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Aims: Amyloid cardiomyopathy is caused by the deposition of light chain (AL) or transthyretin amyloid (ATTR) fibrils, that leads to a restrictive cardiomyopathy, often resulting in heart failure (HF) with preserved or reduced ejection fraction. This study aimed to determine whether cardiac output reduction or ventilation inefficiency plays a predominant role in limiting exercise in patients with amyloid cardiomyopathy., Methods: We conducted a multicentre prospective study in patients with AL or ATTR cardiomyopathy who underwent cardiopulmonary exercise testing across four centres. Patients were compared with a propensity-score matched HF cohort based on age, gender, left ventricular ejection fraction (LVEF), and peak oxygen consumption (VO 2 )., Results: Data from 267 amyloid patients aged 77 (72, 81) years, 86% male, with a median N-terminal pro B-type natriuretic peptide (NT-proBNP) of 2187 (1140, 4383) ng/L, exercise parameters of peak VO 2 of 14.1 (11.6;16.9) mL/min/kg, a minute ventilation to carbon dioxide production (VE/VCO 2 ) slope of 37.4 (32.5, 42.6) and a LVEF of 50% (44%, 59%) were analysed. We identified 251 amyloid cardiomyopathy-HF matches. Amyloid patients had a signifnicantly higher VE/VCO 2 slope [37.4, inter quartile range (IQR): 32.7, 43.1 vs. 32.1, IQR: 28.7, 37.0, P < 0.0001], NT-proBNP (2249, IQR: 1187, 4420 vs. 718, IQR: 405, 2161 ng/L, P < 0.001), peak heart rate (121 ± 28 vs. 115 ± 27 beats/min, P = 0.007) and peak ventilation (51, IQR: 42, 62 vs. 43, IQR: 33, 53 L/min, P < 0.0001) with earlier anaerobic threshold (VO 2 at AT: 8.9, IQR: 6.8, 10.8 vs. 10.8, IQR: 8.9, 12.7 mL/min/kg, P < 0.0001) compared with HF. Between amyloid patients, AL patients (n = 27) were younger (63, IQR: 58, 70 vs. 78, IQR: 72, 81 years, P < 0.0001), had lower VE/VCO 2 slope (35.0, IQR: 30.0, 38.7 vs. 38.0, IQR: 32.8, 43.1, P = 0.019), higher end-tidal carbon dioxide partial pressure both at AT (35.1 ± 4.8 vs. 31.4 ± 4.7 mmHg, P < 0.001) and peak exercise (32, IQR: 28, 35 vs. 30, IQR: 26, 33 mmHg, P = 0.039) as compared with ATTR (n = 233)., Conclusions: A higher VE/VCO 2 slope and an earlier AT, determining functional capacity impairment, was assessed in patients with amyloid cardiomyopathy compared with the matched HF cohort. Additionally, patients with ATTR might display more severe exercise limitations as compared with AL., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: takotsubo syndrome (TTS) is an acute heart failure syndrome characterized by a relevant comorbid background, including chronic obstructive pulmonary disease (COPD). However, TTS patients with COPD are still not well characterized., Aim: to describe the clinical characteristics and outcomes of patients with TTS and COPD., Methods: n = 440 TTS patients were dichotomized according to the presence of COPD. Endpoint of the study were in-hospital complications (composite of death, major arrhythmias, cardiogenic shock and acute pulmonary edema), TTS recurrence and long-term mortality at follow-up., Results: mean age of the population was 72±11, 10 % males. COPD prevalence was 16 % (n = 69). On subgroup analysis, patients with COPD were more likely smokers (41 % vs 13 %, p < 0.001), with higher rates of dyspnea and physical triggers at presentation (52 % vs 18 %, p < 0.001 and 52 % vs 32 %, p = 0.001 respectively) and lower left ventricular ejection fraction (36 % vs 39 %, p = 0.035) In-hospital complications were more common in patients with COPD (26 % vs 13 %, p = 0.006), driven by higher rates of acute pulmonary edema (19 % vs 6 %, p < 0.001) and cardiogenic shock (10 % vs 4 %, p = 0.023). At multivariable logistic regression analysis, COPD was independently associated with in-hospital complications occurrence (Odds Ratio 2.10, 95 % CI 1.09-4.05; p = 0.027). At univariable Cox regression analysis COPD was associated with TTS recurrence (Hazard Ratio (HR 9.82, 95 % CI 3.2-30.12; p < 0.001)), at multivariable Cox regression analysis with long-term mortality (HR 2.97, 95 % CI 1.44-6.12; p = 0.003)., Conclusion: COPD marks a vulnerable TTS phenotype including higher risk of in-hospital complications, long-term recurrence and mortality., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Left ventricular (LV) ring-like scar on cardiac magnetic resonance (CMR) has been linked to malignant arrhythmias in patients with non-ischemic cardiomyopathy. This study aimed to perform a comprehensive evaluation of this phenotype and to identify risk factors for life-threatening arrhythmic events (LAEs), a composite of sudden cardiac death (SCD), aborted SCD, and sustained ventricular tachycardia., Methods and Results: One-hundred-fifteen patients (median age 39 [IQR 28-52], 42% females) were identified at 6 referral centres. Inclusion criteria were ring-like LV scar (≥ 3 contiguous segments with subepicardial/midwall late gadolinium enhancement (LGE) in the same slice) and one among: pathogenic/likely pathogenic genetic variant, family history for cardiomyopathy, or arrhythmogenic cardiomyopathy diagnosis. During the study follow-up, survival-free from LAEs was 60% (3.8 events/100 patients/year); at a median follow-up of 4.6 years (IQR 1.7-8.4) it was 84%. On multivariable analysis, anterior Q waves (HR:1.030, 95% CI:1.014-1.046, p < 0.001), QRS width (HR:4.642, 95% CI:1.296-16.628, p=0.018), and LV end-diastolic volume index (LVEDVi) (HR:1.011, 95% CI:1.001-1.021, per mL/m2 increase, p=0.040) were independently associated with LAEs; with good discrimination power (Harrell's C-index=0.796). Three risk categories were identified: normal ECG, abnormal ECG and no LAEs predictive variables, abnormal ECG and ≥ 1 LAEs predictive variables, with a decreasing survival from 100% to 65% and 49%, respectively (Log-rank test = 0.015)., Conclusions: In this study, the LV ring-like scar phenotype was associated with a high rate of malignant arrhythmias in presence of anterior Q waves, QRS prolongation, and increased LVEDVi. A normal ECG identified a lower risk subgroup., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Immunotherapy is increasingly used in advanced non-small-cell lung cancer (NSCLC), offering a significant anti-tumor response, as well as causing rising immune-related adverse effects. The incidence of immune checkpoint inhibitor-induced myocarditis-myositis-myasthenia gravis is increasing and particularly concerning due to its high mortality rate. Prompt recognition, diagnosis, and management are crucial. A 40-year-old patient, diagnosed with stage IV non-oncogene addicted lung adenocarcinoma, with nivolumab-ipilimumab-chemotherapy as first-line treatment, developed a rare myocarditis-myositis-myasthenia gravis overlap syndrome. Following the treatment, the patient presented with flu-like symptoms and chest pain and subsequently transferred to the cardiac intensive care unit. The physical examination revealed a visual acuity deficit, diplopia, ophthalmoparesis, ptosis, mydriasis, dysphagia, dyspnea, headache, nausea, dry mouth, asthenia, myalgia, and muscle weakness. Imaging and laboratory tests confirmed the triad, showing an elevation of hs-cTnI and CK and positive results for anti-SAE1 and anti-PL-7 Abs. ECG revealed ST segment elevation and RBBB. The echo showed hyperechogenicity of the inferolateral wall, pericardial detachment, and thickening. The cardiac MRI demonstrated hypokinesia, edema, subepicardial LGE, and pericardial effusion. Muscle biopsy revealed muscle fiber necrosis and regeneration with B and T lymphocytic endomysial inflammatory infiltrate and expression of MHC-I. Treatment with oral prednisone, pyridostigmine, and IV Igs was started due to poor clinical response followed by methylprednisolone. Despite stopping immunotherapy, the patient continued to benefit from it, as highlighted on subsequent re-evaluation CT scans by partial disease response, and as the patient was in complete remission, we decided to resume chemotherapy by omitting immunotherapy. At the radiological control following the four cycles of double CHT and during CHT maintenance, there was a further reduction of the disease. This report aims to raise awareness among physicians about these serious side effects. A multidisciplinary approach led to clinical improvement and early intervention, optimizing patient outcomes., 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 © 2024 Mariniello, Arrivi, Tufano, Lauletta, Moro, Tini, Garibaldi, Giusti and Mazzuca.)

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac muscle disease characterized by clinical and genetic heterogeneity. Genetic testing can reveal the presence of disease-causing variants in genes encoding sarcomere proteins. However, it yields inconclusive or negative results in 40-60% of HCM cases, owing to, among other causes, technical limitations such as the inability to detect pathogenic intronic variants. Therefore, we aimed to increase the diagnostic yield of molecular analysis for HCM by improving the in-silico detection of intronic variants in MYBPC3 that may escape detection by algorithms normally used with tagged diagnostic panels. We included 142 HCM probands with negative results in Illumina TruSight Cardio panel analysis, including exonic regions of 174 cardiomyopathy genes. Raw data were re-analyzed using existing bioinformatics tools. The spliceogenic variant c.1224-80G>A was detected in three patients (2.1%), leading us to reconsider their molecular diagnosis. These patients showed late onset and mild symptoms, although no peculiar phenotypic characteristics were shared. Collectively, rare spliceogenic MYBPC3 variants may play a role in causing HCM, and their systematic detection should be performed to provide more comprehensive solutions in genetic testing using multigenic panels.

Aims: Disease staging and prognostic scoring in wild-type transthyretin-related cardiac amyloidosis (ATTRwt-CA) can be captured by two systems (NAC and Columbia scores). However, uncertainty remains as epidemiology of the disease is evolving rapidly. We evaluated features associated with staging systems across ATTRwt-CA patients from different diagnostic pathways, and their association with prognosis., Methods: We performed an analysis on DIAMOND patients with available data to evaluate NAC and Columbia score. DIAMOND was a retrospective study from 17 Italian referral centres for CA, enrolling 1281 patients diagnosed between 2016 and 2021, and aimed at describing characteristics of pathways leading to ATTRwt-CA diagnosis. Of the original cohort, 811 patients were included in this analysis. Each patient had NAC and Columbia score calculated. Patients were grouped according to NAC and Columbia scoring classes. We described characteristics of patients according to staging classes and diagnostic pathways at diagnosis. Prevalence of early diagnoses, defined as NAC Ia, NYHA class I, no use of diuretics, no history of heart failure (HF) hospitalizations nor of atrial fibrillation prior to diagnosis, was investigated. Finally, prognostic variables were tested alone and grouped as NAC or Columbia scores in Cox univariate and multivariate regression analyses. Prognosis was investigated as all-cause mortality, in the whole population and dividing patients in HF versus other diagnostic pathways., Results: Only 1% of the study population had an early ATTRwt-CA diagnosis. Distribution of prognostic variables and of NAC and Columbia classes was heterogeneous across diagnostic pathways. The prevalence of NAC III and Columbia III was higher in the HF diagnostic pathway, but all NAC and Columbia classes were present in all pathways. Both NAC and Columbia scores were associated with all-cause mortality at univariate Cox regression analysis in the whole population, in patients from the HF diagnostic pathway and in those from other pathways. At multivariate analysis, Columbia score remained significantly associated with the outcome, together with age at diagnosis, left ventricular ejection fraction and maximal wall thickness., Conclusions: In this contemporary nationwide cohort, an ATTRwt-CA early diagnosis was very rare. Disease staging with NAC and Columbia scoring systems determined classes of patients with heterogeneous features. Both scores were significantly associated with mortality, but other variables also had prognostic significance., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The introduction of a noninvasive diagnostic algorithm in 2016 led to increased awareness and recognition of cardiac amyloidosis (CA)., Objectives: The purpose of this study was to analyze the impact of the introduction of the noninvasive diagnostic algorithm on diagnosis and prognosis in a multicenter Italian CA cohort., Methods: This was a retrospective analysis of 887 CA patients from 5 Italian Cardiomyopathies Referral Centers: 311 light-chain CA, 87 variant transthyretin (TTR)-related CA, 489 wild-type TTR-related CA. Clinical characteristics and outcomes (all-cause mortality and heart failure [HF] hospitalizations) were compared overall and for each CA subtype between patients diagnosed before versus after 2016. Outcomes were further compared by propensity score weighted Kaplan-Meier analysis and Cox regression analysis., Results: CA diagnoses increased after 2016, in particular for wild-type TTR-related CA. Patients diagnosed after versus before 2016 were older, had less frequently a history of HF prior to diagnosis, and NYHA functional class III-IV at diagnosis. Over a median follow-up of 18 months, 172 (86%) patients diagnosed before 2016 died or had an HF hospitalization, versus 300 (44%) diagnosed after 2016. Propensity score weighted Kaplan-Meier analysis showed worse outcomes ( P  < 0.001) for patients diagnosed before 2016. At Cox regression analysis, CA diagnosis after 2016 was an independent protective factor for the composite outcome (HR: 0.69; P  = 0.001), with interaction by CA subtype (significant in TTR-related CA and null in light-chain)., Conclusions: CA patients diagnosed after 2016 showed a less severe phenotype and a better prognosis. The impact of the noninvasive diagnostic algorithm on outcomes was particularly relevant in TTR-related CA., Competing Interests: The work reported in this publication was funded by the 10.13039/501100003196Italian Ministry of Health, RC-2022-2773270 project. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Aims: The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement., Methods and Results: We included 159 relatives (median age 55.6 [43.2-65.9] years, 52% male) at risk for ATTRv-CM from 10 centres. The primary endpoint, ATTRv-CM diagnosis, was defined as the presence of (i) cardiac tracer uptake in bone scintigraphy; or (ii) transthyretin-positive cardiac biopsy. The secondary endpoint was a composite of heart failure (New York Heart Association class ≥II) and pacemaker-requiring conduction disorders. At baseline, 40/159 (25%) relatives were diagnosed with ATTRv-CM. Of those, 20 (50%) met the secondary endpoint. Indication to screen (≤10 years prior to predicted disease onset and absence of extracardiac amyloidosis) had an excellent negative predictive value (97%). Other pre-screening predictors for ATTRv-CM were infrequently identified variants and male sex. Importantly, 13% of relatives with ATTRv-CM did not show any signs of cardiac involvement on first-line diagnostic tests. The yield of serial evaluation (n = 41 relatives; follow-up 3.1 [2.2-5.2] years) at 3-year interval was 9.4%., Conclusions: Screening according to the 2021 ESC position statement performs well in daily clinical practice. Clinicians should adhere to repeating bone scintigraphy after 3 years, as progressing to ATTRv-CM without signs of ATTRv-CM on first-line diagnostic tests or symptoms is common., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Interpreting the clinical consequences of genetic variants is the central problem in modern clinical genomics, for both hereditary diseases and oncology. However, clinical validation lags behind the pace of discovery, leading to distressing uncertainty for patients, physicians and researchers. This "interpretation gap" changes over time as evidence accumulates, and variants initially deemed of uncertain (VUS) significance may be subsequently reclassified in pathogenic/benign. We previously developed RENOVO, a random forest-based tool able to predict variant pathogenicity based on publicly available information from GnomAD and dbNFSP, and tested on variants that have changed their classification status over time. Here, we comprehensively evaluated the accuracy of RENOVO predictions on variants that have been reclassified over the last four years., Methods: we retrieved 16 retrospective instances of the ClinVar database, every 3 months since March 2020 to March 2024, and analyzed time trends of variant classifications. We identified variants that changed their status over time and compared RENOVO predictions generated in 2020 with the actual reclassifications., Results: VUS have become the most represented class in ClinVar (44.97% vs. 9.75% (likely) pathogenic and 40,33% (likely) benign). The rate of VUS reclassification is linear and slow compared to the rate of VUS reporting, exponential and currently ~ 30x faster, creating a growing divide between what can be sequenced vs. what can be interpreted. Out of 10,196 VUS variants in January 2020 that have undergone a clinically meaningful reclassification to march 2024, RENOVO correctly classified 82.6% in 2020. In addition, RENOVO correctly identified the majority of the few variants that switched clinically meaningful classes (e.g., from benign to pathogenic and vice versa). We highlight variant classes and clinically relevant genes for which RENOVO provides particularly accurate estimates. In particularly, genes characterized by large prevalence of high- or low-impact variants (e.g., POLE, NOTCH1, FANCM etc.). Suboptimal RENOVO predictions mostly concern genes validated through dedicated consortia (e.g., BRCA1/2), in which RENOVO would anyway have a limited impact., Conclusions: Time trend analysis demonstrates that the current model of variant interpretation cannot keep up with variant discovery. Machine learning-based tools like RENOVO confirm high accuracy that can aid in clinical practice and research., (© 2024. The Author(s).)

Background: It has been postulated that cancer hampers the delivery of guideline-directed medical therapy (GDMT) for heart failure (HF). However, few data are available in this regard., Methods: We performed a retrospective analysis from the HF Outpatient Clinic of the IRCCS Ospedale Policlinico San Martino in Genova, Italy. All HF patients evaluated between 2010 and 2019, with a left ventricular ejection fraction <50% and at least two visits ≥3 months apart with complete information about GDMT were included in the study. We assessed the prescription of GDMT-in particular, beta-blockers (BB), renin-angiotensin system inhibitors (RASi), and mineralocorticoid antagonists (MRA)-at the time of the last HF evaluation and compared it between patients with and without incidental cancer. For those with incidental cancer, we also evaluated modifications of GDMT comparing the HF evaluations before and after cancer diagnosis., Results: Of 464 HF patients, 39 (8%) had incidental cancer. There were no statistical differences in GDMT between patients with and without incidental cancer at last evaluation. In the year following cancer diagnosis, of 33 patients with incidental cancer on BB, none stopped therapy, but two had a down-titration to a dosage <50%; of 27 patients on RASi, two patients stopped therapy and three had a down-titration to a dosage <50%; of 19 patients on MRA, four stopped therapy., Conclusions: Although HF patients with incidental cancer may need to have GDMT down-titrated at the time of cancer diagnosis, this does not appear to significantly hinder the delivery of HF therapies during follow-up., Competing Interests: Conflicts of Interest PA received speaker and/or advisor fees from AstraZeneca, Boehringer Ingelheim, Bayer, Daiichi-Sankyo, Janssen, Merck Sharp & Dohme, all outside the submitted work. The other authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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

Cardio-oncology is a rapidly growing field of cardiovascular (CV) medicine that has resulted from the continuously increasing clinical demand for specialized CV evaluation, prevention and management of patients suffering or surviving from malignant diseases. Dealing with CV disease in patients with cancer requires special knowledge beyond that included in the general core curriculum for cardiology. Therefore, the European Society of Cardiology (ESC) has developed a special core curriculum for cardio-oncology, a consensus document that defines the level of experience and knowledge required for cardiologists in this particular field. It is structured into 8 chapters, including (i) principles of cancer biology and therapy; (ii) forms and definitions of cancer therapy-related cardiovascular toxicity (CTR-CVT); (iii) risk stratification, prevention and monitoring protocols for CTR-CVT; (iv) diagnosis and management of CV disease in patients with cancer; (v) long-term survivorship programmes and cardio-oncology rehabilitation; (vi) multidisciplinary team management of special populations; (vii) organization of cardio-oncology services; (viii) research in cardio-oncology. The core curriculum aims at promoting standardization and harmonization of training and evaluation in cardio-oncology, while it further provides the ground for an ESC certification programme designed to recognize the competencies of certified specialists., (© 2023 European Society of Cardiology.)

Background: A minority of patients with hypertrophic cardiomyopathy (HCM) presents advanced heart failure (HF) during their clinical course, in the context of left ventricular (LV) remodeling with reduced LV ejection fraction (LVEF), or of severe diastolic dysfunction without impaired LVEF. Aim of this study was to describe a multicentric end stage (ES) HCM population and analyze clinical course and outcome among its different phenotypes., Methods: Data of all HCM patients from 7 Italian referral centres were retrospectively evaluated. ES was diagnosed in presence of: LVEF <50% (ES-rEF) or NYHA functional class ≥II with severe diastolic dysfunction (ES-pEF). Outcomes were: HCM-related and all-cause mortality; combined arrhythmic events; advanced HF treatments., Results: Study population included 331 ES patients; 87% presented ES-rEF and 13% ES-pEF. At ES recognition, patients with ES-pEF were more commonly females, had more frequently NYHA III/IV, atrial fibrillation and greater maximal LV wall thickness. Over a median follow-up of 5.6 years, 83 (25%) patients died, 46 (15%) experienced arrhythmic events and (26%) 85 received advanced HF treatments. Incidence of HCM-related and all-cause mortality, and of combined arrhythmic events did not differ in ES-pEF and ES-rEF patients, but ES-pEF patients were less likely to receive advanced HF treatments. Older age at ES recognition was an independent predictor of increased HCM-related mortality (p = 0.01) and reduced access to advanced HF treatments (p < 0.0001)., Conclusions: Two different HCM-ES phenotypes can be recognized, with ES-pEF showing distinctive features at ES recognition and receiving less frequently advanced HF treatments. Older age at ES recognition has a major impact on outcomes., Competing Interests: Declaration of competing interest All Authors report no conflicts of interest related to the present work. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Risk and outcome of acute promyelocytic leukemia (APL) are particularly worsened in obese-overweight individuals, but the underlying molecular mechanism is unknown. In established mouse APL models (Ctsg-PML::RARA), we confirmed that obesity induced by high-fat diet (HFD) enhances leukemogenesis by increasing penetrance and shortening latency, providing an ideal model to investigate obesity-induced molecular events in the preleukemic phase. Surprisingly, despite increasing DNA damage in hematopoietic stem cells (HSC), HFD only minimally increased mutational load, with no relevant impact on known cancer-driving genes. HFD expanded and enhanced self-renewal of hematopoietic progenitor cells (HPC), with concomitant reduction in long-term HSCs. Importantly, linoleic acid, abundant in HFD, fully recapitulates the effect of HFD on the self-renewal of PML::RARA HPCs through activation of peroxisome proliferator-activated receptor delta, a central regulator of fatty acid metabolism. Our findings inform dietary/pharmacologic interventions to counteract obesity-associated cancers and suggest that nongenetic factors play a key role., Prevention Relevance: Our work informs interventions aimed at counteracting the cancer-promoting effect of obesity. On the basis of our study, individuals with a history of chronic obesity may still significantly reduce their risk by switching to a healthier lifestyle, a concept supported by evidence in solid tumors but not yet in hematologic malignancies. See related Spotlight, p. 47., (©2023 American Association for Cancer Research.)

Background: Molecular-driven oncology allows oncologists to identify treatments that match a cancer's genomic profile. Clinical trials are promoted as an effective modality to deliver a molecularly matched treatment. We explore the role of geographical accessibility in Italy, and its impact on patient access to clinical trials., Material and Methods: We retrospectively reviewed molecular data from a single-institutional case series of patients receiving next-generation sequencing testing between March 2019 and July 2020. Actionable alterations were defined as the ones with at least one matched treatment on Clinicaltrials.gov at the time of genomic report signature. We then calculated the hypothetical distance to travel to reach the nearest assigned clinical trial., Results: We identified 159 patients eligible for analysis. One hundred and one could be potentially assigned to a clinical trial in Italy, and the median distance that patients needed to travel to reach the closest location with a suitable clinical trial was 76 km (interquartile range = 127.46 km). Geographical distribution of clinical trials in Italy found to be heterogeneous, with Milan and Naples being the areas with a higher concentration. We then found that the probability of having a clinical trial close to a patient's hometown increased over time, according to registered studies between 2015 and 2020., Conclusions: The median distance to be travelled to the nearest trial was generally acceptable for patients, and trials availability is increasing. Nevertheless, many areas are still lacking trials, so efforts are required to increase and homogenize the possibilities to be enrolled in clinical trials for Italian patients with cancer., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Immune-related adverse events (IRAE) pose a significant diagnostic and therapeutic challenge in patients treated with immune-oncology (IO) drugs. IRAEs have been suggested to correlate with better outcome, but studies are conflicting. Estimating the true incidence of IRAEs is particularly difficult in the early phase I/II trial setting. A key issue is the lack of IRAE diagnostic criteria, necessary to discriminate "pure" IRAEs from other treatment-related adverse events not sustained by an autoimmune process., Methods: In patients treated with immune-oncology (IO) drugs in phases I-II trials at our institute, we identified high confidence (HC) or low confidence (LC) IRAEs by clinical consensus. We empirically developed an IRAE likelihood score (ILS) based on commonly available clinical data. Correlation with outcome was explored by multivariate Cox analysis. To mitigate immortal time-bias, analyses were conducted (1) at 2-month landmark and (2) modeling IRAEs as time-dependent covariate., Results: Among 202 IO-treated patients, 29.2% developed >1 treatment-related adverse events (TRAE). Based on ILS >5, we classified patients in no IRAE (n = 143), HC IRAE (n = 24), or LC IRAE (n = 35). hazard ratios (HR) for HC were significantly lower than LC patients (HR for PFS ranging 0.24-0.44, for OS 0.18-0.23, all P < .01)., Conclusion: ILS provides a simple system to identify bona fide IRAEs, pruning for other treatment-related events likely due to different pathophysiology. Applying stringent criteria leads to lower and more reliable estimates of IRAE incidence and identifies events with significant impact on survival., (© The Author(s) 2023. Published by Oxford University Press.)

Takotsubo syndrome (TTS) is characterized by a transient left ventricular systolic dysfunction, burdened by significant acute and long-term mortality and morbidity. The prognosis of TTS, especially in the long-term, is influenced by both non-cardiovascular (non-CV) and CV comorbidities, among which cancer is one of the most common. The presence of a malignancy is proven to be associated with higher mortality in TTS. Moreover, a number of anticancer treatments has been reported to possibly cause TTS as a form of cardiotoxicity, even though clearcut associations are lacking. The aim of this narrative review is to sum up contemporary knowledge on the association of cancer and TTS, addressing unmet needs and practical implications. The importance of a close collaboration between cardiologists and oncologists is herein highlighted, both to allow an adequate management of the acute TTS phase, and to actively and safely return to the oncologic management once the acute setting is resolved., 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. The author(s) 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., (© 2024 Tini, Arcari, Mistrulli, Follesa, Cianca, Sclafani, Tocci, Spallarossa, Battistoni, Cacciotti, Musumeci and Barbato.)

Aims: In the EXPLORER-HCM trial, mavacamten reduced left ventricular outflow tract obstruction (LVOTO) and improved functional capacity of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) patients. We sought to define the potential use of mavacamten by comparing real-world HOCM patients with those enrolled in EXPLORER-HCM and assessing their eligibility to treatment., Methods and Results: We collected information on HOCM patients followed up at 25 Italian HCM outpatient clinics and with significant LVOTO (i.e. gradient ≥30 mmHg at rest or ≥50 mmHg after Valsalva manoeuvre or exercise) despite pharmacological or non-pharmacological therapy. Pharmacological or non-pharmacological therapy resolved LVOTO in 1044 (61.2%) of the 1706 HOCM patients under active follow-up, whereas 662 patients (38.8%) had persistent LVOTO. Compared to the EXPLORER-HCM trial population, these real-world HOCM patients were older (62.1 ± 14.3 vs. 58.5 ± 12.2 years, p = 0.02), had a lower body mass index (26.8 ± 5.3 vs. 29.7 ± 4.9 kg/m 2 , p < 0.0001) and a more frequent history of atrial fibrillation (21.5% vs. 9.8%, p = 0.027). At echocardiography, they had lower left ventricular ejection fraction (LVEF, 66 ± 7% vs. 74 ± 6%, p < 0.0001), higher left ventricular outflow tract gradients at rest (60 ± 27 vs. 52 ± 29 mmHg, p = 0.003), and larger left atrial volume index (49 ± 16 vs. 40 ± 12 ml/m 2 , p < 0.0001). Overall, 324 (48.9%) would have been eligible for enrolment in the EXPLORER-HCM trial and 339 (51.2%) for treatment with mavacamten according to European guidelines., Conclusions: Real-world HOCM patients differ from the EXPLORER-HCM population for their older age, lower LVEF and larger atrial volume, potentially reflecting a more advanced stage of the disease. About half of real-world HOCM patients were found eligible to mavacamten., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Backgorund: Hereditary transthyretin(vATTR) cardiac amyloidosis has extremely different features according to the type of transthyretin(TTR) mutation. Data about electrocardiographic findings(ECG) in vATTR are limited and not informative of genotype correlation. Aim of this study is to analyze ECG characteristics and their correlation to clinical and echocardiographic aspects in patients with vATTR, focusing on different TTR mutations., Methods and Results: This is a multicentric, retrospective, observational study performed in six Italian referral centres. We divided patients in two groups, according to the previously described phenotypic manifestations of the TTR mutation. Of 64 patients with vATTR, 23(36%) had prevalent cardiac(PC) TTR mutations and 41(64%) patients had a prevalent neurological(PN) TTR mutations. Patients with PC mutations were more frequently males and older, with advanced NAC staging. At baseline ECG, atrial fibrillation was more common in patients with PC, while pacemaker induced rhythm in PN mutations. PQ and QRS durations were longer and voltage to mass ratio was lower in PC mutations. Different TTR mutations tend to have distinctive ECG features., Conclusions: ECG in vATTR is extremely heterogeneous and the specific mutations are associated with distinct instrumental and clinical features. The differences between PN and PC vATTR are only partially explained by the different degree of cardiac infiltration., Competing Interests: Declaration of Competing Interest The authors report there are no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)