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The perspective on cardiac amyloidosis has deeply changed over the last 10 years following major advances in diagnosis and treatment options. This heterogeneous disease requires the interaction among experts of different specialties and subspecialties. Suspicion of disease, timely recognition and confirmation of final diagnosis, prognostic stratification, overall management and therapeutic strategies represent ongoing challenges in the clinical setting. Missing or delayed diagnosis may have significant impact on patient outcome, especially in light-chain amyloidosis. The present inter-society consensus document aims to provide a standardized approach to the diagnosis of cardiac amyloidosis in Italy, and to discuss the challenging clinical scenarios encountered in routine activity for cardiologists and physicians of different specialties dealing with patients with suspected or established cardiac amyloidosis. This document may be adapted to the setting of each specific region.

Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) and type 2 myocardial infarction (MI), both presenting as non-ST-elevation MI (NSTEMI), are often grouped together due to overlapping symptoms. The aim of our study is to compare their characteristics and prognosis to distinguish between them., Methods: Among 7815 patients with NSTEMI who underwent coronary angiography between 2005 and 2022 we identified 538 patients with diagnosis of MINOCA (n = 301; 3,9 %) and type 2 MI (n = 237; 3 %). The outcome was a composite of all-cause mortality, non-fatal MI, hospitalisation for heart failure (HF) and transitory ischemic attack or non-fatal stroke., Results: The mean age of the entire cohort was 68 (11.5) years, with women being the most frequently represented group (65 %). Comparing the sub-cohorts, MINOCA patients were younger (66.3 (11.7) Vs. 70.6 (11) years, p < 0.01), and less likely to have typical cardiovascular risk than type 2 MI patients. At multivariable analysis different clinical (age, heart rate, typical chest pain, palpitations, postmenopausal status), and instrumental (cardiac rhythm, ST-segment changes, diastolic dysfunction, hypo/akinesia with non-coronary distribution) variables were independent predictors of MINOCA with AUC of 0.83 [95 % CI, 0.78-0.88], p < 0.01 at ROC analysis. At a median follow-up of 61 (IQR 34-100) months, MINOCA patients had significantly lower rate of the composite endpoint compared to type 2 MI (20 % Vs. 32 %, p < 0.01)., Conclusions: MINOCA cohort was associated with different characteristics compared to type 2 MI and had a better prognosis despite the number of events was not negligible., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: A set of indicators to assess the quality of care for patients hospitalized for heart failure was developed by an expert working group of the Italian Health Ministry. Because a better performance profile measured using these indicators does not necessarily translate to better outcomes, a study to validate these indicators through their relationship with measurable clinical outcomes and healthcare costs supported by the Italian National Health System was carried out., Methods and Results: Residents of four Italian regions (Lombardy, Marche, Lazio, and Sicily) who were newly hospitalized for heart failure (irrespective of stage and New York Heart Association class) during 2014-2015 entered in the cohort and followed up until 2019. Adherence to evidence-based recommendations [i.e. renin-angiotensin-aldosterone system (RAS) inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRAs), and echocardiograms (ECCs)] experienced during the first year after index discharge was assessed. Composite clinical outcomes (cardiovascular hospital admissions and all-cause mortality) and healthcare costs (hospitalizations, drugs, and outpatient services) were assessed during the follow-up. The restricted mean survival time at 5 years (denoted as the number of months free from clinical outcomes), the hazard of clinical outcomes (according to the Cox model), and average annual healthcare cost (expressed in euros per person-year) were compared between adherent and non-adherent patients. A non-parametric bootstrap method based on 1000 resamples was used to account for uncertainty in cost-effectiveness estimates. A total of 41 406 patients were included in this study (46.3% males, mean age 76.9 ± 9.4 years). Adherence to RAS inhibitors, beta-blockers, MRAs, and ECCs were 64%, 57%, 62%, and 20% among the cohort members, respectively. Compared with non-adherent patients, those who adhered to ECCs, RAS inhibitors, beta-blockers, and MRAs experienced (i) a delay in the composite outcome of 1.6, 1.9, 1.6, and 0.6 months and reduced risks of 9% (95% confidence interval, 2-14%), 11% (7-14%), 8% (5-11%), and 4% (-1-8%), respectively; and (ii) lower (€262, €92, and €571 per year for RAS inhibitors, beta-blockers, and MRAs, respectively) and higher costs (€511 per year for ECC). Adherence to RAS inhibitors, beta-blockers, and MRAs showed a delay in the composite outcome and a saving of costs in 98%, 84%, and 93% of the 1000 bootstrap replications, respectively., Conclusions: Strict monitoring of patients with heart failure through regular clinical examinations and drug therapies should be considered the cornerstone of national guidelines and audits., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Low-Density Lipoprotein (LDL) cholesterol is one of the main target for cardiovascular (CV) prevention and therapy. In the last years, Proprotein Convertase Subtilisin-Kexin type 9 inhibitors (PCSK9-i) has emerged as a key therapeutic target to lower LDL and were introduced for prevention of CV events. Recently (June 2022) the Italian Medicines Agency (AIFA) modified the eligibility criteria for the use of PCSK9-i. We designed an observational study to estimate the prevalence of eligible subjects and evaluate the effectiveness of PCSK9-i applying a Target Trial Emulation (TTE) approach based on Electronic Health Records (EHR). Subjects meeting the eligibility criteria were identified from July 2017 (when PCSK9-i became available) to December 2020. Outcomes were all-cause death and the first hospitalization. Among eligible subjects, we identified those treated at date of the first prescription. Inverse Probability of Treatment Weights (IPTW) were estimated including demographic and clinical covariates, history of treatment with statins and the month/year eligibility date. Competing risk models on weighted cohorts were used to derive the Average Treatment Effect (ATE) and the Conditional Average Treatment Effect (CATE) in subgroups of interest. Out of 1976 eligible subjects, 161 (8%) received treatment with PCSK9-i. Treated individuals were slightly younger, predominantly male, had more severe CV conditions, and were more often treated with statin compared to the untreated subjects. The latter exhibited a higher prevalence of non-CV comorbidities. A significant absolute and relative risk reduction of death and a lower relative risk for the first hospitalization was observed. The risk reduction for death was confirmed in CATE analysis. PCSk9-i were prescribed to a minority of eligible subjects. Within the TTE framework, the analysis confirmed the association between PCSK9-i and lower risk of events, aligning with findings from randomized clinical trials (RCTs). In our study, PCSK9-i provided protection specifically against all-cause death, expanding upon the evidence from RCTs that had primarily focused on composite CV outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Barbati et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cardiovascular disease is associated with progression to severe COVID-19 and patients with the condition are among those in whom early antiviral therapy should be warranted. The combination of nirmatrelvir/ritonavir (Paxlovid®) has been approved for clinical use by the Food and Drug Administration and European Medicines Agency. Because patients with cardiovascular disease are often on polypharmacy, physicians need to be aware of potential drug-drug interactions (DDIs) when treating COVID-19 with nirmatrelvir/ritonavir. Guidance is given for avoiding DDIs, emphasising that preventing and managing potential DDIs with nirmatrelvir/ritonavir requires thorough assessment and knowledge. The present review summarises the clinical pharmacology of nirmatrelvir/ritonavir and provides details on potential DDIs with a focus on daily practice in patients with cardiovascular disease. Particular attention is needed for drugs that are predominantly metabolised by cytochrome P450 3A4, are substrates of P-glycoprotein and have a narrow therapeutic index. Proper management of potential DDIs must balance the benefit of nirmatrelvir/ ritonavir to prevent severe disease with the risk of serious adverse events., Competing Interests: Disclosure: ADL, NF and ML were consultants paid by Pfizer in connection with the development of this manuscript. NF has received consulting fees from Daiichi Sankyo. EAM and LP are employees of Pfizer Italia., (Copyright © The Author(s), 2024. Published by Radcliffe Group Ltd.)

Heart failure with preserved ejection fraction (HFpEF) has been for decades a nosological entity lacking specific therapy, with some even questioning its existence. Recently, targeted therapies have been introduced for specific, albeit rare, phenotypes such as Fabry disease, hypertrophic cardiomyopathy and amyloidosis. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), originally developed as anti-diabetic drugs, have fortuitously emerged as effective molecules in improving the prognosis for both patients with heart failure with reduced ejection fraction (HFrEF) and those with HFpEF, reducing heart failure exacerbations by almost a third. Although there are some epidemiological differences, depending on the country and the context analyzed, it is generally agreed that HFpEF is the most represented phenotype of heart failure, and its prevalence has been increasing in recent years due to the increase in life expectancy, improved diagnostic sensitivity and accuracy, and an exponential increase in risk factors such as diabetes, hypertension, renal failure, chronic obstructive pulmonary disease and obesity. These are often associated, turning out to be an epiphenomenon of a more complex cardio-nephro-metabolic disease. However, data and characteristics from major trials are not always aligned with the features and needs of these patients in real-world settings.The Cardiovascular Observatory of Friuli-Venezia Giulia is a powerful clinical governance tool that allows us to specifically characterize these patients, identifying and directing them towards the most appropriate diagnostic and therapeutic pathways, contributing significantly to improved prognosis and reduced expenditure paid by the National Health System.The use of SGLT2i in HFrEF patients is poised to match that of historic neurohormonal treatments, while, being the only class of drugs currently recommended by the international guidelines, they should even surpass them in HFpEF patients. However, given the high prevalence of HFpEF, it is unlikely for its treatment to be a prerogative of cardiologists alone. In this regard, it will be crucial in the near future to implement shared and integrated pathways with other medical specialists (internists, diabetologists, and nephrologists), and especially with general practitioners, who most frequently encounter these patients, to select the cases with greater complexity and potential for effective therapeutic intervention.

Objectives: This study aims to show the application of flexible statistical methods in real-world cost-effectiveness analyses applied in the cardiovascular field, focusing specifically on the use of proprotein convertase subtilisin-kexin type 9 inhibitors for hyperlipidemia., Methods: The proposed method allowed us to use an electronic health database to emulate a target trial for cost-effectiveness analysis using multistate modeling and microsimulation. We formally established the study design and provided precise definitions of the causal measures of interest while also outlining the assumptions necessary for accurately estimating these measures using the available data. Additionally, we thoroughly considered goodness-of-fit assessments and sensitivity analyses of the decision model, which are crucial to capture the complexity of individuals' healthcare pathway and to enhance the validity of this type of health economic models., Results: In the disease model, the Markov assumption was found to be inadequate, and a "time-reset" timescale was implemented together with the use of a time-dependent variable to incorporate past hospitalization history. Furthermore, the microsimulation decision model demonstrated a satisfying goodness of fit, as evidenced by the consistent results obtained in the short-term horizon compared with a nonmodel-based approach. Notably, proprotein convertase subtilisin-kexin type 9 inhibitors revealed their favorable cost-effectiveness only in the long-term follow-up, with a minimum willingness to pay of 39 000 Euro/life years gained., Conclusions: The approach demonstrated its significant utility in several ways. Unlike nonmodel-based or alternative model-based methods, it enabled to (1) investigate long-term cost-effectiveness comprehensively, (2) use an appropriate disease model that aligns with the specific problem under study, and (3) conduct subgroup-specific cost-effectiveness analyses to gain more targeted insights., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Background: Heart failure (HF) significantly affects the morbidity, mortality, and quality of life of patients. New therapeutic strategies aim to improve the functional capacity and quality of life of patients while controlling HF-related risks. Real-world data on both the functional and cardiopulmonary exercise capacities of patients with HF with reduced ejection fraction upon sacubitril/valsartan use are lacking., Methods: A multicenter, retrospective, cohort study, called REAL.IT, was performed based on the data collected from the electronic medical records of nine specialized HF centers in Italy. Cardiopulmonary exercise testing was performed at baseline and after 12 months of sacubitril/valsartan therapy, monitoring carbon dioxide production (VCO 2 ) and oxygen consumption (VO 2 )., Results: The functional capacities of 170 patients were evaluated. The most common comorbidities were hypertension and diabetes (i.e., 53.5 and 32.4%, respectively). At follow-up, both the VO 2 peak (from 15.1 ± 3.7 ml/kg/min at baseline to 17.6 ± 4.7 ml/kg/min at follow-up, p  < 0.0001) and the predicted % VO 2 peak (from 55.5 ± 14.1 to 65.5 ± 16.9, p  < 0.0001) significantly increased from baseline. The VO 2 at the anaerobic threshold (AT-VO 2 ) increased from 11.5 ± 2.6 to 12.5 ± 3.3 ml/kg/min ( p  = 0.021), and the rate ratio between the oxygen uptake and the change in work (ΔVO 2 /Δwork slope) improved from 9.1 ± 1.5 to 9.9 ± 1.6 ml/min/W ( p  < 0.0001)., Conclusions: Sacubitril/valsartan improves the cardiopulmonary capacity of patients with HFrEF in daily clinical practice in Italy., Competing Interests: MI: Lectures or consultant for Novartis, Vifor Pharma, Boehringer, Lilly, Bayer, AstraZeneca, Roche Diagnostics, Neopharmed Gentili. ADL: Lectures for Novartis, Vifor Pharma, Boheringer, Daiichi, Bayer, Pfizer, AstraZeneca, Research Funds from Novartis, Amgen, AstraZeneca, Vifor Pharma, Bayer. CDA, EP, and SP are employees of Novartis. LDE was employed by company CliCon S.r.l. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. The authors declare that this study received funding from Novartis Farma. The funder had the following involvement in the study: study design, data collection and analysis, supporting manuscript preparation., (© 2024 Sarullo, Nugara, Sarullo, Iacoviello, Di Gesaro, Miani, Driussi, Correale, Bilato, Passantino, Carluccio, Villani, Degli Esposti, D'Agostino, Peruzzi, Poli and Di Lenarda.)

Background: Traditional scores as CHADS2 and CHA2DS2-Vasc are suitable for predicting stroke and systemic embolism in patients with atrial fibrillation (AF) and have shown to be also associated with mortality. Other more complex scores have been recommended for survival prediction. The purpose of our analysis was to test the performance of different clinical scores in predicting 1-year mortality in AF patients., Material and Methods: CHADS2 and CHA2DS2-Vasc scores were calculated for AF patients of the BLITZ-AF register and compared to R2-CHADS2, R2-CHA2DS2-Vasc and CHA2DS2VASc-RAF scores in predicting 1-year survival. Scores including renal function were calculated both with glomerular filtration rate (GFR) and creatinine clearance., Results: One-year vital status (1960 alive and 199 dead) was available in 2159 patients. Receiver-operating characteristic curves displayed an association of each score to all-cause mortality, with R2(ClCrea)-CHADS2 being the best [area under the curve (AUC) 0.734]. Differences among the AUCs of the eight scores were not so evident, and a significant difference was found only between R2(ClCrea)-CHADS2 and CHADS2, CHA2DS2VASc, (ClCrea)-CHA2DS2-VASC-RAF.All the scores showed a similar performance for cardiovascular (CV) mortality, with CHA2DS2VASc-RAF being the best (AUC 0.757), with a significant difference with respect to CHADS2, CHA2DS2VASc, and (ClCrea)CHA2DS2Vasc-RAF., Conclusions: More complex scores, even if with better statistical performance, do not show a clinically relevant higher capability to discriminate alive or dead patients at 12 months. The classical and well known CHA2DS2VASc score, which is routinely used all around the world, has a high sensitivity in predicting all-cause mortality (AUC 0.695; Sensit. 80.4%) and CV mortality (AUC 0.691; Sensit. 80.0%)., Graphical Abstract: http://links.lww.com/JCM/A632., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Technological innovation provides easily accessible tools capable of simplifying healthcare processes. Notably, digital technology application in the cardiology field can improve prognosis, reduce costs, and lead to an overall improvement in healthcare. The digitization of health data, with the use of electronic health records and of electronic health files in Italy, represents one of the fields of application of digital technologies in medicine. The 2023 States General of the Italian Association of Hospital Cardiologists (ANMCO) provided an opportunity to focus attention on the potential benefits and critical issues associated with the implementation of the aforementioned digital tools, artificial intelligence, and telecardiology. This document summarizes key aspects that emerged during the event.

Aims: The current European Society of Cardiology (ESC) guidelines provide clear indications for the treatment of acute and chronic heart failure (HF). Nevertheless, there is a constant need for real-world evidence regarding the effectiveness, adherence, and persistence of drug therapy. We investigated the use of sacubitril/valsartan for the treatment of HF with reduced ejection fraction in real-world clinical practice in Italy., Methods and Results: An observational, retrospective, non-interventional cohort study based on electronic medical records from nine specialized hospital HF centres in Italy was carried out on patients with prescription of sacubitril/valsartan. Overall, 948 patients had a prescription of sacubitril/valsartan, with 924 characterized over 6 months and followed up for 12 months. Pharmacoutilization data at 1 year of follow-up were available for 225 patients {mean age 69.7 years [standard deviation (SD) = 10.8], 81.8% male}. Of those, 398 (45.2%) reached the target dose of sacubitril/valsartan of 97/103 mg in a mean time of 6.9 (SD = 6.2) weeks. Blood pressure and hypotension in 61 patients (65%) and worsening of chronic kidney disease in 10 patients (10.6%) were the main reasons for not reaching the target dose. Approximatively 50% of patients had a change in sacubitril/valsartan dose during follow-up, and 158 (70.2%) were persistent with the treatment during the last 3 months of follow-up. A sensitivity analysis (persistence during the last 4 months of follow-up) showed persistence for 162 patients (72.0%). Adherence data, available for 387 patients, showed full adherence for 205 (53%). Discontinuation (102/717 patients, 14.2%) was mainly due to hypotension and occurred after a mean time of 34.3 (SD = 28.7) weeks. During follow-up, out of 606 patients with available data, 434 patients (71.6%) had an HF add-on drug or drugs concomitant with sacubitril/valsartan. HF-related hospitalization during follow-up was numerically higher in non-persistent (16/67 patients, 23.9%) vs. patients persistent to sacubitril/valsartan (30/158, 19%) (P = 0.405)., Conclusions: Real-world data on the use of sacubitril/valsartan in clinical practice in Italy show a rapid titration to the target dose, high therapeutic adherence enabling a good level of therapeutic management in line with ESC guidelines for patients with reduced ejection fraction., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Chronotropic incompetence (CI) is a strong predictor of outcome in heart failure with reduced ejection fraction, however no data on its clinical and prognostic impacts in heart failure with mildly reduced ejection fraction (HFmrEF) are available. Therefore, the study aims to investigate, in a large multicentre HFmrEF cohort, the prevalence of CI as well as its relationship with exercise capacity and its prognostic role over the cardiopulmonary exercise testing (CPET) parameters., Methods and Results: Within the Metabolic Exercise combined with Cardiac and Kidney Indexes (MECKI) database, we analysed data of 864 HFmrEF out of 1164 stable outpatients who performed a maximal CPET at the cycle ergometer and who had no significant rhythm disorders or comorbidities. The primary study endpoint was cardiovascular (CV) death. All-cause death was also explored. Chronotropic incompetence prevalence differed depending on the method (peak heart rate, pHR% vs. pHR reserve, pHRR%) and the cut-off adopted (pHR% from ≤75% to ≤60% and pHRR% ≤ 65% to ≤50%), ranging from 11% to 62%. A total of 84 (9.7%) CV deaths were collected, with 39 (4.5%) occurring within 5 years. At multivariate analysis, both pHR% [hazard ratio 0.97 (0.95-0.99), P < 0.05] and pHRR% [hazard ratio 0.977 (0.961-0.993), P < 0.01] were associated with the primary endpoint. A pHR% ≤ 75% and a pHRR% ≤ 50% represented the most accurate cut-off values in predicting the outcome., Conclusion: The study suggests an association between blunted exercise-HR response, functional capacity, and CV death risk among patients with HFmrEF. Whether the CI presence might be adopted in daily HFmrEF management needs to be addressed in larger prospective studies., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Improvement of left ventricular ejection fraction is a major goal of heart failure (HF) treatment. However, data on clinical characteristics, exercise performance and prognosis in HF patients who improved ejection fraction (HFimpEF) are scarce. The study aimed to determine whether HFimpEF patients have a distinct clinical phenotype, biology and prognosis than HF patients with persistently reduced ejection fraction (pHFrEF)., Methods and Results: A total of 7948 patients enrolled in the Metabolic Exercise Cardiac Kidney Indexes (MECKI) score database were evaluated (median follow-up of 1490 days). We analysed clinical, laboratory, electrocardiographic, echocardiographic, exercise, and survival data from HFimpEF (n = 1504) and pHFrEF (n = 6017) patients. The primary endpoint of the study was the composite of cardiovascular death, left ventricular assist device implantation, and urgent heart transplantation. HFimpEF patients had lower HF severity: left ventricular ejection fraction 44.0 [41.0-47.0] versus 29.7 [24.1-34.5]%, B-type natriuretic peptide 122 [65-296] versus 373 [152-888] pg/ml, haemoglobin 13.5 [12.2-14.6] versus 13.7 [12.5-14.7] g/dl, renal function by the Modification of Diet in Renal Disease equation 72.0 [56.7-89.3] versus 70.4 [54.5-85.3] ml/min, peak oxygen uptake 62.2 [50.7-74.1] versus 52.6 [41.8-64.3]% predicted, minute ventilation-to-carbon dioxide output slope 30.0 [26.9-34.4] versus 32.1 [28.0-38.0] in HFimpEF and pHFrEF, respectively (p < 0.001 for all). Cardiovascular mortality rates were 26.6 and 46.9 per 1000 person-years for HFimpEF and pHFrEF, respectively (p < 0.001). Kaplan-Meier analysis showed that HFimpEF had better a long-term prognosis compared with pHFrEF patients. After adjustment for variables differentiating HFimpEF from pHFrEF, except echocardiographic parameters, the Kaplan-Meier curves showed the same prognosis., Conclusions: Heart failure with improved ejection fraction represents a peculiar group of HF patients whose clinical, laboratory, electrocardiographic, echocardiographic, and exercise characteristics parallel the recovery of systolic function. Nonetheless, these patients remain at risk for adverse outcome., (© 2023 European Society of Cardiology.)

Epidemiologic, genetic, and clinical intervention studies have indisputably shown that low-density lipoprotein cholesterol (LDL-C) is causal in the development of atherosclerotic cardiovascular disease (ASCVD). However, LDL-C variability could be related to increased ASCVD risk in patients already treated with statins. The aim of the present retrospective real-life study was to assess the prognostic impact of LDL-C variability on all-cause mortality and cardiovascular hospitalizations in patients with stable cardiovascular artery disease. A total of 3398 patients were enrolled and followed up for a median of 56 months. Considering LDL-C < 70 mg/dL as the therapeutical target, during follow-up, the percentage of patients who achieved this goal raised from 20.7% to 31.9%. In total, 1988 events were recorded, of which 428 were all-cause deaths and 1560 were cardiovascular hospitalizations. At the last medical examination, each increase in LDL-C levels of 20 mg/dL corresponded to a 6% raise in the risk of any event (HR 1.06; 95%CI, 1.03 to 1.09). In conclusion, our real-world study supports the hypothesis that a continuous and progressive downward trend in LDL-C levels is needed to achieve and maintain a cardiovascular benefit, at least in secondary prevention.

Background: Machine learning (ML) methods to build prediction models starting from electrocardiogram (ECG) signals are an emerging research field. The aim of the present study is to investigate the performances of two ML approaches based on ECGs for the prediction of new-onset atrial fibrillation (AF), in terms of discrimination, calibration and sample size dependence., Methods: We trained two models to predict new-onset AF: a convolutional neural network (CNN), that takes as input the raw ECG signals, and an eXtreme Gradient Boosting model (XGB), that uses the signal's extracted features. A penalized logistic regression model (LR) was used as a benchmark. Discrimination was evaluated with the area under the ROC curve, while calibration with the integrated calibration index. We investigated the dependence of models' performances on the sample size and on class imbalance corrections introduced with random under-sampling., Results: CNN's discrimination was the most affected by the sample size, outperforming XGB and LR only around n = 10.000 observations. Calibration showed only a small dependence on the sample size for all the models considered. Balancing the training set with random undersampling did not improve discrimination in any of the models. Instead, the main effect of imbalance corrections was to worsen the models' calibration (for CNN, integrated calibration index from 0.014 [0.01, 0.018] to 0.17 [0.16, 0.19]). The sample size emerged as a fundamental point for developing the CNN model, especially in terms of discrimination (AUC = 0.75 [0.73, 0.77] when n = 10.000, AUC = 0.80 [0.79, 0.81] when n = 150.000). The effect of the sample size on the other two models was weaker. Imbalance corrections led to poorly calibrated models, for all the approaches considered, reducing the clinical utility of the models., Conclusions: Our results suggest that the choice of approach in the analysis of ECG should be based on the amount of data available, preferring more standard models for small datasets. Moreover, imbalance correction methods should be avoided when developing clinical prediction models, where calibration is crucial., (© 2023. The Author(s).)

Background: Pressure/volume (P/V) loops provide useful information on left ventricular performance and prognosis in patients with heart failure (HF) but do not lend themselves to routine clinical practice. The authors developed a noninvasive method to compute individualized P/V loops to predict adverse clinical outcomes in patients with stable HF, which the authors believe can be used clinically., Methods: A derivation cohort (n = 443 patients) was used to develop an echocardiography P/V loop model, using brachial arterial pressure and trans-thoracic two-dimensional Doppler echocardiographic data. Each patient's P/V loop was depicted as an irregular pentagon, and a centroid was derived for each loop. The centroid distance (CD) from a reference centroid (derived from 101 healthy control subjects) was computed. This model was prospectively applied to 435 patients who constituted the validation cohort. The study end point was a composite of cardiac death or hospitalization for HF among study patients., Results: In the derivation cohort, CD was threefold greater among patients who experienced adverse events than those who did not. During a follow-up period of 30 months (15-45 months), event rates were 35% (72 of 206 patients) and 12% (29 of 237 patients P < .001), respectively, among patients with CD > 33 mL/mm Hg and those with CD ≤33 mL/mm Hg (prognostic cutoff derived by receiver operating characteristic analysis). Multivariate Cox analysis identified CD as an independent predictor of adverse outcome (hazard ratio, 1.61; 95% CI, 1.03-2.50) independently of left ventricular end-diastolic volume, pulmonary capillary wedge pressure, and left ventricular ejection fraction. These conclusions were confirmed in the validation cohort., Conclusions: The authors propose a method to create a noninvasive P/V loop and its centroid. These data provide useful pathophysiologic and prognostic information in patients with HF., (Copyright © 2023 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background:  New diagnosis, risk stratification, and treatment strategies became recently available for patients with acute pulmonary embolism (PE) leading to changes in clinical practice and potentially influencing short-term patients' outcomes., Research Question:  The COntemporary management of PE (COPE) study is aimed at assessing the contemporary clinical management and outcomes in patients with acute symptomatic PE., Study Design and Methods:  Prospective, noninterventional, multicenter study. The co-primary study outcomes, in-hospital and 30-day death, were reported overall and by risk categories according to the European Society of Cardiology (ESC) and American Heart Association guidelines., Results:  Among 5,213 study patients, PE was confirmed by computed tomography in 96.3%. In-hospital, 289 patients underwent reperfusion (5.5%), 92.1% received parenteral anticoagulants; at discharge, 75.6% received direct oral anticoagulants and 6.7% vitamin K antagonists. In-hospital and 30-day mortalities were 3.4 and 4.8%, respectively. In-hospital death occurred in 20.3% high-risk patients ( n =  177), in 4.0% intermediate-risk patients ( n =  3,281), and in 0.5% low-risk patients ( n =  1,702) according to ESC guidelines. Further stratification in intermediate-high and intermediate-low risk patients did not reach statistical significance, but intermediate-risk patients with sPESI > 0 alone had lower mortality compared to those with one or both among right ventricular dilation at echocardiography or increased troponin. Death or clinical deterioration occurred in 1.5, 5.0, and 9.4% of patients at low, intermediate-low, and intermediate-high risk for death according to ESC guidelines., Conclusion:  For the majority of patients with PE, contemporary initial management includes risk stratification and treatment with direct oral anticoagulants. In-hospital mortality remains high in intermediate and high-risk patients calling for and informing research focused on its reduction., Trial Registration Number: NCT03631810., Competing Interests: C.B. reports lecture fees and consultancies from Bayer, Bristol Myers Squibb, Pfizer, and Daiichi Sankyo; G.A. reports lecture fees and consultancies from Bayer, Bristol Myers Squibb, and Pfizer; A.P.M., D.L., and M.M.G. declare payments made to their institution from Daiichi Sankyo; F.D. reports lecture fees from Bayer, Bristol Myers Squibb, Pfizer, and Daiichi Sankyo; A.F., I.E., F.P., M.P.R., A.D.L., L.A.C., G.P., and S.C. reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objectives: The aim of this clinical observational study was to assess the efficacy of L-PRF as a hemostatic agent in patients under treatment with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs)., Materials and Methods: Patients under oral anticoagulant therapy (VKA or DOACs) who needed a single simple tooth extraction were enrolled. L-PRF plug was positioned inside the alveolus and secured with non-absorbable sutures. Surgical time, pain-VAS, paracetamol intake, intra-operative, post-operative biological complications, and bleeding events have been registered., Results: A total of 112 patients (59 patients for DOAC and 53 for VKA group) were enrolled. Post-operative bleeding was recorded in nine patients (17%) for VKA group and nine patients (15.3%) for DOACs group. None of the patients needed a medical support for managing of bleeding. Seven days after surgery, no cases of post-extractive complications occurred., Conclusions: The use of L-PRF resulted in limited mild late post-operative bleedings without the need of medical intervention., Clinical Relevance: The use of L-PRF can be adopted for an uneventful post-operative curse in anticoagulated patients without chasing their therapy for single tooth extraction., (© 2023. The Author(s).)

Left ventricular (LV) systolic function is an essential parameter for the evaluation of patients with ischaemic heart disease, and therapeutic choices are significantly driven by LV ejection fraction (LVEF) in the early stage of the disease and during follow-up. After an acute coronary syndrome, ventricular dysfunction may be reversible when caused by transient myocardial stunning. Therefore, the identification of clinical, laboratory, and instrumental predictors of improvement in LV systolic function (in addition to LVEF) is essential for an adequate prognostic stratification. In the setting of chronic ischaemic heart disease, there is no evidence that an improvement in LV systolic function is invariably associated with a better prognosis and LVEF is only one of many parameters that should be considered for the risk stratification. This state-of-the-art review will critically analyse the scientific evidence regarding known predictors of LVEF recovery, trying to elucidate their pathophysiological principles and clinical value., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Left ventricular ejection function (LVEF) is not reliable in identifying subtle systolic dysfunction. Speckle Tracking (ST) plays a promising role and hemodynamic forces (HDFs) are emerging as marker of LV function. The role of LV myocardial deformation and HDFs was investigated in a cohort of patients with aortic stenosis (AS) and normal LVEF. Two hundred fifty three patients (median age 79 years, IQR 73 - 83 years) with mild (n = 87), moderate (n =77) and severe AS (n =89) were retrospectively enrolled. 2D echocardiographic global longitudinal strain (GLS), circumferential strain (GCS) and HDFs were determined. The worsening of AS was associated with raising inappropriate LV mass (p < 0.001) and declined LVEF, despite being in the normal range (p < 0.001). ST and HDFs parameters declined as the AS became severe (p<0.0001, for all). When patients were grouped based on the median of LV endocardial GLS value (> -19,9%) and LV systolic longitudinal force (LVsysLF) value (< 12,49), patients with impaired ST and lower HDFs components had increased incidence of aortic valve replacement (AVR) and worse survival (p <0.024 and p <0.037, respectively). Among ST and HDFs parameters, only LVsysLF was independently associated with AVR and all causes mortality on multivariable Cox regression analysis (HR 0.94; 95% CI 0.89-0.99; p= 0.012). Reduced values of LVsysLF were associated with AVR and reduced survival in AS patients. LVsysLF could provide useful information in the stratification of patients with AS and possibly in the choice of timing for AVR., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Patients with type 2 diabetes mellitus (T2DM) have more than twice the risk of developing heart failure (HF) compared to patients without diabetes. The present study is aimed to build an artificial intelligence (AI) prognostic model that takes in account a large and heterogeneous set of clinical factors and investigates the risk of developing HF in diabetic patients. We carried out an electronic health records- (EHR-) based retrospective cohort study that included patients with cardiological clinical evaluation and no previous diagnosis of HF. Information consists of features extracted from clinical and administrative data obtained as part of routine medical care. The primary endpoint was diagnosis of HF (during out-of-hospital clinical examination or hospitalization). We developed two prognostic models using (1) elastic net regularization for Cox proportional hazard model (COX) and (2) a deep neural network survival method (PHNN), in which a neural network was used to represent a non-linear hazard function and explainability strategies are applied to estimate the influence of predictors on the risk function. Over a median follow-up of 65 months, 17.3% of the 10,614 patients developed HF. The PHNN model outperformed COX both in terms of discrimination (c-index 0.768 vs 0.734) and calibration (2-year integrated calibration index 0.008 vs 0.018). The AI approach led to the identification of 20 predictors of different domains (age, body mass index, echocardiographic and electrocardiographic features, laboratory measurements, comorbidities, therapies) whose relationship with the predicted risk correspond to known trends in the clinical practice. Our results suggest that prognostic models for HF in diabetic patients may improve using EHRs in combination with AI techniques for survival analysis, which provide high flexibility and better performance with respect to standard approaches., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gandin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cardiac amyloidosis, in the three forms of immunoglobulin light chain (AL), transthyretin (ATTR) wild type (ATTRwt) and mutated (ATTRv) amyloidosis, is an increasingly known and recognized disease in the cardiovascular setting. The first stage of the patient's journey is the clinical suspicion of the disease, which is placed, in presence of a hypertrophic phenotype, by the identification of red flags, both extracardiac and cardiac clues whose presence increase the probability of being faced with a patient with this disease. The second stage is represented by diagnosis, which occurs with certainty through the identification of amyloid substance in cardiac tissue. This stage is spotted in wo parts, i.e. disease confirmation and disease etiology definition (AL vs ATTRwt vs ATTRv). However, it is possible in some selected cases to make a diagnosis of ATTR without the need for tissue assessment, in presence of a positive grade 2-3 bisphosphonate scintigraphy and absence of monoclonal component. Once the diagnosis has been made, the third stage is the assessment of prognosis, the fourth is the patient therapy pathway and fifth is the follow-up plan. Prognosis evaluation is based on different staging systems at the onset of the disease, whose applicability in the era of new effective therapies is still to be defined. To date, the transthyretin tetramer stabilizer tafamidis is the only approved treatment for both wild-type and mutant ATTR cardiomyopathy without polyneuropathy, while ATTRv with associated neuropathy can benefit from treatment with patisiran, an inhibitor of hepatic protein synthesis. Therapies for complications and comorbidities, must be addressed individually, due to the lack of specific clinical trials on this category of patients. In fact, it is important to take into consideration the risks linked to the use of some drugs due to the infiltration of the conduction tissue by the amyloid substance, which increases the risk of bradycardia and heart blocks, the tendency towards hypotension and the increased thromboembolic risk. It is also essential to follow the course of the disease and the efficacy of the treatment in affected patients with a standardized follow-up, and to identify early the signs/symptoms of the disease in asymptomatic TTR mutation carriers.This ANMCO position paper on amyloidosis aims to provide the clinical cardiologist with a practical summary of the disease, to accompany the patient with amyloidosis in the various stages of his journey.

The perspective on amyloidosis has changed deeply over the last 10 years following major advances in diagnosis and treatment options, especially in cardiac amyloidosis. This intrinsically heterogeneous disease exposes to the risk of fragmentation of knowledge and requires the interaction among experts of different specialties and subspecialties. Suspicion of disease, timely recognition and confirmation of final diagnosis, prognostic stratification, clinical management and therapeutic strategies represent essential steps to be taken. Missing or delaying the diagnosis may have dramatic impact on patient outcome, as in the case of chemotherapy in unrecognized light-chain amyloidosis. Therefore, there is an urgent need for the foundation of an Italian Amyloidosis Network to deal with the challenges of this condition and orient clinical management at national and local levels. The present consensus document aims to provide the rationale and scopes of the Italian Amyloidosis Network, which has been conceived as an organizational framework for professionals managing patients with amyloidosis.

Sacubitril/valsartan reduces heart failure (HF)-related hospitalizations and cardiovascular mortality in PARADIGM-HF and has become a foundational treatment for HF with reduced ejection fraction (HFrEF). However, data of its routine real-world use are limited, and evidence from Italian settings is lacking. The REAL.IT study aimed to characterize the demographics, pharmacotherapy, clinical characteristics and outcomes of sacubitril/valsartan-treated Italian patients with HFrEF. Electronic medical records of patients initiating sacubitril/valsartan from October 2016 to June 2019 at nine specialized hospital outpatient HF centers across Italy were reviewed. Overall, 924 adults (mean age 64.5 years, 84.6% male) were included. At baseline, 38.7% had an ischemic HF etiology, 45.9% hypertension, 23.2% atrial fibrillation, 25.4% diabetes mellitus, 26.1% an implantable cardioverter-defibrillator and 31.9% coronary artery bypass grafting. There were no clear patterns of patient selection over time. During follow-up, NYHA class improved in 37.5% of patients after a mean of 5.3 ± 3.8 months; 36.1% and 16.7% of patients were in NYHA class III during characterization and after one year of follow-up, respectively. Left ventricular ejection fraction (LVEF) improved ≥5% in 56.3% of patients at one year; 39.7% had ≥30% reduction of N-terminal pro-B-type natriuretic peptide; 2.2% had hyperkalemia during characterization and 2.6% during follow-up; and 3.8% had hypotension during characterization and 12% during follow-up. A total of 50 (5.8%) of patients had device implantation (ICD/CRT) during follow-up. HF-related hospitalization was recorded in 19.6% of patients during follow-up; 3.8% of patients died, approximately 1.3% from cardiovascular causes. Our real-world data confirm the favorable effectiveness and tolerability of sacubitril/valsartan observed in pivotal randomized controlled trials.

Aims: To assess adherence to guideline recommendations among a large network of Italian cardiology sites in the management of acute and chronic heart failure (HF) and to evaluate if an ad-hoc educational intervention can improve their performance on several pharmacological and non-pharmacological indicators., Methods and Results: BLITZ-HF was a cross-sectional study based on a web-based recording system with pop-up reminders on guideline recommendations used during two 3-month enrolment periods carried out 3 months apart (Phase 1 and 3), interspersed by face-to-face macro-regional benchmark analyses and educational meetings (Phase 2). Overall, 7218 patients with acute and chronic HF were enrolled at 106 cardiology sites. During the enrolment phases, 3920 and 3298 patients were included, respectively, 84% with chronic HF and 16% with acute HF in Phase 1, and 74% with chronic HF and 26% with acute HF in Phase 3. At baseline, adherence to guideline recommendations was already overall high for most indicators. Among acute HF patients, an improvement was obtained in three out of eight indicators, with a significant rise in echocardiographic evaluation. Among chronic HF patients with HF and preserved or mid-range ejection fraction, performance increased in two out of three indicators: creatinine and echocardiographic evaluations. An overall performance improvement was observed in six out of nine indicators in ambulatory HF with reduced ejection fraction patients with a significant increase in angiotensin receptor-neprilysin inhibitor prescription rates., Conclusions: Within a context of an already elevated level of adherence to HF guideline recommendations, a structured multifaceted educational intervention could be useful to improve performance on specific indicators. Extending this approach to other non-cardiology healthcare professionals, who usually manage patients with HF, should be considered., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Predicting maximal heart rate (MHR) in heart failure with reduced ejection fraction (HFrEF) still remains a major concern. In such a context, the Keteyian equation is the only one derived in a HFrEF cohort on optimized β-blockers treatment. Therefore, using the Metabolic Exercise combined with Cardiac and Kidney Indexes (MECKI) data set, we looked for a possible MHR equation, for an external validation of Keteyien formula and, contextually, for accuracy of the historical MHR formulas and their relationship with the HR measured at the anaerobic threshold (AT)., Methods and Results: Data from 3487 HFrEF outpatients on optimized β-blockers treatment from the MECKI data set were analyzed. Besides excluding all possible confounders, the new equation was derived by using HR data coming from maximal cardiopulmonary exercise test. The simplified derived equation was [109-(0.5*age) + (0.5*HR rest) + (0.2*LVEF)-(5 if haemoglobin &lt;11 g/dL)]. The R2 and the standard error of the estimate were 0.24 and 17.5 beats min-1 with a mean absolute percentage error (MAPE) = 11.9%. The Keteyian equation had a slightly higher MAPE = 12.3%. Conversely, the Fox and Tanaka equations showed extremely higher MAPE values. The range 75-80% of MHR according to the new and the Keteyian equations was the most accurate in identifying the HR at the AT (MAPEs = 11.3-11.6%)., Conclusion: The derived equation to estimate the MHR in HFrEF patients, by accounting also for the systolic dysfunction degree and anaemia, improved slightly the Keteyian formula. Both formulas might be helpful in identifying the true maximal effort during an exercise test and the intensity domain during a rehabilitation programme., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Mineralocorticoid receptor antagonists (MRAs) are a class of drugs still underused in heart failure with reduced ejection fraction. Hyperkalemia, worsening of renal function and gynecomastia are the main causes of the MRA missed prescription but also an inadequate knowledge of this class of drugs may represent a reason for their underuse. The aim of this project was to evaluate the possible usefulness of a unique and innovative web-based platform in order to identify the main issues related to the underuse of MRAs and to discuss shared strategies of interventions to overcome the obstacles to MRA prescription., Methods: The "HF Clinical Practice project" enrolled 55 hospital cardiologists. It was based on the development and production of the eCaseTrack platform which was capable of activating a content-sharing system between professionals and specialists, using a mixed-methods study consisting of a survey, shared clinical experiences, training and consensus mini-Delphi method., Results: The results of the survey showed that the respondents substantially agreed about the criteria for MRA prescription (NYHA class, left ventricular ejection fraction, glomerular filtration rate and serum potassium). This agreement was confirmed by mini-Delphi, by which the use of MRAs in patients with hypotension, hyperkalemia and gynecomastia emerged as the most controversial issue., Conclusions: A web-based system of sharing clinical experiences and discussing controversial issues, is useful to implement the introduction of a proven efficacious therapeutic strategy which is still underused in current clinical practice.

The appropriateness of prescribing direct oral anticoagulants [dabigatran, rivaroxaban, apixaban, and edoxaban (DOACs)] is regulated on the criteria established in Phase III trials. These criteria are reported in the summary of the product characteristics of the four DOACs. In clinical practice, prescriptions are not always in compliance with established indications. In particular, the use of lower doses than those recommended in drug data sheets is not uncommon. Literature data show that the inappropriate prescription of reduced doses causes drug underexposure and up to a three-fold increase in the risk of stroke/ischaemic transient attack, systemic thromboembolism, and hospitalization. Possible causes of the deviation between the dose that should be prescribed and that prescribed in the real world include erroneous prescription, an overstated haemorrhagic risk perception, and the presence of frail and complex patients in clinical practice who were not included in pivotal trials, which makes it difficult to apply study results to the real world. For these reasons, we summarize DOAC indications and contraindications. We also suggest the appropriate use of DOACs in common clinical scenarios, in accordance with what international guidelines and national and international health regulatory bodies recommend., (Published on behalf of the European Society of Cardiology. © The Author(s) 2022.)

Aims: The present study sought to examine the effect of the COVID-19 pandemic and lockdown measures on the prescription of sacubitril/valsartan in patients with heart failure (HF) in Italy., Methods and Results: Data from Italian Medicines Agency (AIFA) monitoring registries were analysed. The sacubitril/valsartan monitoring registry is based on 6-month prescriptions. A monthly aggregation on new activations throughout the observational period was computed. From March to December 2020, the initiation of new HF patients on sacubitril/valsartan decreased by nearly 40% with prescriptions dropping to values similar to 2018 when the registry was still operated off-line. A slight increase in prescriptions was observed after the lockdown measures were lifted, but prescriptions remained constantly below the pre-lockdown period., Conclusion: A marked and worrisome decline during the COVID-19 pandemic in the activation of a life-saving treatment such as sacubitril/valsartan was observed. This decline was clearly linked to the lockdown measures instated to counteract the COVID-19 pandemic. Upcoming studies should analyse the occurrence of new cases of HF as well as the severity of patients admitted to hospitals and their mortality compared to pre-pandemic levels., (© 2022 European Society of Cardiology.)

Heart failure is a complex clinical syndrome with a severe prognosis, despite therapeutic progress. The management of the advanced stages of the syndrome is particularly complex in patients who are referred to palliative care as well as in those who are candidates for cardiac replacement therapy. For the latter group, a prompt recognition of the transition to the advanced stage as well as an early referral to the centers for cardiac replacement therapy are essential elements to ensure that patients follow the most appropriate diagnostic-therapeutic pathway. The aim of this document is to focus on the main diagnostic and therapeutic aspects related to the advanced stages of heart failure and, in particular, on the management of patients who are candidates for cardiac replacement therapy.

Background: New management, risk stratification and treatment strategies have become available over the last years for patients with acute pulmonary embolism (PE), potentially leading to changes in clinical practice and improvement of patients' outcome., Methods: The COntemporary management of Pulmonary Embolism (COPE) is a prospective, non-interventional, multicentre study in patients with acute PE evaluated at internal medicine, cardiology and emergency departments in Italy. The aim of the COPE study is to assess contemporary management strategies in patients with acute, symptomatic, objectively confirmed PE concerning diagnosis, risk stratification, hospitalization and treatment and to assess rates and predictors of in-hospital and 30-day mortality. The composite of death (either overall or PE-related) or clinical deterioration at 30 days from the diagnosis of PE, major bleeding occurring in hospital and up to 30 days from the diagnosis of PE and adherence to guidelines of the European Society of Cardiology (ESC) are secondary study outcomes. Participation in controlled trials on the management of acute PE is the only exclusion criteria. Expecting a 10-15%, 3% and 0.5% incidence of death for patients with high, intermediate or low-risk PE, respectively, it is estimated that 400 patients with high, 2100 patients with intermediate and 2500 with low-risk PE should be included in the study. This will allow to have about 100 deaths in study patients and will empower assessment of independent predictors of death., Conclusions: COPE will provide contemporary data on in-hospital and 30-day mortality of patients with documented PE as well as information on guidelines adherence and its impact on clinical outcomes., Trail Registration: NCT number: NCT03631810., (© 2022. The Author(s).)

Background: It is unknown whether patients who survived two or multiple episodes of myocardial infarction (MI) present different clinical characteristics and management than patients at their first MI., Methods: The EYESHOT post-MI was a prospective, observational, nationwide study aimed to evaluate the management of patients presenting to cardiologists 1 to 3 years from the last MI event. In 3 months of enrolment, 165 Italian cardiology centers included 1633 consecutive post-MI patients. In the present analysis, we stratified the study cohort according to the number of prior MI episodes (i.e., 1, 2 or ≥3)., Results: Among the 1618 patients enrolled with complete data on MI history, 1335 (82.5%) were at their first MI episode, 209 (12.9%) had a history of 2 MIs, and the remaining 74 (4.6%) had ≥ 3 prior MIs. Patients with a history of multiple MIs were increasingly older and presented a significantly higher rate of risk factors compared to those at their first MI. During the year prior to enrolment, patients with 2 or ≥3 MI episodes more frequently underwent coronary angiography compared to the other group ( p < 0.0001). In addition, several lifesaving and antianginal drugs were more frequently prescribed in patients presenting with a history of multiple MIs compared to those at their first MI., Conclusions: Our data suggest that patients with multiple MIs managed by cardiologists in routine clinical practice present an incremental clinical risk, more frequently undergo coronary angiography, and are more intensively managed with pharmacological therapies compared to patients at their first MI episode., Competing Interests: Prof. De Luca. reports personal fees from Amgen, Aspen, Astra Zeneca, Bayer, Boeringer Ingelhaim, Daiichi Sankyo, Menarini, Pfizer, outside the submitted work; Lucci is an employee of Heart Care Foundation, which conducted the study with an unrestricted grant of research from Astra Zeneca, Italy. All other authors have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article., (Copyright © 2022 Leonardo De Luca et al.)

The coronavirus disease 2019 (COVID-19), a deadly pandemic that has affected millions of people worldwide, is associated with cardiovascular complications, including venous and arterial thromboembolic events. Viral spike proteins, in fact, may promote the release of prothrombotic and inflammatory mediators. Vaccines, coding for the spike protein, are the primary means for preventing COVID-19. However, some unexpected thrombotic events at unusual sites, most frequently located in the cerebral venous sinus but also splanchnic, with associated thrombocytopenia, have emerged in subjects who received adenovirus-based vaccines, especially in fertile women. This clinical entity was soon recognized as a new syndrome, named vaccine-induced immune thrombotic thrombocytopenia, probably caused by cross-reacting anti-platelet factor-4 antibodies activating platelets. For this reason, the regulatory agencies of various countries restricted the use of adenovirus-based vaccines to some age groups. The prevailing opinion of most experts, however, is that the risk of developing COVID-19, including thrombotic complications, clearly outweighs this potential risk. This point-of-view aims at providing a narrative review of epidemiological issues, clinical data, and pathogenetic hypotheses of thrombosis linked to both COVID-19 and its vaccines, helping medical practitioners to offer up-to-date and evidence-based counseling to their often-alarmed patients with acute or chronic cardiovascular thrombotic events.

COVID-19, a deadly pandemic that has affected millions of people worldwide, is also associated with cardiovascular complications, such as venous and arterial thromboembolic events. The viral spike protein, in fact, may promote the release of prothrombotic and inflammatory mediators. Vaccines, coding for the spike protein, are the primary measure for preventing COVID-19. However, some unexpected thrombotic events at unusual sites, most frequently the cerebral venous and splanchnic districts, with associated thrombocytopenia, have emerged in subjects who received adenovirus-based vaccines, especially in fertile women. This clinical entity has been rapidly recognized as a new syndrome, named vaccine-induced immune thrombotic thrombocytopenia, probably caused by cross-reacting antiplatelet factor 4 antibodies activating platelets. This prompted the regulatory agencies of various countries to restrict the use of adenovirus-based vaccines to specific age groups. The prevailing opinion of most experts, however, is that the risk of developing COVID-19 disease, including thrombosis, clearly outweighs this potential extremely low risk.This paper aims at providing a comprehensive review of epidemiological issues, clinical data and pathogenetic hypotheses of thrombosis linked to both COVID-19 and its vaccines, helping cardiologists to offer an up-to-date and evidence-based counseling to their often-alarmed patients with acute or chronic coronary syndromes.

The prescription appropriateness of direct oral anticoagulants (DOACs [dabigatran, rivaroxaban, apixaban, and edoxaban]) is carefully regulated, taking into account the criteria established in phase III trials and listed in the summary of the product characteristics of the four DOACs. In clinical practice, prescriptions are not always in compliance with established indications. In particular, the use of doses lower than those recommended in drug data sheets is relatively frequent. Literature data show that the inappropriate prescription of DOAC doses causes drug underexposure and an up to three-fold increase in the risk of stroke/transient ischemic attack, systemic thromboembolism, and hospitalizations. Possible causes of the deviation between the dose that should be prescribed and that actually employed may include erroneous prescriptions, an overstated bleeding risk perception, and the presence of frail patients, who were not included in pivotal trials. For these reasons, we summarize DOAC indications and contraindications and suggest the appropriate use of DOACs in common clinical scenarios, in accordance with what international guidelines and national and international health regulatory agencies recommend.

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.)

This study aims to provide real-world data about starting-dose of NOACs and dose-adjustment in patients with atrial fibrillation (AF). In fact, even if new oral anticoagulation agents (NOACs) have a predictable effect without need for regular monitoring, dose-adjustments should be performed according to the summary of product information and international guidelines. We employed the Italian Medicines Agency monitoring registries comprising data on a nationwide cohort of patients with AF treated with NOACs from 2013 to 2018. Logistic regression analysis was used to evaluate the determinants of dosage choice. During the reference period, treatment was commenced for 866,539 patients. Forty-five percent of the first prescriptions were dispensed at a reduced dose (dabigatran 60.3%, edoxaban 45.2%, apixaban 40.9%, rivaroxaban 37.4%). The prescription of reduced dose was associated with older age, renal disease, bleeding risk and the concomitant use of drugs predisposing to bleeding, but not with CHA 2 DS 2 -VASc and HAS-BLED. A relative reduction of the proportion of patients treated with low dosages was evident overtime for dabigatran and rivaroxaban; whereas prescription of low dose apixaban and edoxaban increased progressively among elderly patients. Evidence based on real-world data shows a high frequency of low dose prescriptions of NOACs in AF patients. Except for older age, renal disease, bleeding risk and the concomitant use of drugs predisposing to bleeding, other factors that may determine the choice of reduced dose could not be ascertained. There may be potential under-treatment of AF patients, but further evaluation is warranted., (© 2021. The Author(s).)

The triple therapy (angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists) certificated by the 2012 guidelines for symptomatic patients with heart failure and reduced ejection fraction, reaffirmed in the following document of 2016 with the introduction of angiotensin receptor-neprilysin inhibitors (ARNI), has not yet reached an adequate implementation in clinical practice (where the majority of patients is only treated with the double treatment of ACE-inhibitors or angiotensin receptor blockers and beta-blockers). Among the reasons for this general failure, we should consider the enrollment of unselected cases from the real world, without exclusion criteria for age, comorbidity and stage of the disease, the therapeutic inertia of many cardiologists and not least the clinical and organizational complexity of the conventional scheme of implementation of therapy indicated by the guidelines. Not only the prescription of triple therapy is inadequate, but also the "target doses" defined by the large randomized controlled trials should be considered unrealistic in the majority of patients, who often achieve a therapeutic effect at lower doses, generally better tolerated ("target effect"). The new guidelines forthcoming will certify a further step forward with the quadruple therapy (sodium-glucose co-transporter 2 inhibitors, ARNI, beta-blockers and mineralocorticoid receptor antagonists), underlining how a fourfold intervention with different pharmacological mechanisms is able to determine the greatest benefits in patients with systolic heart failure. The discussion is open on the possibility of simplifying and speeding up the conventional implementation scheme of treatment, exploiting the ability of all these pharmacological principles to exert a significant and rapid favorable effect on prognosis already at a low dose in the first 4-8 weeks of treatment.

Sacubitril/valsartan (S/V) has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in chronic heart failure with reduced ejection fraction compared to enalapril. After 7 years since the publication of the results of PARADIGM-HF, further insight has been gained with potential new indications. Two prospective randomized multicenter studies (PIONEER-HF and TRANSITION) in patients hospitalized for acute heart failure (AHF) have shown an improved clinical outcome and biomarker profile as compared to enalapril, and good tolerability, safety and feasibility of initiating in-hospital administration of S/V. Furthermore, some studies have highlighted the favorable effects of S/V in attenuating adverse myocardial remodeling, supporting an early benefit after treatment. Observational data from non-randomized studies in AHF report that in-hospital and pre-discharge prescription of evidence-based drugs associated with better survival still remains suboptimal. Additionally, the COVID-19 pandemic has also negatively impacted on outpatient activities. Therefore, hospitalization, a real crossroads in the history of heart failure, must become a management and therapeutic opportunity for our patients. The objective of this ANMCO position paper is to encourage and facilitate early S/V administration in stabilized patients during hospitalization after an AHF episode, with the aim of improving care efficiency and clinical outcome.

Since the Italian iodoprophylaxis strategy is based on the use of iodized salt, we assessed the relationship between dietary salt consumption and iodine intake in the Italian adult population. We estimated the relative contribution given by the use of iodized salt and by the iodine introduced by foods to the total iodine intake. The study population included 2219 adults aged 25-79 years (1138 men and 1081 women) from all Italian regions, participating to the Osservatorio Epidemiologico Cardiovascolare/Health Examination Survey 2008-2012 (OEC/HES), and examined for sodium and iodine intake in the framework of the MINISAL-GIRCSI Programme. Dietary sodium and total iodine intake were assessed by the measurement of 24 h urinary excretion, while the EPIC questionnaire was used to evaluate the iodine intake from food. Sodium and iodine intake were significantly and directly associated, upon accounting for age, sex, and BMI (Spearman rho = 0.298; p < 0.001). The iodine intake increased gradually across quintiles of salt consumption in both men and women ( p < 0.001). The European Food Safety Authority (EFSA) adequacy level for iodine intake was met by men, but not women, only in the highest quintile of salt consumption. We estimated that approximately 57% of the iodine intake is derived from food and 43% from salt. Iodized salt contributed 24% of the total salt intake, including both discretionary and non-discretionary salt consumption. In conclusion, in this random sample of the Italian general adult population examined in 2008-2012, the total iodine intake secured by iodized salt and the iodine provision by food was insufficient to meet the EFSA adequate iodine intake.

The use of the direct oral anticoagulants dabigatran, rivaroxaban, apixaban and edoxaban (DOACs) offers some major advantages over warfarin and other vitamin K antagonists (VKAs). One advantage is the possibility to use a fixed dose in normal-weight patients, overweight patients and patients with obesity. However, the "one size fits all" strategy raised a concern regarding the possibility to undertreat patients with a high body mass index. No randomized controlled trials (RCTs) have ever compared VKAs and DOACs in this population. We analyzed data from the literature on DOAC pharmacokinetics and pharmacodynamics, results from the four pivotal phase III trials on non-valvular atrial fibrillation, retrospective observational studies and metanalyses. While we are aware of the limitation imposed by the absence of specific RCTs, we propose the position of the Italian Association of Hospital Cardiologists (ANMCO) on the use of DOACs in patients with obesity based on the existing evidence.

Aims: Recently, the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial demonstrated that dual therapy reduced cardiovascular outcomes compared with aspirin alone in patients with stable atherosclerotic disease., Methods and Results: We sought to assess the proportion of patients eligible for the COMPASS trial and to compare the epidemiology and outcome of these patients with those without COMPASS inclusion or with any exclusion criteria in a contemporary, nationwide cohort of patients with stable coronary artery disease. Among the 4068 patients with detailed information allowing evaluation of eligibility, 1416 (34.8%) did not fulfil the inclusion criteria (COMPASS-Not-Included), 841 (20.7%) had exclusion criteria (COMPASS-Excluded), and the remaining 1811 (44.5%) were classified as COMPASS-Like. At 1 year, the incidence of major adverse cardiovascular event (MACE), a composite of cardiovascular death, myocardial infarction, and stroke, was 0.9% in the COMPASS-Not-Included and 2.0% in the COMPASS-Like (P = 0.01), and 5.0% in the COMPASS-Excluded group (P < 0.0001 for all comparisons). Among the COMPASS-Like population, patients with multiple COMPASS enrichment criteria presented a significant increase in the risk of MACE (from 1.0% to 3.3% in those with 1 and ≥3 criteria, respectively; P = 0.012), and a modest absolute increase in major bleeding risk (from 0.2% to 0.4%, respectively; P = 0.46)., Conclusion: In a contemporary real-world cohort registry of stable coronary artery disease, most patients resulted as eligible for the COMPASS. These patients presented a considerable annual risk of MACE that consistently increases in the presence of multiple risk factors., (Published on behalf of the European Society of Cardiology.)

The COVID-19 pandemic represents an unprecedented event that has brought deep changes in hospital facilities with reshaping of the health system organization, revealing inadequacies of current hospital and local health systems. When the COVID-19 emergency will end, further evaluation of the national health system, new organization of acute wards, and a further evolution of the entire health system will be needed to improve care during the chronic phase of disease. Therefore, new standards for healthcare personnel, more efficient organization of hospital facilities for patients with acute illnesses, improvement of technological approaches, and better integration between hospital and territorial services should be pursued. With experience derived from the COVID-19 pandemic,new models, paradigms, interventional approaches, values and priorities should be suggested and implemented., (Published on behalf of the European Society of Cardiology. © The Author(s) 2021.)

The European Society of Cardiology guidelines on non-ST-elevation acute coronary syndromes suggest different temporal strategies for the angiographic study depending on the risk profile. The scientific evidence underlying the guideline recommendations and the critical issues currently existing in Italy, that often do not allow either an extended strategy of revascularization within 24 h or the application of the principle of the same day transfer from a spoke to a hub centre, are analysed. The position paper focuses, in particular, on the subgroup of patients with a defined diagnosis of non-ST-elevation myocardial infarction by proposing a timing of coronary angiography/revascularization that takes into account the available scientific evidence and the organizational possibilities of a considerable part of national cardiology services., (Published on behalf of the European Society of Cardiology. © The Author(s) 2021.)

Sacubitril/valsartan (S/V) has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in chronic heart failure with reduced ejection fraction compared with enalapril. After 7 years since the publication of the results of PARADIGM-HF, further insight has been gained with potential new indications. Two prospective randomized multicentre studies (PIONEER-HF and TRANSITION) in patients hospitalized for acute heart failure (AHF) have shown an improved clinical outcome and biomarker profile as compared with enalapril, and good tolerability, safety, and feasibility of initiating in-hospital administration of S/V. Furthermore, some studies have highlighted the favourable effects of S/V in attenuating adverse myocardial remodelling, supporting an early benefit after treatment. Observational data from non-randomized studies in AHF report that in-hospital and pre-discharge prescription of evidence-based drugs associated with better survival still remain suboptimal. Additionally, the COVID-19 pandemic has also negatively impacted on outpatient activities. Therefore, hospitalization, a real crossroad in the history of heart failure, must become a management and therapeutic opportunity for our patients. The objective of this ANMCO position paper is to encourage and facilitate early S/V administration in stabilized patients during hospitalization after an AHF episode, with the aim of improving care efficiency and clinical outcome., (Published on behalf of the European Society of Cardiology. © The Author(s) 2021.)