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Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. Cardiac magnetic resonance (CMR) imaging has emerged as a powerful tool for the non-invasive assessment of HCM. CMR can accurately quantify the extent and distribution of hypertrophy, assess the presence and severity of myocardial fibrosis, and detect associated abnormalities. We will study basic and advanced features of CMR in 2 groups of HCM patients with negative and positive genotype, respectively., Materials and Methods: The study population consisted in consecutive HCM patients referred to Centro Cardiologico Monzino who performed both CMR and genetic testing. Clinical CMR images were acquired at 1.5 T Discovery MR450 scanner (GE Healthcare, Milwaukee, Wisconsin)) using standardized protocols T1 mapping, T2 mapping and late gadolinium enhancement (LGE). Population was divided in 2 groups: group 1 with HCM patients with a negative genotype and group 2 with a positive genotype., Results: The analytic population consisted of 110 patients: 75 in group 1 and 35 patients in group 2. At CMR evaluation, patients with a positive genotype had higher LV mass (136 vs. 116 g, p = 0.02), LV thickness (17.5 vs. 16.9 mm), right ventricle ejection fraction (63 % vs. 58 %, p = 0.002). Regarding the LGE patients with positive genotype have a higher absolute (33.8 vs 16.7 g, p = 0.0003) and relative LGE mass (31.6 % vs 14.6 %, p = 0.0007). On a segmental analysis all the septum (segments 2, 8, 9, and 14) had a significantly increased native T1 compared to others segments. ECV in the mid antero and infero-septum (segments 8 and 9) have lower values in positive genotype HCM. Interestingly the mean T2 was lower in positive genotype HCM as compared to negative genotype HCM (50,1 ms vs 52,4)., Conclusions: Our paper identifies the mid septum (segments 8 and 9) as a key to diagnose a positive genotype HCM., Competing Interests: Declaration of competing interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objective: Invasive fractional flow reserve (FFR) measurement is the gold standard method for coronary artery disease (CAD) diagnosis. FFR-CT exploits computational fluid dynamics (CFD) for non-invasive evaluation of FFR, simulating coronary flow in virtual geometries reconstructed from computed tomography (CT), but suffers from cost-intensive computing process and uncertainties in the definition of patient specific boundary conditions (BCs). In this work, we investigated the use of time-averaged steady BCs, compared to pulsatile to reduce the computational time and deployed a self-adjusting method for the tuning of BCs to patient-specific clinical data., Methods: 133 coronary arteries were reconstructed form CT images of patients suffering from CAD. For each vessel, invasive FFR was measured. After segmentation, the geometries were prepared for CFD simulation by clipping the outlets and discretizing into tetrahedral mesh. Steady BCs were defined in two steps: (i) rest BCs were extrapolated from clinical and image-derived data; (ii) hyperemic BCs were computed from resting conditions. Flow rate was iteratively adjusted during the simulation, until patient's aortic pressure was matched. Pulsatile BCs were defined exploiting the convergence values of steady BCs. After CFD simulation, lesion-specific hemodynamic indexes were computed and compared between group of patients for which surgery was indicated and not. The whole pipeline was implemented as a straightforward process, in which each single step is performed automatically., Results: Steady and pulsatile FFR-CT yielded a strong correlation (r = 0.988, p < 0.001) and correlated with invasive FFR (r = 0.797, p < 0.001). The per-point difference between the pressure and FFR-CT field predicted by the two methods was below 1 % and 2 %, respectively. Both approaches exhibited a good diagnostic performance: accuracy was 0.860 and 0.864, the AUC was 0.923 and 0.912, for steady and pulsatile case, respectively. The computational time required by steady BCs CFD was approximatively 30-folds lower than pulsatile case., Conclusions: This work shows the feasibility of using steady BCs CFD for computing the FFR-CT in coronary arteries, as well as its computational and diagnostic performance within a fully automated pipeline., Competing Interests: Declaration of competing interest All authors disclose that they have no conflict of interest, no financial arrangement with products figuring in the submitted manuscript or with a company making a competing product. All those who fulfil the criteria for authorship have been included as authors and each author contributed significantly to the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The aim of this study is to describe resources and outcomes of coronary computed tomography angiography plus Stress CT perfusion (CCTA ​+ ​Stress-CTP) and stress cardiovascular magnetic resonance (Stress-CMR) in symptomatic patients with suspected or known CAD., Methods: Six hundred and twenty-four consecutive symptomatic patients with intermediate to high-risk pretest likelihood for CAD or previous history of revascularization referred to our hospital for clinically indicated CCTA ​+ ​Stress-CTP or Stress-CMR were enrolled. Stress-CTP scans were performed in 223 patients while 401 patients performed Stress-CMR. Patient follow-up was performed at 1 year after index test performance. Endpoints were all cardiac events, as a combined endpoint of revascularization, non-fatal MI and death, and hard cardiac events, as combined endpoint of non-fatal MI and death., Results: Twenty-nine percent of patients who underwent CCTA ​+ ​Stress-CTP received revascularization, 7% of subjects assessed with Stress-CMR were treated invasively, and a low number of non-fatal MI and death was observed with both strategies (hard events in 0.4% of patients that had CCTA ​+ ​Stress-CTP as index test, and in 3% of patients evaluated with Stress-CMR). According to the predefined endpoints, CCTA ​+ ​Stress-CTP group showed high rate of all cardiac events and low rate of hard cardiac events, respectively. The cumulative costs were 1970 ​± ​2506 Euro and 733 ​± ​1418 Euro for the CCTA ​+ ​Stress-CTP group and Stress-CMR group, respectively., Conclusions: The use of CCTA ​+ ​Stress-CTP strategy was associated with high referral to revascularization but with a favourable trend in terms of hard cardiac events and diagnostic yield in identifying individuals at lower risk of adverse events despite the presence of CAD., Competing Interests: Declaration of competing interest All authors have nothing to disclose., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background and Aims: This study investigated the additional prognostic value of epicardial adipose tissue (EAT) volume for major adverse cardiovascular events (MACE) in patients undergoing stress cardiac magnetic resonance (CMR) imaging., Methods: 730 consecutive patients [mean age: 63 ± 10 years; 616 men] who underwent stress CMR for known or suspected coronary artery disease were randomly divided into derivation (n = 365) and validation (n = 365) cohorts. MACE was defined as non-fatal myocardial infarction and cardiac deaths. A deep learning algorithm was developed and trained to quantify EAT volume from CMR. EAT volume was adjusted for height (EAT volume index). A composite CMR-based risk score by Cox analysis of the risk of MACE was created., Results: In the derivation cohort, 32 patients (8.7 %) developed MACE during a follow-up of 2103 days. Left ventricular ejection fraction (LVEF) < 35 % (HR 4.407 [95 % CI 1.903-10.202]; p<0.001), stress perfusion defect (HR 3.550 [95 % CI 1.765-7.138]; p<0.001), late gadolinium enhancement (LGE) (HR 4.428 [95%CI 1.822-10.759]; p = 0.001) and EAT volume index (HR 1.082 [95 % CI 1.045-1.120]; p<0.001) were independent predictors of MACE. In a multivariate Cox regression analysis, adding EAT volume index to a composite risk score including LVEF, stress perfusion defect and LGE provided additional value in MACE prediction, with a net reclassification improvement of 0.683 (95%CI, 0.336-1.03; p<0.001). The combined evaluation of risk score and EAT volume index showed a higher Harrel C statistic as compared to risk score (0.85 vs. 0.76; p<0.001) and EAT volume index alone (0.85 vs.0.74; p<0.001). These findings were confirmed in the validation cohort., Conclusions: In patients with clinically indicated stress CMR, fully automated EAT volume measured by deep learning can provide additional prognostic information on top of standard clinical and imaging parameters., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gianluca Pontone reports a relationship with G.E. Healthcare, Bracco, Heartflow, Boheringher that includes: funding grants and speaking and lecture fees. The other authors have nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: In chronic heart failure (HF), exercise-induced increase in pulmonary capillary pressure may cause an increase of pulmonary congestion, or the development of pulmonary oedema. We sought to assess in HF patients the exercise-induced intra-thoracic fluid movements, by measuring plasma brain natriuretic peptide (BNP), lung comets and lung diffusion for carbon monoxide (DLCO) and nitric oxide (DLNO), as markers of hemodynamic load changes, interstitial space and alveolar-capillary membrane fluids, respectively., Methods and Results: Twenty-four reduced ejection fraction HF patients underwent BNP, lung comets and DLCO/DLNO measurements before, at peak and 1 h after the end of a maximal cardiopulmonary exercise test. BNP significantly increased at peak from 549 (328-841) to 691 (382-1207, p < 0.0001) pg/mL and almost completely returned to baseline value 1 h after exercise. Comets number increased at peak from 9.4 ± 8.2 to 24.3 ± 16.7, returning to baseline (9.7 ± 7.4) after 1 h (p < 0.0001). DLCO did not change significantly at peak (from 18.01 ± 4.72 to 18.22 ± 4.73 mL/min/mmHg), but was significantly reduced at 1 h (16.97 ± 4.26 mL/min/mmHg) compared to both baseline (p = 0.0211) and peak (p = 0.0174). DLNO showed a not significant trend toward lower values 1 h post-exercise., Conclusions: Moderate/severe HF patients have a 2-step intra-thoracic fluid movement with exercise: the first during active exercise, from the vascular space toward the interstitial space, as confirmed by comets increase, without any effect on diffusion, and the second, during recovery, toward the alveolar-capillary membrane, clearing the interstitial space but worsening gas diffusion., Competing Interests: Declaration of competing interest The Authors report no relationships that could be construed as a conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Chronic coronary syndrome (CCS) is one of the leading cardiovascular causes of morbidity, mortality, and use of medical resources. After the introduction by international guidelines of the same level of recommendation to non-invasive imaging techniques in CCS evaluation, a large debate arose about the dilemma of choosing anatomical (with coronary computed tomography angiography (CCTA)) or functional imaging (with stress echocardiography (SE), cardiovascular magnetic resonance (CMR), or nuclear imaging techniques) as a first diagnostic evaluation. The determinant role of the atherosclerotic burden in defining cardiovascular risk and prognosis more than myocardial inducible ischemia has progressively increased the use of a first anatomical evaluation with CCTA in a wide range of pre-test probability in CCS patients. Functional testing holds importance, both because the role of revascularization in symptomatic patients with proven ischemia is well defined and because functional imaging, particularly with stress cardiac magnetic resonance (s-CMR), gives further prognostic information regarding LV function, detection of myocardial viability, and tissue characterization. Emerging techniques such as stress computed tomography perfusion (s-CTP) and fractional flow reserve derived from CT (FFRCT), combining anatomical and functional evaluation, appear capable of addressing the need for a single non-invasive examination, especially in patients with high risk or previous revascularization. Furthermore, CCTA in peri-procedural planning is promising to acquire greater importance in the non-invasive planning and guiding of complex coronary revascularization procedures, both by defining the correct strategy of interventional procedure and by improving patient selection. This review explores the different roles of non-invasive imaging techniques in managing CCS patients, also providing insights into preoperative planning for percutaneous or surgical myocardial revascularization.

Coronary computed tomography angiography (CCTA) allows detailed assessment of early markers associated with coronary artery disease (CAD), such as coronary artery calcium (CAC) and tortuosity (CorT). However, their analysis can be time-demanding and biased. We present a fully automated pipeline that performs (i) coronary artery segmentation and (ii) CAC and CorT objective analysis. Our method exploits supervised learning for the segmentation of the lumen, and then, CAC and CorT are automatically quantified. 281 manually annotated CCTA images were used to train a two-stage U-Net-based architecture. The first stage employed a 2.5D U-Net trained on axial, coronal, and sagittal slices for preliminary segmentation, while the second stage utilized a multichannel 3D U-Net for refinement. Then, a geometric post-processing was implemented: vessel centerlines were extracted, and tortuosity score was quantified as the count of branches with three or more bends with change in direction forming an angle >45°. CAC scoring relied on image attenuation. CAC was detected by setting a patient specific threshold, then a region growing algorithm was applied for refinement. The application of the complete pipeline required <5 min per patient. The model trained for coronary segmentation yielded a Dice score of 0.896 and a mean surface distance of 1.027 mm compared to the reference ground truth. Tracts that presented stenosis were correctly segmented. The vessel tortuosity significantly increased locally, moving from proximal, to distal regions (p < 0.001). Calcium volume score exhibited an opposite trend (p < 0.001), with larger plaques in the proximal regions. Volume score was lower in patients with a higher tortuosity score (p < 0.001). Our results suggest a linked negative correlation between tortuosity and calcific plaque formation. We implemented a fast and objective tool, suitable for population studies, that can help clinician in the quantification of CAC and various coronary morphological parameters, which is helpful for CAD risk assessment., Competing Interests: The authors have no conflicts to disclose., (© 2024 Author(s).)

Objectives: Aortic valve neocuspidalization aims to replace the 3 aortic cusps with autologous pericardium pre-treated with glutaraldehyde, and it is a surgical alternative to the classical aortic valve replacement (AVR). Image-based patient-specific computational fluid dynamics allows the derivation of shear stress on the aortic wall [wall shear stress (WSS)]. Previous studies support a potential link between increased WSS and histological alterations of the aortic wall. The aim of this study is to compare the WSS of the ascending aorta in patients undergoing aortic valve neocuspidalization versus AVR with biological prostheses., Methods: This is a prospective nonrandomized clinical trial. Each patient underwent a 4D-flow cardiac magnetic resonance scan after surgery, which informed patient-specific computational fluid dynamics models to evaluate WSS at the ascending aortic wall. The adjusted variables were calculated by summing the residuals obtained from a multivariate linear model (with ejection fraction and left ventricle outflow tract-aorta angle as covariates) to the mean of the variables., Results: Ten patients treated with aortic valve neocuspidalization were enrolled and compared with 10 AVR patients. The aortic valve neocuspidalization group showed a significantly lower WSS in the outer curvature segments of the proximal and distal ascending aorta as compared to AVR patients (P = 0.0179 and 0.0412, respectively). WSS levels remained significantly lower along the outer curvature of the proximal aorta in the aortic valve neocuspidalization population, even after adjusting the WSS for the ejection fraction and the left ventricle outflow tract-aorta angle [2.44 Pa (2.17-3.01) vs 1.94 Pa (1.72-2.01), P = 0.02]., Conclusions: Aortic valve neocuspidalization hemodynamical features are potentially associated with a lower WSS in the ascending aorta as compared to commercially available bioprosthetic valves., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Circulating small extracellular vesicles (sEVs) contribute to inflammation, coagulation and vascular injury, and have great potential as diagnostic markers of disease. The ability of sEVs to reflect myocardial damage assessed by Cardiac Magnetic Resonance (CMR) in ST-segment elevation myocardial infarction (STEMI) is unknown. To fill this gap, plasma sEVs were isolated from 42 STEMI patients treated by primary percutaneous coronary intervention (pPCI) and evaluated by CMR between days 3 and 6. Nanoparticle tracking analysis showed that sEVs were greater in patients with anterior STEMI ( p = 0.0001), with the culprit lesion located in LAD ( p = 0.045), and in those who underwent late revascularization ( p = 0.038). A smaller sEV size was observed in patients with a low myocardial salvage index (MSI, p = 0.014). Patients with microvascular obstruction (MVO) had smaller sEVs ( p < 0.002) and lower expression of the platelet marker CD41-CD61 ( p = 0.039). sEV size and CD41-CD61 expression were independent predictors of MVO/MSI (OR [95% CI]: 0.93 [0.87-0.98] and 0.04 [0-0.61], respectively). In conclusion, we provide evidence that the CD41-CD61 expression in sEVs reflects the CMR-assessed ischemic damage after STEMI. This finding paves the way for the development of a new strategy for the timely identification of high-risk patients and their treatment optimization.

Biological valve failure (BVF) is an inevitable condition that compromises the durability of biological heart valves (BHVs). It stems from various causes, including rejection, thrombosis, and endocarditis, leading to a critical state of valve dysfunction. Echocardiography, cardiac computed tomography, cardiac magnetic resonance, and nuclear imaging play pivotal roles in the diagnostic multimodality workup of BVF. By providing a comprehensive overview of the pathophysiology of BVF and the diagnostic approaches in different clinical scenarios, this review aims to aid clinicians in their decision-making process. The significance of early detection and appropriate management of BVF cannot be overstated, as these directly impact patients' prognosis and their overall quality of life. Ensuring timely intervention and tailored treatments will not only improve outcomes but also alleviate the burden of this condition on patients' life. By prioritizing comprehensive assessments and adopting the latest advancements in diagnostic technology, medical professionals can significantly enhance their ability to manage BVF effectively.

Background: Cardiac computed tomography (CCT) was recently validated to measure extracellular volume (ECV) in the setting of cardiac amyloidosis, showing good agreement with cardiovascular magnetic resonance (CMR). However, no evidence is available with a whole-heart single source, single energy CT scanner in the clinical context of newly diagnosed left ventricular dysfunction. Therefore, the aim of this study was to test the diagnostic accuracy of ECV CCT in patients with a recent diagnosis of dilated cardiomyopathy, having ECV CMR as the reference technique., Methods: 39 consecutive patients with newly diagnosed dilated cardiomyopathy (LVEF <50%) scheduled for clinically indicated CMR were prospectively enrolled. Myocardial segment evaluability assessment with each technique, agreement between ECV CMR and ECV CCT , regression analysis, Bland-Altman analysis and interclass correlation coefficient (ICC) were performed., Results: Mean age of enrolled patients was 62 ​± ​11 years, and mean LVEF at CMR was 35.4 ​± ​10.7%. Overall radiation exposure for ECV estimation was 2.1 ​± ​1.1 ​mSv. Out of 624 myocardial segments available for analysis, 624 (100%) segments were assessable by CCT while 608 (97.4%) were evaluable at CMR. ECV CCT demonstrated slightly lower values compared to ECV CMR (all segments, 31.8 ​± ​6.5% vs 33.9 ​± ​8.0%, p ​< ​0.001). At regression analysis, strong correlations were described (all segments, r ​= ​0.819, 95% CI: 0.791 to 0.844). On Bland-Altman analysis, bias between ECV CMR and ECV CCT for global analysis was 2.1 (95% CI: -6.8 to 11.1). ICC analysis showed both high intra-observer and inter-observer agreement for ECV CCT calculation (0.986, 95%CI: 0.983 to 0.988 and 0.966, 95%CI: 0.960 to 0.971, respectively)., Conclusions: ECV estimation with a whole-heart single source, single energy CT scanner is feasible and accurate. Integration of ECV measurement in a comprehensive CCT evaluation of patients with newly diagnosed dilated cardiomyopathy can be performed with a small increase in overall radiation exposure., Competing Interests: Declaration of competing interest Gianluca Pontone declares the following conflict of interest: Honorarium as speaker/consultant and/or research grant from GE Healthcare, Bracco, Heartflow, Boheringher., (Copyright © 2023 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Introduction: Cardiac amyloidosis (CA) shares similar clinical and imaging characteristics (e.g., hypertrophic phenotype) with aortic stenosis (AS), but its prognosis is generally worse than severe AS alone. Recent studies suggest that the presence of CA is frequent (1 out of 8 patients) in patients with severe AS. The coexistence of the two diseases complicates the prognosis and therapeutic management of both conditions. Thus, there is an urgent need to standardize and optimize the diagnostic process of CA and AS. The aim of this study is to develop a robust and reliable radiomics-based pipeline to differentiate the two pathologies., Methods: Thirty patients were included in the study, equally divided between CA and AS. For each patient, a cardiac computed tomography (CCT) was analyzed by extracting 107 radiomics features from the LV wall. Feature robustness was evaluated by means of geometrical transformations to the ROIs and intra-class correlation coefficient (ICC) computation. Various correlation thresholds (0.80, 0.85, 0.90, 0.95, 1), feature selection methods [ p -value, least absolute shrinkage and selection operator (LASSO), semi-supervised LASSO, principal component analysis (PCA), semi-supervised PCA, sequential forwards selection] and machine learning classifiers (k-nearest neighbors, support vector machine, decision tree, logistic regression and gradient boosting) were assessed using a leave-one-out cross-validation. Data augmentation was performed using the synthetic minority oversampling technique. Finally, explainability analysis was performed by using the SHapley Additive exPlanations (SHAP) method., Results: Ninety-two radiomic features were selected as robust and used in the further steps. Best performances of classification were obtained using a correlation threshold of 0.95, PCA (keeping 95% of the variance, corresponding to 9 PCs) and support vector machine classifier reaching an accuracy, sensitivity and specificity of 0.93. Four PCs were found to be mainly dependent on textural features, two on first-order statistics and three on shape and size features., Conclusion: These preliminary results show that radiomics might be used as non-invasive tool able to differentiate CA from AS using clinical routine available images., Competing Interests: GP declares the following conflict of interest: Honorarium as speaker/consultant and/or research grant from GE Healthcare, Bracco, Heartflow, Boheringher. 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 GP, VC 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., (© 2023 Lo Iacono, Maragna, Pontone and Corino.)

Ischaemic heart disease (IHD) is one of the world's leading causes of morbidity and mortality. Likewise, the diagnosis and risk stratification of patients with coronary artery disease (CAD) have always been based on the detection of the presence and extent of ischaemia by physical or pharmacological stress tests with or without the aid of imaging methods (e.g. exercise stress, test, stress echocardiography, single-photon emission computed tomography, or stress cardiac magnetic resonance). These methods show high performance to assess obstructive CAD, whilst they do not show accurate power to detect non-obstructive CAD. The introduction into clinical practice of coronary computed tomography angiography, the only non-invasive method capable of analyzing the coronary anatomy, allowed to add a crucial piece in the puzzle of the assessment of patients with suspected or chronic IHD. The current review evaluates the technical aspects and clinical experience of coronary computed tomography in the evaluation of atherosclerotic burden with a special focus about the new emerging application such as functional relevance of CAD with fractional flow reserve computed tomography (CT)-derived (FFRct), stress CT perfusion, and imaging inflammatory makers discussing the strength and weakness of each approach., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: The 2010 Task Force Criteria (TFC) require that both right ventricular (RV) regional wall-motion abnormalities (WMA) and specific RV size cut-offs be met in order to fulfil one of the major criterion for arrhythmogenic right ventricular cardiomyopathy (ARVC) diagnosis. Currently, 2D echocardiography (2DE) and cardiovascular magnetic resonance imaging (cMRI) are used to determine if these criteria are met. Little is known about the diagnostic value of 3D echocardiography (3DE) in ARVC. The aim of this study was to determine whether a combination of 2DE-3DE is non-inferior to the currently used 2DE-cMRI combination in the diagnosis of patients with ARVC., Methods and Results: Thirty-nine individuals (47±15 years) with suspected ARVC underwent evaluation of the RV with cMRI, 2DE, and 3DE. 3DE and cMRI were independently used to obtain RV volumes, ejection fraction (EF) and determine the presence of segmental RV WMA. Studies were blindly classified as meeting criteria for ARVC in accordance with the 2010 TFC. Kappa statistics were used to test the concordance between 2DE-cMRI and 2DE-3DE approaches. Using the 2DE-cMRI approach, 3/39 were not affected, 5/39 possible, 8/39 borderline, and 23/39 definite ARVC. The proposed 2DE-3DE approach yielded 5/39 not affected, 7/39 possible, 8/39 borderline, and 19/39 definite diagnoses. The two approaches were highly concordant (k = 0.71; 95% confidence interval: 0.44-0.84). Although 3DE underestimated RV volumes in comparison with cMRI, interfering, in some instances with the fulfilment of a major criterion, it was able to identify more RV WMA (28/39) than 2DE (11/39), with a detection-rate comparable to cMRI (33/39) highlighting a unique advantage., Conclusion: The combination of 2DE-3DE for ARVC diagnosis is comparable to the conventional 2DE-cMRI approach. 3DE should be performed in all suspected ARVC patients to aide in the detection of WMA., Competing Interests: Conflict of interest: R.M.L. serves on the Speakers’ and advisory bureau, and has received research grants from Philips Medical Imaging. All other authors have no relevant disclosures., (© 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: Segmentation of cardiovascular magnetic resonance (CMR) images is an essential step for evaluating dimensional and functional ventricular parameters as ejection fraction (EF) but may be limited by artifacts, which represent the major challenge to automatically derive clinical information. The aim of this study is to investigate the accuracy of a deep learning (DL) approach for automatic segmentation of cardiac structures from CMR images characterized by magnetic susceptibility artifact in patient with cardiac implanted electronic devices (CIED)., Methods: In this retrospective study, 230 patients (100 with CIED) who underwent clinically indicated CMR were used to developed and test a DL model. A novel convolutional neural network was proposed to extract the left ventricle (LV) and right (RV) ventricle endocardium and LV epicardium. In order to perform a successful segmentation, it is important the network learns to identify salient image regions even during local magnetic field inhomogeneities. The proposed network takes advantage from a spatial attention module to selectively process the most relevant information and focus on the structures of interest. To improve segmentation, especially for images with artifacts, multiple loss functions were minimized in unison. Segmentation results were assessed against manual tracings and commercial CMR analysis software cvi 42 (Circle Cardiovascular Imaging, Calgary, Alberta, Canada). An external dataset of 56 patients with CIED was used to assess model generalizability., Results: In the internal datasets, on image with artifacts, the median Dice coefficients for end-diastolic LV cavity, LV myocardium and RV cavity, were 0.93, 0.77 and 0.87 and 0.91, 0.82, and 0.83 in end-systole, respectively. The proposed method reached higher segmentation accuracy than commercial software, with performance comparable to expert inter-observer variability (bias ± 95%LoA): LVEF 1 ± 8% vs 3 ± 9%, RVEF - 2 ± 15% vs 3 ± 21%. In the external cohort, EF well correlated with manual tracing (intraclass correlation coefficient: LVEF 0.98, RVEF 0.93). The automatic approach was significant faster than manual segmentation in providing cardiac parameters (approximately 1.5 s vs 450 s)., Conclusions: Experimental results show that the proposed method reached promising performance in cardiac segmentation from CMR images with susceptibility artifacts and alleviates time consuming expert physician contour segmentation., (© 2022. The Author(s).)

Background: The right ventricle (RV) plays a pivotal role in cardiovascular diseases and 3-dimensional echocardiography (3DE) has gained acceptance for the evaluation of RV volumes and function. Recently, a new artificial intelligence (AI)-based automated 3DE software for RV evaluation has been proposed and validated against cardiac magnetic resonance. The aims of this study were three-fold: (i) feasibility of the AI-based 3DE RV quantification, (ii) comparison with the semi-automatic 3DE method and (iii) assessment of 2-dimensional echocardiography (2DE) and strain measurements obtained automatically., Methods: A total of 203 subject (122 normal and 81 patients) underwent a 2DE and both the semi-automatic and automatic 3DE methods for Doppler standard, RV volumes and ejection fraction (RVEF) measurements., Results: The automatic 3DE method was highly feasible, faster than 2DE and semi-automatic 3DE and data obtained were comparable with traditional measurements. Both in normal subjects and patients, the RVEF was similar to the two 3DE methods and 2DE and strain measurements obtained by the automated system correlated very well with the standard 2DE and strain ones., Conclusions: results showed that rapid analysis and excellent reproducibility of AI-based 3DE RV analysis supported the routine adoption of this automated method in the daily clinical workflow.

Purpose: To evaluate the diagnostic accuracy of a deep learning (DL) algorithm predicting hemodynamically significant coronary artery disease (CAD) by using a rest dataset of myocardial computed tomography perfusion (CTP) as compared to invasive evaluation., Methods: One hundred and twelve consecutive symptomatic patients scheduled for clinically indicated invasive coronary angiography (ICA) underwent CCTA plus static stress CTP and ICA with invasive fractional flow reserve (FFR) for stenoses ranging between 30 and 80%. Subsequently, a DL algorithm for the prediction of significant CAD by using the rest dataset (CTP-DL rest ) and stress dataset (CTP-DL stress ) was developed. The diagnostic accuracy for identification of significant CAD using CCTA, CCTA + CTP stress, CCTA + CTP-DL rest , and CCTA + CTP-DL stress was measured and compared. The time of analysis for CTP stress, CTP-DL rest , and CTP-DL Stress was recorded., Results: Patient-specific sensitivity, specificity, NPV, PPV, accuracy, and area under the curve (AUC) of CCTA alone and CCTA + CTP Stress were 100%, 33%, 100%, 54%, 63%, 67% and 86%, 89%, 89%, 86%, 88%, 87%, respectively. Patient-specific sensitivity, specificity, NPV, PPV, accuracy, and AUC of CCTA + DL rest and CCTA + DL stress were 100%, 72%, 100%, 74%, 84%, 96% and 93%, 83%, 94%, 81%, 88%, 98%, respectively. All CCTA + CTP stress, CCTA + CTP-DL Rest , and CCTA + CTP-DL Stress significantly improved detection of hemodynamically significant CAD compared to CCTA alone (p < 0.01). Time of CTP-DL was significantly lower as compared to human analysis (39.2 ± 3.2 vs. 379.6 ± 68.0 s, p < 0.001)., Conclusion: Evaluation of myocardial ischemia using a DL approach on rest CTP datasets is feasible and accurate. This approach may be a useful gatekeeper prior to CTP stress . ., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Coronary artery disease (CAD) represents the most common cardiovascular disease, with high morbidity and mortality. Historically patients with chest pain of suspected coronary origin have been assessed with functional tests, capable to detect haemodynamic consequences of coronary obstructions through depiction of electrocardiographic changes, myocardial perfusion defects or regional wall motion abnormalities under stress condition. Stress echocardiography (SE), single-photon emission computed tomography (SPECT), positron emission tomography (PET) and cardiovascular magnetic resonance (CMR) represent the functional techniques currently available, and technical developments contributed to increased diagnostic performance of these techniques. More recently, cardiac computed tomography angiography (cCTA) has been developed as a non-invasive anatomical test for a direct visualisation of coronary vessels and detailed description of atherosclerotic burden. Cardiovascular imaging techniques have dramatically enhanced our knowledge regarding physiological aspects and myocardial implications of CAD. Recently, after the publication of important trials, international guidelines recognised these changes, updating indications and level of recommendations. This review aims to summarise current standards with main novelties and specific limitations, and a diagnostic algorithm for up-to-date clinical management is also proposed.

Objectives: The European System for Cardiac Operation Risk Evaluation II (EuroSCORE II) is the most common tool used to evaluate the perioperative risk of mortality after cardiac surgery in Europe, and its use is currently recommended by the relevant guidelines. However, recently, its role has been questioned: Several papers have suggested that these algorithms may no longer be adequate for risk prediction due to an overestimation of adult cardiac surgical risk. Our goal was to validate the EuroSCORE II in the prediction of 30-day in-hospital mortality in patients undergoing open cardiac surgery in a high-volume hospital., Methods: In this retrospective cohort study, we included all patients who underwent cardiac surgery from January 2016 to May 2022 within the departments of cardiac surgery of the Monzino Cardiology Centre in Milan, Italy. We evaluated the discrimination power of the EuroSCORE II by using the receiver operating characteristic curve and the corresponding area under the curve. We performed calibration plots to assess the concordance between the model's prediction and the observed outcomes., Results: A total of 4,034 patients were included (mean age = 65.1 years; 68% males), of which 674 (16.7%) underwent isolated coronary artery bypass grafting. The EuroSCORE II showed a good discrimination power in predicting 30-day in-hospital mortality (area under the curve = 0.834). However, for interventions performed in an elective setting, very low values of the EuroSCORE II overestimated the observed mortality, whereas for interventions performed in an emergency setting, EuroSCORE II values above 10 extensively underestimated the observed mortality., Conclusions: Our study suggests that the EuroSCORE II seems not to be a reliable score in estimating the true risk of death, especially in high-risk patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background Endomyocardial biopsy (EMB) is part of 2010 Task Force Criteria (TFC) for arrhythmogenic right ventricular cardiomyopathy (ARVC). However, its usage has been curtailed because of its low presumed diagnostic yield, and it is now a poorly used tool. This study aims to analyze the contribution of EMB to the final diagnosis of ARVC. Methods and Results We included 104 consecutive patients evaluated for a suspicion of ARVC, who were referred for EMB. Patients with suspected left dominant pattern were excluded from the primary analysis. Subjects were initially stratified according to TFC without considering EMB. After EMB, patients were reclassified accordingly, and the reclassification rate was calculated. EMB yielded a diagnostic finding in 92 patients (85.5%). After including EMB evaluation, 20 (43%) more patients "at risk" received a definite diagnosis of ARVC. Overall, 59 patients received a definite diagnosis of ARVC, 34% only after EMB. EMB appeared to be the better-performing exam with respect to the final diagnosis (β, 2.2; area uder the curve, 0.73; P <0.05). The reclassification improvement after EMB measured 28%. TFC score increased from 3.5±1.3 to 4.3±1.4 ( P <0.001). Notably, active inflammation was present in 6 (10%) patients. Minor complications were reported in only 2% of the cohort. In patients with suspected left-dominant disease, conventional TFC performed poorly. Conclusions Electroanatomic voltage mapping-guided EMB was safe and yielded an optimal diagnostic yield. It allowed upgrading of the diagnosis of nearly one-third of the patients considered "at risk." Classical TFC without EMB performed poorly in patients with the left dominant form of ARVC.

Coronary artery disease (CAD) represents one of the most important causes of death around the world. Multimodality imaging plays a fundamental role in both diagnosis and risk stratification of acute and chronic CAD. For example, the role of Coronary Computed Tomography Angiography (CCTA) has become increasingly important to rule out CAD according to the latest guidelines. These changes and others will likely increase the request for appropriate imaging tests in the future. In this setting, artificial intelligence (AI) will play a pivotal role in echocardiography, CCTA, cardiac magnetic resonance and nuclear imaging, making multimodality imaging more efficient and reliable for clinicians, as well as more sustainable for healthcare systems. Furthermore, AI can assist clinicians in identifying early predictors of adverse outcome that human eyes cannot see in the fog of "big data." AI algorithms applied to multimodality imaging will play a fundamental role in the management of patients with suspected or established CAD. This study aims to provide a comprehensive overview of current and future AI applications to the field of multimodality imaging of ischemic heart disease., Competing Interests: The 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., (Copyright © 2021 Maragna, Giacari, Guglielmo, Baggiano, Fusini, Guaricci, Rossi, Rabbat and Pontone.)

During the COVID-19 pandemic, the use of protective masks has been essential to reduce contagions. However, public opinion is that there is an associated subjective shortness of breath. We evaluated cardiorespiratory parameters at rest and during maximal exertion to highlight any differences with the use of protective masks.12 healthy subjects performed three identical cardiopulmonary exercise tests, one without wearing a protective mask, one wearing a surgical mask and one with a filtering face piece particles class 2 (FFP2) mask. Dyspnoea was assessed using the Borg scale. Standard pulmonary function tests were also performed.All the subjects (40.8±12.4 years; six male) completed the protocol with no adverse events. Spirometry showed a progressive reduction of forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) from no mask to surgical to FFP2 (FEV 1 : 3.94±0.91 L, 3.23±0.81 L, 2.94±0.98 L; FVC: 4.70±1.21 L, 3.77±1.02 L, 3.52±1.21 L; p<0.001). Rest ventilation, O 2 uptake ( V˙ O 2 ) and CO 2 production ( V˙ CO 2 ) were progressively lower, with a reduction in respiratory rate. At peak exercise, subjects had a progressively higher Borg scale when wearing surgical and FFP2 masks. Accordingly, at peak exercise, V˙ O 2 (31.0±23.4 mL·kg -1 ·min -1 , 27.5±6.9 mL·kg -1 ·min -1 , 28.2±8.8 mL·kg -1 ·min -1 ; p=0.001), ventilation (92±26 L, 76±22 L, 72±21 L; p=0.003), respiratory rate (42±8 breaths·min -1 , 38±5 breaths·min -1 , 37±4 breaths·min -1 ; p=0.04) and tidal volume (2.28±0.72 L, 2.05±0.60 L, 1.96±0.65 L; p=0.001) were gradually lower. There was no significant difference in oxygen saturation.Protective masks are associated with significant but modest worsening of spirometry and cardiorespiratory parameters at rest and peak exercise. The effect is driven by a ventilation reduction due to increased airflow resistance. However, because exercise ventilatory limitation is far from being reached, their use is safe even during maximal exercise, with a slight reduction in performance., Competing Interests: Conflict of interest: M. Mapelli has nothing to disclose. Conflict of interest: E. Salvioni has nothing to disclose. Conflict of interest: F. De Martino has nothing to disclose. Conflict of interest: I. Mattavelli has nothing to disclose. Conflict of interest: P. Gugliandolo has nothing to disclose. Conflict of interest: C. Vignati has nothing to disclose. Conflict of interest: S. Farina has nothing to disclose. Conflict of interest: P. Palermo has nothing to disclose. Conflict of interest: J. Campodonico has nothing to disclose. Conflict of interest: R. Maragna has nothing to disclose. Conflict of interest: G. Lo Russo has nothing to disclose. Conflict of interest: A. Bonomi has nothing to disclose. Conflict of interest: S. Sciomer has nothing to disclose. Conflict of interest: P. Agostoni reports non-financial support from Menarini, Novartis and Boehringer, grants from Daiichi Sankyo and Bayer, and grants and non-financial support from Actelion, outside the submitted work., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

After 15 years from its advent in the clinical field, coronary computed tomography (CCTA) is now widely considered as the best first-step test in patients with low-to-moderate pre-test probability of coronary artery disease. Technological innovation was of pivotal importance for the extensive clinical and scientific interest in CCTA. Recently, the advent of last generation wide-coverage CT scans paved the way for new clinical applications of this technique beyond coronary arteries anatomy evaluation. More precisely, both biventricular volume and systolic function quantification and myocardial fibrosis identification appeared to be feasible with last generation CT. In the present review we would focus on potential applications of cardiac computed tomography (CCT), beyond CCTA, for a comprehensive assessment patients with newly diagnosed cardiomyopathy, from technical requirements to novel clinical applications., Competing Interests: The 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., (Copyright © 2021 Conte, Mushtaq, Muscogiuri, Formenti, Annoni, Mancini, Ricci, Melotti, Gigante, Lorenza, Guglielmo, Baggiano, Maragna, Giacari, Carbucicchio, Catto, Pepi, Andreini and Pontone.)

Introduction: A hypercoagulable condition was described in patients with coronavirus disease 2019 (COVID-19) and proposed as a possible pathogenic mechanism contributing to disease progression and lethality., Aim: We evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients., Methods: In a retrospective observational study, 2,574 unselected patients hospitalized in 30 clinical centers in Italy from February 19, 2020 to June 5, 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection were analyzed. The primary endpoint in a time-to event analysis was in-hospital death, comparing patients who received heparin (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores., Results: Out of 2,574 COVID-19 patients, 70.1% received heparin. LMWH was largely the most used formulation (99.5%). Death rates for patients receiving heparin or not were 7.4 and 14.0 per 1,000 person-days, respectively. After adjustment for propensity scores, we found a 40% lower risk of death in patients receiving heparin (hazard ratio = 0.60; 95% confidence interval: 0.49-0.74; E-value = 2.04). This association was particularly evident in patients with a higher severity of disease or strong coagulation activation., Conclusion: In-hospital heparin treatment was associated with a lower mortality, particularly in severely ill COVID-19 patients and in those with strong coagulation activation. The results from randomized clinical trials are eagerly awaited to provide clear-cut recommendations., Competing Interests: None declared., (Thieme. All rights reserved.)

The efficacy of hydroxychloroquine (HCQ) in treating SARS-CoV-2 infection is harshly debated, with observational and experimental studies reporting contrasting results. To clarify the role of HCQ in Covid-19 patients, we carried out a retrospective observational study of 4,396 unselected patients hospitalized for Covid-19 in Italy (February-May 2020). Patients' characteristics were collected at entry, including age, sex, obesity, smoking status, blood parameters, history of diabetes, cancer, cardiovascular and chronic pulmonary diseases, and medications in use. These were used to identify subtypes of patients with similar characteristics through hierarchical clustering based on Gower distance. Using multivariable Cox regressions, these clusters were then tested for association with mortality and modification of effect by treatment with HCQ. We identified two clusters, one of 3,913 younger patients with lower circulating inflammation levels and better renal function, and one of 483 generally older and more comorbid subjects, more prevalently men and smokers. The latter group was at increased death risk adjusted by HCQ (HR[CI95%] = 3.80[3.08-4.67]), while HCQ showed an independent inverse association (0.51[0.43-0.61]), as well as a significant influence of cluster∗HCQ interaction ( p < 0.001). This was driven by a differential association of HCQ with mortality between the high (0.89[0.65-1.22]) and the low risk cluster (0.46[0.39-0.54]). These effects survived adjustments for additional medications in use and were concordant with associations with disease severity and outcome. These findings suggest a particularly beneficial effect of HCQ within low risk Covid-19 patients and may contribute to clarifying the current controversy on HCQ efficacy in Covid-19 treatment., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Augusto Di Castelnuovo et al.)

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients. Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients. Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores. Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs. Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients., Competing Interests: The 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., (Copyright © 2021 Di Castelnuovo, Costanzo, Antinori, Berselli, Blandi, Bonaccio, Bruno, Cauda, Gialluisi, Guaraldi, Menicanti, Mennuni, My, Parruti, Patti, Perlini, Santilli, Signorelli, Stefanini, Vergori, Ageno, Aiello, Agostoni, Al Moghazi, Arboretti, Aucella, Barbieri, Barchitta, Bartoloni, Bologna, Bonfanti, Caiano, Carrozzi, Cascio, Castiglione, Chiarito, Ciccullo, Cingolani, Cipollone, Colomba, Colombo, Crosta, Dalena, Dal Pra, Danzi, D'Ardes, de Gaetano Donati, Di Gennaro, Di Tano, D'Offizi, Filippini, Maria Fusco, Gaudiosi, Gentile, Gini, Grandone, Guarnieri, Lamanna, Larizza, Leone, Lio, Losito, Maccagni, Maitan, Mancarella, Manuele, Mapelli, Maragna, Marra, Maresca, Marotta, Mastroianni, Mazzitelli, Mengozzi, Menichetti, Milic, Minutolo, Molena, Mussinelli, Mussini, Musso, Odone, Olivieri, Pasi, Perroni, Petri, Pinchera, Pivato, Poletti, Ravaglia, Rossato, Rossi, Sabena, Salinaro, Sangiovanni, Sanrocco, Scorzolini, Sgariglia, Simeone, Spinicci, Trecarichi, Veronesi, Vettor, Vianello, Vinceti, Visconti, Vocciante, De Caterina, Iacoviello and The COVID-19 RISK and Treatments (CORIST) Collaboration.)

Aims: Peak exercise oxygen uptake (VO 2 ) and cardiac output (CO) are strong prognostic indexes in heart failure (HF) but unrelated to real-life physical activity, which is associated to submaximal effort., Methods and Results: We analysed maximal cardiopulmonary exercise test with rest, mid-exercise, and peak exercise non-invasive CO measurements (inert gas rebreathing) of 231 HF patients and 265 healthy volunteers. HF patients were grouped according to exercise capacity (peak VO 2  < 50% and ≥50% pred, Groups 1 and 2). To account for observed differences, data regarding VO 2 , CO, stroke volume (SV), and artero-venous O 2 content difference [ΔC(a-v)O 2 ] were adjusted by age, gender, and body mass index. A multiple regression analysis was performed to predict peak VO 2 from mid-exercise cardiopulmonary exercise test and CO parameters among HF patients. Rest VO 2 was lower in HF compared with healthy subjects; meanwhile, Group 1 patients had the lowest CO and highest ΔC(a-v)O 2 . At mid-exercise, Group 1 patients achieved a lower VO 2 , CO, and SV [0.69 (interquartile range 0.57-0.80) L/min; 5.59 (4.83-6.67) L/min; 62 (51-73) mL] than Group 2 [0.94 (0.83-1.1) L/min; 7.6 (6.56-9.01) L/min; 77 (66-92) mL] and healthy subjects [1.15 (0.93-1.30) L/min; 9.33 (8.07-10.81) L/min; 87 (77-102) mL]. Rest to mid-exercise SV increase was lower in Group 1 than Group 2 (P = 0.001) and healthy subjects (P < 0.001). At mid-exercise, ΔC(a-v)O 2 was higher in Group 2 [13.6 (11.8-15.4) mL/100 mL] vs. healthy patients [11.6 (10.4-13.2) mL/100 mL] (P = 0.002) but not different from Group 1 [13.6 (12.0-14.9) mL/100 mL]. At peak exercise, Group 1 patients achieved a lower VO 2 , CO, and SV than Group 2 and healthy subjects. ΔC(a-v)O 2 was the highest in Group 2. At multivariate analysis, a model comprising mid-exercise VO 2 , carbon dioxide production (VCO 2 ), CO, haemoglobin, and weight predicted peak VO 2 , P < 0.001. Mid-exercise VO 2 and CO, haemoglobin, and weight added statistically significantly to the prediction, P < 0.050., Conclusions: Mid-exercise VO 2 and CO portend peak exercise values and identify severe HF patients. Their evaluation could be clinically useful., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background and Aims: There is poor knowledge on characteristics, comorbidities and laboratory measures associated with risk for adverse outcomes and in-hospital mortality in European Countries. We aimed at identifying baseline characteristics predisposing COVID-19 patients to in-hospital death., Methods and Results: Retrospective observational study on 3894 patients with SARS-CoV-2 infection hospitalized from February 19th to May 23rd, 2020 and recruited in 30 clinical centres distributed throughout Italy. Machine learning (random forest)-based and Cox survival analysis. 61.7% of participants were men (median age 67 years), followed up for a median of 13 days. In-hospital mortality exhibited a geographical gradient, Northern Italian regions featuring more than twofold higher death rates as compared to Central/Southern areas (15.6% vs 6.4%, respectively). Machine learning analysis revealed that the most important features in death classification were impaired renal function, elevated C reactive protein and advanced age. These findings were confirmed by multivariable Cox survival analysis (hazard ratio (HR): 8.2; 95% confidence interval (CI) 4.6-14.7 for age ≥85 vs 18-44 y); HR = 4.7; 2.9-7.7 for estimated glomerular filtration rate levels <15 vs ≥ 90 mL/min/1.73 m 2 ; HR = 2.3; 1.5-3.6 for C-reactive protein levels ≥10 vs ≤ 3 mg/L). No relation was found with obesity, tobacco use, cardiovascular disease and related-comorbidities. The associations between these variables and mortality were substantially homogenous across all sub-groups analyses., Conclusions: Impaired renal function, elevated C-reactive protein and advanced age were major predictors of in-hospital death in a large cohort of unselected patients with COVID-19, admitted to 30 different clinical centres all over Italy., Competing Interests: Declaration of Competing Interest All Authors declare no competing interests., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Long QT syndrome (LQTS) is a common inheritable arrhythmogenic disorder, often secondary to mutations in the KCNQ1, KCNH2, and SCN5A genes. The disease is characterized by a prolonged ventricular repolarization (QTc interval) that confers susceptibility to life-threatening arrhythmic events (LAEs)., Objectives: This study sought to create an evidence-based risk stratification scheme to personalize the quantification of the arrhythmic risk in patients with LQTS., Methods: Data from 1,710 patients with LQTS followed up for a median of 7.1 years (interquartile range [IQR]: 2.7 to 13.4 years) were analyzed to estimate the 5-year risk of LAEs based on QTc duration and genotype and to assess the antiarrhythmic efficacy of beta-blockers., Results: The relationship between QTc duration and risk of events was investigated by comparison of linear and cubic spline models, and the linear model provided the best fit. The 5-year risk of LAEs while patients were off therapy was then calculated in a multivariable Cox model with QTc and genotype considered as independent factors. The estimated risk of LAEs increased by 15% for every 10-ms increment of QTc duration for all genotypes. Intergenotype comparison showed that the risk for patients with LQT2 and LQT3 increased by 130% and 157% at any QTc duration versus patients with LQT1. Analysis of response to beta-blockers showed that only nadolol reduced the arrhythmic risk in all genotypes significantly compared with no therapy (hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.93; p = 0.03)., Conclusions: The study provides an estimator of risk of LAEs in LQTS that allows a granular estimate of 5-year arrhythmic risk and demonstrate the superiority of nadolol in reducing the risk of LAEs in LQTS., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Short QT syndrome (SQTS) is a rare and life-threatening arrhythmogenic syndrome characterized by abbreviated repolarization. Hydroquinidine (HQ) prolongs the QT interval in SQTS patients, although whether it reduces cardiac events is currently unknown., Objectives: This study investigated whether long-term treatment with HQ reduces the occurrence of life-threatening arrhythmic events (LAE) (cardiac arrest or sudden cardiac death) in SQTS patients., Methods: In this cohort study on consecutive SQTS patients, 2 analyses were performed: 1) a matched-period analysis for the occurrence of LAE in 17 SQTS patients who received long-term HQ; and 2) a comparison of the annual incidence of LAE off- and on-HQ in 16 SQTS patients who survived a cardiac arrest., Results: A total of 17 patients (82% male, age 29 ± 3 years, QTc before treatment 331 ± 3 ms) received HQ therapy (584 ± 53 mg/day). Therapy was stopped in 2 cases (12%) due to gastrointestinal intolerance, and 15 patients continued treatment for 6 ± 1 year. QTc prolongation was observed in all patients (by 60 ± 6 ms; p < 0.001). We compared the occurrence of LAE during 6 ± 1 years before and after HQ, observing that patients on HQ experienced a reduction in both the rate of LAE from 40% to 0% (p = 0.03) and the number of LAE per patient from 0.73 ± 0.3 to 0 (p = 0.026). Furthermore, the annual rate of LAE in the 16 patients with a previous cardiac arrest dropped from 12% before HQ to 0 on therapy (p = 0.028)., Conclusions: We demonstrated for the first time that treatment with HQ was associated with a lower incidence of LAE in SQTS patients. These data point to the importance that quinidine, that in several countries has been removed from the market, remains available worldwide for patients with SQTS. In the present study, therapy with HQ has been proven to be safe, with a relatively low rate of side effects., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: In this chapter we will discuss the most recent and relevant evidences published in the field of inherited arrhythmogenic disorders, focusing on the so called 'channelopathies' that are associated with sudden cardiac death (SCD) in children: long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT)., Recent Findings: We will discuss the latest diagnostic criteria for channelopathies released by the European Society of Cardiology, the new data on BrS in children and the recent evidence supporting a genotype-specific therapy for LQTS type 3. Moreover, we will present further insights into the risk stratification of the children affected by LQTS, analyzing the role of imaging for the prediction of life-threatening arrhythmias. In addition, we will offer a perspective on how to deal with genetic results in families affected by SCD at very young ages., Summary: The selected publications will aid pediatricians in their clinical work when managing little patients with inherited arrhythmias, providing the most recent information for diagnosis, risk stratification, and management.

Purpose of Review: In this article, we discuss the most recent and relevant studies published in the field of inherited arrhythmogenic disorders, focusing in particular on channelopathies (Long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia) and arrhythmogenic right ventricular cardiomyopathy (ARVC)., Recent Findings: We discuss the updated diagnostic criteria for channelopathies released by the European Society of Cardiology, the new results on the value of programmed electrical stimulation in patients with Brugada syndrome, and the recent evidences supporting a genotype-specific therapy for Long QT syndrome type 3. Moreover, we will present further insights into the clinical course and risk stratification of patients affected by ARVC, analyzing in particular the role of antiarrhythmic drugs for the prevention of life-threatening arrhythmias. Finally, we will explore the innovative therapeutic approaches that may be available in the future for patients with inherited arrhythmogenic disorders, such as the gene therapy., Summary: The review will aid physicians in their clinical work when managing patients with inherited arrhythmias and ARVC, providing the most recent information for diagnosis, risk stratification, and management.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a leading cause of sudden cardiac death, but its progression over time and predictors of arrhythmias are still being defined., Objectives: This study sought to describe the clinical course of ARVC and occurrence of life-threatening arrhythmic events (LAE) and cardiovascular mortality; identify risk factors associated with increased LAE risk; and define the response to therapy., Methods: We determined the clinical course of 301 consecutive patients with ARVC using the Kaplan-Meier method adjusted to avoid the bias of delayed entry. Predictors of LAE over 5.8 years of follow-up were determined with Cox multivariable analysis. Treatment efficacy was assessed comparing LAE rates during matched time intervals., Results: A first LAE occurred in 1.5 per 100 person-years between birth and age 20 years, in 4.0 per 100 person-years between ages 21 and 40 years, and in 2.4 per 100 person-years between ages 41 and 60 years. Cumulative probability of a first LAE at follow-up was 14% at 5 years, 23% at 10 years, and 30% at 15 years. Higher risk of LAE was predicted by atrial fibrillation (hazard ratio [HR]: 4.38; p = 0.002), syncope (HR: 3.36; p < 0.001), participation in strenuous exercise after the diagnosis (HR: 2.98; p = 0.028), hemodynamically tolerated sustained monomorphic ventricular tachycardia (HR: 2.19; p = 0.023), and male sex (HR: 2.49; p = 0.012). No difference was observed in the occurrence of LAE before and after treatment with amiodarone, beta-blockers, sotalol, or ablation. A total of 81 patients received an implantable cardioverter-defibrillator, 34 were successfully defibrillated., Conclusions: The high risk of life-threatening arrhythmias in patients with ARVC spans from adolescence to advanced age, reaching its peak between ages 21 and 40 years. Atrial fibrillation, syncope, participation in strenuous exercise after the diagnosis of ARVC, hemodynamically tolerated sustained monomorphic ventricular tachycardia, and male sex predicted lethal arrhythmias at follow-up. The lack of efficacy of antiarrhythmic therapy and the life-saving role of the implantable cardioverter-defibrillator highlight the importance of risk stratification for patient management., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Long QT syndrome type 3 (LQT3) is a lethal disease caused by gain-of-function mutations in the SCN5A gene, coding for the alpha-subunit of the sodium channel NaV1.5. Mexiletine is used to block late sodium current and to shorten QT interval in LQT3 patients., Objectives: The aim of this study was to determine whether mexiletine prevents arrhythmic events (arrhythmic syncope, aborted cardiac arrest, or sudden cardiac death) in LQT3 patients., Methods: The endpoint of this retrospective cohort study, which studied consecutive LQT3 patients who were referred to our center and treated with mexiletine, was to evaluate the antiarrhythmic efficacy of mexiletine by comparing the number of arrhythmic events per patient and the annual rate of arrhythmic events during observation periods of equal duration before and after the beginning of therapy with mexiletine., Results: The study population comprised 34 LQT3 patients, 19 (56%) of whom were male. The median age at beginning of treatment with mexiletine was 22 years, and median QTc interval before therapy 509 ms. The median duration of oral mexiletine therapy was 36 months, at an average daily dose of 8 ± 0.5 mg/kg. Mexiletine significantly shortened QTc (by 63 ± 6 ms; p < 0.0001) and reduced the percentage of patients with arrhythmic events (from 22% to 3%; p = 0.031), the mean number of arrhythmic events per patient (from 0.43 ± 0.17 to 0.03 ± 0.03; p = 0.027), and the annual rate of arrhythmic events (from 10.3% to 0.7%; p = 0.0097)., Conclusions: Besides shortening QTc interval, mexiletine caused a major reduction of life-threatening arrhythmic events in LQT3 patients, thus representing an efficacious therapeutic strategy., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)