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Real-life data comparing the long-term outcome in patients with different heart diseases carrying an implantable cardioverter defibrillator (ICD) are scarce. This study aimed to compare the long-term risk of the first appropriate ICD intervention and overall survival in patients with ICD and heart disease of different etiologies. Patients with an ICD implanted between January 1, 2010, and December 31, 2022, followed in our center were included. Study outcomes were all-cause mortality and first appropriate ICD intervention. A comparison between ischemic heart disease (IHD) and non-IHD (NIHD) was performed. In NIHD different etiologies of dilated cardiomyopathy (DCM) were analyzed. Overall, 1184 patients (592 IDH; 592 NIHD) were included. During a median follow-up of 53 months all-cause death occurred in 399 patients (34%) whereas first appropriate ICD intervention occurred in 320 (27%). All-cause mortality was significantly higher in IHD vs NIHD patients (60% vs 43%; p <0.0001) but no differences in appropriate ICD intervention rate at 10 years (34% vs 40%; p = 0.125) were observed. In patients with NIHD, a higher 10-year mortality rate was found in valvular heart disease, post-radio/chemotherapy DCM (rctDCM), and hypertensive DCM. Hypertrophic cardiomyopathy, alcoholic DCM, and rctDCM were the least arrhythmic phenotypes in NIHD. Of note, inappropriate interventions in alcoholic DCM and rctDCM were higher than appropriate ones. In conclusion, the rate of ICD-appropriate interventions and mortality is different according to the etiology of heart disease and cardiovascular risk profile; this should be taken into consideration in the prognostic stratification of these patients at the time of implantation., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Extracorporeal cardiopulmonary resuscitation (E-CPR) may improve survival with favorable neurological outcome in patients with refractory out-of-hospital cardiac arrest (OHCA). Unfortunately, recent results from randomized controlled trials were inconclusive. We performed a meta-analysis to investigate the impact of E-CPR on neurological outcome compared to conventional cardiopulmonary resuscitation (C-CPR)., Methods: A systematic research for articles assessing outcomes of adult patients with OHCA either treated with E-CPR or C-CPR up to April 27, 2023 was performed. Primary outcome was survival with favorable neurological outcome at discharge or 30 days. Overall survival was also assessed., Results: Eighteen studies were included. E-CPR was associated with better survival with favorable neurological status at discharge or 30 days (14% vs 7%, OR 2.35, 95% CI 1.61-3.43, I 2  = 80%, p < 0.001, NNT = 17) than C-CPR. Results were consistent if the analysis was restricted to RCTs. Overall survival to discharge or 30 days was also positively affected by treatment with E-CPR (OR = 1.71, 95% CI = 1.18-2.46, I 2  = 81%, p = 0.004, NNT = 11)., Conclusions: In this meta-analysis, E-CPR had a positive effect on survival with favorable neurological outcome and, to a smaller extent, on overall mortality in patients with refractory OHCA., Competing Interests: Declaration of competing interest No competing interests to declared., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Amyloidosis is a heterogenous group of disorders, caused by the deposition of insoluble fibrils derived from misfolded proteins in the extracellular space of various organs. These proteins have an unstable structure that causes them to misfold, aggregate, and deposit as amyloid fibrils with the pathognomonic histologic property of green birefringence when viewed under cross-polarized light after staining with Congo red. Amyloid fibrils are insoluble and degradation-resistant; resistance to catabolism results in progressive tissue amyloid accumulation. The outcome of this process is organ disfunction independently from the type of deposited protein, however there can be organ that are specifically targeted from certain proteins., Competing Interests: Disclosure No conflicts of interest to declare for any author in relation to the submitted work. Outside the submitted work: G. Sinagra received personal fees for occasional educational activities from Biotronik, Boston Scientific, Astra Zeneca and Novartis; M. Merlo received congress fees from Novartis, Vifor Pharma, Astra Zeneca and Novo Nordisk and research grant and congress fees from Pfizer, without any control on intellectual contents., (Copyright © 2024 Elsevier Inc. 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.

Background and Aims: The discordance between QRS voltages on electrocardiogram (ECG) and left ventricle (LV) wall thickness (LVWT) on echocardiogram (echo) is a recognized red flag (RF) of amyloid cardiomyopathy (AC) and can be measured by specific indexes. No head-to-head comparison of different ECG/echo indexes among subjects with echocardiographic suspicion of AC has yet been undertaken. The study aimed at evaluating the performance and the incremental diagnostic value of different ECG/echo indexes in this subset of patients., Methods: Electrocardiograms of subjects with LV hypertrophy, preserved ejection fraction and ≥ 1 echocardiographic RF of AC participating in the AC-TIVE study, an Italian prospective multicenter study, were independently analyzed by two cardiologists. Low QRS voltages and 8 different ECG/echo indexes were evaluated. Cohort specific cut-offs were computed., Results: Among 170 patients, 55 (32 %) were diagnosed with AC. Combination of low QRS voltages with interventricular septum ≥ 1,6 cm was the most specific (specificity 100 %, positive predictive value 100 %) ECG/echo index, while the ratio between the sum of all QRS voltages and LVWT <7,8 was the most sensitive and accurate (sensitivity 94 %, negative predictive value 97 %, accuracy 82 %). When the latter index was added to a model using easily-accessible clinical variables, the diagnostic accuracy for AC greatly increased (AUC from 0,84 to 0,95; p = 0,007)., Conclusions: Among patients with non-dilated hypertrophic ventricles with normal ejection fraction and echocardiographic RF of AC, easily-measurable ECG/echo indexes, mainly when added to few clinical variables, can help the physician orient second level investigations. External validation of the results is warranted., Competing Interests: Declaration of Competing Interest No conflicts of interest to declare for any Author in relation to the submitted work., (Copyright © 2023. Published by Elsevier B.V.)

In hypertrophic cardiomyopathy (HCM), late gadolinium enhancement (LGE) extent ≥15% of left ventricular mass is considered a prognostic risk factor. LGE extent increases over time and the clinical role of the progression of LGE over time (LGE rate) was not prospectively evaluated. We sought to evaluate the prognostic role of the LGE rate in HCM. We enrolled 105 patients with HCM who underwent cardiac magnetic resonance (CMR) at baseline (CMR-I) and after ≥2 years of follow-up (CMR-II). LGE rate was defined as the ratio between the increase of LGE extent (grams) and the time interval (months) between examinations. A combined end point of sudden cardiac death, resuscitated cardiac arrest, appropriate Implanted Cardioverter Defibrillator (ICD) intervention, and sustained ventricular tachycardia was used (hard events). The percentage of patients with LGE extent ≥15% increased from 9% to 20% from CMR-I to CMR-II (p = 0.03). During a median follow-up of 52 months, 25 hard events were recorded. The presence of LGE ≥15% at CMR-II allowed a significant reclassification of the risk of patients than at LGE ≥15% at CMR-I (net reclassification improvement 0.21, p = 0.046). On the MaxStat analysis, the optimal prognostic cut point for LGE rate was >0.07 g/month. On the Kaplan-Meier curve, patients with LGE rate >0.07 had worse prognosis than those without (p <0.0001). LGE rate >0.07 allowed a significant reclassification of the risk compared with LGE ≥15% at CMR-I and at CMR-II (net reclassification improvement 0.49, p = 0.003). In the multivariable models, LGE rate >0.07 was the best independent predictor of hard events. In conclusion, CMR should be repeated after 2 years to reclassify the risk for sudden death of those patients. A high LGE rate may be considered a novel prognostic factor in HCM., Competing Interests: Declaration of Competing Interest The authors have no competing interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The LV myocardial strain and hemodynamic forces (HDFs) are innovative markers of LV function. Aortic coarctation is safely repaired in infancy; however, mortality and morbidity remain increased in later life. The study investigated the role of left ventricular myocardial deformation and HDFs in asymptomatic patients who underwent successful aortic coarctation repair., Methods: Clinical and echocardiographic data were analyzed from 42 repaired CoA, 32 ± 20 years after surgery, 2D echocardiographic global longitudinal strain (GLS), circumferential strain (GCS) and HDFs were determined. CoA patients were compared with 42 patients affected by blood hypertension and 84 healthy controls; all matched for age and gender., Results: All groups had normal LV ejection fraction (LVEF), dimensions, and volumes. CoA patients showed a significantly higher rate of LV mass indexed (p < .001) and left atrial volumes indexed (p < .001). LV myocardial and endocardial global longitudinal and circumferential strain were decreased in CoA patients (p < .001, p < .001; p = .032 and p < .001, respectively). HDF parameters such as LV longitudinal force, LV systolic longitudinal force and LV impulse (LVim) were uniformly reduced (p = .006, p = .001, and p = .001, respectively). LV myocardial strain and HDF parameter values were independently associated with hospitalization for heart failure on univariable Cox regression analysis., Conclusion: Despite preserved LVEF, patients with CoA had lower LV myocardial strain and HDF parameters values, independently associated with hospitalization for heart failure., (© 2024 Wiley Periodicals LLC.)

Trypanosomatids are a diverse group of uniflagellate protozoan parasites that include globally relevant pathogens such as Trypanosoma cruzi, the causative agent of Chagas disease. Trypanosomes lack the fatty acid synthase system typically used for de novo fatty acid (FA) synthesis in other eukaryotes. Instead, these microbes have evolved a modular FA elongase (ELO) system comprised of individual ELO enzymes (ELO1-4) that can operate processively to generate long chain- and very long chain-FAs. The importance of ELO's for maintaining lipid homeostasis in trypanosomatids is currently unclear, given their ability to take up and utilize exogenous FAs for lipid synthesis. To assess ELO function in T. cruzi, we generated individual KO lines, Δelo1, Δelo2, and Δelo3, in which the genes encoding ELO1-3 were functionally disrupted in the parasite insect stage (epimastigote). Using unbiased lipidomic and metabolomic analyses, in combination with metabolic tracing and biochemical approaches, we demonstrate that ELO2 and ELO3 are required for global lipid homeostasis, whereas ELO1 is dispensable for this function. Instead, ELO1 activity is needed to sustain mitochondrial activity and normal growth in T. cruzi epimastigotes. The cross-talk between microsomal ELO1 and the mitochondrion is a novel finding that, we propose, merits further examination of the trypanosomatid ELO pathway as critical for central metabolism., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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

Aims: An algorithm for non-invasive diagnosis of amyloid transthyretin cardiac amyloidosis (ATTR-CA) and novel disease-modifying therapies have prompted an active search for CA. We examined the prevalence of CA in different settings based on literature data., Methods and Results: We performed a systematic search for screening studies on CA, focusing on the prevalence, sex and age distribution in different clinical settings. The prevalence of CA in different settings was as follows: bone scintigraphy for non-cardiac reasons (n = 5 studies), 1% (95% confidence interval [CI] 0%-1%); heart failure with preserved ejection fraction (n = 6), 12% (95% CI 6%-20%); heart failure with reduced or mildly reduced ejection fraction (n = 2), 10% (95% CI 6%-15%); conduction disorders warranting pacemaker implantation (n = 1), 2% (95% CI 0%-4%); surgery for carpal tunnel syndrome (n = 3), 7% (95% CI 5%-10%); hypertrophic cardiomyopathy phenotype (n = 2), 7% (95% CI 5%-9%); severe aortic stenosis (n = 7), 8% (95% CI 5%-13%); autopsy series of 'unselected' elderly individuals (n = 4), 21% (95% CI 7%-39%). The average age of CA patients in the different settings ranged from 74 to 90 years, and the percentage of men from 50% to 100%. Many patients had ATTR-CA, but the average percentage of patients with amyloid light-chain (AL) CA was up to 18%., Conclusions: Searching for CA in specific settings allows to identify a relatively high number of cases who may be eligible for treatment if the diagnosis is unequivocal. ATTR-CA accounts for many cases of CA across the different settings, but AL-CA is not infrequent. Median age at diagnosis falls in the eighth or ninth decades, and many patients diagnosed with CA are women., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The reduced availability of human donor hearts compared with the needs of patients with advanced heart failure refractory to medical therapy has promoted the search for therapeutic alternatives to cardiac allografts. Porcine heart xenotransplantation represents one of the most promising frontiers in this field today. From the first researches in the 1960s to today, the numerous advances achieved in the field of surgical techniques, genetic engineering and immunosuppression have made it possible at the beginning of 2022 to carry out the first swine-to-human heart transplant, attaining a survival of 2 months after surgery. The main intellectual and experimental stages that have marked the history of xenotransplantation, the latest acquisitions in terms of genetic editing, as well as the improvement of immunosuppressive therapy are discussed analytically in this article in order to illustrate the underlying complexity of this therapeutic model., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: Natural history of cardiac amyloidosis (CA) is poorly understood. We aimed to examine the changing mortality of different types of CA over a 30-year period., Patients and Methods: Consecutive patients included in the "Trieste CA Registry" from January 1, 1990 through December 31, 2021 were divided into a historical cohort (diagnosed before 2016) and a contemporary cohort (diagnosed after 2016). Light chain (AL), transthyretin (ATTR) and other forms of CA were defined according to international recommendations. The primary and secondary outcome measures were all-cause mortality and cardiac death, respectively., Results: We enrolled 182 patients: 47.3% AL-CA, 44.5% ATTR-CA, 8.2% other etiologies. The number of patients diagnosed with AL and ATTR-CA progressively increased over time, mostly ATTR-CA patients (from 21% before 2016 to 67% after 2016) diagnosed non-invasively. The more consistent increase in event-rate was observed in the long-term (after 50 months) in ATTR-CA compared to the early increase in mortality in AL-CA. In the contemporary cohort, during a median follow up of 16 [4-30] months, ATTR-CA was associated with improved overall and cardiac survival compared to AL-CA. At multivariable analysis, ATTR-CA (HR 0.42, p = 0.03), eGFR (HR 0.98, p = 0.033) and ACE-inhibitor therapy (HR 0.24, p < 0.001) predicted overall survival in the contemporary cohort., Conclusion: Incidence and prevalence rates of ATTR-CA and, to a less extent, of AL-CA have been increasing over time, with significant improvements in 2-year survival of ATTR-CA patients from the contemporary cohort. Reaching an early diagnosis and starting disease-modifying treatments will improve long-term survival in CA., 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 © 2022 Porcari, Allegro, Saro, Varrà, Pagura, Rossi, Lalario, Longo, Korcova, Dal Ferro, Perkan, Dore, Bussani, De Sabbata, Zaja, Merlo and Sinagra.)

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

Chronic kidney disease and cardiovascular disease are strictly connected each other with a bidirectional interaction. Thus, the prevention of cardio-renal damage, as its appropriate treatment, are essential steps for a correct management of long-term patients' prognosis. Several preventive and therapeutic strategies, pharmacological and not, are now available for cardio-renal damage prevention and treatment, and for the management of its complications. The second part of this consensus document focuses on the management and treatment of cardio-renal damage, directing the attention on the correct use of drugs that may slow renal disease progression, on the application of preventive strategies in case of invasive cardiac procedures with the use of contrast agents, and on the accurate use of cardiological drugs in patients with chronic kidney disease.

Chronic kidney disease (CKD) and cardiovascular (CV) disease are highly prevalent conditions in the general population and are strictly connected to each other with a bidirectional interaction. In patients affected by CKD, the leading cause of morbidity and mortality is represented by CV disease, since CKD promotes the atherosclerotic process increasing inflammation, and modifying lipid and bone mineral metabolism. On the other side, a strict relationship exists between CKD and CV risk factors, which are prevalent in nephropathic patients and impose a stringent assessment of the risk of CV events in this population together with an optimized pharmacological approach, complicated by the coexistence of the two pathological conditions. The first part of this consensus document focuses on the mechanisms of cardio-renal damage and on the impact, as well as the management, of the main CV risk factors in the context of CKD.

Aim: To investigate the prevalence of amyloid cardiomyopathy (AC) and the diagnostic accuracy of echocardiographic red flags of AC among consecutive adult patients undergoing transthoracic echocardiogram for reason other than AC in 13 Italian institutions., Methods and Results: This is an Italian prospective multicentre study, involving a clinical and instrumental work-up to assess AC prevalence among patients ≥55 years old with an echocardiogram suggestive of AC (i.e. at least one echocardiographic red flag of AC in hypertrophic, non-dilated left ventricles with preserved ejection fraction). The study was registered at ClinicalTrials.gov (NCT04738266). Overall, 381 patients with an echocardiogram suggestive of AC were identified among a cohort of 5315 screened subjects, and 217 patients completed the investigations. A final diagnosis of AC was made in 62 patients with an estimated prevalence of 29% (95% confidence interval 23%-35%). Transthyretin-related AC (ATTR-AC) was diagnosed in 51 and light chain-related AC (AL-AC) in 11 patients. Either apical sparing or a combination of ≥2 other echocardiographic red flags, excluding interatrial septum thickness, provided a diagnostic accuracy >70%., Conclusion: In a cohort of consecutive adults with echocardiographic findings suggestive of AC and preserved left ventricular ejection fraction, the prevalence of AC (either ATTR or AL) was 29%. Easily available echocardiographic red flags, when combined together, demonstrated good diagnostic accuracy., (© 2022 European Society of Cardiology.)

The epidemiology of cardiac amyloidosis (CA), traditionally considered a rare and incurable disease, has changed drastically over the last ten years, particularly due to the advances in diagnostic methods and therapeutic options in the field of transthyretin CA (ATTR-CA). On the one hand, the possibility of employing cardiac scintigraphy with bone tracers to diagnose ATTR-CA without a biopsy has unveiled the real prevalence of the disease; on the other, the emergence of effective treatments, such as tafamidis, has rendered an early and accurate diagnosis critical. Interestingly, the following subgroups of patients have been found to have a higher prevalence of CA: elderly subjects > 75 years, patients with cardiac hypertrophy hospitalized for heart failure with preserved ejection fraction, subjects operated on for bilateral carpal tunnel syndrome, patients with cardiac hypertrophy not explained by concomitant factors and individuals with aortic valve stenosis. Many studies investigating the prevalence of CA in these particular populations have contributed to rewriting the epidemiology of the disease, increasing the awareness of the medical community for a previously underappreciated condition. In this review, we summarized the latest evidence on the epidemiology of CA according to the different clinical settings typically associated with the disease.

Eosinophilic myocarditis is a rare form of myocardial inflammation characterized by interstitial infiltration by eosinophils. Clinical presentation may vary from complete absence of symptoms to fulminant myocarditis with cardiogenic shock, to chronic heart failure due to progression to restrictive cardiomyopathy. The main causes of eosinophilic myocarditis are hypersensitivity reactions secondary to drug exposure, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome and infections. Antibiotics and agents acting on the central nervous system are the most frequently reported drugs capable of causing hypersensitivity myocarditis. Infections are usually due to intestinal parasites. Imaging techniques together with clinical and laboratory data help rising the suspicion of eosinophilic myocarditis. However, the definite diagnosis is made by endomyocardial biopsy. The evidence of eosinophilic infiltrate among myocytes allows to start an immunosuppressive treatment, usually based on corticosteroids, that are the cardinal therapy for eosinophilic myocarditis. Anticoagulation should be undertaken in case of endoventricular thrombosis, which frequently complicates eosinophilic myocarditis, mainly those cases associated with hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis. In this focused review, we will try to provide answers to the most common questions on the causes, presentation, diagnosis, treatment, and outcomes of eosinophilic myocarditis.

Aims: Carpal tunnel (CT) syndrome is a recognized red-flag of cardiac amyloidosis (CA) and increased cardiovascular (CV) morbidity. We designed this study to characterize the CV profile of patients with CT syndrome at the time of first surgery and to identify high-risk presentations., Methods and Results: We retrospectively reviewed 643 patients who underwent CT surgery between 2007 and 2019. Of them, 130 patients (77 years, 45% male patients, left ventricular ejection fraction 62%) with available CV characterization within ±12 months from CT surgery were included. Abnormal loading conditions causing cardiac left ventricular hypertrophy (LVH) were investigated to distinguish explained LVH (Ex-LVH) from unexplained LVH (Un-LVH). LVH was found in 66 (51%) patients, 33% of them presented Un-LVH. Compared with the others, Un-LVH patients were older (77 and 75 vs. 70 years in Un-LVH, Ex-LVH, and non-LVH, respectively; P = 0.002), had higher rates of electrocardiogram-echo discrepancy (70%, 14.3%, and 1.6%, respectively; P < 0.001) and of echocardiographic findings of CA (24%, 7%, and 0%, P < 0.001). Among Un-LVH patients, 9 (43%) experienced death and 7 (33%) developed heart failure (HF) at 3.8 and 2.4 years from CT surgery, respectively. Compared with the others, death and HF development rates were higher in Un-LVH patients both at unadjusted (P = 0.01 and P = 0.02, respectively) and adjusted analysis for age, gender, and renal insufficiency (P = 0.00038 and P = 0.050, respectively)., Conclusions: At the time of CT surgery, Un-LVH was found in more than 30% of patients with LVH, and 24% of them showed echocardiographic features suggesting an underdiagnosed CA. Un-LVH was associated with higher all-cause mortality and HF development., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The prevalence of cardiac amyloidosis (CA) is unknown. Aims and Methods: We sought to (a) determine the prevalence of CA in unselected patients ≥75 years undergoing autopsy, (b) characterize cardiological profiles of CA and non-CA patients by providing clinical-histological correlations, and (c) compare their cardiological profiles. After dedicated staining, the localization (interstitial or vascular) and the distribution (non-diffuse or diffuse) of amyloid deposition were analyzed. Cardiological data at last evaluation were retrospectively assessed for the presence of CA red-flags. Results: CA (50% light chains, 50% transthyretin) was found in 43% ( n = 24/56) of the autopsied hearts. Atria were involved in 96% of cases. Amyloid localized both at the perivascular and interstitial levels (95.5 and 85%, respectively) with a slightly predominant non-diffuse distribution (58% of cases). Compared to the other patients, CA patients had a more frequent history of heart failure (HF) (79 vs. 47%, p = 0.014), advanced NYHA functional class (III-IV 25 vs. 6%, p = 0.047), atrial fibrillation (68 vs. 36%, p = 0.019), discrepancy between QRS voltage and left ventricular (LV) thickness (70 vs. 12%, p < 0.001), thicker LV walls (15 vs. 11 mm, p < 0.001), enlarged left atrium (49 vs. 42 mm, p = 0.019) and restrictive filling pattern (56 vs. 19%, p = 0.020). The presence of right ventricular amyloidosis seemed to identify hearts with a higher amyloid burden. Among the CA patients, >30% had ≥3 echocardiographic red-flags of disease. Conclusion: CA can be found in 43% of autopsied hearts from patients ≥75 years old, especially in patients with HF, LV hypertrophy and atrial fibrillation., 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 Porcari, Bussani, Merlo, Varrà, Pagura, Rozze and Sinagra.)

There is limited evidence on characterization and natural history of supraventricular tachycardia (SVT)-induced left ventricular (LV) dysfunction. The aim of this work was to characterize clinical features and long-term evolution of SVT-induced LV dysfunction. Patients consecutively admitted with sustained SVT and heart rate >100 bpm as the only known cause of a new onset LV systolic dysfunction (i.e., LV ejection fraction [EF] <50%) were analyzed. Patients were then revaluated periodically. Recovered LVEF (i.e., ≥50%) and a composite of death, heart transplant or first episode of major ventricular arrhythmias were evaluated as study end-points. We enrolled 83 patients. After SVT therapy, 56 (67%) showed a recovered LVEF at the last follow-up of median 54 (interquartile range 36 to 87) months. Seventeen (30%) of those patients had a temporary new drop in LVEF during follow-up associated to high-rate SVT relapse. At presentation, patients with recovered LVEF were younger (52 vs 67 years respectively, p <0.001) and had higher LVEF (34% vs 27% respectively, p = 0.005) compared to non-recovered LVEF patients. Finally, 4% of recovered LVEF patients vs 26% of nonrecovered LVEF patients experienced death/heart transplant/major ventricular arrhythmias during follow-up (p = 0.004). In conclusion, after almost 5 years of follow-up, two-thirds of patients with high-rate SVT causing a newly diagnosed LV systolic dysfunction recovered and maintained normal LV function after SVT control, with a subsequent benign outcome. Long term individual surveillance is required in those patients, as arrhythmic recurrences and new drops in LVEF are common in the long term., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The pressure overload due to the progressive narrowing of the valve area determines the development of the left ventricular hypertrophy which characterizes aortic stenosis (AS). The onset of myocardial fibrosis marks the inexorable decline of an initially compensatory response towards heart failure. However, myocardial fibrosis does not yet represent a key element in the prognostic and therapeutic framework of AS. In this context, cardiac magnetic resonance imaging plays a major role by highlighting both the focal irreversible fibrotic replacement, using the late gadolinium enhancement (LGE) technique, and the earlier diffuse reversible interstitial fibrosis, using the T1 mapping techniques. For this reason, the presence of myocardial fibrosis would be useful to identify a subgroup of patients at greater risk of events among the subjects with severe AS. Actually, more and more evidences seem to identify the presence of LGE as a powerful prognostic factor to be used to optimize the timing of prosthetic valve replacement. Randomized clinical trials, such as the EVoLVeD trial currently underway, will be needed to better define the importance of myocardial fibrosis assessment in the management of patients with AS., (Published on behalf of the European Society of Cardiology. © The Author(s) 2021.)

Pharmacological approach to heart failure with reduced ejection fraction (HFrEF) is evolving, as recently published large randomized clinical trials have implemented the disposal of HFrEF treatments with four new classes of drugs, namely angiotensin receptor/neprilysin inhibitor , sodium-glucose co-transporters 2 inhibitors , soluble guanylate cyclase modulators and myosin activators, which have proved to further improve patients' quality of life and long-term outcomes. As these novel drugs target additional pathways not already intercepted by the guideline-directed medical therapy, integration of them in the management of HFrEF is desirable. This review paper aims to provide an overview of the current evolving concepts of HFrEF therapy joining the most recent evidences and to furnish practical suggestions for the use of these new classes of drugs in clinical practice., (Copyright © 2021. Published by Elsevier B.V.)

The association between left ventricular (LV) myocardial deformation and hemodynamic forces is still mostly unexplored. The normative values and the effects of demographic and technical factors on hemodynamic forces are not known. The authors studied the association between LV myocardial deformation and hemodynamic forces in a large cohort of healthy volunteers. One-hundred seventy-six consecutive subjects (age range, 16-82; 51% women), with no cardiovascular risk factors or any relevant diseases, were enrolled. All subjects underwent an echo-Doppler examination. Both 2D global myocardial and endocardial longitudinal strain (GLS), circumferential strain (GCS), and the hemodynamic forces were measured with new software that enabled to calculate all these values and parameters from the three apical views. Higher LV mass index and larger LV volumes were found in males compared to females (85 ± 17 vs 74 ± 15 g/m 2 and 127 ± 28 vs 85 ± 18 ml, p < 0.0001 respectively) while no differences of the mean values of endocardial and myocardial GLS and of myocardial GCS were found (p = ns) and higher endocardial GCS in women (- 30.6 ± 4.2 vs - 31.8 ± 3.7; p = 0.05). LV longitudinal force, LV systolic longitudinal force and LV impulse were higher in men (16.2 ± 5.3 vs 13.2 ± 3.6; 25.1 ± 7.9 vs 19.4 ± 5.6 and 20.4 ± 7 vs 16.6 ± 5.2, p < 0.0001, respectively). A weak but statistically significant decline with age (p < 0.0001) was also found for these force parameters. This new integrated approach could differentiate normality from pathology by providing average deformation values and hemodynamic forces parameters, differentiated by age and gender.

Aim: To characterize, by means of univariate and multivariate approaches, the T helper (Th)-1 and Th-2 responses during the different phases of tumor immunoediting., Materials & Methods: We used a multivariate principal component analysis applied to analyze the joint behavior of serum concentrations of IFN-γ, IL-2, IL-10 and IL-4, during the different phases of tumor immunoediting, in CBi/L mice challenged with M-406 mammary adenocarcinoma., Results & Conclusion: Animals in equilibrium phase showed the widest variations in values of the four cytokines. In this experimental model, the role of IFN-γ would be related to tumor growth and progression, while IL-10 would participate in the antitumor immune response., Competing Interests: Financial & competing interests disclosure The work was supported by grants of Universidad Nacional de Rosario to VRR (1MED471) and Foundation AJ Roemmers. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2020 Antonela Del Giúdice.)

Background: Recent trends of surgery for atrial fibrillation (AF) are towards more safe and effective energy sources, as well as to simplified sets of atrial lesions., Methods: One hundred eighteen (mean age, 67.4 ± 9.2 years) selected patients with paroxysmal/persistent AF and mitral valve (MV) disease underwent cryoablation of AF combined with conventional (not via mini-thoracotomy) MV surgery; the lesion set was limited to only the left atrium. Multivariable analyses identified predictors of cardiac rhythm at hospital discharge and follow-up., Results: There were 7 (5.9%) hospital deaths; 33 (28%) patients were discharged on AF. Higher values of preoperative left atrial volume index (odds ratio [OR] = 1.07, 95% confidence interval [95%CI]: 1.01-1.13) and mixed etiology of MV disease (OR = 4.19, 95%CI: 1.23-14.2) were predictors of hospital discharge on AF. Seventy-four (66.7%) patients were on stable sinus rhythm at follow-up (median period, 6.6 years); the 1, 5, and 10-year nonparametric estimates of adjusted freedom from AF were 98.1%, 89.2% and 45.6%, respectively. Higher values of preoperative systolic pulmonary artery pressure (hazard ratio [HR] = HR = 1.04, 95%CI: 1.01-1.08) and AF at hospital discharge (HR = 4.14, 95%CI: 1.50-11.4) were predictors of AF at follow-up., Conclusions: During conventional MV surgery, a cryo-lesion set limited to only the left atrium may give good, immediate and long-term results. Left atrial dilation and mixed etiology of MV disease were predictors of hospital discharge on AF. Preoperative pulmonary hypertension and AF at discharge combined with an increased risk of AF at follow-up., Competing Interests: The authors report no relationships that could be construed as a conflict of interest., (© 2020 Published by Elsevier B.V.)

Purpose of Review: Cardiac masses frequently present significant diagnostic and therapeutic clinical challenges and encompass a broad set of lesions that can be either neoplastic or non-neoplastic. We sought to provide an overview of cardiac tumors using a cardiac chamber prevalence approach and providing epidemiology, imaging, histopathology, diagnostic workup, treatment, and prognoses of cardiac tumors., Recent Findings: Cardiac tumors are rare but remain an important component of cardio-oncology practice. Over the past decade, the advances in imaging techniques have enabled a noninvasive diagnosis in many cases. Indeed, imaging modalities such as cardiac magnetic resonance, computed tomography, and positron emission tomography are important tools for diagnosing and characterizing the lesions. Although an epidemiological and multimodality imaging approach is useful, the definite diagnosis requires histologic examination in challenging scenarios, and histopathological characterization remains the diagnostic gold standard. A comprehensive clinical and multimodality imaging evaluation of cardiac tumors is fundamental to obtain a proper differential diagnosis, but histopathology is necessary to reach the final diagnosis and subsequent clinical management.

Heme is an essential cofactor for many biological processes in aerobic organisms, which can synthesize it de novo through a conserved pathway. Trypanosoma cruzi , the etiological agent of Chagas disease, as well as other trypanosomatids relevant to human health, are heme auxotrophs, meaning they must import it from their mammalian hosts or insect vectors. However, how these species import and regulate heme levels is not fully defined yet. It is known that the membrane protein Tc HTE is involved in T. cruzi heme transport, although its specific role remains unclear. In the present work, we studied endogenous Tc HTE in the different life cycle stages of the parasite to gain insight into its function in heme transport and homeostasis. We have confirmed that Tc HTE is predominantly detected in replicative stages (epimastigote and amastigote), in which heme transport activity was previously validated. We also showed that in epimastigotes, Tc HTE protein and mRNA levels decrease in response to increments in heme concentration, confirming it as a member of the heme response gene family. Finally, we demonstrated that T. cruzi epimastigotes can sense intracellular heme by an unknown mechanism and regulate heme transport to adapt to changing conditions. Based on these results, we propose a model in which T. cruzi senses intracellular heme and regulates heme transport activity by adjusting the expression of Tc HTE. The elucidation and characterization of heme transport and homeostasis will contribute to a better understanding of a critical pathway for T. cruzi biology allowing the identification of novel and essential proteins., Competing Interests: Conflict of interest—The authors declare that they have no conflict of interest with the content of this article., (© 2020 Pagura et al.)

L-Proline is an important amino acid for the pathogenic protists belonging to Trypanosoma and Leishmania genera. In Trypanosoma cruzi , the etiological agent of Chagas disease, this amino acid is involved in fundamental biological processes such as ATP production, differentiation of the insect and intracellular stages, the host cell infection and the resistance to a variety of stresses. In this study, we explore the L-Proline uptake as a chemotherapeutic target for T. cruzi . Novel inhibitors have been proposed containing the amino acid with a linker and a variable region able to block the transporter. A series of sixteen 1,2,3-triazolyl-proline derivatives have been prepared for in vitro screening against T. cruzi epimastigotes and proline uptake assays. We successfully obtained inhibitors that interfere with the amino acid internalization, which validated our design targeting the metabolite's transport. The presented structures are one of few examples of amino acid transporter inhibitors. The unprecedent application of this strategy on the development of new chemotherapy against Chagas disease, opens a new horizon on antiparasitic drug development against parasitic diseases and other pathologies., (Copyright © 2020 Fargnoli, Panozzo-Zénere, Pagura, Barisón, Cricco, Silber and Labadie.)

Trypanosoma cruzi, the etiological agent of Chagas' disease, presents nutritional requirements for several metabolites. It requires heme for the biosynthesis of several heme-proteins involved in essential metabolic pathways like mitochondrial cytochromes and respiratory complexes, as well as enzymes involved in the biosynthesis of sterols and unsaturated fatty acids. However, this parasite lacks a complete route for its synthesis. In view of these facts, T. cruzi has to incorporate heme from the environment during its life cycle. In other words, their hosts must supply the heme for heme-protein synthesis. Although the acquisition of heme is a fundamental issue for the parasite's replication and survival, how this cofactor is imported and distributed is poorly understood. In this work, we used different fluorescent heme analogs to explore heme uptake along the different life-cycle stages of T. cruzi, showing that this parasite imports it during its replicative stages: the epimastigote in the insect vector and the intracellular amastigote in the mammalian host. Also, we identified and characterized a T. cruzi protein (TcHTE) with 55% of sequence similarity to LHR1 (protein involved in L. amazonensis heme transport), which is located in the flagellar pocket, where the transport of nutrients proceeds in trypanosomatids. We postulate TcHTE as a protein involved in improving the efficiency of the heme uptake or trafficking in T. cruzi.