BACKGROUND:Cardiac amyloidosis (CA) is an increasingly recognized cause of worsening heart failure (WHF) and is associated with poor outcomes, yet patients with CA-related WHF remain poorly characterized in real-world outpatient settings. METHODS:Patients with CA-related WHF, followed in a dedicated WHF Day Hospital clinic, were compared with matched (for age, sex, ejection fraction) non-CA WHF controls. Clinical outcomes included all-cause mortality and HF hospitalization. Frailty was assessed using the Frailty Index (FI) alongside functional and patient-reported measures. Associations with all-cause mortality were evaluated using Kaplan-Meier and Weibull models stratified by CA status. RESULTS:Among 154 WHF patients, 21 had CA and were matched to 42 non-CA controls. Median age was 81 (76-85) years, 23.8% were females. All-cause mortality was significantly higher in the CA-related WHF cohort, with an estimated occurrence of 72.0% vs. 25.9% (95%CI 50.7%-89.9% vs. 14.5%-43.7%) at 120 weeks (log-rank p = 0.001). As expected, in CA patients, the FI ≥ 0.38 and impaired health-related quality of life (EQ-5D) were associated with mortality (log-rank p = 0.002, p = 0.012, respectively). Among biomarkers, natriuretic peptides did not significantly discriminate risk among CA-related WHF, while discriminating in non-CA WHF. sST2 showed a similar prognostic relevance at the upper quartile in CA and non-CA WHF (log-rank p = 0.028, p = 0.009, respectively). CONCLUSIONS:In real-world WHF, despite comparable baseline biomarker profiles and frailty burden, CA identifies a subgroup with an adverse prognosis, worse than comparable patients with a different etiology. Frailty and biomarker profiles show etiology-specific prognostic behavior, supporting a phenotype-driven risk stratification strategy in WHF.

INTRODUCTION:Heart failure with preserved or mildly reduced ejection fraction (HFmrEF/HFpEF) is a complex syndrome common in elderly patients with multiple comorbidities. Age and sex affect the clinical phenotypes and outcomes of this condition. This study aimed to identify age- and sex-specific factors influencing prognosis in elderly patients with HFmrEF/HFpEF to improve risk stratification and guide personalized treatment. METHODS:This observational, ambispective study was conducted at Papa Giovanni XXIII Hospital, Bergamo, from June 2017 to August 2022, enrolling patients >65 years with HFmrEF/HFpEF [New York Heart Association (NYHA) Class II-IV] according to ESC guidelines. Data collected included demographics, medical history, echocardiograms, and lab tests. Follow-up lasted at least 1 year, with outcomes defined as a composite of all-cause death, urgent heart transplant, HF hospitalization, and emergency department referral for decompensated HF. Findings were validated using the Swedish HF registry with a similar cohort. RESULTS:Among 2263 HF patients, 971 HFmrEF/HFpEF patients (56.8% males, mean age 79.2 years) were analysed. Males had a higher prevalence of cardiovascular risk factors (e.g. diabetes, obesity, coronary artery disease). The composite outcome occurred more frequently in males (20.6 vs 17.14 per 100 patient years; IRR = 1.20, P = .035). Multivariable analysis identified male sex (HR 1.40, 95% CI 1.13-1.73), age >80 years (HR 1.91, 95% CI 1.22-3.00), higher NYHA class, chronic kidney disease, and severe valvular heart disease as independent predictors of worse outcomes. Males had a 40% higher risk of the outcome compared with women (HR 1.40, 95% CI 1.13-1.73), while patients >80 years old had nearly double the risk compared with those aged 65-70 (HR 1.91, 95% CI 1.22-3.00). The validation analysis in the SwedeHF, adapting the same multiple Cox regression model on 20 950 selected patients, median age 79 years and 57.8% men, and observed between January 2017 and August 2022, showed similar independent risk factors for the composite outcome. CONCLUSION:This study highlights significant sex disparities in elderly HFmrEF/HFpEF patients, with higher age and male sex being an independent predictor for poor outcomes. These findings emphasize the need for personalized treatment strategies based on these demographic factors.

In the field of heart failure, sodium-glucose cotransporter 2 inhibitors (SGLT2-i) have demonstrated robust efficacy and have received a Class I, Level A recommendation for reducing the risk of heart failure hospitalizations and cardiovascular mortality across the entire spectrum of left ventricular ejection fraction. The therapeutic effect occurs early, with the first statistical significance observed as soon as 12-28 days after treatment initiation. Evidence suggests that early introduction during hospitalization may reduce the short-term risk of cardiovascular death or worsening heart failure. SGLT2 inhibitors display a favourable safety and tolerability profile, without an increased incidence of adverse events compared with placebo. Furthermore, they are indicated for the treatment of type 2 diabetes mellitus and chronic kidney disease, irrespective of the presence of heart failure. Therefore, we propose that in patients presenting with signs and/or symptoms of heart failure and elevated natriuretic peptide levels, SGLT2 inhibitors may be initiated even before echocardiographic confirmation of the diagnosis. Given the favourable risk-benefit profile, this approach may help avoid therapeutic delay, which could otherwise be associated with an increased risk of early adverse events, and may ultimately improve prognosis.

Cardiac glycosides represent one of the oldest therapeutic pillars in medicine, although their role has progressively diminished in the modern era of neurohormonal therapy for heart failure (HF). Following publication of the Digitalis Investigation Group (DIG) trial in 1997, no randomized clinical trials evaluating this drug class were conducted for almost three decades, while observational studies and meta-analyses accumulated, often yielding conflicting results. The DIGIT-HF randomized clinical trial (2025) addressed a major unmet need by evaluating digitoxin in patients with HF with reduced ejection fraction in the contemporary era of guideline-directed medical therapy. Treatment with digitoxin was associated with favourable outcomes, including a reduction in the composite endpoint of all-cause mortality and hospitalizations for HF, thereby reopening a long-standing debate on the role of digitalis, which had remained marginal for many years. This article reviews the history of digitalis, the main evidence generated over recent decades, the evolution of clinical guidelines from 1997 to 2022, and the conceptual and clinical implications of the DIGIT-HF trial.

Background Worsening heart failure (WHF) patients experience frequent hospitalizations and reduced quality of life (QoL). Palliative care (PC) is recognized as essential for HF management, but its integration represent an unmet need. Objective This study aimed to assess PC needs in WHF patients using the Palliative Care Needs Assessment Tool (PCNAT), and correlate the findings with biomarkers, clinical outcomes and prognostic scores. Methods 144 WHF patients were prospectively evaluated at the dedicated facility in Papa Giovanni XXIII Hospital in Bergamo, Northern Italy. Patients were stratified by the highest tertile of PCNAT, identifying two groups with PCNAT≥10 or < 10. The primary outcome was the composite of all-cause mortality, HF hospitalization (HHF), emergency room (ER) visits or urgent clinical evaluation and referral to PC specialist. Results The median follow-up was 91 days. Thirty-three percent of patients (47/144) had a PCNAT score ≥ 10. These patients had lower body mass index, worse NYHA class and more comorbidities, including chronic kidney disease, diabetes, and atrial fibrillation. They also showed worse biomarkers and lower guideline directed medical therapy use, with higher diuretic doses. Prognostic scores and QoL were significantly correlated with PCNAT score. Kaplan-Meier analysis confirmed higher clinical event rates in patients with higher PCNAT scores. Univariate and multivariate Cox regression analysis showed that PCNAT score was a significant independent predictor of clinical outcomes. Conclusion PCNAT effectively stratifies WHF patients by PC needs, correlating with poorer clinical outcomes. Early integration of PC could improve patient-centred care, highlighting the need for systematic referral pathways.

Background Although treatment options for heart failure (HF) have improved, advanced HF (AdHF) remains a challenging condition, impacting over 10% of patients with a poor prognosis. In severe cases, patients may experience resistance to or intolerance of conventional therapies, leading to frequent hospitalisations and a heightened risk of death. Vericiguat, a novel treatment for HF with reduced ejection fraction (HFrEF), has shown promise in improving outcomes for patients with worsening HF. The VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial demonstrated that vericiguat can reduce the risk of adverse events in patients with EF<45% following a worsening HF event. However, its safety and efficacy in AdHF patients previously receiving chronic levosimendan infusions remain unclear. Methods and results In this prospective study, we evaluated the safety and tolerability of vericiguat in AdHF patients treated with monthly levosimendan infusions at our clinic. Among 18 patients, 8 were eligible for vericiguat, which was associated with better echocardiographic findings, improved quality of life and lower 1-year mortality compared with non-eligible patients. However, 37.5% of patients discontinued the drug due to symptomatic hypotension, highlighting a key challenge in managing this fragile population. Despite this, vericiguat was generally well-tolerated, and no severe adverse effects were observed. Discussion This study provides the first prospective evidence supporting the safe use of vericiguat in AdHF patients on chronic levosimendan. However, careful monitoring for hypotension is essential, and titration may be more difficult in this population. Further research is needed to optimise treatment strategies for these high-risk patients.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to reduce cardiovascular (CV) mortality and heart failure (HF) hospitalizations, independently from left ventricular ejection fraction (EF). Their efficacy has been assessed both in patients with reduced and preserved EF, with notable benefits in renal outcomes as well. The initiation of SGLT2i in the early phase of hospitalization for acute HF has proven to be safe and beneficial. The EMPULSE and DICTATE-AHF trials support early empagliflozin and dapagliflozin use, respectively, reducing worsening HF events, improving quality of life, and enhancing diuretic efficiency. Notably, these benefits emerge shortly after the initiation of therapy, underscoring the importance of early integration into guideline-directed medical therapy (GDMT). Despite concerns regarding deterioration of renal function, SGLT2i appear to be safe even in patients with low estimated glomerular filtration rates (eGFR). Data suggest that SGLT2i benefits persist without increased safety risks, reassuring clinicians of their efficacy in patients experiencing renal decline. Concerns about volume depletion induced by SGLT2i have also been addressed, with documented enhanced diuresis without adverse renal impacts. Moreover, SGLT2i have been associated with a lower risk of hyperkalaemia events, thus allowing for better optimization of GDMT, including the use of mineralocorticoid receptor antagonists. Overall, these findings highlight the broad CV, renal, and metabolic benefits of SGLT2i, advocating for their early and widespread use in HF management, regardless of EF or eGFR.

Excess or dysfunctional adipose tissue is a key pathophysiological factor in cardiovascular-kidney-metabolic syndrome. However, until very recently, there was no evidence that pharmacological treatments for obesity could significantly impact major cardiovascular outcomes. Recently, the SELECT study represented the first, and to date the only, cardiovascular outcome trial conducted in the context of pharmacological treatment for obesity, and subcutaneous (s.c.) semaglutide 2.4 mg is the first molecule capable of leading to a statistically significant reduction in the primary composite outcome of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in obese, non-diabetic patients with pre-existing cardiovascular disease. Furthermore, in the context of heart failure with preserved ejection fraction with obesity-related phenotype, s.c. semaglutide 2.4 mg and tirzepatide have been shown to improve prognosis, functional capacity, and quality of life. The main limiting factors for the implementation of semaglutide and tirzepatide are represented by the suboptimal adherence to treatment due to gastrointestinal intolerance, as well as by the reduced accessibility and economic sustainability. It is therefore necessary to wait to see how the drug regulatory agencies and international guidelines will implement the evidence of semaglutide and tirzepatide in the specific setting of the cardiovascular risk of obese patients.

Background The exercise assessment of the right ventricular‐pulmonary arterial (PA) coupling adds diagnostic and prognostic value in patients with heart failure. In patients with ischemic mitral regurgitation undergoing surgery, data on the exercise assessment of the right ventricular‐PA coupling are not available. Resting and exercise echocardiographic predictors of functional outcome in patients with ischemic mitral regurgitation were tested. Methods Six‐minute walking test and exercise echocarrdiogram performed at baseline, at 1 years, and at a median follow‐up of 6 years (interquartile range, 3.70; range, 4.5–8) on 50 patients (67±8 years; ejection fraction: 35±5%) undergoing valve replacement or repair. Linear mixed models were used to evaluate the predictive value of preoperative echocardiographic parameters on the longitudinal distribution of the 6‐minute walking test. Results Preoperative exercise tricuspid annular plane systolic excursion (TAPSE)/PA systolic pressure strongly correlated with the long‐term 6‐minute walking test (r=0.81, P<0.01). The receiver operating characteristic analysis found a preoperative exercise TAPSE/PA systolic pressure <0.34 predicted the lowest quartile of the 6‐minute walking test in the long term (sensitivity: 79%; specificity: 100%) as well as a composite outcome of heart failure and death from any cause (positive predictive value: 91.3%, negative predictive value: 100%). On multivariable analysis, TAPSE and TAPSE/PA systolic pressure were significantly associated with a better long‐term 6‐minute walking test. Conclusions A preoperative exercise TAPSE/PA systolic pressure <0.34 predicts a poor functional performance and a higher likelihood of clinical adverse events. In patients with ischemic mitral regurgitation the exercise right ventricular ‐PA coupling could improve risk stratification. Larger studies are needed.

Moderate aortic stenosis is associated with a worse prognosis than milder degrees. Pathophysiologically, this condition in a dysfunctional ventricle could lead to a further mechanism of haemodynamic worsening, so its treatment should lead to clinical advantages for the patient. The low risk of complications associated with percutaneous correction of aortic valve disease (transcatheter aortic valve implantation) should also be considered, which would seem to favour an interventional approach even in the aforementioned condition. However, sparse data and small population studies make this approach still controversial. Three randomized controlled trials are underway to shed definitive light on the topic.

Right ventricular dysfunction is a prognostic factor for morbidity and mortality across a broad spectrum of cardiovascular diseases. While the role of the right ventricle in surgical patients has emerged, the prognostic impact of right ventricular dysfunction remains unclear in a large cardiac surgery population. We reviewed the existing literature about the role of right ventricular dysfunction in adults undergoing different kinds of cardiac surgery either present before or developed after surgery itself. Pre- and post-operative right ventricular dysfunction has demonstrated substantial prognostic implications. However, there remains a lack of consensus regarding its definition and diagnostic criteria. The available literature is limited to small-sized studies, underscoring the need for studies with larger populations.

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterised by the presence of diastolic dysfunction and elevated left ventricular filling pressure, in the setting of a left ventricular ejection fraction of at least 50%. Despite the epidemiological prevalence of HFpEF, a prompt diagnosis is challenging and many uncertainties exist. HFpEF is characterised by different phenotypes driven by various cardiac and non-cardiac comorbidities. This is probably the reason why several HFpEF clinical trials in the past did not reach strong outcomes to recommend a single therapy for this syndrome; however, this paradigm has recently changed, and the unmet clinical need for HFpEF treatment found a proper response as a result of a new class of drug, the sodium–glucose cotransporter 2 inhibitors, which beneficially act through the whole spectrum of left ventricular ejection fraction. The aim of this review was to focus on the therapeutic target of HFpEF, the role of new drugs and the potential role of new devices to manage the syndrome.

Background:The differential diagnosis of tricuspid masses remains challenging. Case summary:This case involves the incidental detection of a lesion with a non-solid appearance, exhibiting the characteristic 'finger-in-glove' and 'garland-like' morphology, resembling a blind-ended protrusion of the tricuspid leaflet. This presentation is consistent with a tricuspid valve aneurysm, without significant associated stenosis or regurgitation. Discussion:Given the lesion's morphological features, the patient's asymptomatic status, and the absence of a precipitating event suggestive of an alternative diagnosis, we concluded that the most likely diagnosis is aseptic tricuspid valve aneurysm. Following a multidisciplinary heart team discussion, surgical intervention was deemed unnecessary.

BACKGROUND:Frailty and comorbidity influence the therapeutic approach in everyday clinical practice. The DOACs genericization opens a reflection on their differences from a pharmacological and bioavailability point of view, particularly in elderly frail patients. The aim of this project was to create a national Delphi consensus on the topic of the use of DOACs for atrial fibrillation (AF) in such patients, in light of the genericization of the class. METHODS AND RESULTS:The consensus dealt with 3 main topics: a) efficacy and safety of DOACs in elderly and/or frail patients; b) therapeutic choice in specific frailty scenarios; c) DOACs genericization. 56 cardiologists, two internists and two neurologists from Italy expressed their level of agreement on each statement by using a 5-point Likert scale (1: strongly disagree, 2: disagree, 3: uncertain, 4: agree, 5: strongly agree). A positive consensus was reached if the percentage of agreement (vote 1-2, positive consensus) or disagreement (votes 4-5, negative consensus) was >66%; otherwise, no consensus was reached. Results are displayed accordingly. CONCLUSIONS:After 10 years of everyday clinical management of DOACs for AF, specific elements differentiating a molecule from another, either for efficacy or for safety, are consolidated. However, some uncertainties still exist in particular contexts, such as chronic kidney disease or cancer patients. Clinicians have an unsure attitude towards generic drugs, because clinical practice is lacking as well as a proper knowledge of the topic. Albeit being an alternative, the choice of the generic drug must remain the responsibility of the clinician.

Background: The treatment of secondary ischemic mitral regurgitation is challenging and predictors of functional and clinical outcome are pivotal in order to define the best therapeutic strategy. In these patients there is growing evidence that assessing the right ventricular (RV)-pulmonary arterial (PA) coupling during exercise has additive diagnostic and prognostic value. To date, no data are available as regard the exercise assessment of the RV- PA coupling in patients undergoing surgery for ischemic mitral regurgitation Research Question: in patients with ischemic mitral regurgitation the evaluation of the exercise RV-PA coupling could play a crucial role for patients selection and prognosis Aim: to test resting and exercise echocardiographic predictors of functional capacity and clinical outcome in patients referred to surgery Methods: A 6-minute walking test and exercise stress echo performed at preoperative baseline, at 1 year and at median FU of 6 years (IQR: 3.70; range: 4.5– 8) on 50 patients (age: 67 ± 8 year; EF: 35 ± 5%), undergoing surgery by valve replacement or repair. Generalized linear mixed models were used to evaluate the predictive value of preoperative echocardiographic parameters on the longitudinal distribution of the 6-MWT. Results: Preoperative exercise tricuspid annular plane systolic excursion (TAPSE)/ pulmonary artery systolic pressure (PASP) ratio showed the strongest correlation with long-term six-minute walking test (r=0.81, p< 0.01) (Figure 1).The receiver operating characteristic analysis found that a preoperative exercise TAPSE/PASP < 0.34 predicted the lowest quartile of six-minute walking test at long-term (sensitivity: 79%; specificity: 100%) (Figure 2) and a composite clinical outcome of heart failure and death for any cause (PPV 91.3%, NPV 100%). On multivariable analysis TAPSE (Estimates:4.05; SE:0.90; p < 0.01) and TAPSE/PASP ratio (Estimates:106.9; SE: 31.54, p <0.01) were significantly associated with better long-term six-minute walking test (Table 1) Conclusions: A preoperative exercise TAPSE/PAPS < 0.34 predicts a poor six-minute walking test performance and an higher likelihood of clinical adverse events over time. In patients with secondary ischemic mitral regurgitation the exercise RV-PA coupling could add value in order to improve risk stratification. These findings need to be comfirmed by larger studies

The 2021 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure (HF) have abandoned the sequential approach for optimal drug therapy and propose four drug classes (enzyme inhibitors conversion agents, angiotensin receptor antagonists, beta-blockers, and sodium-glucose cotransporter inhibitors 2) to be initiated and titrated in all patients with an ejection fraction <35%. This new approach offers advantages such as rapid introduction and titration, better tolerability, and early instrumental re-evaluation. In the VICTORIA study, the molecule vericiguat, a soluble guanylate cyclase activator, was shown to reduce the composite outcome of death from cardiovascular causes and first hospitalization for HF in a high-risk population. An additional randomized clinical trial (VICTOR) is ongoing to evaluate the efficacy and safety of vericiguat in a population with HF on optimized therapy and with no recent episodes of stabilization.

Le linee guida, pur costituendo un punto di riferimento oggettivo per operare scelte terapeutiche corrette, contengono delle zone grigie, dove le raccomandazioni non sono supportate da solide evidenze. Nel V Congresso Nazionale Grey Zones tenutosi a Bergamo in giugno 2022, si è cercato di evidenziare alcune delle principali zone grigie della Cardiologia e, attraverso un confronto tra esperti, di trarre delle conclusioni condivise che possano illuminare la nostra pratica clinica. Il presente manoscritto contiene gli atti del simposio riguardante le incertezze sui fattori di rischio cardiovascolare. Il manoscritto ricalca l’impostazione del convegno, con una iniziale revisione delle attuali linee guida inerenti l’argomento seguita dalla presentazione, da parte di esperti, delle argomentazioni a favore (White) o contro (Black) relativamente a quelli che sono stati individuati come i principali “gaps in evidence” sull’argomento. Per ogni punto è successivamente riportato il “verdetto” derivante dalla votazione degli esperti e del pubblico, un commento riassuntivo ed infine gli Highlights, che costituiscono dei pratici “take home messages” da utilizzare nella pratica clinica quotidiana. Il primo “gap in evidence” di cui si discute è l’indicazione alla terapia con inibitori del cotrasportatore sodio-glucosio di tipo 2 (SGLT2i) per tutti i pazienti diabetici ad elevato rischio cardiovascolare. Il secondo esamina la possibilità di utilizzare gli SGLT2i in tutti i pazienti con insufficienza renale, indipendentemente dall’albuminuria. L’ultimo “gap in evidence” riguarda il possibile utilizzo degli agonisti del recettore del glucagon-like peptide-1 come arma contro l’obesità.

Sciatti, Edoardo; Merlo, Anna; Grosu, Aurelia; Balestrieri, Giulio; Veritti, Umbertina; Duino, Vincenzo; Senni, Michele Author Information