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Aims: Secondary mitral regurgitation (MR) negatively affects prognosis in acutely decompensated heart failure (ADHF), but can be rapidly sensitive to changes in volume status and medical interventions. We sought to assess the evolution of secondary MR in patients hospitalized for ADHF and its prognostic implications., Methods: We retrospectively enrolled 782 patients admitted for ADHF with at least two in-hospital echocardiographic evaluations of MR. We classified MR severity as none-mild or moderate-severe. Based on MR evolution, patients were divided into 'persistent moderate-severe MR', 'improved MR' (from moderate-severe to none-mild) and 'persistent none-mild MR'., Results: Four hundred and forty patients (56%) had moderate-severe MR at first evaluation, of whom 144 (33% of patients with baseline moderate-severe MR) had 'improved MR', while 296 (67%) had 'persistent moderate-severe MR'. Patients with improved MR had better clinical, laboratory and echocardiographic parameters of decongestion at discharge compared with those with persistent moderate-severe MR and showed a higher up-titration of recommended therapies. Left ventricular volume, ejection fraction and serum urea were the predictors of improved MR at multivariable analysis. After adjustment, no differences in 5-years survival (primary outcome) were observed according to baseline MR severity. When patients were stratified according to the in-hospital changes in MR severity, improved MR was associated with lower risk of 5-years mortality, compared with both persistent none-mild MR [hazard ratio (HR) = 0.505, P = 0.032] and persistent moderate-severe MR (HR = 0.556, P = 0.040)., Conclusions: The severity of MR frequently improved during hospitalization for ADHF; the extent and the changes in MR severity during the in-hospital stay identified distinct patient phenotypes, and seemed to portend different long-term outcomes, with higher 5-years survival associated with improvement in MR., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Colchicine is one of the oldest drugs in medicine. Traditionally used to treat and prevent gouty attacks, it has been introduced into cardiovascular medicine for the treatment and prevention of pericarditis, starting from the positive experience in the treatment and prevention of polyserositis in familial mediterranean fever. Colchicine is a lipophilic drug that enters the cells and is eliminated by glycoprotein P. As granulocytes are lacking in this protein, colchicine is able to concentrate in these cells, exerting a substantial anti-inflammatory action, even with low oral doses. As these cells may trigger acute cardiovascular events, colchicine has been shown to be efficacious and safe to prevent acute coronary syndromes and ischemic stroke with an efficacy comparable to more established treatments, such as antiplatelet agents and statins. On this basis, colchicine seems a promising, efficacious, well tolerated, and cheap option for the prevention of several cardiovascular events, and it may become an additional pillar in the pharmacologic treatment of cardiovascular diseases., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Italian Federation of Cardiology.)

Introduction: A growing body of scientific evidence shows that simulation-guided auscultatory training can significantly improve the skills of medical students. Nevertheless, it remains to be elucidated if this training has any long-term impact on auscultatory skills. We sought to ascertain whether there were differences in heart and lung auscultation among residents who received simulation-guided auscultatory training before graduation vs. those who did not., Materials and Methods: A total of 43 residents were included in the study; 20 of them entered into Cardiology specialty school (C) and 23 of them entered into Internal and Occupational Medicine specialty schools (M) at the University of Trieste. Based on the history of simulation-guided auscultatory training before graduation (yes = Y; no = N), four groups were formed: CY, CN, MY, and MN. Residents were evaluated in terms of their ability to recognize six heart and five lung sounds, which were reproduced in a random order with the Kyoto-Kagaku patient simulator. Associations between history of simulation training, specialty choice and auscultatory skills were evaluated with Kruskal-Wallis test and logistic regression analysis., Results: Auscultatory skills of residents were associated with simulation-guided training before graduation, regardless of the specialty chosen. Simulation-guided training had a higher impact on residents in Medicine. Overall, heart and lung sounds were correctly recognized in 41% of cases. Logistic regression analysis showed that simulation-guided training was associated with recognition of aortic stenosis, S2 wide split, fine crackles, and pleural rubs. Specialty choice was associated with recognition of aortic stenosis as well as aortic and mitral regurgitation., Discussion: History of simulation-guided auscultatory training was associated with better auscultatory performance in residents, regardless of the medical specialty chosen. Choice of Cardiology was associated with better scores in aortic stenosis as well as aortic and mitral regurgitation. Nevertheless, overall auscultatory proficiency was quite poor, which suggests that simulation-guided training may help but is probably still too short., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Italian Federation of Cardiology.)

Background: LMNA ( lamin A/C )-related dilated cardiomyopathy is a rare genetic cause of heart failure. In a phase 2 trial and long-term extension, the selective p38α MAPK (mitogen-activated protein kinase) inhibitor, ARRY-371797 (PF-07265803), was associated with an improved 6-minute walk test at 12 weeks, which was preserved over 144 weeks., Methods: REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic LMNA -related dilated cardiomyopathy. Patients with confirmed LMNA variants, New York Heart Association class II/III symptoms, left ventricular ejection fraction ≤50%, implanted cardioverter-defibrillator, and reduced 6-minute walk test distance were randomized to ARRY-371797 400 mg twice daily or placebo. The primary outcome was a change from baseline at week 24 in the 6-minute walk test distance using stratified Hodges-Lehmann estimation and the van Elteren test. Secondary outcomes using similar methodology included change from baseline at week 24 in the Kansas City Cardiomyopathy Questionnaire-physical limitation and total symptom scores, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration. Time to a composite outcome of worsening heart failure or all-cause mortality and overall survival were evaluated using Kaplan-Meier and Cox proportional hazards analyses., Results: REALM-DCM was terminated after a planned interim analysis suggested futility. Between April 2018 and October 2022, 77 patients (aged 23-72 years) received ARRY-371797 (n=40) or placebo (n=37). No significant differences ( P >0.05) between groups were observed in the change from baseline at week 24 for all outcomes: 6-minute walk test distance (median difference, 4.9 m [95% CI, -24.2 to 34.1]; P =0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 [95% CI, -6.4 to 11.2]; P =0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 [95% CI, -4.3 to 14.9]; P =0.48); and NT-proBNP concentration (-339.4 pg/mL [95% CI, -1131.6 to 452.7]; P =0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 [95% CI, 0.11-1.74]; P =0.23) and overall survival (hazard ratio, 1.19 [95% CI, 0.23-6.02]; P =0.84) were similar between groups. No new safety findings were observed., Conclusions: Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with LMNA -related dilated cardiomyopathy., Registration: URL: https://classic.clinicaltrials.gov; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856., Competing Interests: Dr Garcia-Pavia reports speaking fees from Alnylam Pharmaceuticals, AstraZeneca, Bristol Myers Squibb (BMS), Bridgebio, Ionis Pharmaceuticals, NovoNordisk, and Pfizer; consulting fees from Alexion, Alnylam Pharmaceuticals, AstraZeneca, ATTRalus, BMS, Bridgebio, Cytokinetics, General Electric, Intellia, Lexeo Therapeutics, Neurimmune, NovoNordisk, Pfizer, and Rocket Pharmaceuticals; reports research/educational support to his institution from Alnylam Pharmaceuticals, AstraZeneca, Bridgebio, Intellia, NovoNordisk, and Pfizer. Dr Barriales-Villa received consultancy fees from Alnylam, Amicus, BMS, Chiesi, Cytokinetics, Pfizer, and Sanofi. Dr Lakdawala has received consulting fees from Array BioPharma, BMS, MyoKardia, Pfizer, and Tenaya Therapeutics. Dr Gottlieb consulted for Alnylam and Gilead Sciences; participated in scientific advisory board meetings for AbbVie, Alnylam, AstraZeneca, Eli Lilly, Gilead Sciences, GlaxoSmithKline, and Roche; received research support from CareDx; has been a member of a speaker’s bureau for Alnylam and Pfizer; and has been a National Principal Investigator (unrelated field) for Johnson & Johnson. Dr Elliott has received consultancy fees from Alnylam and Pfizer and educational grants from Pfizer. Dr Lee, H. Li, and Dr Angeli are full-time employees of Pfizer and hold stock and/or stock options. Dr Judge received consultancy fees from Alexion, Alleviant Medical, Cytokinetics, Novo Nordisk, Pfizer, Renovacor, and Tenaya Therapeutics. Dr MacRae consulted for Adrestia, Affinia, Array BioPharma, AstraZeneca, Bayer, BMS, Design Therapeutics, Dewpoint Therapeutics, DINAQOR, Merck, MyoKardia, Novartis, Novo Nordisk, Nuevocor, and Pfizer; and received grant support from Apple, AstraZeneca, Bayer, Janssen, Merck, Microsoft, Novartis, Quest Diagnostics, Sanofi, and Verily. The other authors report no conflicts.

Hypertrophic cardiomyopathy is an important cause of heart failure and arrhythmias, including sudden death, with a major impact on the healthcare system. Genetic causes and different phenotypes are now increasingly being identified for this condition. In addition, specific medications, such as myosin inhibitors, have been recently shown as potentially able to modify its symptoms, hemodynamic abnormalities and clinical course. Our article aims to provide a comprehensive outline of the epidemiology, diagnosis and treatment of hypertrophic cardiomyopathy in the current era., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Italian Federation of Cardiology.)

Abstract: Myocarditis is an inflammatory disease of the myocardium characterized by a great heterogeneity of presentation and evolution. Treatment of myocarditis is often supportive, and the evidence for immunosuppression is scarce and debated. Conventional treatment is based on clinical presentation, ranging from conservative to advanced mechanical assist devices. In this setting, immunosuppression and immunomodulation therapies are mostly reserved for patients presenting with major clinical syndromes. In this review, we will summarize the current evidence and strategies for conventional and immunosuppressive treatments for patients presenting with acute myocarditis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin amyloid cardiomyopathy (ATTR-CM) might reflect cardiac amyloid burden and be associated with outcome., Methods: Consecutive patients with ATTR-CM who underwent diagnostic bone tracer scintigraphy with acquisition of whole-body planar and cardiac single-photon emission computed tomography (SPECT) images from the National Amyloidosis Centre and 4 Italian centers were included. Cardiac uptake was defined according to the Perugini classification: 0=absent cardiac uptake; 1=mild uptake less than bone; 2=moderate uptake equal to bone; and 3=high uptake greater than bone. Extent of right ventricular (RV) uptake was defined as focal (basal segment of the RV free wall only) or diffuse (extending beyond basal segment) on the basis of SPECT imaging. The primary outcome was all-cause mortality., Results: Among 1422 patients with ATTR-CM, RV uptake accompanying left ventricular uptake was identified by SPECT imaging in 100% of cases at diagnosis. Median follow-up in the whole cohort was 34 months (interquartile range, 21 to 50 months), and 494 patients died. By Kaplan-Meier analysis, diffuse RV uptake on SPECT imaging (n=936) was associated with higher all-cause mortality compared with focal (n=486) RV uptake (77.9% versus 22.1%; P <0.001), whereas Perugini grade was not associated with survival ( P =0.27 in grade 2 versus grade 3). On multivariable analysis, after adjustment for age at diagnosis (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04]; P <0.001), presence of the p.(V142I) TTR variant (HR, 1.42 [95% CI, 1.20-1.81]; P =0.004), National Amyloidosis Centre stage (each category, P <0.001), stroke volume index (HR, 0.99 [95% CI, 0.97-0.99]; P =0.043), E/e' (HR, 1.02 [95% CI, 1.007-1.03]; P =0.004), right atrial area index (HR, 1.05 [95% CI, 1.02-1.08]; P =0.001), and left ventricular global longitudinal strain (HR, 1.06 [95% CI, 1.03-1.09]; P <0.001), diffuse RV uptake on SPECT imaging (HR, 1.60 [95% CI, 1.26-2.04]; P <0.001) remained an independent predictor of all-cause mortality. The prognostic value of diffuse RV uptake was maintained across each National Amyloidosis Centre stage and in both wild-type and hereditary ATTR-CM ( P <0.001 and P =0.02, respectively)., Conclusions: Diffuse RV uptake of bone tracer on SPECT imaging is associated with poor outcomes in patients with ATTR-CM and is an independent prognostic marker at diagnosis., Competing Interests: Disclosures The authors report no conflicts in relation to the submitted work. They report the following conflicts outside the submitted work: Dr Rapezzi served on the Italian scientific advisory board of Pfizer and received unrestricted research grants and personal fees from Pfizer and personal fees from Alnylam Pharmaceuticals. Dr Biagini received advisory board fees from Sanofi, Genzyme, and Takeda. Dr Cappelli received advisory board fees from Pfizer and Akcea and research grants from Pfizer. Dr Sinagra received personal fees for occasional educational activities from Biotronik, Boston Scientific, AstraZeneca, and Novartis. Dr Canepa received speaker and advisor fees from Akcea Therapeutics, Menarini, Novartis, Pfizer, Sanofi e Sanofi Genzyme, and Vifor Pharma, as well as 2 investigator-initiated grants from Pfizer. Dr Fontana is supported by a British Heart Foundation intermediate clinical research fellowship (FS/18/21/33447). Dr Merlo received congress fees from Novartis and Vifor Pharma and research grant and congress fees from Pfizer. Dr Gillmore receives advisory board fees from Pfizer, Alnylam, ATTRalus, Intellia, AstraZeneca, and BridgeBio.

Aims: Data regarding hypertrophic cardiomyopathy (HCM)-related mortality in United States young adults, defined as those aged between 25 and 44 years, are lacking. We sought to assess the trends in HCM-related mortality among US young adults between 1999 and 2019 and determine differences by sex, race, ethnicity, urbanization and census region., Methods: Mortality data were retrieved by the Centers for Disease Control and Prevention (CDC) Wide-Ranging Online Data for Epidemiologic Research (WONDER) dataset from January 1999 to December 2019. Age-adjusted mortality rates (AAMRs) were assessed using the Joinpoint regression modeling and expressed as estimated average annual percentage change (AAPC) with relative 95% confidence intervals (95% CIs)., Results: Over 20-year period, the AAMR from HCM in US young adults linearly decreased, with no differences between sexes [AAPC: -5.3% (95% CI -6.1 to -4.6), P  < 0.001]. The AAMR decrease was more pronounced in Black patients [AAPC: -6.4% (95% CI -7.6 to -5.1), P  < 0.001], Latinx/Hispanic patients [AAPC: -4.8% (95% CI -7.2 to -2.36), P  < 0.001] and residents of urban areas [AAPC: -5.4% (95% CI -6.2 to -4.6), P  < 0.001]. The higher percentages of HCM-related deaths occurred in the South of the country and at the patient's home., Conclusion: HCM-related mortality in US young adults has decreased over the last two decades in the United States. Subgroup analyses by race, ethnicity, urbanization and census region showed ethnoracial and regional disparities that will require further investigation., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Assessing myocardial strain by cardiac magnetic resonance feature tracking (FT) has been found to be useful in patients with overt hypertrophic cardiomyopathy (HCM). Little is known, however, of its role in sarcomere gene mutation carriers without overt left ventricular hypertrophy (subclinical HCM)., Methods: Thirty-eight subclinical HCM subjects and 42 healthy volunteers were enrolled in this multicenter case-control study. They underwent a comprehensive cardiac magnetic resonance study. Two-dimensional global radial, circumferential, and longitudinal strain of the left ventricle (LV) were evaluated by FT analysis., Results: The subclinical HCM sample was 41 (22-51) years old and 32% were men. FT analysis revealed a reduction in global radial strain (29±7.2 versus 47.9±7.4; P <0.0001), global circumferential strain (-17.3±2.6 -versus -20.8±7.4; P <0.0001) and global longitudinal strain (-16.9±2.4 versus -20.5±2.6; P <0.0001) in subclinical HCM compared with control subjects. The significant differences persisted when considering the 23 individuals free of all the structural and functional ECG and cardiac magnetic resonance abnormalities previously described. Receiver operating characteristic curve analyses showed that the differential diagnostic performances of FT in discriminating subclinical HCM from normal subjects were good to excellent (global radial strain with optimal cut-off value of 40.43%: AUC, 0.946 [95% CI, 0.93-1.00]; sensitivity 90.48%, specificity 94.44%; global circumferential strain with cut-off, -18.54%: AUC, 0.849 [95% CI, 0.76-0.94]; sensitivity, 88.10%; specificity, 72.22%; global longitudinal strain with cut-off, -19.06%: AUC, 0.843 [95% CI, 0.76-0.93]; sensitivity, 78.57%; specificity, 78.95%). Similar values were found for discriminating those subclinical HCM subjects without other phenotypic abnormalities from healthy volunteers (global radial strain with optimal cut-off 40.43%: AUC, 0.966 [95% CI, 0.92-1.00]; sensitivity, 90.48%; specificity, 95.45%; global circumferential strain with cut-off, -18.44%: AUC, 0.866 [95% CI, 0.76-0.96]; sensitivity, 92.86%; specificity, 77.27%; global longitudinal strain with cut-off, -17.32%: AUC, 0.838 [95% CI, 0.73-0.94]; sensitivity, 90.48%; specificity, 65.22%)., Conclusions: Cardiac magnetic resonance FT-derived parameters are consistently lower in subclinical patients with HCM, and they could emerge as a good tool for discovering the disease during a preclinical phase., Competing Interests: Disclosures None.

Aims: To evaluate the role of tricuspid regurgitation in advanced heart failure., Methods: The multicenter observational HELP-HF registry enrolled consecutive patients with heart failure and at least one 'I NEED HELP' criterion evaluated at four Italian centers between January 2020 and November 2021. Patients with no data on tricuspid regurgitation and/or receiving tricuspid valve intervention during follow-up were excluded. The population was stratified by no/mild tricuspid regurgitation vs. moderate tricuspid regurgitation vs. severe tricuspid regurgitation. Variables independently associated with tricuspid regurgitation, as well as the association between tricuspid regurgitation and clinical outcomes were investigated. The primary outcome was all-cause mortality., Results: Among the 1085 patients included in this study, 508 (46.8%) had no/mild tricuspid regurgitation, 373 (34.4%) had moderate tricuspid regurgitation and 204 (18.8%) had severe tricuspid regurgitation. History of atrial fibrillation, any prior valve surgery, high dose of furosemide, preserved left ventricular ejection fraction, moderate/severe mitral regurgitation and pulmonary hypertension were found to be independently associated with an increased likelihood of severe tricuspid regurgitation. Estimated rates of 1-year all-cause death were of 21.4, 24.5 and 37.1% in no/mild tricuspid regurgitation, moderate tricuspid regurgitation and severe tricuspid regurgitation, respectively (log-rank P  < 0.001). As compared with nonsevere tricuspid regurgitation, severe tricuspid regurgitation was independently associated with a higher risk of all-cause mortality (adjusted hazard ratio 1.38, 95% confidence interval 1.01-1.88, P  = 0.042), whereas moderate tricuspid regurgitation did not., Conclusion: In a contemporary, real-world cohort of patients with advanced heart failure, several clinical and echocardiographic characteristics are associated with an increased likelihood of severe tricuspid regurgitation. Patients with severe tricuspid regurgitation have an increased risk of mortality., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Hospitalization is associated with poor outcomes in patients with heart failure, but its prognostic role in advanced heart failure is still unsettled. We evaluated the prognostic role of heart failure hospitalization in patients with advanced heart failure., Methods: The multicenter HELP-HF registry enrolled consecutive patients with heart failure and at least one high-risk 'I NEED HELP' marker. Characteristics and outcomes were compared between patients who were hospitalized for decompensated heart failure (inpatients) or not (outpatients) at the time of enrolment. The primary endpoint was the composite of all-cause mortality or first heart failure hospitalization., Results: Among the 1149 patients included [mean age 75.1 ± 11.5 years, 67.3% men, median left ventricular ejection fraction (LVEF) 35% (IQR 25-50%)], 777 (67.6%) were inpatients at the time of enrolment. As compared with outpatients, inpatients had lower LVEF, higher natriuretic peptides and a worse clinical profile. The 1-year rate of the primary endpoint was 50.9% in inpatients versus 36.8% in outpatients [crude hazard ratio 1.70, 95% confidence interval (CI) 1.39-2.07, P < 0.001]. At multivariable analysis, inpatient status was independently associated with a higher risk of the primary endpoint (adjusted hazard ratio 1.54, 95% CI 1.23-1.93, P < 0.001). Among inpatients, the independent predictors of the primary endpoint were older age, lower SBP, heart failure association criteria for advanced heart failure and glomerular filtration rate 30 ml/min/1.73 m2 or less., Conclusion: Hospitalization for heart failure in patients with at least one high-risk 'I NEED HELP' marker is associated with an extremely poor prognosis supporting the need for specific interventions, such as mechanical circulatory support or heart transplantation., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: There are limited data on implantable-cardioverter-defibrillator (ICD) implantation after ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). Therefore, we evaluated when and how frequently an ICD is implanted after pPCI, the rate of appropriate ICD interventions, and predictors of ICD implantation., Methods: We analyzed STEMI patients treated with pPCI at the University Hospital of Trieste, Italy, between January 2010 and December 2019. We cross-matched patients' data with those present in the Trieste ICD registry., Results: Among 1805 consecutive patients treated with pPCI, 3.6% underwent ICD implantation during a median follow-up of 6.7 [interquartile range (IQR) 4.3-9.2] years. At 12 months, the mean number of ICD implantations was 2.3/100 patients [95% confidence interval (95% CI) 1.7-3.1] and remained stable over time (at 24 months: 2.5/100 patients, 95% CI 2.0-3.5 and at 36 months: 2.6/100 patients, 95% CI 2.3-3.8); 83.1% of ICDs were implanted for primary prevention, and more than half (55%) were implanted in patients with ejection fraction more than 35% at the moment of STEMI discharge. The rate of appropriate ICD interventions was 16.9% at a median follow-up of 5.7 years (IQR 3.3-8.3 years) after ICD implantation. At 12 months, the mean number of appropriate ICD interventions was 5/100 patients and 7/100 patients after 24 months. In patients with ejection fraction more than 35% at STEMI discharge (median ejection fraction 43%; IQR 40-48), independent predictors of ICD implantation were male sex, anterior STEMI and troponin peak more than 100 000 ng/dl., Conclusion: The rate of ICD implantations after pPCI is low; however, the rate of appropriate ICD interventions is high. A relevant subgroup of patients received ICD implantations at follow-up despite a nonsevere ejection fraction at discharge after STEMI. Among these patients, those with high troponin release deserve strict follow-up and full optimal medical treatment., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: The "I Need Help" markers have been proposed to identify patients with advanced heart failure (HF). We evaluated the prognostic impact of these markers on clinical outcomes in a real-world, contemporary, multicenter HF population., Methods: We included consecutive patients with HF and at least 1 high-risk "I Need Help" marker from 4 centers. The impact of the cumulative number of "I Need Help" criteria and that of each individual "I Need Help" criterion was evaluated. The primary end point was the composite of all-cause mortality or first HF hospitalization., Results: Among 1149 patients enrolled, the majority had 2 (30.9%) or 3 (22.6%) "I Need Help" criteria. A higher cumulative number of "I Need Help" criteria was independently associated with a higher risk of the primary end point (adjusted hazard ratio for each criterion increase, 1.19 [95% CI, 1.11-1.27]; P <0.001), and patients with >5 criteria had the worst prognosis. Need of inotropes, persistently high New York Heart Association classes III and IV or natriuretic peptides, end-organ dysfunction, >1 HF hospitalization in the last year, persisting fluid overload or escalating diuretics, and low blood pressure were the individual criteria independently associated with a higher risk of the primary end point., Conclusions: In our HF population, a higher number of "I Need Help" criteria was associated with a worse prognosis. The individual criteria with an independent impact on mortality or HF hospitalization were need of inotropes, New York Heart Association class or natriuretic peptides, end-organ dysfunction, multiple HF hospitalizations, persisting edema or escalating diuretics, and low blood pressure., Competing Interests: Disclosures Dr Pagnesi reports personal fees from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, and Vifor Pharma, all outside the submitted work. Dr Stolfo reports personal fees from Novartis, Merck, GlaxoSmithKline, and Acceleron, all outside the submitted work. Dr Adamo reports speaker fees from Abbott Vascular and Medtronic. Dr Merlo reports personal fees for congresses from Novartis, Vifor Pharma, and Pfizer and unrestricted research grant from Pfizer, all outside the submitted work. Dr Sinagra reports consulting fees from Novartis, Impulse Dynamics, and Biotronik and speaker fees and honoraria from Novartis, Bayer, AstraZeneca, Boston Scientific, Vifor Pharma, Menarini, and Akcea Therapeutics, all outside the submitted work. Dr Metra reports personal consulting honoraria of minimal amount from Abbott, Amgen, Bayer, Edwards Therapeutics, LivaNova, and Vifor Pharma for participation to advisory board meetings and executive committees of clinical trials. The other authors report no conflicts.

Background: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM., Methods: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction., Results: The genome-wide association study identified a highly suggestive locus that mapped to the 5'-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P =7.12×10 -7 ). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis., Conclusions: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis., Competing Interests: Disclosures R.M. Weinshilboum is a cofounder of and stockholder in OneOme, LLC. The other authors report no conflicts.

Background: Variants in RBM20 are reported in 2% to 6% of familial cases of dilated cardiomyopathy and may be associated with fatal ventricular arrhythmia and rapid heart failure progression. We sought to determine the risk of adverse events in RBM20 variant carriers and the impact of sex on outcomes., Methods: Consecutive probands and relatives carrying RBM20 variants were retrospectively recruited from 12 cardiomyopathy units. The primary end point was a composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure (ESHF). MVA and ESHF end points were also analyzed separately and men and women compared. Left ventricular ejection fraction (LVEF) contemporary to MVA was examined. RBM20 variant carriers with left ventricular systolic dysfunction ( RBM20 LVSD ) were compared with variant-elusive patients with idiopathic left ventricular systolic dysfunction., Results: Longitudinal follow-up data were available for 143 RBM20 variant carriers (71 men; median age, 35.5 years); 7 of 143 had an MVA event at baseline. Thirty of 136 without baseline MVA (22.0%) reached the primary end point, and 16 of 136 (11.8%) had new MVA with no significant difference between men and women (log-rank P =0.07 and P =0.98, respectively). Twenty of 143 (14.0%) developed ESHF (17 men and 3 women; log-rank P <0.001). Four of 10 variant carriers with available LVEF contemporary to MVA had an LVEF >35%. At 5 years, 15 of 67 (22.4%) RBM20 LVSD versus 7 of 197 (3.6%) patients with idiopathic left ventricular systolic dysfunction had reached the primary end point (log-rank P <0.001). RBM20 variant carriage conferred a 6.0-fold increase in risk of the primary end point., Conclusions: RBM20 variants are associated with a high risk of MVA and ESHF compared with idiopathic left ventricular systolic dysfunction. The risk of MVA in male and female RBM20 variant carriers is similar, but male sex is strongly associated with ESHF., Competing Interests: Disclosures Dr Sengupta reports speakers fees from Pfizer. Dr Elliott reports consultancies for Pfizer, Sarepta, Bristol Myers Squibb, Biomarin, Leal, and Novo Nordisk. The other authors report no conflict.

Aims: In Italy, 12-month survival in the general population between 90 and 94 years old is 26%. In very old patients, the benefit of pacemaker implantation in terms of quality and duration of life is unclear. The aim of our study was to analyse clinical characteristics, outcome and factors associated with survival in patients at least 90 years old at the time of the first pacemaker implant., Methods: Clinical parameters, device characteristics, survival and predictors of outcome in patients at least 90 years old treated with a pacemaker in our centre in 2019-2020 were evaluated., Results: Among the 554 patients undergoing pacemaker implantation in our centre during the study interval, 69 (12%) were at least 90 years old; a complete/advanced atrioventricular block was present in 65%. A cardiological comorbidity (excluding atrial fibrillation) was present in 22 patients (32%). Oncological, pulmonary and neurological comorbidities were present in 12 (17%), 19 (28%) and 32 (46%), respectively. Renal impairment was present in 25 patients (36%). After pacemaker implantation, a pneumothorax developed in two patients and lead dislodgment in one. During follow-up (median 17 months, interquartile range: 13-24), 32 patients died (46%), with a 12-month mortality probability of 24.6%. At multivariate analysis, the presence of oncological (hazard ratio (HR) 5.31; P < 0.001) and neurological (HR 6.44; P < 0.001) comorbidities was associated with mortality. Truncating the outcome at 6 months, renal impairment (HR 8.01; P = 0.003), anticoagulant therapy (HR 8.14; P = 0.003), oncological comorbidities (HR 14.1; P < 0.001) and left ventricular function (5% increase of left ventricular ejection fraction: HR 0.66; P < 0.001) were significantly associated with outcome., Conclusion: At our centre, patients at least 90 years old underwent pacemaker implantation mainly for advanced atrioventricular block. One-year survival was excellent, even better than expected in the general population., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Competing Interests: Disclosures None.

Aims: Data regarding the dilated cardiomyopathy (DCM)-related mortality and relative time trends in the Italian population remain scant. We sought to assess the DCM mortality rates and relative trends among the Italian population between 2005 and 2017., Methods: Annual death rates by sex and 5-year age group were extracted from the WHO global mortality database. The age-standardized mortality rates, with relative 95% confidence intervals (95% CIs), also stratified by sex, were calculated using the direct method. Joinpoint regression analyses were used to identify periods with statistically distinct log linear trends in DCM-related death rates. To calculate nationwide annual trends in DCM-related mortality, we assessed the average annual percentage change (AAPC) and relative 95% CIs., Results: In Italy, the DCM age-standardized annual mortality rate decreased from 4.99 (95% CI: 4.97-5.02) deaths per 100 000 to 2.51 (95% CI: 2.49-2.52) deaths per 100 000 population. Over the entire period, men had a higher DCM-related mortality rates than women. Moreover, the mortality rate increased with age, with a seemingly exponential distribution and showing a similar trend among men and women. Joinpoint regression analysis revealed a linear decrease in age-standardized DCM-related mortality from 2005 to 2017 [AAPC: -5.1% (95% CI: -5.9 to -4.3, P < 0.001)] in the entire Italian population. However, the decline was more pronounced among women [AAPC: -5.6 (95% CI: -6.4 to -4.8, P < 0.001)] compared with men [AAPC: -4.9 (95% CI: -5.8 to -4.1, P < 0.001)]., Conclusion: In Italy, the DCM-related mortality rates linearly declined from 2005 to 2017., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Tricuspid regurgitation (TR) is common in chronic heart failure (HF) and is associated with negative prognosis. However, evidence on prognostic implications of TR in acute HF is lacking. We sought to investigate the association between TR and mortality and the interaction with pulmonary hypertension (PH) in patients admitted for acute HF., Methods: We enrolled 1176 consecutive patients with a primary diagnosis of acute HF and with available noninvasive estimation of TR and pulmonary arterial systolic pressure., Results: Moderate-severe TR was present in 352 patients (29.9%) and was associated with older age and more comorbidities. The prevalence of PH (ie, pulmonary arterial systolic pressure >40 mm Hg), right ventricular dysfunction, and mitral regurgitation was higher in moderate-severe TR. At 1 year, 184 (15.6%) patients died. Moderate-severe TR was associated with higher 1-year mortality risk after adjustment for other echocardiographic parameters (pulmonary arterial systolic pressure, left ventricle ejection fraction, right ventricular dysfunction, mitral regurgitation, left and right atrial indexed volumes; hazard ratio, 1.718; P =0.009), and the association with outcome was maintained when clinical variables (eg, natriuretic peptides, serum creatinine and urea, systolic blood pressure, atrial fibrillation) were added to the multivariable model (hazard ratio, 1.761; P =0.024). The association between moderate-severe TR and outcome was consistent in patients with versus without PH, with versus without right ventricular dysfunction, and with versus without left ventricle ejection fraction <50%. Patients with coexistent moderate-severe TR and PH had 3-fold higher 1-year mortality risk compared with patients with no TR or PH (hazard ratio, 3.024; P <0.001)., Conclusions: In patients hospitalized for acute HF, the severity of TR is associated with 1-year survival, regardless of the presence of PH. The coexistence of moderate-severe TR and estimated PH was associated with a further increase in mortality risk. Our data must be interpreted in the context of potential underestimation of pulmonary arterial systolic pressure in patients with severe TR., Competing Interests: Disclosures Dr Stolfo reports personal fees from Novartis, Merck, GSK, and Acceleron outside the submitted work. Dr Merlo reports consultant and unrestricted fees at congresses, congress fees from Novartis and Vifor Pharma. Dr Sinagra reports consulting fees from Novartis, Impulse Dynamics and Biotronik, and speaker and honoraria from Novartis, Bayer, Astrazeneca, Boston Scientific, Vifor Pharma, Menarini and Akcea Therapeutics outside the submitted work. The other authors report no conflicts

Aims: Vaccination represents a cornerstone of prevention in the COVID-19 pandemic. Rare adverse events including acute pericarditis and myopericarditis have been reported., Methods: All consecutive patients referred to our referral center for pericardial diseases following COVID-19 vaccination from 1 April 2021 to 15 April 2022 were included. Acute pericarditis and myopericarditis were diagnosed according to ESC guidelines. Patients with SARS-CoV-2 infection were excluded from the study., Results: Twenty-four patients (79% men) aged 39.7 ± 19.8 years were referred to our center with pericarditis after receiving COVID-19 vaccination. Thirteen (54%) patients were diagnosed with myopericarditis. The mean time between vaccination and symptoms onset was 7.0 ± 4.9 days, and the most frequent symptom was pericarditic chest pain (83%). Respectively, 50 and 33% of patients presented after the second and the third dose of the vaccine. Almost all patients were treated with both nonsteroidal anti-inflammatory drugs and colchicine. Five patients (21%) experienced a recurrence of pericarditis. No patient died or developed constrictive pericarditis. Mean follow-up was 8.0 ± 3.2 months., Conclusion: COVID-19 vaccine-related pericarditis typically manifest with mild clinical signs, in young male individuals, a few days after the second or third vaccine dose and are commonly characterized by a rapid complete recovery., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Diagnostic and therapeutic advances have led to much greater awareness of transthyretin cardiac amyloidosis (ATTR-CA). We aimed to characterize changes in the clinical phenotype of patients diagnosed with ATTR-CA over the past 20 years., Methods: This is a retrospective observational cohort study of all patients referred to the National Amyloidosis Centre (2002-2021) in whom ATTR-CA was a differential diagnosis., Results: We identified 2995 patients referred with suspected ATTR-CA, of whom 1967 had a diagnosis of ATTR-CA confirmed. Analysis by 5-year periods revealed an incremental increase in referrals, with higher proportions of patients having been referred after bone scintigraphy and cardiac magnetic resonance imaging (2% versus 34% versus 51% versus 55%, chi-square P <0.001). This was accompanied by a greater number of ATTR-CA diagnoses, predominantly of the wild-type nonhereditary form, which is now the most commonly diagnosed form of ATTR-CA (0% versus 54% versus 67% versus 66%, chi-square P <0.001). Over time, the median duration of associated symptoms before diagnosis fell from 36 months between 2002 and 2006 to 12 months between 2017 and 2021 (Mann-Whitney P <0.001), and a greater proportion of patients had early-stage disease at diagnosis across the 5-year periods (National Amyloidosis Centre stage 1: 34% versus 42% versus 44% versus 53%, chi-square P <0.001). This was associated with more favorable echocardiographic parameters of structure and function, including lesser interventricular septal thickness (18.0±3.8 mm versus 17.2±2.6 mm versus 16.9±2.3 mm versus 16.6±2.4 mm, P =0.01) and higher left ventricular ejection fraction (46.0%±8.9% versus 46.8%±11.0% versus 47.8%±11.0% versus 49.5%±11.1%, P <0.001). Mortality decreased progressively during the study period (2007-2011 versus 2012-2016: hazard ratio, 1.57 [95% CI, 1.31-1.89], P <0.001; and 2012-2016 versus 2017-2021: hazard ratio, 1.89 [95% CI, 1.55-2.30], P <0.001). The proportion of patients enrolled into clinical trials and prescribed disease-modifying therapy increased over the 20-year period, but even when censoring at the trial or medication start date, year of diagnosis remained a significant predictor of mortality (2012-2016 versus 2017-2021: hazard ratio, 1.05 [95% CI, 1.03-1.07], P <0.001)., Conclusions: There has been a substantial increase in ATTR-CA diagnoses, with more patients being referred after local advanced cardiac imaging. Patients are now more often diagnosed at an earlier stage of the disease, with substantially lower mortality. These changes may have important implications for initiation and outcome of therapy and urgently need to be factored into clinical trial design.

Introduction: Cardiac tumors are rare and heterogeneous entities which still remain a diagnostic and therapeutic challenge. The treatment for most cardiac tumors is prompt surgical resection. We sought to provide an overview of surgical results from a series of consecutive patients treated at our tertiary care center during almost a 20-year experience., Methods and Results: In this single center study, 55 consecutive patients with diagnosis of cardiac tumor underwent surgical treatment from January 2002 to April 2021. Of these, 23 (42%) were male and the mean age was 62 ± 12 years. Fifteen (27%) patients were symptomatic at the time of the diagnosis, mostly for dyspnea and palpitations. The most frequent benign cardiac tumor was myxoma (32; 58%), occurring mainly in the left atrium (31; 97%). Pleomorphic sarcoma was the most frequent primary malignant cardiac tumor (4; 7%), mainly located in the ventricles (1; 25% in the left ventricle; 2; 50% in the right ventricle). In all cases of benign tumors surgery was successful with no relapses. Two (50%) pleomorphic sarcomas showed subsequent relapses. After a median follow-up of 44 months, 15 (27%) patients died. Although malignant tumors presented a limited survival, benign tumors showed a very good prognosis., Conclusion: Cardiac tumors require a multidisciplinary approach to guarantee a prompt diagnosis and appropriate treatment. In our surgical experience, outcome after surgery of benign tumors was excellent, while malignant tumors had poor prognosis despite radical surgery., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Several risk factors have been identified to predict worse outcomes in patients affected by SARS-CoV-2 infection. Machine learning algorithms represent a novel approach to identifying a prediction model with a good discriminatory capacity to be easily used in clinical practice. The aim of this study was to obtain a risk score for in-hospital mortality in patients with coronavirus disease infection (COVID-19) based on a limited number of features collected at hospital admission., Methods and Results: We studied an Italian cohort of consecutive adult Caucasian patients with laboratory-confirmed COVID-19 who were hospitalized in 13 cardiology units during Spring 2020. The Lasso procedure was used to select the most relevant covariates. The dataset was randomly divided into a training set containing 80% of the data, used for estimating the model, and a test set with the remaining 20%. A Random Forest modeled in-hospital mortality with the selected set of covariates: its accuracy was measured by means of the ROC curve, obtaining AUC, sensitivity, specificity and related 95% confidence interval (CI). This model was then compared with the one obtained by the Gradient Boosting Machine (GBM) and with logistic regression. Finally, to understand if each model has the same performance in the training and test set, the two AUCs were compared using the DeLong's test. Among 701 patients enrolled (mean age 67.2 ± 13.2 years, 69.5% male individuals), 165 (23.5%) died during a median hospitalization of 15 (IQR, 9-24) days. Variables selected by the Lasso procedure were: age, oxygen saturation, PaO2/FiO2, creatinine clearance and elevated troponin. Compared with those who survived, deceased patients were older, had a lower blood oxygenation, lower creatinine clearance levels and higher prevalence of elevated troponin (all P < 0.001). The best performance out of the samples was provided by Random Forest with an AUC of 0.78 (95% CI: 0.68-0.88) and a sensitivity of 0.88 (95% CI: 0.58-1.00). Moreover, Random Forest was the unique model that provided similar performance in sample and out of sample (DeLong test P = 0.78)., Conclusion: In a large COVID-19 population, we showed that a customizable machine learning-based score derived from clinical variables is feasible and effective for the prediction of in-hospital mortality., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Maximal left ventricular wall thickness (MLVWT) is a risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). In adults, the severity of left ventricular hypertrophy has a nonlinear relationship with SCD, but it is not known whether the same complex relationship is seen in childhood. The aim of this study was to describe the relationship between left ventricular hypertrophy and SCD risk in a large international pediatric HCM cohort., Methods: The study cohort comprised 1075 children (mean age, 10.2 years [±4.4]) diagnosed with HCM (1-16 years) from the International Paediatric Hypertrophic Cardiomyopathy Consortium. Anonymized, noninvasive clinical data were collected from baseline evaluation and follow-up, and 5-year estimated SCD risk was calculated (HCM Risk-Kids)., Results: MLVWT Z score was <10 in 598 (58.1%), ≥10 to <20 in 334 (31.1%), and ≥20 in 143 (13.3%). Higher MLVWT Z scores were associated with heart failure symptoms, unexplained syncope, left ventricular outflow tract obstruction, left atrial dilatation, and nonsustained ventricular tachycardia. One hundred twenty-two patients (71.3%) with MLVWT Z score ≥20 had coexisting risk factors for SCD. Over a median follow-up of 4.9 years (interquartile range, 2.3-9.3), 115 (10.7%) had an SCD event. Freedom from SCD event at 5 years for those with MLVWT Z scores <10, ≥10 to <20, and ≥20 was 95.6%, 87.4%, and 86.0, respectively. The estimated SCD risk at 5 years had a nonlinear, inverted U-shaped relationship with MLVWT Z score, peaking at Z score +23. The presence of coexisting risk factors had a summative effect on risk., Conclusions: In children with HCM, an inverted U-shaped relationship exists between left ventricular hypertrophy and estimated SCD risk. The presence of additional risk factors has a summative effect on risk. While MLVWT is important for risk stratification, it should not be used either as a binary variable or in isolation to guide implantable cardioverter defibrillator implantation decisions in children with HCM.

Introduction: The role of sex compared to comorbidities and other prognostic variables in patients with coronavirus disease (COVID-19) is unclear., Methods: This is a retrospective observational study on patients with COVID-19 infection, referred to 13 cardiology units. The primary objective was to assess the difference in risk of death between the sexes. The secondary objective was to explore sex-based heterogeneity in the association between demographic, clinical and laboratory variables, and patients' risk of death., Results: Seven hundred and one patients were included: 214 (30.5%) women and 487 (69.5%) men. During a median follow-up of 15 days, deaths occurred in 39 (18.2%) women and 126 (25.9%) men. In a multivariable Cox regression model, men had a nonsignificantly higher risk of death vs. women (P = 0.07).The risk of death was more than double in men with a low lymphocytes count as compared with men with a high lymphocytes count [overall survival hazard ratio (OS-HR) 2.56, 95% confidence interval (CI) 1.72-3.81]. In contrast, lymphocytes count was not related to death in women (P = 0.03).Platelets count was associated with better outcome in men (OS-HR for increase of 50 × 103 units: 0.88 95% CI 0.78-1.00) but not in women. The strength of association between higher PaO2/FiO2 ratio and lower risk of death was larger in women (OS-HR for increase of 50 mmHg/%: 0.72, 95% CI 0.59-0.89) vs. men (OS-HR: 0.88, 95% CI 0.80-0.98; P = 0.05)., Conclusions: Patients' sex is a relevant variable that should be taken into account when evaluating risk of death from COVID-19. There is a sex-based heterogeneity in the association between baseline variables and patients' risk of death., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Despite prognostic improvements in ST-elevation myocardial infarction (STEMI), patients presenting with cardiogenic shock (CS) have still high mortality. Which are the relevant early prognostic factors despite revascularization in this high-risk population is poorly investigated., Methods: We analyzed STEMI patients treated with primary percutaneous coronary intervention (PCI) and enrolled at the University Hospital of Trieste between 2012 and 2018. A decision tree based on data available at first medical contact (FMC) was built to stratify patients for 30-day mortality. Multivariate analysis was used to explore independent factors associated with 30-day mortality., Results: Among 1222 STEMI patients consecutively enrolled, 7.5% presented with CS. CS compared with no-CS patients had worse 30-day mortality (33% vs 3%, P < 0.01). Considering data available at FMC, CS patients with a combination of age ≥76 years, anterior STEMI and an expected ischemia time > 3 h and 21 min were at the highest mortality risk, with a 30-day mortality of 85.7%. In CS, age (OR 1.246; 95% CI 1.045-1,141; P = 0.003), final TIMI flow 2-3 (OR 0.058; 95% CI 0.004-0.785; P = 0.032) and Ischemia Time (OR = 1.269; 95% CI 1.001-1.609; P = 0.049) were independently associated with 30-day mortality., Conclusions: In a contemporary real-world population presenting with CS due to STEMI, age is a relevant negative factor whereas an early and successful PCI is positively correlated with survival. However, a subgroup of elderly patients had severe prognosis despite revascularization. Whether pPCI may have an impact on survival in a very limited number of irreversibly critically ill patients remains uncertain and the identification of irreversibly shocked patients remains nowadays challenging., (Copyright © 2021 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Since 1989, SIC Sport and a FMSI, in partnership with leading Italian Cardiological Scientific Associations (ANCE, ANMCO and SIC) have produced Cardiological Guidelines for Completive Sports Eligibility for athletes with heart disease (COCIS -- 1989, 1995, 2003, 2009 and 2017). The English version of the Italian Cardiological Guidelines for Competitive Sports Eligibility for athletes with heart disease was published in 2013 in this Journal. This publication is an update with respect to the document previously published in English in 2013. It includes the principal innovations that have emerged over recent years, and is divided into five main chapters: arrhythmias, ion channel disorders, congenital heart diseases, acquired valve diseases, cardiomyopathies, myocarditis and pericarditis and ischemic heart disease. Wherever no new data have been introduced with respect to the 2013 publication, please refer to the previous version. This document is intended to complement recent European and American guidelines but an important difference should be noted. The European and American guidelines indicate good practice for people engaging in physical activity at various levels, not only at the competitive level. In contrast, the COCIS guidelines refer specifically to competitive athletes in various sports including those with high cardiovascular stress. This explains why Italian guidelines are more restrictive than European and USA ones. COCIS guidelines address 'sports doctors' who, in Italy, must certify fitness to participate in competitive sports. In Italy, this certificate is essential for participating in any competition., (Copyright © 2021 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Filamin C truncating variants ( FLNCtv ) cause a form of arrhythmogenic cardiomyopathy: the mode of presentation, natural history, and risk stratification of FLNCtv remain incompletely explored. We aimed to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers., Methods: FLNCtv carriers were identified from 10 tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), nonarrhythmic death/HT/LVAD, and sudden cardiac death/major ventricular arrhythmias. Previously established cohorts of 46 patients with LMNA and 60 with DSP -related arrhythmogenic cardiomyopathies were used for prognostic comparison., Results: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% men, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) experienced nonarrhythmic death/HT/LVAD, and 23 (27%) experienced sudden cardiac death/major ventricular arrhythmias. The sudden cardiac death/major ventricular arrhythmias incidence of FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, left ventricular ejection fraction was associated with the risk of D/HT/LVAD and nonarrhythmic death/HT/LVAD., Conclusions: Among patients referred to tertiary referral centers, FLNCtv arrhythmogenic cardiomyopathy is phenotypically heterogeneous and characterized by a high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of left ventricular dysfunction.

CoronaVIrus Disease-19 (COVID-19) had a huge impact on human health and economy. However, to this date, the effects of the pandemic on the training of young cardiologists are only partially known. To assess the consequences of the pandemic on the education of the cardiologists in training, we performed a 23-item national survey that has been delivered to 1443 Italian cardiologists in training, registered in the database of the Italian Society of Cardiology (SIC). Six hundred and thirty-three cardiologists in training participated in the survey. Ninety-five percent of the respondents affirmed that the training programme has been somewhat stopped or greatly jeopardized by the pandemic. For 61% of the fellows in training (FITs), the pandemic had a negative effect on their education. Moreover, 59% of the respondents believe that they would not be able to fill the gap gained during that period over the rest of their training. A negative impact on the psycho-physical well being has been reported by 86% of the FITs. The COVID-19 pandemic had an unparalleled impact on the education, formation and mental state of the cardiologists in training. Regulatory agencies, universities and politicians should make a great effort in the organization and reorganization of the teaching programs of the cardiologists of tomorrow., (Copyright © 2021 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Aims: To evaluate the prevalence and predictors of persistent sinus rhythm in a recent cohort of unselected patients undergoing electrical cardioversion for atrial fibrillation., Methods: We enrolled all consecutive patients undergoing elective electrical cardioversion for atrial fibrillation between January 2017 and December 2018. We analysed baseline clinical and echocardiographic data as well as pharmacological antiarrhythmic therapy. Primary endpoint was the maintenance of sinus rhythm at 12 months after electrical cardioversion., Results: Of the 300 patients enrolled, 270 (90%) had successful electrical cardioversion and among them, 201 patients have 12-month follow-up data (mean age 70 ± 10 years; 74% men). At 12 months, only 45.7% were in sinus rhythm. Patients without sinus rhythm compared with persistent sinus rhythm at 12 months had a lower baseline left ventricle ejection fraction (LVEF) (49.1 ± 16 vs. 59.7 ± 9%, P = 0.02) and had more frequently a history of atrial fibrillation more than 12 months (55 vs. 34% P = 0.003). At the multivariate analysis, only the duration of the disease beyond 12 months (OR 0.26, 95% CI: 0.08-0.88, P = 0.032), LVEF (OR 1.06, 95% CI: 1.01-1.12, P = 0.012) and the presence of sinus rhythm at 1-month follow-up (OR 18.28, 95% CI: 3.3-100, P = 0.001) were associated with the probability of maintaining sinus rhythm at 12 months., Conclusion: In unselected patients with atrial fibrillation undergoing elective electrical cardioversion, only 45.7% were in sinus rhythm at 12 months. The presence of sinus rhythm at 1-month follow-up emerged as an independent predictor of maintenance of sinus rhythm. This highlights that early re-evaluation of these patients appears useful for assessing longer term outcomes also from the perspective of a possible selective approach to ablation strategies., (Copyright © 2021 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: The analysis of the circadian rhythm of heart rate variability (HRV) represents a relevant physiological tool to assess the vagal system. However, the influence of age (mostly >75 years) on HRV is not widely known., Aims: The aim of this study was to evaluate the influence of age on HRV, particularly in the elderly and to identify a model of this relationship. The study was carried out by examining linear and nonlinear parameters extracted from HRV, including individuals over 75 years for which there is no research available., Methods: Data from 140 healthy subjects were sex matched and divided into young (young group: 15-39 years old), adult (adult group: 40-64 years old) and senior (senior group: 65-90 years old) groups. 24-h Holter monitoring was used and several HRV parameters were extracted from time, and spectral and nonlinear analyses were examined., Results: Time-domain parameters, mainly standard deviation of the NN interval (SDNN) and number of successive differences of intervals which differ by more than 50 ms, presented significant differences between the young group and the other two groups during the 24-h period, while normalized spectral parameters (LFn, HFn and low frequency/high frequency), as well as nonlinear parameters, mainly β exponent and fractal dimension, showed significant difference between the senior group and the other two groups. All these parameters showed a similar circadian rhythm with significant differences between the mean day and night values, especially in young and adult group cohorts. Moreover, a parabolic relationship between these parameters and age was highlighted with an opposite trend over about 60 years compared with younger people., Conclusion: A progressive physiological autonomic imbalance is present in ageing. The inverse trend in the relation between HRV parameters and age found in the senior group could be mainly due to a faster fluctuation of RR. This should be considered when studying changes in the cardiac autonomic nervous control., (Copyright © 2020 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Public health emergencies such as the COVID-19 outbreak may impact on the incidence rate of ST-elevation myocardial infarction (STEMI) in severely affected areas. However, this phenomenon demands attention also in areas where media and patients were focused on the COVID-19 pandemic, but the healthcare system was not overwhelmed by the huge number of COVID-19 patients., Methods and Results: In this observational study, we compared the incidence rate of all consecutive STEMI patients admitted at the University Hospital of Trieste, Italy, during March and April 2020 with the same 2 months of the previous 5 years (2015-2019). Patient characteristics were compared between 2020 and 2019.The incidence rate of STEMI admission in March-April 2020 was lower than those in March-April 2015-2019, 36 vs. 56 cases per 100 000 inhabitants/year [relative risk (RR) 0.65, 95% confidence interval (95% CI) 0.42-0.96, P = 0.045]. Considering that the incidence rates were constant in the past years (P = 0.24), the turnaround in 2020 is most likely due to the COVID-19 outbreak. Interestingly, this reduction was a dynamic phenomenon with a U-shaped curve during the 2-month period. System-of-care times were similar between 2020 and 2019; however in 2020, patients presented more frequently signs of heart failure compared to 2019 (Killip class ≥2 in 68% vs. 29%, P = 0.003)., Conclusion: During the COVID-19 outbreak, we observed a marked reduction in the STEMI incidence rate. This U-shaped phenomenon demands attention because a potential cause for the decrease in STEMI incidence may include the avoidance of medical care. Public campaigns aiming to increase awareness of ischemic symptoms may be needed during community outbreak., (Copyright © 2021 Italian Federation of Cardiology - I.F.C. All rights reserved.)

: Nonischemic-dilated cardiomyopathy (NIDCM) is an entity that gathers extremely heterogeneous diseases. This awareness, although leading to continuous improvement in survival, has increased the complexity of NIDCM patients' management. Even though the endorsed 'red-flags' approach helps clinicians in pursuing an accurate etiological definition in clinical practice, it is not clear when and how peripheral centers should interact with referral centers with specific expertise in challenging scenarios (e.g. postmyocarditis and genetically determined dilated cardiomyopathy) and with easier access to second-line diagnostic tools and therapies. This position paper will summarize each step in NIDCM management, highlighting the multiple interactions between peripheral and referral centers, from first-line diagnostic workup and therapy to advanced heart failure management and long-term follow-up.

Background: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers., Methods: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%)., Results: Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P =0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; P =0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; P <0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis ( P =0.07)., Conclusions: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.

Background: Population aging has increased together with the need for cardiovascular care. Understanding the relevance of cardiovascular conditions in the very old is crucial to developing a specific and rationale therapeutic approach. Centenarians can be considered a model of successful aging, although the impact of cardiovascular disease in this population is still unclear., Aim: To evaluate the cardiovascular health status of a subset of centenarians enrolled in the Centenari a Trieste study and living in the province of Trieste to describe the prevalence of cardiovascular conditions among them., Methods: The current study included 20 individuals born before 1919 and living in the province of Trieste as of 1 May 2019. All centenarians were able to give consent and were subjected to an in-home complete clinical assessment focused on cardiovascular conditions, ECG and echocardiography., Results: The majority of centenarians were women (85%) and were not taking any chronic cardiovascular medication (55%). No centenarians had a history of ischemic heart disease while about one-third had signs suggestive of heart failure at examination (20%). Atrial fibrillation was present in 20% of individuals and conduction disorders were uncommon. Although the majority of individuals had a preserved left ventricular function, diastolic function was abnormal in 80% of enrolled centenarians that, however, was mild in 73% of cases., Conclusion: This is the second study to perform in-home echocardiography in centenarians and the first to characterize the cardiovascular status of centenarians living in Trieste. The majority of centenarians had asymptomatic diastolic dysfunction and were naïve from cardiovascular therapy. The recruitment of new individuals from the Trieste area is continuing to perform analyses on clinical, genetic and environmental factors that may predict greater longevity in this geographical context and unveil mechanisms that regulate cardiac aging associated with increased lifespan.

Purpose of Review: Cardiomyopathies are rare in the pediatric population, but significantly impact on morbidity and mortality. The present review aims to provide an overview of cardiomyopathies in children and some practical guidelines for their prognostic stratification and management., Recent Findings: Pediatric cardiomyopathies may present as isolated cardiac muscle disease or in the context of complex clinical syndromes. The etiologic characterization represents an important step in the diagnosis and treatment of cardiomyopathies because of its impact on prognosis and on therapeutic measures. Indeed, replacement therapy is nowadays widely available and changes the natural history of the disease. More complex is the management of isolated cardiomyopathies, which lack specific therapies, mainly aimed at symptomatic relief. In this context, heart transplantation shows excellent outcomes in children, but wait-list mortality is still very high. Device therapy for sudden cardiac death prevention and the use of mechanical assist devices are becoming more common in the clinical practice and may help to reduce mortality., Summary: Providing insight into pediatric cardiomyopathies classification helps in the prognostication and management of such diseases. Recent years witnessed a significant improvement in mortality, but future research is still needed to improve quality of life and life expectations in the pediatric population.

Background: Late gadolinium enhancement (LGE) is an important prognostic marker in hypertrophic cardiomyopathy and an extent >15% it is associated with high risk of sudden cardiac death. We proposed a novel method, the LGE-dispersion mapping, to assess heterogeneity of scar, and evaluated its prognostic role in patients with hypertrophic cardiomyopathy., Methods: One hundred eighty-three patients with hypertrophic cardiomyopathy and a low- or intermediate 5-year risk of sudden cardiac death underwent cardiac magnetic resonance imaging. A parametric map was generated from each LGE image. A score from 0 to 8 was assigned at every pixel of these maps, indicating the number of the surrounding pixels having different quality (nonenhancement, mild-enhancement, or hyperenhancement) from the central pixel. The Global Dispersion Score (GDS) was calculated as the average score of all the pixels of the images., Results: During a median follow-up time of 6 (25th-75th, 4-10) years, 22 patients had hard cardiac events (sudden cardiac death, appropriate implantable cardioverter-defibrillator therapy, resuscitated cardiac arrest, and sustained ventricular tachycardia). Kaplan-Meier analysis showed that patients with GDS>0.86 had worse prognosis than those with lower GDS ( P <0.0001). GDS>0.86 was the only independent predictor of cardiac events (hazard ratio, 9.9 [95% CI, 2.9-34.6], P =0.0003). When compared with LGE extent >15%, GDS improved the classification of risk in these patients (net reclassification improvement, 0.39 [95% CI, 0.11-0.72], P <0.019)., Conclusions: LGE-dispersion mapping is a marker of scar heterogeneity and provides a better risk stratification than LGE presence and its extent in patients with hypertrophic cardiomyopathy and a low-intermediate 5-year risk of sudden cardiac death.

While clinical gene therapy celebrates its first successes, with several products already approved for clinical use and several hundreds in the final stages of the clinical approval pipeline, there is not a single gene therapy approach that has worked for the heart. Here, we review the past experience gained in the several cardiac gene therapy clinical trials that had the goal of inducing therapeutic angiogenesis in the ischemic heart and in the attempts at modulating cardiac function in heart failure. Critical assessment of the results so far achieved indicates that the efficiency of cardiac gene delivery remains a major hurdle preventing success but also that improvements need to be sought in establishing more reliable large animal models, choosing more effective therapeutic genes, better designing clinical trials, and more deeply understanding cardiac biology. We also emphasize a few areas of cardiac gene therapy development that hold great promise for the future. In particular, the transition from gene addition studies using protein-coding cDNAs to the modulation of gene expression using small RNA therapeutics and the improvement of precise gene editing now pave the way to applications such as cardiac regeneration after myocardial infarction and gene correction for inherited cardiomyopathies that were unapproachable until a decade ago.