed for the identification of potential sources of heterogeneity., Setting and Participants: COVID-19-positive patients reported in literature and national reports., Measures: All-cause mortality by age., Results: A total of 611,1583 subjects were analyzed and 141,745 (23.2%) were aged ≥80 years. The percentage of octogenarians was different in the 5 registries, the lowest being in China (3.2%) and the highest in the United Kingdom and New York State. The overall mortality rate was 12.10% and it varied widely between countries, the lowest being in China (3.1%) and the highest in the United Kingdom (20.8%) and New York State (20.99%). Mortality was <1.1% in patients aged <50 years and it increased exponentially after that age in the 5 national registries. As expected, the highest mortality rate was observed in patients aged ≥80 years. All age groups had significantly higher mortality compared with the immediately younger age group. The largest increase in mortality risk was observed in patients aged 60 to 69 years compared with those aged 50 to 59 years (odds ratio 3.13, 95% confidence interval 2.61-3.76)., Conclusions and Implications: This meta-analysis with more than half million of COVID-19 patients from different countries highlights the determinant effect of age on mortality with the relevant thresholds on age >50 years and, especially, >60 years. Older adult patients should be prioritized in the implementation of preventive measures., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

To study the proportion of leadless pacemaker (LL-PM) implants and the factors influencing the choice of LL-PM vs. transvenous pacemaker (TV-PM) across tertiary centres in Europe with routine availability of the LL-PM. A European Heart Rhythm Association (EHRA) prospective snapshot survey using electronically distributed questionnaire sent to participating centres. Participating tertiary cardiac pacing centres prospectively included consecutive patients implanted between November 2018 and January 2019. Questions covered standards of care and policies used for patient management, focusing particularly on the reasons for choosing LL-PM vs. TV-PM. Overall, 21 centres from four countries (France, Netherlands, Spain, and Italy) participated, with eventual data from 798 patients (n = 472, 59% male). With 69 implants, LL-PM represented only 9% of all implants and 36% of the single-chamber pacing group; double-chamber transvenous pacemakers were implanted in 528 patients and biventricular (cardiac resynchronization pacemaker) in 79. The two major reasons reported in favour of LL-PM implantation were an anticipated high risk of infection or low rate of ventricular pacing. Compared to TV-PM, LL-PM patients were more often male (74% vs. 54%, P = 0.009), with greater proportion of valvular heart disease (45% vs. 35%, P = 0.01) and atrial fibrillation (AF; 65% vs. 23%, P < 0.0001), with significantly more comorbidities (≥ one comorbidity, 66% vs. 52%, P = 0.02). This contemporary multicentre European survey shows that LL-PM constitutes a small proportion of all PM implants. Patients implanted with LL-PM were more likely to have AF and a high anticipated risk of infection., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Familial hypercholesterolemia (FH) is a monogenic disease characterized by high levels of low-density lipoprotein cholesterol and premature atherosclerotic cardiovascular disease. FH is caused by loss of function mutations in genes encoding LDL receptor (LDLR), and Apolipoprotein B (APOB) or gain of function (GOF) mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, we identified a novel variant in PCSK9, p.(Arg499His), located in the C-terminal domain, in two unrelated FH patients from Spain and Italy., Methods: We studied familial segregation and determined variant activity in vitro., Results: We determined PCSK9 expression, secretion and activity of the variant in transfected HEK293 cells; extracellular activity of the recombinant p.(Arg499His) PCSK9 variant in HEK 293 and HepG2 cells; PCSK9 affinity to the LDL receptor at neutral and acidic pH; the mechanism of action of the p.(Arg499His) PCSK9 variant by co-transfection with a soluble construct of the LDL receptor and by determining total PCSK9 intracellular accumulation when endosomal acidification is impaired and when an excess of soluble LDLr is present in the culture medium. Our results show high LDL-C concentrations and FH phenotype in p.(Arg499His) carriers. In vitro functional characterization shows that p.(Arg499His) PCSK9 variant causes a reduction in LDLr expression and LDL uptake. An intracellular activity for this variant is also shown when blocking the activity of secreted PCSK9 and by inhibiting endosomal acidification., Conclusions: We demonstrated that p.(Arg499His) PCSK9 variant causes a direct intracellular degradation of LDLr therefore causing FH by reducing LDLr availability., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Limited evidence suggests that epigenetic mechanisms may partially mediate the adverse effects of air pollution on health. Our aims were to identify new genomic loci showing differential DNA methylation associated with long-term exposure to air pollution and to replicate loci previously identified in other studies., Methods: A two-stage epigenome-wide association study was designed: 630 individuals from the REGICOR study were included in the discovery and 454 participants of the EPIC-Italy study in the validation stage. DNA methylation was assessed using the Infinium HumanMethylation450 BeadChip. NOX, NO2, PM10, PM2.5, PMcoarse, traffic intensity and traffic load exposure were measured according to the ESCAPE protocol. A systematic review was undertaken to identify those cytosine-phosphate-guanine (CpGs) associated with air pollution in previous studies and we screened for them in the discovery study., Results: In the discovery stage of the epigenome-wide association study, 81 unique CpGs were associated with air pollution (p-value <10 -5 ) but none of them were validated in the replication sample. Furthermore, we identified 15 CpGs in the systematic review showing differential methylation with a p-value fulfilling the Bonferroni criteria and 1673 CpGs fulfilling the false discovery rate criteria, all of which were related to PM 2.5 or NO 2 . None of them was replicated in the discovery study, in which the top hits were located in an intergenic region on chromosome 1 (cg10893043, p-value = 6.79·10 -5 ) and in the LRRC45 and PXK genes (cg05088605, p-value = 2.15·10 -04 ; cg16560256, p-value = 2.23·10 -04 )., Conclusions: Neither new genomic loci associated with long-term air pollution were identified, nor previously identified loci were replicated. Continued efforts to test this potential association are warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)