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Aims: Individual prognostic assessment and disease evolution pathways are undefined in chronic heart failure (HF). The application of unsupervised learning methodologies could help to identify patient phenotypes and the progression in each phenotype as well as to assess adverse event risk., Methods and Results: From a bulk of 7948 HF patients included in the MECKI registry, we selected patients with a minimum 2-year follow-up. We implemented a topological data analysis (TDA), based on 43 variables derived from clinical, biochemical, cardiac ultrasound, and exercise evaluations, to identify several patients' clusters. Thereafter, we used the trajectory analysis to describe the evolution of HF states, which is able to identify bifurcation points, characterized by different follow-up paths, as well as specific end-stages conditions of the disease. Finally, we conducted a 5-year survival analysis (composite of cardiovascular death, left ventricular assist device, or urgent heart transplant). Findings were validated on internal (n = 527) and external (n = 777) populations. We analyzed 4876 patients (age = 63 [53-71], male gender n = 3973 (81.5%), NYHA class I-II n = 3576 (73.3%), III-IV n = 1300 (26.7%), LVEF = 33 [25.5-39.9], atrial fibrillation n = 791 (16.2%), peak VO 2 % pred = 54.8 [43.8-67.2]), with a minimum 2-year follow-up. Nineteen patient clusters were identified by TDA. Trajectory analysis revealed a path characterized by 3 bifurcation and 4 end-stage points. Clusters survival rate varied from 44% to 100% at 2 years and from 20% to 100% at 5 years, respectively. The event frequency at 5-year follow-up for each study cohort cluster was successfully compared with those in the validation cohorts (R = 0.94 and R = 0.84, P < 0.001, for internal and external cohort, respectively). Finally, we conducted a 5-year survival analysis (composite of cardiovascular death, left ventricular assist device, or urgent heart transplant observed in 22% of cases)., Conclusions: Each HF phenotype has a specific disease progression and prognosis. These findings allow to individualize HF patient evolutions and to tailor assessment., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Heart failure (HF) is strongly associated with inflammation. In pressure overload (PO)-induced HF, cardiac stress triggers adaptive immunity, ablation or inhibition of which blocks disease progression. We hypothesized that PO-HF might fulfill the often-used criteria of autoimmunity: if so, the associated adaptive immune response would be not only necessary but also sufficient to induce HF; it should also be possible to identify self-antigens driving the autoimmune response. Finally, we hypothesized that such an antigen-specific response can be manipulated to preventively reduce the severity of PO-HF in a tolerizing vaccine., Methods: We used the transfer of lymphocytes or serum from PO-HF mice into healthy recipients to assess whether the adaptive response is sufficient to induce disease. We devised a novel pipeline to identify self-antigens driving the response. We immunized healthy mice with novel antigens to assess whether they induce disease. To determine whether these antigens could be present in human patients, we sought to detect existing responses against these antigens in patients with HF. Finally, we used the antigens in an oral tolerance protocol to preventively protect mice from subsequently induced PO-HF, analyzing the results with next-generation sequencing., Results: We found that PO-HF fulfills the criteria of an autoimmune disease, albeit partially, and identified novel cardiac self-antigens, capable of inducing cardiac dysfunction. The novel antigens in a tolerizing vaccine formulation preemptively reduced the severity of disease triggered by subsequent application of PO, via induction of effector regulatory T cells, enabling a potent reduction of PO-driven loss of systolic function, cardiac inflammation, and proinflammatory CD4 + T-cell clonal expansion., Conclusions: We demonstrate that PO-HF is triggered by hemodynamic stress and then sets off an autoimmune-like response against cardiac self-antigens. The antigens can be used to reduce the severity of future-onset disease, via oral tolerization, effectively acting as a protective vaccine., Competing Interests: The authors have no competing interests to disclose. E. Martini, G. Condorelli, and M. Kallikourdis are listed as inventors in pending patent applications stemming from the contents of this work.

Heart Failure with Preserved Ejection Fraction (HFpEF) represents a significant challenge in modern cardiovascular medicine, characterized by diastolic dysfunction and a chronic pro-inflammatory milieu. The high prevalence of comorbidities such as diabetes, visceral obesity, and aging, which contribute to systemic inflammation, plays a pivotal role in the pathogenesis and progression of HFpEF. Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs), a class of glucose-lowering drugs, have demonstrated a wide range of pleiotropic effects that extend beyond glycaemic control. These effects include the reduction of inflammation and oxidative stress, vasodilation, decreased arterial stiffness, and a reduction in myocardial fibrosis-key factors in the pathophysiology of HFpEF. Recent evidence from the STEP-HFpEF and STEP-HFpEF-DM trials provides the first robust data supporting the efficacy of GLP-1 RAs, specifically semaglutide, in improving the quality of life in obese patients with HFpEF. These trials also demonstrated a significant reduction in C-Reactive Protein (CRP) levels, reinforcing the hypothesis that suppressing the pro-inflammatory state may yield substantial clinical benefits in this patient population. These findings suggest that GLP-1 RAs could play a crucial role in the management of HFpEF, particularly in patients with obesity, by targeting the underlying inflammatory processes and contributing to better overall cardiovascular outcomes., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s).)

Aims: A paucity of studies addressed sex-related differences in clinical outcomes in the long term following acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). In these patients, it remains uncertain whether heart failure (HF) might exert a differential impact on the prognosis in the long term., Methods: We queried a large-scale database of ACS patients undergoing PCI. The primary endpoint was new-onset HF. Secondary endpoints included mortality, myocardial infarction, re-PCI and ischaemic stroke. Propensity score matching was generated to balance group characteristics. A total of 3334 patients after propensity score matching were analysed. Follow-up was assessed at the 5 year term., Results: At 5 year follow-up, HF risk increased significantly in males versus females {17.9% vs. 14.8%, hazard ratio [HR] [95% confidence interval (CI)] = 1.22 [1.03-1.44], P = 0.02}. At 5 year follow-up, mortality was significantly higher in the male cohort as compared with the female cohort [HR (95% CI) = 1.23 (1.02-1.47), P = 0.02]. On landmark analysis, differences in mortality emerged after the first year and were maintained thereafter. Ischaemic outcomes were comparable between cohorts., Conclusions: Following ACS, males experienced a greater long-term risk of developing new-onset HF as compared with females. This difference remained consistent across all prespecified subgroups. Mortality was significantly higher in males. No differences were observed in ischaemic outcomes. New-onset HF emerges as a primary contributor to long-term gender disparities after ACS and a strong predictor of mortality in men with HF., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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

Aims: Secondary tricuspid regurgitation (TR) is associated with poor prognosis in acute decompensated heart failure (ADHF). However, its dynamic evolution in response to volume status and treatment has never been previously investigated. In this study, we sought to explore the in-hospital evolution of TR in ADHF patients and to assess its prognostic implications., Methods and Results: We retrospectively enrolled patients admitted for ADHF with ≥2 in-hospital echocardiographic evaluations of TR. Patients were categorized, according to TR evolution, into persistent moderate-severe TR, improved TR (from moderate-severe to trivial-mild) and persistent trivial-mild TR. The primary endpoint was a composite of 5-year all-cause mortality and heart failure hospitalization (HFH). A total of 1054 patients were included. Of 318 patients (30%) with moderate-severe TR at admission, 49% improved TR severity and showed better trends of decongestion, whereas those who maintained persistent moderate-severe TR had characteristics of more severe heart failure at admission and discharge. Atrial fibrillation, previous heart failure and higher dosage of loop diuretics before admission were associated with a lower probability of improved TR. After adjustment, improved TR was associated with lower risk of 5-year all-cause mortality/HFH compared with persistent moderate-severe TR (hazard ratio [HR] 0.524, p = 0.008) and no different from persistent trivial-mild TR (HR 0.878, p = 0.575). Results were consistent across all subgroups of in-hospital variation of mitral regurgitation., Conclusion: Among ADHF patients with moderate-severe TR at admission, 49% had an in-hospital improvement in TR severity, which was associated with a reduction in risk of 5-year all-cause mortality and morbidity outcomes., (© 2024 European Society of Cardiology.)

Purpose: Heart failure (HF) is a major health problem affecting millions of people worldwide. In the latest years, many efforts have been made to identify predictors of poor prognosis in these patients. The aim of this systematic review and meta-analysis was to enlighten the correlation between liver stiffness (LS), assessed by Shear Wave Elastography techniques, and HF, particularly focusing on the prognostic value of LS on cardiovascular outcomes., Methods: We searched the PUBMED databases (up to May 1st, 2023) for studies that enlightened the correlation between LS and cardiovascular outcomes in patients hospitalized for acute decompensated heart failure (ADHF). We performed a meta-analysis to estimate the efficacy of LS in predicting the prognosis of patients with ADHF., Results: We analyzed data from 7 studies, comprising 677 patients, that assessed the prognostic value of LS in predicting cardiovascular outcomes in patients hospitalized for ADHF. The pooled analysis showed that increased liver stiffness was associated with higher risk of adverse cardiac events (hazard ratio 1.07 [1.03, 1.12], 95% CI)., Conclusion: Increased LS is associated with poor prognosis in patients hospitalized for HF and might help effectively identify those patients at high risk for worse outcomes., (© 2024. The Author(s).)

Background: Left ventricular assist device (L-VAD) implantation is increasingly used in patients with heart failure (HF) and most patients also have an implantable cardioverter defibrillator (ICD). Limited data are available on the incidence of ICD therapies and complications in this special setting. The aim of this study was to analyze the real-world incidence and predictors of ICD therapies, complications and interactions between ICD and L-VAD., Methods: We conducted a multicenter retrospective observational study in patients with advanced HF implanted with ICD and a continuous-flow L-VAD, followed-up in five advanced HF centers in Northern Italy., Results: A total of 234 patients (89.7% male, median age 59, 48.3% with ischemic etiology) were enrolled. After a median follow-up of 21 months, 66 patients (28.2%) experienced an appropriate ICD therapy, 22 patients (9.4%) an inappropriate ICD therapy, and 17 patients (7.3%) suffered from an interaction between ICD and L-VAD. The composite outcome of all ICD-related complications was reported in 41 patients (17.5%), and 121 (51.7%) experienced an L-VAD-related complication. At multivariable analysis, an active ventricular tachycardia (VT) zone and a prior ICD generator replacement were independent predictors of ICD therapies and of total ICD-related complications, respectively., Conclusions: Real-world patients with both L-VAD and ICD experience a high rate of ICD therapies and complications. Our findings suggest the importance of tailoring device programming in order to minimize the incidence of unnecessary ICD therapies, thus sparing the need for ICD generator replacement, a procedure associated to a high risk of complications., (© 2024 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

A 66-year-old patient with recent instrumental findings (echocardiogram, cardiac magnetic resonance imaging) of right ventricular failure was hospitalized due to worsening signs and symptoms of right heart failure, while waiting for diagnostic definition. Pulmonary computed tomography angiography revealed findings compatible with bilateral pulmonary thromboembolism involving the main pulmonary artery. Anticoagulant therapy was initiated with initial benefit, partial relief of symptoms, and moderate improvement in right ventricular function. However, after 4 weeks, the patient was readmitted for recurrence of heart failure and signs of low cardiac output. Echocardiography showed the presence of a conspicuous, mobile, isoechoic mass occupying much of the main pulmonary artery, once again suggestive of thrombosis. The patient underwent surgical thromboendoarterectomy; postoperatively, the procedure was complicated by severe refractory heart failure unresponsive to pharmacological treatments and mechanical support, leading to death in the subsequent days. Unexpectedly, histological analysis revealed a primary angiosarcoma of the endothelium of the main pulmonary artery, a very rare cause of pulmonary artery obstruction generally associated with worst prognosis and presenting with clinical features similar to pulmonary thromboembolism.

Heart failure with preserved ejection fraction (HFpEF) has a high prevalence, affecting more than 50% of patients with heart failure. HFpEF is associated with multiple comorbidities, and obesity is one of the most common. A distinct phenotype has been proposed for obese patients with HFpEF. Recent data show the beneficial role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for weight loss in diabetic and non-diabetic patients with obesity or overweight when given as adjunctive therapy to diet and exercise. The mechanisms of action are related to paracrine and endocrine signalling pathways within the gastrointestinal tract, pancreas, and central nervous system that delay gastric emptying, decrease appetite, augment pancreatic beta-cell insulin secretion, and suppress pancreatic glucagon release. These drugs are therefore potentially indicated for treatment of patients with HFpEF and obesity or overweight. Efficacy and safety need to be shown by clinical trials with a first one, Semaglutide Treatment Effect in People with obesity and heart failure with preserved ejection fraction (STEP HFpEF), recently concluded. The aim of the present review is to provide the pathophysiological and pharmacological rationale for GLP-1 RA administration to obese patients with HFpEF., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of 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.)

Background: The impact on age on the short-term and long-term prognosis in patients with Takotsubo syndrome (TTS) is unclear. We aimed to evaluate whether age has prognostic implications during hospital stay and long-term follow-up of TTS patients., Methods: 688 consecutive patients were admitted for TTS in 7 tertiary centers from January-2008 to June-2021. We divided our cohort into two groups (patients <75 years and ≥75 years). Clinical, analytical, and hemodynamic variables as well as in-hospital management were registered and compared between groups. Mortality rates during hospital stay and follow-up were assessed. Adverse cardiovascular events (ACE) were defined as the composite of cardiovascular death, heart failure event, acute myocardial infarction, stroke and symptomatic arrhythmia., Results: Median age was 74.7 years and 49.4 % were ≥75 years. 86.9 % were women and 22.3 % were secondary forms of TTS. In-hospital mortality was 3.6 % (1.5 % cardiovascular). Median clinical follow-up was 4.3 years. Mortality during the follow-up period was 23 % (5.0 % cardiovascular) while ACE were 22.5 %, mainly due to heart failure events. Kaplan-Meier curves showed both higher rates of mortality and ACE in ≥75 years group (30.2 % vs 15.8 %; p < 0.001 and 28.3 % vs 16.7 %; p < 0.001). Age was independently associated with higher rates of overall mortality and ACE in patients with TTS. Hypertension, absence of sinus rhythm, Killip class > I and a more impaired coronary microvascular resistance were also associated to ACE in TTS patients., Conclusions: Advanced age was associated with higher rate of overall mortality and ACE during long-term follow-up in TTS patients., Competing Interests: Declaration of competing interest Dr. Hector M. Garcia-Garcia reports the following institutional grant support: Biotronik, Boston Scientific, Medtronic, Abbott, Neovasc, Shockwave, Phillips and Corflow. The following is the supplementary data related to this article. Supplementary data to this article can be found online at https://doi.org/10.1016/j.carrev.2023.10.018., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Impact of gender on heart remodeling after acute coronary syndrome (ACS) and consequently on development of heart failure (HF) remains to be elucidated., Methods: CORALYS is a multicenter, retrospective, observational registry enrolling consecutive patients admitted for ACS and treated with percutaneous coronary intervention. HF hospitalization was the primary endpoint while all-cause mortality and the composite endpoint of incidence of first HF hospitalization and cardiovascular mortality were the secondary ones., Results: Among 14,699 patients enrolled in CORALYS registry, 4578 (31%) were women and 10,121 (69%) males. Women were older, had more frequently hypertension and diabetes and less frequently smoking habit. History of myocardial infarction (MI), STEMI at admission and multivessel disease were less common in women. After median follow up of 2.9 ± 1.8 years, women had higher incidence of primary and secondary endpoints and female sex was an independent predictor of HF hospitalization (HR 1.26;1.05-1.50; p = 0.011) and cardiovascular death/HF hospitalization (HR 1.18;1.02-1.37; p = 0.022). At multivariable analysis women and men share as predictors of HF diabetes, history of cancer, chronic kidney disease, atrial fibrillation, complete revascularization and left ventricular ejection fraction. Chronic obstructive pulmonary disease (HR 2.34;1.70-3.22, p < 0.001) and diuretics treatment (HR 1.61;1.27-2.04, p < 0.001) were predictor of HF in men, while history of previous MI (HR 1.46;1.08-1.97, p = 0.015) and treatment with inhibitors of renin-angiotensin system (HR 0.69;0,49-0.96 all 95% CI, p = 0.030) in women., Conclusions: Women are at increased risk of HF after ACS and gender seems to be an outcome-modifier of the relationship between a variable and primary outcome., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Clinical evaluation of central venous pressure is difficult, depends on experience, and is often inaccurate in patients with chronic advanced heart failure. We assessed the ultrasound-assessed internal jugular vein (JV) distensibility by ultrasound as a noninvasive tool to identify patients with normal right atrial pressure (RAP ≤7 mm Hg) in this population., Methods: We measured JV distensibility as the Valsalva-to-rest ratio of the vein diameter in a calibration cohort (N=100) and a validation cohort (N=101) of consecutive patients with chronic heart failure with reduced ejection fraction who underwent pulmonary artery catheterization for advanced heart failure therapies workup., Results: A JV distensibility threshold of 1.6 was identified as the most accurate to discriminate between patients with RAP ≤7 versus >7 mm Hg (area under the receiver operating characteristic curve, 0.74 [95% CI, 0.64-0.84]) and confirmed in the validation cohort (receiver operating characteristic, 0.82 [95% CI, 0.73-0.92]). A JV distensibility ratio >1.6 had predictive positive values of 0.86 and 0.94, respectively, to identify patients with RAP ≤7 mm Hg in the calibration and validation cohorts. Compared with patients from the calibration cohort with a high JV distensibility ratio (>1.6; n=42; median RAP, 4 mm Hg; pulmonary capillary wedge pressure, 11 mm Hg), those with a low JV distensibility ratio (≤1.6; n=58; median RAP, 8 mm Hg; pulmonary capillary wedge pressure, 22 mm Hg; P <0.0001 for both) were more likely to die or undergo a left ventricular assist device implant or heart transplantation (event rate at 2 years: 42.7% versus 18.2%; log-rank P =0.034)., Conclusions: Ultrasound-assessed JV distensibility identifies patients with chronic advanced heart failure with normal RAP and better outcomes., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03874312., Competing Interests: Disclosures The authors disclose that Dr Ammirati received a grant from the Italian Ministry of Health (GR-2019-12368506) and a grant from the NextGenerationEU (M6C2/2.1 PNRR-MAD-2022-12376225—CUP H43C21000140006) and served as a consultant for Kiniksa Pharmaceuticals, Cytokinetics, and AstraZeneca. Dr Pellicori has received consultancy honoraria and sponsorship support from Boehringer Ingelheim, Pharmacosmos, Novartis, Vifor, AstraZeneca, and Caption Health and research support from Bristol Myers Squibb in the past 5 years, not connected with this article. Prof Metra is the outgoing Editor-in-Chief of the European Journal of Heart Failure. The other authors report no conflicts.

Gene therapy is defined by the introduction of new genes or the genetic modification of existing genes and/or their regulatory portions via gene replacement and gene editing strategies, respectively. The genetic material is usually delivered though cardiotropic vectors such as adeno-associated virus 9 or engineered capsids. The enthusiasm for gene therapy has been hampered somewhat by adverse events observed in clinical trials, including dose-dependent immunologic reactions such as hepatotoxicity, acquired hemolytic uremic syndrome and myocarditis. Notably, gene therapy for Duchenne muscular dystrophy has recently been approved and pivotal clinical trials are testing gene therapy approaches in rare myocardial conditions such as Danon disease and Fabry disease. Furthermore, promising results have been shown in animal models of gene therapy in hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy. This review summarizes the gene therapy techniques, the toxicity risk associated with adeno-associated virus delivery, the ongoing clinical trials, and future targets., Competing Interests: Funding Support and Author Disclosures Dr Argiro is a consultant for Lexeo Therapeutics. Dr Bui has received the 2023 Janice Weisman Young Investigator Grant from Ionis; and has served as a consultant for Lexeo Therapeutics. Dr Ammirati has received a grant from the Italian Ministry of Health (GR-2019-12368506; and a grant from Italian Ministry of Health and NextGenerationEU (PNRR-MAD-2022-12376225); has served as the principal investigator of the investigator-driven MYTHS (Myocarditis Therapy with Steroids) trial; and is a consultant for Kiniksa and Cytokinetics. Dt Olivotto has received grants from Bayer, MyoKardia, Inc, which is a wholly owned subsidiary of Bristol Myers Squibb, Sanofi Genzyme, and Shire, which is now part of Takeda; personal fees from Bayer, Sanofi Genzyme, and Shire/Takeda; and payments as a consultant from MyoKardia, Inc. Dr Adler has served on Scientific Advisory Boards for Medtronic, Fuji, and Sana; as Chief Scientific Officer for Lexeo Therapeutics; as a consultant to Abiomed, AstraZeneca, Ionis, Medtronic, Abbott, and Novartis; on the Advisory Board and is a shareholder of Rocket Pharmaceuticals; and is a founder, member of the Scientific Board, and shareholder of ResQue Therapeutics. Dr Hong has reported that she has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The multi-systemic effects of heart failure (HF) resemble the spread observed during cancer. We propose a new score, named HLM, analogous to the TNM classification used in oncology, to assess the prognosis of HF. HLM refers to H: heart damage, L: lung involvement, and M: systemic multiorgan involvement. The aim was to compare the HLM score to the conventional New York Heart Association (NYHA) classification, American College of Cardiology/American Heart Association (ACC/AHA) stages, and left ventricular ejection fraction (LVEF), to assess the most accurate prognostic tool for HF patients., Methods and Results: We performed a multicentre, observational, prospective study of consecutive patients admitted for HF. Heart, lung, and other organ function parameters were collected. Each patient was classified according to the HLM score, NYHA classification, ACC/AHA stages, and LVEF assessed by transthoracic echocardiography. The follow-up period was 12 months. The primary endpoint was a composite of all-cause death and rehospitalization due to HF. A total of 1720 patients who completed the 12 month follow-up period have been enrolled in the study. 520 (30.2%) patients experienced the composite endpoint of all-cause death and rehospitalization due to HF. 540 (31.4%) patients were female. The mean age of the study population was 70.5 ± 12.9. The mean LVEF at admission was 42.5 ± 13%. Regarding the population distribution across the spectrum of HLM score stages, 373 (21.7%) patients were included in the HLM-1, 507 (29.5%) in the HLM-2, 587 (34.1%) in the HLM-3, and 253 (14.7%) in the HLM-4. HLM was the most accurate score to predict the primary endpoint at 12 months. The area under the receiver operating characteristic curve (AUC) was greater for the HLM score compared with the NYHA classification, ACC/AHA stages, or LVEF, regarding the composite endpoint (HLM = 0.645; NYHA = 0.580; ACC/AHA = 0.589; LVEF = 0.572). The AUC of the HLM score was significantly better compared with the LVEF (P = 0.002), ACC/AHA (P = 0.029), and NYHA (P = 0.009) AUC., Conclusions: The HLM score has a greater prognostic power compared with the NYHA classification, ACC/AHA stages, and LVEF assessed by transthoracic echocardiography in terms of the composite endpoint of all-cause death and rehospitalization due to HF at 12 months of follow-up., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Cardiac resynchronization therapy has evolved in recent years to provide a reduction of morbidity and mortality for many patients with heart failure. Its application and optimization is an evolving field and its use requires a multidisciplinary approach for patient and device selection, technical preprocedural planning, and optimization. While echocardiography has always been considered the first line for the evaluation of patients, additional imaging techniques have gained increasing evidence in recent years. Today different details about heart anatomy, function, dissynchrony can be investigated by magnetic resonance, cardiac computed tomography, nuclear imaging, and more, with the aim of obtaining clues to reach a maximal response from the electrical therapy. The purpose of this review is to provide a practical analysis of the single and combined use of different imaging techniques in the preoperative and perioperative phases of cardiac resynchronization therapy, underlining their main advantages, limitations, and information provided., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.)

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

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

Left ventricular non compaction (LVNC) comprises a heterogeneous group of diseases that can cause heart failure, arrhythmias, and thromboembolic events. In particular, the prevalence of thromboembolism in patients with LVNC is relevant compared to the general population. Atrial fibrillation and left ventricular thrombosis are strong predictors and require anticoagulant treatment in primary or secondary prevention, with a significant reduction in the risk of events. Long-term oral anticoagulation can be considered in patients with LVNC associated with left ventricular systolic dysfunction and sinus rhythm. On the contrary, it is not entirely clear whether the presence of deep intertrabecular recesses that cause blood flow stagnation can itself represent a thrombogenic substrate even in the absence of ventricular dysfunction and in sinus rhythm, thus indicating the use of anticoagulation.This article addresses the open question of the indication for anticoagulant therapy in LVNC, through a review of the current evidence on thromboembolic risk stratification and the initiation of anticoagulant therapy and by proposing a flow-chart as a guide to decision-making according to the clinical picture of the patient.

The present study aimed to identify patients at a higher risk of hospitalization for heart failure (HF) in a population of patients with acute coronary syndrome (ACS) treated with percutaneous coronary revascularization without a history of HF or reduced left ventricular (LV) ejection fraction before the index admission. We performed a Cox regression multivariable analysis with competitive risk and machine learning models on the incideNce and predictOrs of heaRt fAiLure After Acute coronarY Syndrome (CORALYS) registry (NCT04895176), an international and multicenter study including consecutive patients admitted for ACS in 16 European Centers from 2015 to 2020. Of 14,699 patients, 593 (4.0%) were admitted for the development of HF up to 1 year after the index ACS presentation. A total of 2 different data sets were randomly created, 1 for the derivative cohort including 11,626 patients (80%) and 1 for the validation cohort including 3,073 patients (20%). On the Cox regression multivariable analysis, several variables were associated with the risk of HF hospitalization, with reduced renal function, complete revascularization, and LV ejection fraction as the most relevant ones. The area under the curve at 1 year was 0.75 (0.72 to 0.78) in the derivative cohort, whereas on validation, it was 0.72 (0.67 to 0.77). The machine learning analysis showed a slightly inferior performance. In conclusion, in a large cohort of patients with ACS without a history of HF or LV dysfunction before the index event, the CORALYS HF score identified patients at a higher risk of hospitalization for HF using variables easily accessible at discharge. Further approaches to tackle HF development in this high-risk subset of patients are needed., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) is the second most important cardiac risk factor for stroke after atrial fibrillation (AF). Few data are available on mechanical thrombectomy (MT) in acute ischemic stroke (AIS) patients with HF., Methods: The source of data is the multicentre Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS). All AIS patients ≥ 18 years receiving MT were categorised in two groups: HF and no-HF. Baseline clinical and neuroradiological findings on admission were analysed., Results: Of 8924 patients, 642 (7.2%) had HF. Compared to the no-HF group, HF patients had higher prevalence of cardiovascular risk factors. Rate of complete recanalisation (TICI 2b-3) was 76.9% in HF vs 78.1% in no-HF group (p = 0.481). Rate of symptomatic intracerebral haemorrhage at 24-h non-contrast computed tomography (NCCT) was 7.6% in HF vs 8.3% in no-HF patients (p = 0.520). At 3 months, 36.4% of HF patients and 48.2% of no-HF patients (p < 0.001) had mRS 0-2, and mortality was, respectively, 30.7% and 18.5% (p < 0.001). In multivariate logistic regression, HF was independently associated with mortality at 3 months (OR 1.53, 1.24-1.88 95% CI, p < 0.001). In multivariate ordinal regression, HF patients had a probability of transitioning to a higher mRS level of 1.23 (1.05-1.44 95% CI, p = 0.012). The propensity score analysis of two groups matched for age, sex, and NIHSS at admission yielded the same results., Conclusion: MT is safe and effective in HF patients with AIS. Patients with HF and AIS suffered from higher 3-month mortality and unfavourable outcome regardless of acute treatments., (© 2023. Fondazione Società Italiana di Neurologia.)

Introduction: Intravenous inotropic support represents an important therapeutic option in advanced heart failure (HF) as bridge to heart transplantation, bridge to mechanical circulatory support, bridge to candidacy or as palliative therapy. Nevertheless, evidence regarding risks and benefits of its use is lacking., Methods: we conducted a retrospective single center study, analysing the effect of inotropic therapies in an outpatient cohort, evaluating the burden of hospitalizations, the improvement in quality of life, the incidence of adverse events and the evolution of organ damage., Results: twenty-seven patients with advanced HF were treated in our Day Hospital service from 2014 to 2021. Nine patients were treated as bridge to heart transplant while eighteen as palliation. Comparing data regarding the year before and after the beginning of inotropic infusion, we observed a reduction of hospitalization (46 vs 25, p<0,001), an improvement of natriuretic peptides, renal and hepatic function since the first month (p<0,001) and a better quality of life in 53% of the population treated. Two hospitalizations for arrhythmias and seven hospitalizations for catheter-related complications were registered., Conclusions: in a selected population of advanced HF patients, continuous home inotropic infusion were able to reduce hospitalizations, improving end organ damage and quality of life. We provide a practical guidance on starting and maintaining home inotropic infusion while monitoring a challenging group of patients., Competing Interests: Declaration of Competing Interest None of the authors have conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Heart failure (HF) with preserved ejection fraction (HFpEF) causes a progressive limitation of functional capacity, poor quality of life (QoL) and increased mortality, yet unlike HF with reduced ejection fraction (HFrEF) there are no effective device-based therapies. Both HFrEF and HFpEF are associated with dysregulations in myocardial cellular calcium homeostasis and modifications in calcium-handling proteins, leading to abnormal myocardial contractility and pathological remodelling. Cardiac contractility modulation (CCM) therapy, based on a pacemaker-like implanted device, applies extracellular electrical stimulation to myocytes during the absolute refractory period of the action potential, which leads to an increase in cytosolic peak calcium concentrations and thereby the force of isometric contraction promoting positive inotropism. Subgroup analysis of CCM trials in HFrEF has demonstrated particular benefits in patients with LVEF between 35% and 45%, suggesting its potential effectiveness also in patients with higher LVEF values. Available evidence on CCM in HFpEF is still preliminary, but improvements in terms of symptoms and QoL have been observed. Future large, dedicated, prospective studies are needed to evaluate the safety and efficacy of this therapy in patients with HFpEF., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

An 80-year-old man was referred to our center for heart failure and severe degenerative mitral regurgitation (MR). Transesophageal echocardiography revealed severe MR due to anterior leaflet prolapse, mainly in its central portion (A2) in the context of fibroelastic deficiency.

Background: The role of TAPSE/PASP, a measurement of right ventricular to pulmonary artery coupling, in patients hospitalized for acute heart failure (AHF) is poorly described., Objectives: To evaluate the prognostic impact of TAPSE/PASP in AHF., Methods: This retrospective single-center study included patients hospitalized for AHF between January 2004 and May 2017. TAPSE/PASP was evaluated as a continuous variable and as tertiles according to its value on admission. The main outcome was the composite of 1-year all-cause death or heart failure hospitalization., Results: A total of 340 patients were included [mean age 68.8 ± 11.8 years; 76.2% men, mean left ventricular ejection fraction (LVEF) 30.4 ± 13.3%]. Patients with lower TAPSE/PASP had more comorbidities and a more advanced clinical profile, and received higher doses of intravenous furosemide in the first 24 h. There was a significant, linear, inverse relationship between TAPSE/PASP values and the incidence of the main outcome (P = 0.003). In two multivariable analyses including clinical (model 1), biochemical and imaging parameters (model 2) TAPSE/PASP ratio was independently associated with the primary end point [model 1: hazard ratio 0.813, 95% confidence interval (CI) 0.708-0.932, P = 0.003; model 2: hazard ratio 0.879, 95% CI 0.775-0.996, P = 0.043]. Patients with TAPSE/PASP greater than 0.47 mm/mmHg had a significantly lower risk of the primary end point (model 1: hazard ratio 0.473, 95% CI 0.277-0.808, P = 0.006; model 2: hazard ratio 0.582, 95% CI 0.355-0.955, P = 0.032; both compared with TAPSE/PASP <0.34 mm/mmHg). Similar findings were observed for 1-year all-cause mortality., Conclusion: TAPSE/PASP on admission demonstrated a prognostic value among patients with AHF., (Copyright © 2023 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background The impact of complete revascularization (CR) on the development of heart failure (HF) in patients with acute coronary syndrome and multivessel coronary artery disease undergoing percutaneous coronary intervention remains to be elucidated. Methods and Results Consecutive patients with acute coronary syndrome with multivessel coronary artery disease from the CORALYS (Incidence and Predictors of Heart Failure After Acute Coronary Syndrome) registry were included. Incidence of first hospitalization for HF or cardiovascular death was the primary end point. Patients were stratified according to completeness of coronary revascularization. Of 14 699 patients in the CORALYS registry, 5054 presented with multivessel disease. One thousand four hundred seventy-three (29.2%) underwent CR, while 3581 (70.8%) did not. Over 5 years follow-up, CR was associated with a reduced incidence of the primary end point (adjusted hazard ratio [HR], 0.66 [95% CI, 0.51-0.85]), first HF hospitalization (adjusted HR, 0.67 [95% CI, 0.49-0.90]) along with all-cause death and cardiovascular death alone (adjusted HR, 0.74 [95% CI, 0.56-0.97] and HR, 0.56 [95% CI, 0.38-0.84], respectively). The results were consistent in the propensity-score matching population and in inverse probability treatment weighting analysis. The benefit of CR was consistent across acute coronary syndrome presentations (HR, 0.59 [95% CI, 0.39-0.89] for ST-segment elevation myocardial infarction and HR, 0.71 [95% CI, 0.50-0.99] for non-ST-elevation acute coronary syndrome) and in patients with left ventricular ejection fraction >40% (HR, 0.52 [95% CI, 0.37-0.72]), while no benefit was observed in patients with left ventricular ejection fraction ≤40% (HR, 0.77 [95% CI, 0.37-1.10], P for interaction 0.04). Conclusions CR after acute coronary syndrome reduced the risk of first hospitalization for HF and cardiovascular death, as well as first HF hospitalization, and cardiovascular and overall death both in patients with ST-segment elevation myocardial infarction and non-ST-elevation acute coronary syndrome. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04895176.

Background: Acute Kidney Injury (AKI) represents a major complication of acute heart failure and cardiogenic shock (CS). There is a paucity of data on AKI complicating acutely decompensated heart failure patients presenting with CS (ADHF-CS). We aimed to investigate AKI prevalence, risk factors and outcomes in this subgroup of patients., Methods: Retrospective observational study on patients admitted for ADHF-CS to our 12-bed Intensive Care Unit (ICU), between January 2010 and December 2019. Demographic, clinical, and biochemical variables were collected at baseline and during hospital stay., Results: Eighty-eight patients were consecutively recruited. The predominant etiologies were idiopathic dilated cardiomyopathy (47%), followed by post-ischemic (24%). AKI was diagnosed in 70 (79.5%) of patients. Forty-three out of 70 patients met the criteria for AKI at ICU admission. On multivariate analysis, a central venous pressure (CVP) higher than 10 mmHg (OR 3.9; 95%CI 1.2-12.6; p = 0.025) and serum lactate higher than 3 mmol/L (OR 4.1; 95%CI 1.01-16.3; p = 0.048) were identified to be independently associated with AKI. Age and AKI stage were independent predictors of 90-day mortality., Conclusion: AKI is a common and early complication of ADHF-CS. Venous congestion and severe hypoperfusion are risk factors for AKI development. Early detection and prevention of AKI could lead to better outcome in this clinical subgroup., Competing Interests: Declaration of Competing Interest Non declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) represents a highly heterogeneous clinical syndrome affected in its development and progression by many comorbidities. The left ventricular diastolic dysfunction may be a manifestation of various combinations of cardiovascular, metabolic, pulmonary, renal, and geriatric conditions. Thus, in addition to treatment with sodium-glucose cotransporter 2 inhibitors in all patients, the most effective method of improving clinical outcomes may be therapy tailored to each patient's clinical profile. To better outline a phenotype-based approach for the treatment of HFpEF, in this joint position paper, the Heart Failure Association of the European Society of Cardiology, the European Heart Rhythm Association and the European Hypertension Society, have developed an algorithm to identify the most common HFpEF phenotypes and identify the evidence-based treatment strategy for each, while taking into account the complexities of multiple comorbidities and polypharmacy., (© 2023 European Society of Cardiology.)

Introduction: In patients receiving conduction system pacing (CSP), it is not well established how to program the sensed atrioventricular delay (sAVD), with respect to the type of capture obtained (selective, nonselective His-bundle [HB] capture or left bundle branch [LBB] capture). The aim of this study was to acutely assess the effectiveness of an electrophysiology (EP)-guided method for sAVD optimization by comparing it with the echocardiogram-guided optimization., Methods and Results: Consecutive patients undergoing HB or LBB pacing were enrolled. The EP-guided sAVD was defined as the sAVD leading to a PR interval of 150 ms on surface electrocardiogram (ECG). In HB pacing patients, EP-guided sAVD was obtained subtracting the time from the onset of the P wave on ECG to the local atrial electrogram (EGM) recorded by the atrial lead (right atrial sensing latency, RASL) and the His-ventricular interval from 150 ms; in LBB pacing patients, subtracting RASL from 150 ms. Transmitral flow assessment by pulsed wave Doppler was used to find the echo-optimized sAVD by a modified iterative method. The discordance between the EP-guided and the echo-optimized sAVD was recorded., Results: Seventy-one patients were enrolled: 12 with selective, 32 nonselective HB capture, and 27 LBB capture. Overall, the rate of concordance between the EP-guided and the echo-optimized sAVD was 71.8%, with no significant differences between the three groups., Conclusion: In CSP patients, an optimal sAVD can be programmed, in more than 70% of cases, considering only simple EGM intervals to obtain a physiological PR interval on surface ECG., (© 2023 Wiley Periodicals LLC.)

Background: The aim of this study was to determine the safety and feasibility of in-hospital sacubitril/valsartan initiation after clinical stabilization in patients with acute decompensated heart failure (ADHF) and reduced ejection fraction (EF)., Methods: This retrospective, multicenter observational study included patients admitted for ADHF in 2 Italian centers between February 2017 and January 2022. Feasibility was evaluated by assessing the proportion of patients discharged on sacubitril/valsartan. Key safety endpoints were the incidences of adverse events during hospitalization and during follow-up planned at 1 month, 3-6 months and 12-18 months after discharge., Results: One hundred and twenty-two patients were included. Median age was 71 (60-78) years, 78% male, 63% New York Heart Association (NYHA) Class III at admission with a median left ventricular ejection fraction (EF) of 25% (20-30). During hospitalization, 94 (77%) patients were treated with intravenous diuretics, 39 (32%) with inotrope/vasopressor, 51 (42%) with continuous positive airway pressure ventilation and 7 (6%) were assisted with an intra-aortic balloon pump. Median time from hospitalization to sacubitril/valsartan initiation was 4 (2-7) days. Sacubitril/valsartan was started at a dosage of 12/13 mg in 52 (43%) patients, 24/26 mg in 61 (50%) patients and 49/51 mg in 8 (7%) patients. Overall, 111 (91%) patients were discharged on sacubitril/valsartan. At 12-18-month follow-up, the vast majority of patients were still on sacubitril/valsartan therapy., Conclusions: In-hospital initiation of sacubitril/valsartan treatment in real-world ADHF patients may be a safe and feasible treatment option.

Aim: Epidemiology of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) remains poorly defined. A better characterization of pathways leading to ATTRwt-CA diagnosis is of key importance, and potentially informative of disease course and prognosis. The aim of this study was to describe the characteristics of contemporary pathways leading to ATTRwt-CA diagnosis, and their potential association with survival., Methods and Results: This was a retrospective study of patients diagnosed with ATTRwt-CA at 17 Italian referral centres for CA. Patients were categorized into different 'pathways' according to the medical reason that triggered the diagnosis of ATTRwt-CA (hypertrophic cardiomyopathy [HCM] pathway, heart failure [HF] pathway, incidental imaging or incidental clinical pathway). Prognosis was investigated with all-cause mortality as endpoint. Overall, 1281 ATTRwt-CA patients were included in the study. The diagnostic pathway leading to ATTRwt-CA diagnosis was HCM in 7% of patients, HF in 51%, incidental imaging in 23%, incidental clinical in 19%. Patients in the HF pathway, as compared to the others, were older and had a greater prevalence of New York Heart Association (NYHA) class III-IV and chronic kidney disease. Survival was significantly worse in the HF versus other pathways, but similar among the three others. In multivariate model, older age at diagnosis, NYHA class III-IV and some comorbidities but not the HF pathway were independently associated with worse survival., Conclusions: Half of contemporary ATTRwt-CA diagnoses occur in a HF setting. These patients had worse clinical profile and outcome than those diagnosed either due to suspected HCM or incidentally, although prognosis remained primarily related to age, NYHA functional class and comorbidities rather than the diagnostic pathway itself., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Maternal cardiovascular changes, occurring since the beginning of pregnancy, are necessary for normal placentation and regular evolution of pregnancy., Objective: This study aimed to compare the hemodynamic profiles and cardiac remodeling of women with hypertensive disorders of pregnancy and either appropriate for gestational age fetuses or growth-restricted fetuses, women with normotensive pregnancies complicated by fetal growth restriction, and women with uncomplicated pregnancies, during pregnancy and the postpartum period., Study Design: A prospective longitudinal case-control design was used for this study. Over the study period, 220 eligible women with singleton pregnancies were selected for the analysis and divided into 4 groups: (1) hypertensive disorders of pregnancy with appropriate for gestational age fetuses; (2) hypertensive disorders of pregnancy with fetal growth restriction; (3) normotensive fetal growth restriction; and (4) controls. Ultrasound fetal biometry and fetoplacental Doppler velocimetry were performed at recruitment. Maternal hemodynamic assessment using transthoracic echocardiography was performed at the time of recruitment by a dedicated cardiologist blinded to maternal clinical data. The same assessments were performed in 104 patients at 32 weeks (interquartile range, 24-40) after delivery by the same cardiologist., Results: During pregnancy, women in the hypertensive-disorders-of-pregnancy-fetal-growth-restriction group showed significantly lower cardiac output and increased compared with those in the control group. These values were associated with concentric remodeling of the left ventricle owing to relatively increased wall thickness, which was not accompanied by an increase in left ventricular mass. Isolated fetal growth restriction presented similar but less important hemodynamic changes; however, there was no change in relative wall thickness. At postpartum follow-up, the hemodynamic parameters of women in the hypertensive-disorders-of-pregnancy-fetal-growth-restriction and isolated-fetal-growth-restriction groups reverted to values similar to those of the control group. Only 8.3% of women in these groups experienced hypertension even in the postpartum period, and asymptomatic stage-B cardiac failure was observed for 17% at echocardiography. In the group of women with hypertensive disorders of pregnancy and appropriate for gestational age fetuses, cardiac output increased as in normal pregnancies, but total vascular resistance was significantly higher; hypertension then occurred, along with ventricular concentric hypertrophy and diastolic dysfunction. At postpartum follow-up, women in the hypertensive-disorders-of-pregnancy-appropriate-for-gestational-age-fetus group showed significantly higher mean arterial pressure, total vascular resistance, and left ventricular mass compared with those in the control group. Persistent hypertension and asymptomatic stage-B cardiac failure were observed in 39.1% and 13% of women in the former group, respectively., Conclusion: Pregnancies with hypertensive disorders of pregnancy and fetal growth restriction and normotensive pregnancies with fetal growth restriction were associated with the hemodynamic profile of lower heart rate and cardiac output, most likely because of abnormal adaptation to pregnancy, as confirmed by abnormal changes from pregnancy to the postpartum period. The heart rates and cardiac output of women in the hypertensive-disorders-of-pregnancy-appropriate-for-gestational-age-fetus group showed changes opposite to those observed in the hypertensive-disorders-of-pregnancy-fetal-growth-restriction and fetal-growth-restriction groups. Obesity and other metabolic risk factors, significantly prevalent in women in the hypertensive-disorders-of-pregnancy-appropriate-for-gestational-age-fetus group, predispose to hypertension and cardiovascular diseases during pregnancy and the postpartum period, potentially offering a window for personalized prevention. Such preventive strategies could differ in women with hypertensive disorders of pregnancy and fetal growth restriction characterized by poor early placental development., (Published by Elsevier Inc.)

Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of heart failure hospital admissions in the last years and is burdened by high mortality and poor quality of life. Providing effective management for HFpEF patients is a major unmet clinical need. Increase in left atrial pressure is the key determinant of pulmonary congestion, with consequent dyspnoea and exercise limitation. Evidence on benefits of medical treatment in HFpEF patients is limited. Thus, alternative strategies, including devices able to reduce left atrial pressure, through an interatrial communication determining a left-right shunt, were developed. This review aims to summarize evidence regarding the use of percutaneous interatrial shunting devices. These devices are safe and effective in improving hemodynamic and clinical parameters, including pulmonary capillary wedge pressure, 6-min walking distance, and New York Heart Association functional class. Data on cardiovascular mortality and re-hospitalization for heart failure are still scarce., (© 2022. The Author(s).)

Aims: Adenosine has been tested in several randomized controlled trials (RCTs) to minimize the incidence of coronary microvascular obstruction (CMVO). The aim of this study was to pool all the RCTs comparing intracoronary or intravenous adenosine versus placebo in patients with acute coronary syndrome (ACS) undergoing myocardial revascularization., Methods and Results: PubMed and Scopus electronic databases were scanned for eligible studies up to 5th June 2022. A total of 26 RCTs with 5843 patients were included. Efficacy endpoints were major adverse cardiac events (MACE), all-cause death, non-fatal myocardial infarction, and heart failure. Atrioventricular blocks and ventricular fibrillation/sustained ventricular tachycardia (VF/SVT) were the safety endpoints. Myocardial blush grade, thrombolysis in myocardial infarction (TIMI) flow grade, left ventricular ejection fraction (LVEF), infarct size, and ST-segment resolution were also assessed. Adenosine administration was not associated with any clinical benefit in terms of MACE, all-cause death, non-fatal myocardial infarction, and heart failure. However, adenosine was associated with an increased rate of advanced atrioventricular blocks and of VF/SVT in studies with total mean ischaemic time >3 h, compared to placebo. Remarkably, among patients undergoing percutaneous coronary intervention, adenosine was associated with reduced myocardial blush grade 0-1 and TIMI flow grade 0-2, compared to placebo. Furthermore, adenosine did not show favourable effects on LVEF and infarct size., Conclusion: Adenosine infusion, as adjunctive therapy in ACS, was associated with an increased risk of advanced atrioventricular blocks and increased rates of adenosine-triggered ventricular arrhythmias in patients with long ischaemic time, without providing any clinical benefit compared to placebo., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Heart failure (HF) is a complex syndrome that affects mortality/morbidity and acts at different levels in the patient's life, resulting in a drastic impairment in multiple aspects of daily activities (e.g. physical, mental/emotional, and social) and leading to a reduction in quality of life. The definition of disease status and symptom severity has been traditionally based on the physician assessment, while the patient's experience of disease has been long overlooked. The active participation of patients in their own care is necessary to better understand the perception of disease and the multiple aspects of life affected, and to improve adherence to treatments. Patient-reported outcomes (PROs) aim to switch traditional care to a more patient-centred approach. Although PROs demonstrated precision in the evaluation of disease status and have a good association with prognosis in several randomized controlled trials, their implementation into clinical practice is limited. This review discusses the modalities of use of PROs in HF, summarizes the most largely adopted PROs in HF care, and provides an overview on the application of PROs in trials and the potential for their transition to clinical practice. By discussing the advantages and the disadvantages of their use, the reasons limiting their application in daily clinical routine, and the strategies that may promote their implementation, this review aims to foster the systematic integration of the patient's standpoint in HF care., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The prognostic role of moderate hyperkalemia in reduced ejection fraction (HFrEF) patients is still controversial. Despite this, it affects the use of renin-angiotensin-aldosterone system inhibitors (RAASi) with therapy down-titration or discontinuation., Objectives: Aim of the study was to assess the prognostic impact of moderate hyperkalemia in chronic HFrEF optimally treated patients., Methods and Results: We retrospectively analyzed MECKI (Metabolic Exercise test data combined with Cardiac and Kidney Indexes) database, with median follow-up of 4.2 [IQR 1.9-7.5] years. Data on K + levels were available in 7087 cases. Patients with K + plasma level ≥ 5.6 mEq/L and < 4 mEq/L were excluded. Remaining patients were categorized into normal >4 and < 5 mEq/L (n = 4826, 68%) and moderately high ≥5.0 and ≤ 5.5 mEq/L (n = 496, 7%) K + . Then patients were matched by propensity score in 484 couplets of patients. MECKI score value was 7% [IQR 3.1-14.1%] and 7.3% [IQR 3.4-15%] (p = 0.678) in patients with normal and moderately high K + values while cardiovascular mortality events at two years follow-up were 41 (4.2%) and 33 (3.4%) (p = 0.333) in each group respectively., Conclusions: Moderate hyperkalemia does not influence patients' outcome in a large cohort of ambulatory HFrEF patients., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Heart failure is a leading and growing cause of morbidity and mortality worldwide and clinically is defined by the presence of typical symptoms and signs due structural or functional cardiac abnormalities. In addition to family history of heart failure, genetic predisposition to cardiomyopathies and exposure to cardiotoxic agents, risk factors for heart failure with reduced ejection fraction are the same as for chronic coronary syndrome. Genome editing technologies can provide the tools to correct genetic defects responsible for various diseases, including cardiomyopathies. These technologies aim to reverse specific mutations. The same methods can also be applied to modulate and improve heart function. This chapter will briefly explain the pathophysiological and genetic aspects of heart failure and then discuss the clinical applications of genome editing in patients with heart failure., (© 2023. The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.)

Background: Previous studies investigating predictors of Heart Failure (HF) after acute coronary syndrome (ACS) were mostly conducted during fibrinolytic era or restricted to baseline characteristics and diagnoses prior to admission. We assessed the incidence and predictors of HF hospitalizations among patients treated with percutaneous coronary intervention (PCI) for ACS., Methods and Results: CORALYS is a multicenter, retrospective, observational registry including consecutive patients treated with PCI for ACS. Patients with known history of HF or reduced left ventricular ejection fraction (LVEF) were excluded. Incidence of HF hospitalizations was the primary endpoint. The composite of HF hospitalization or cardiovascular death, and cardiovascular and all-cause death were the secondary endpoints. Predictors of HF hospitalizations and the impact of HF hospitalization on cardiovascular and all-cause death were assessed by means of multivariable Cox proportional hazards model.14699 patients were included. After 2.9 ± 1.8 years, the incidence of HF hospitalizations was 12.7%. Multivariable analysis identified age, diabetes, chronic kidney disease, previous myocardial infarction, atrial fibrillation, pulmonary disease, GRACE risk-score ≥ 141, peripheral artery disease, cardiogenic shock at admission and LVEF ≤40% as independently associated with HF hospitalizations. Complete revascularization was associated with a lower risk of HF (HR 0.46,95%CI 0.39-0.55). HF hospitalization was associated with higher risk of CV and all-cause death (HR 1.89,95%CI 1.5-2.39 and HR 1.85,95%CI 1.6-2.14, respectively)., Conclusions: Incidence of HF hospitalizations among patients treated with PCI for ACS is not negligible and is associated with detrimental impact on patients' prognosis. Several variables may help to assess the risk of HF after ACS., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022. Published by Elsevier B.V.)

In this case, review of OCT images after successful closure of a coronary perforation (CP) showed that the initial CP was visible as an abrupt interruption of the intimal tissue and the presence of a crater with blood reaching the external layers of vessel wall. CP was probably caused by overstretch of the vessel wall in an intramural segment of the left anterior descending coronary artery. CP is a possible complication of PTCA that is rarely documented with intracoronary imaging due to its rapid and dramatic evolution. We report the unique images of how an initial CP appears at OCT.

Background and Objectives: In patients with acute heart failure (AHF), there is no definite evidence on the relationship between high-sensitivity cardiac troponin (hs-cTnI) and the left ventricular ejection fraction (LVEF) comparing the reduced and preserved EF conditions. Materials and Methods: Between January and April 2022, we retrospectively analyzed the data from 386 patients admitted to the emergency departments (ED) of five hospitals in Rome, Italy, for AHF. The criteria for inclusion were a final diagnosis of AHF; a cardiac ultrasound and hs-cTnI evaluations in the ED; and age > 18 yrs. We excluded patients with acute coronary syndrome (ACS). Based on echocardiography and hs-cTnI evaluations, the patients were grouped for (1) preserved (HFpEF) or (2) reduced LVEF (HFrEF) and a a) negative (within the normal range value) or b) positive (above the normal range value) of hs-cTnI, respectively. Results: There was a significant negative relationship between a positive test for hs-cTnI and LVEF. When compared to the group with a negative hs-cTnI test, the patients with a positive test, both from the HFpEF and HFrEF subgroups, were significantly more likely to have an adverse outcome, such as being admitted to the intensive care unit (ICU) or dying in the ED. Moreover, a reduced ejection fraction was linked with a final disposition to a higher level of care. Conclusions: In patients admitted to the ED for AHF without ACS, there is a negative relationship between hs-cTnI and a reduced LVEF, although a significant percentage of patients with a preserved LVEF also resulted to have high levels of hs-cTnI. In the absence of ACS, hs-cTnI seems to be a reliable biomarker of myocardial injury in AHF in the ED and should be considered as a risk stratification parameter for these subjects regardless of the left ventricular function. Further larger prospective studies are needed to confirm these preliminary data.

Background: Results of cardiovascular outcome trials enabled a shift from "treat-to-target" to "treat-to-benefit" paradigm in the management of type 2 diabetes (T2D). However, studies validating such approach are limited. Here, we examined whether treatment according to international recommendations for the pharmacological management of T2D had an impact on long-term outcomes., Methods: This was an observational study conducted on outpatient data collected in 2008-2018 (i.e. prior to the "treat-to-benefit" shift). We defined 6 domains of treatment based on the ADA/EASD consensus covering all disease stages: first- and second-line treatment, intensification, use of insulin, cardioprotective, and weight-affecting drugs. At each visit, patients were included in Group 1 if at least one domain deviated from recommendation or in Group 2 if aligned with recommendations. We used Cox proportional hazard models with time-dependent co-variates or Cox marginal structural models (with inverse-probability of treatment weighing evaluated at each visit) to adjust for confounding factors and evaluate three outcomes: major adverse cardiovascular events (MACE), hospitalization for heart failure or cardiovascular mortality (HF-CVM), and all-cause mortality., Results: We included 5419 patients, on average 66-year old, 41% women, with a baseline diabetes duration of 7.6 years. Only 11.7% had pre-existing cardiovascular disease. During a median follow-up of 7.3 years, patients were seen 12 times at the clinic, and we recorded 1325 MACE, 1593 HF-CVM, and 917 deaths. By the end of the study, each patient spent on average 63.6% of time in Group 1. In the fully adjusted model, being always in Group 2 was associated with a 45% lower risk of MACE (HR 0.55; 95% C.I. 0.46-0.66; p < 0.0001) as compared to being in Group 1. The corresponding HF-CVM and mortality risk were similar (HR 0.56; 95%CI 0.47-0.66, p < 0.0001 and HR 0.56; 95% C.I. 0.45-0.70; p < 0.0001. respectively). Sensitivity analyses confirmed these results. No single domain individually explained the better outcome of Group 2, which remained significant in all subgroups., Conclusion: Managing patients with T2D according to a "treat-to-benefit" approach based international standards was associated with a lower risk of MACE, heart failure, and mortality. These data provide ex-post validation of the ADA/EASD treatment algorithm., (© 2022. The Author(s).)

Background: In clinical practice, anaerobic threshold (AT) is used to guide training and rehabilitation programs, to define risk of major thoracic or abdominal surgery, and to assess prognosis in heart failure (HF). AT of oxygen uptake (V.O 2 ; V.O 2 AT) has been reported as an absolute value (V.O 2 ATabs), as a percentage of predicted peak V.O 2 (V.O 2 AT%peak&#95;pred), or as a percentage of observed peak V.O 2 (V.O 2 AT%peak&#95;obs). A direct comparison of the prognostic power among these different ways to report AT is missing., Research Question: What is the prognostic power of these different ways to report AT?, Study Design and Methods: In this observational cohort study, we screened data of 7,746 patients with HF with a history of reduced ejection fraction (< 40%) recruited between 1998 and 2020 and enrolled in the Metabolic Exercise Combined With Cardiac and Kidney Indexes register. All patients underwent a maximum cardiopulmonary exercise test, executed using a ramp protocol on an electronically braked cycle ergometer., Results: This study considered 6,157 patients with HF with identified AT. Follow-up was median, 4.2 years (25th-75th percentiles, 1.9-5.0 years). Both V.O 2 ATabs (mean ± SD, 823 ± 305 mL/min) and V.O 2 AT%peak&#95;pred (mean ± SD, 39.6 ± 13.9%), but not V.O 2 AT%peak&#95;obs (mean ± SD, 69.2 ± 17.7%), well stratified the population regarding prognosis (composite end point: cardiovascular death, urgent heart transplant, or left ventricular assist device). Comparing area under the receiver operating characteristic curve (AUC) values, V.O 2 ATabs (0.680) and V.O 2 AT%peak&#95;pred (0.688) performed similarly, whereas V.O 2 AT%peak&#95;obs (0.538) was significantly weaker (P < .001). Moreover, the V.O 2 AT%peak&#95;pred AUC value was the only one performing as well as the AUC based on peak V.O 2 (0.710), with an even a higher AUC (0.637 vs 0.618, respectively) in the group with severe HF (peak V.O 2  < 12 mL/min/kg). Finally, the combination of V.O 2 AT%peak&#95;pred with peak V.O 2 and V. per CO 2 production shows the highest prognostic power., Interpretation: In HF, V.O 2 AT%peak&#95;pred is the best way to report V.O 2 at AT in relationship to prognosis, with a prognostic power comparable to that of peak V.O 2 and, remarkably, in patients with severe HF., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)