INTRODUCTION:ESC/ERS guidelines recommend risk stratification of prevalent patients with pulmonary arterial hypertension (PAH) using noninvasive parameters, whereas right heart haemodynamic parameters are left to the clinician's discretion if deemed necessary. The study aimed to define the possible contribution of invasive haemodynamic parameters in predicting both the risk of death from all causes and the risk of clinical worsening (CW) in patients with PAH categorized at follow-up by the noninvasive ESC/ERS 4-strata risk stratification model. METHODS:We evaluated incident patients with PAH enrolled in 11 Italian centres between 2005 and 2021 who had a first follow-up right heart catheterization within 6-12 months of diagnosis. In each noninvasive risk category, patients were subsequently stratified in a subgroup with a good haemodynamic profile if stroke volume index was ⩾38 mL/m2 and right atrial pressure was <8 mmHg and a subgroup with a poor haemodynamic profile if stroke volume index <38 ml/m2 and/or right atrial pressure ⩾8 mmHg. Median follow-up was 3.7 years (interquartile range 1.2-6.8) months. RESULTS:Among low-risk patients (n = 162) survival was similar, but the CW rate was better in the good haemodynamic compared with the poor haemodynamic subgroup (P = .033). Among patients at intermediate-low risk (n = 240), both survival and CW rates were significantly better in the good haemodynamic subgroup compared with the poor haemodynamic subgroup (P = .028 and P = .011, respectively). Among patients at intermediate-high risk (n = 339), the CW rate was similar but survival was significantly better in the good haemodynamic than in the poor haemodynamic subgroup (P = .015). In the high-risk group, only 1 out of 28 patients had a good haemodynamic profile. CONCLUSION:In prevalent patients with PAH, a good haemodynamic profile predicts better survival in intermediate-risk patients and, importantly, a lower CW rate in low-risk patients.

Preclinical research in cancer therapy-related cardiovascular toxicity (CTR-CVT) is a major domain of cardio-oncology and has provided biological explanation for the cardiovascular adverse effects of many cancer therapies. However, the choice of the experimental models to investigate the mechanisms of CTR-CVT is often based on personal experience and opinion, rather than on established principles and available evidence. Moreover, presentation of methods and results is frequently approximate. This Scientific Statement outlines potential quality standards regarding methodology and reporting in preclinical cardio-oncology research, with the goal of promoting accurate, reliable, and reproducible studies. Quality standards are distinguished in first-tier, when considered essential for robustness unless there is a strong justification for their omission, and second-tier standards, when desirable, but not necessary. First-tier standards ensure credible, self-sustaining research, while second-tier ones enhance quality of investigations and accelerate understanding of CTR-CVT. Adherence to the proposed quality standards is expected to benefit researchers embarking on new investigations, facilitate funding allocation, and inform the development of novel oncological therapies, eventually moving cardio-oncology science forward.

AIMS:Several diuretic strategies, including furosemide i.v. boluses (FB) or continuous infusion (FC), are used in acute heart failure (AHF). METHODS AND RESULTS:We systematically searched phase 3 randomized clinical trials (RCTs) evaluating diuretic regimens in admitted AHF patients within 48 h and irrespective of clinical stabilization. We calculated the odds ratio (OR) of FC or FB plus another diuretic (sequential nephron blockade, SNB) compared to FB alone on 24 h weight loss (WL) and worsening renal function (WRF), with a random-effects model with inverse variance weighting. Urine output, hypokalaemia, hyponatremia, and all-cause mortality/rehospitalization were secondary endpoints. In 25 selected RCTs (7149 patients, mean age 68.9 ± 8.7 years, mean left ventricular ejection fraction 38.2 ± 10.7%), FC [OR 1.55 (95% confidence interval 1.39-1.63)], FB plus tolvaptan [OR 1.57 (1.39-1.77)], FB plus SGLT2i [OR 1.23 (1.06-1.42)], and FB plus thiazide [OR 1.63 (1.37-1.94)] were associated with greater WL than FB. FB plus SGLT2i [OR 1.52 (1.19-1.94)] and FB plus acetazolamide [OR 1.81 (1.31-2.49)] were associated with WRF. FB plus thiazide was associated with both WRF [OR 1.78 (1.43-2.21)] and hypokalaemia [OR 1.69 (1.32-2.16)]. Results were consistent in sensitivity analyses considering urine output, RCTs protocol-established furosemide doses, or daily furosemide dose. Congestion/decongestion scores and clinical outcomes were reported in around 50% of RCTs. In an underpowered exploratory analysis, mortality/rehospitalization was non-significantly lower with SGLT2i [OR 0.45 (0.19-1.07)]. CONCLUSION:FC and SNB improve surrogates of response to FB in AHF. SNB is also connoted by WRF and may induce hypokalaemia. The endpoints of diuretic RCTs should be revised and harmonized.

BACKGROUND:In pulmonary arterial hypertension (PAH), echocardiographic ventriculoarterial coupling is traditionally assessed with the ratio between tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP). We aimed to validate the prognostic significance of the fractional area change (FAC)/PASP ratio in PAH. METHODS:This study included patients diagnosed with PAH between April 2001 and November 2023 enrolled in the multicentre FOCUS-PAH registry. Only patients with both FAC and PASP data available at PAH diagnosis were considered. The primary outcome of the study was to assess the predictive value of FAC/PASP for 1-year and 5-year all-cause mortality. RESULTS:347 patients were included. Mean age at PAH diagnosis was 56 ± 17 years; 144 (41.5%) patients were males. The median FAC/PASP ratio at diagnosis was 0.34%/mmHg [IQR 0.25 to 0.52%/mmHg]). 23 (6.6%) patients died during the first year of follow-up and 84 (24.2%) patients died within 5 years. At univariable Cox regression analyses, both low baseline FAC/PASP (i.e., lower than 0.37%/mmHg) and low TAPSE/PASP (i.e., lower than 0.18 mm/mmHg) significantly predicted 1-year all-cause mortality (HR 3.05 [95%CI 1.13-8.22], p-value 0.027, and HR 2.61 [95%CI 1.12-6.10], p-value 0.027, respectively); conversely, low FAC/PASP was associated with significantly higher all-cause mortality at 5 years (HR 1.69 [95%CI 1.08-2.65], p-value 0.023), whereas low TAPSE/PASP ratio was not (HR 1.21 [95%CI 0.77-1.91], p-value 0.405). In a clinical multivariable Cox regression model adjusting for age and World Health Organization functional class, a low FAC/PASP ratio was independently associated with a significantly increased risk of all-cause mortality, both at 1 year (HR 3.00 [95%CI 1.09-8.28], p-value = 0.034) and at 5 years (HR 1.72 [95%CI 1.09-2.72], p-value = 0.021). CONCLUSIONS:In this multicentre, observational registry on patients with incident PAH, low baseline FAC/PASP was associated with significantly higher 1-year and 5-year all-cause mortality.

INTRODUCTION:Pulmonary arterial hypertension (PAH) remains burdened by suboptimal outcomes despite contemporary therapy. Sotatercept showed clinical benefit in STELLAR and ZENITH, yet trial criteria may limit real-world implementation. We quantified real-world eligibility at baseline and during follow-up and identified baseline predictors of non-eligibility. METHODS:We retrospectively analyzed 657 patients with incident PAH (2001-2024), excluding 116 with incomplete follow-up data. Inclusion criteria mirroring STELLAR were WHO functional class II/III, PVR ≥5 WU, and stable background therapy. Exclusion criteria included severe comorbidities or recent cardiovascular events. Multivariable models identified predictors of non-eligibility. Extended eligibility per ZENITH criteria was also assessed. RESULTS:Among 541 analyzed patients, 104 (19%) were ineligible at baseline, mainly due to non-permitted PAH subtypes (71%) or vasoreactivity (29%). During a median 45-month follow-up, cumulative follow-up eligibility (i.e., patients who met criteria at least once after baseline) was 50%, with most exclusions due to PVR <5 WU (53%) or recent therapy changes (53%). Older age (HR 1.011, p = 0.003) and triple therapy (HR 2.841, p < 0.001) predicted non-eligibility, while idiopathic PAH was protective (HR 0.742, p = 0.025). Integrating ZENITH criteria increased eligibility to 56% (+6% vs. STELLAR). CONCLUSION:STELLAR criteria exclude a substantial portion of real-world PAH patients, particularly during follow-up, when therapy intensification is often required per the 7th World Symposium algorithm. ZENITH criteria offer only a modest improvement. Tailored selection strategies and optimal timing for initiation are needed to enhance sotatercept's applicability. Future trials should consider enrichment strategies to broaden treatment eligibility.

BACKGROUND:Desmin is a critical intermediate filament protein in muscle cells that maintains myofibril integrity and proper force transmission. Rare variants in the DES gene are known to cause cardiomyopathy with or without concomitant skeletal myopathy. RESULTS:We identified the c.322G>A p.(Glu108Lys) variant in the DES gene (NM_001927.4) in three unrelated patients, all of whom exhibited arrhythmic manifestations and progressive left ventricular (LV) dysfunction over time. Additionally, two other patients harboring the same variant presented with a nondilated left ventricular cardiomyopathy (NDLVC) phenotype defined by the presence of nonischemic LV scarring or global LV hypokinesia in the absence of LV dilatation. MAJOR FINDINGS:The classification of the DES c.322G>A p.(Glu108Lys) variant has been debated. However, the clinical features observed in the reported cases strengthen the evidence supporting its likely pathogenic role in cardiomyopathy.

INTRODUCTION:The ESC/ERS-recommended four-strata mortality risk stratification of prevalent patients with pulmonary arterial hypertension (PAH) does not incorporate echocardiographic or right heart catheterization (RHC) measures. METHODS:Within the multicentre, observational study FOCUS-PAH, we selected those patients who underwent both echocardiography and RHC (primary analysis) or at least one of these exams (secondary analysis) in the first 12 months after PAH diagnosis and with known vital status over the following 6 years. The association of echocardiographic and RHC variables with all-cause mortality was evaluated by Cox regression. Risk prediction model performance was assessed using ROC curves and net reclassification improvement. RESULTS:The primary analysis included 197 patients (58% female; median age 55 years). In multivariable analyses, right atrial area (RAA, HR 1.09 per 1-cm2 increase) and the percentage change in pulmonary vascular resistance (ΔPVR, HR 1.01 per 1% change) at follow-up were independent predictors of all-cause mortality when added to ESC/ERS categories. The four-strata model AUC was 0.66 and improved to 0.73 (P=0.02), 0.74 (P=0.002), and 0.77 (P=0.0005), respectively, with RAA, ΔPVR, or both. Including RAA and ΔPVR reclassified 25% of patients into more appropriate risk groups. RA pressure, instead of RAA, also predicted mortality (HR 1.08 per 1-mmHg increase) and similarly enhanced ESC/ERS four-strata discrimination (AUC 0.73 vs 0.66, P=0.009). Moreover, RAA (AUC 0.73, P=0.007) and/or ΔPVR (AUC 0.68, P=0.004) improved ESC/ERS risk prediction in the secondary analysis including 394 patients. CONCLUSIONS:Adding one echocardiographic or RHC parameter interchangeably improves mortality risk prediction by the ESC/ERS four-strata model in PAH.

Background and Aims The aim of this study was to evaluate whether echocardiography-derived phenotypes describing different degrees of right ventricular (RV) remodelling and dysfunction add prognostic information to that of current risk stratification tools in patients with pulmonary arterial hypertension (PAH) at first follow-up.Methods In 11 centres of the Italian Pulmonary Hypertension NETwork (IPHNET), data were prospectively collected from patients with PAH who underwent re-evaluation between 6 and 12 months after diagnosis. Echocardiographic variables were combined a priori to define four phenotypes representing different degrees of RV dilatation and right ventricular-pulmonary arterial (RV-PA) coupling: a mildly dilated right ventricle with preserved RV-PA coupling defined phenotype-1; a mildly dilated right ventricle with poor RV-PA coupling defined phenotype-2; a severely dilated right ventricle with preserved RV-PA coupling defined phenotype-3; a severely dilated right ventricle with poor RV-PA coupling, either with or without tricuspid regurgitation of moderate degree or more, defined phenotype-4. Patients were followed up for all-cause death for a median of 3.7 years.Results These echocardiographic phenotypes were present in all European Society of Cardiology/European Respiratory Society or REVEAL 2.0 risk groups except for the high-risk groups, which included only phenotype-3 and phenotype-4. In each risk group, RV phenotype-4 identified patients with a poorer prognosis; RV phenotype-1 identified patients with better survival in intermediate risk groups.Conclusions Echocardiography-derived phenotypes describing different degrees of RV remodelling and dysfunction provide prognostic information which is independent of and additional to the clinically defined risk in PAH patients at first follow-up.

AIMS:Heart failure (HF) and acute myocardial infarction (AMI) may contribute to cancer development through shared and disease-related pathophysiological pathways. We investigated the mid-term risk of incident cancer in patients with HF or AMI using a large, real-world dataset. METHODS:Adults with a first hospitalization for acute HF or AMI between October 2015 and October 2024 were included from the TriNetX Global Collaborative Research Network. Patients with prior or concurrent cancer were excluded. Each cohort was matched 1:1 with controls without HF or AMI using propensity score matching. The primary end-point was any new cancer diagnosis occurring during follow-up, starting 6 months after the index hospitalization. RESULTS:After matching, 120 783 patients with HF and 7896 patients with AMI were included. Over a median follow-up of 13 months in the HF cohort and 16 months in the AMI cohort (after the 6-month landmark), both groups showed an higher incidence of cancer compared with controls (HF: HR 2.80 [95% CI, 2.69; 2.91]; AMI: HR 2.02 [95% CI, 1.71; 2.39]; both P < .001). In both cohorts, the excess risk was more pronounced for haematologic than for solid malignancies (HF: HR: 6.78 vs 2.53; AMI: HR: 4.45 vs 1.77). HF with preserved ejection fraction was associated with a slightly higher cancer incidence than HF with reduced or mildly reduced ejection fraction (HR 1.10 [95% CI, 1.04; 1.17], P = .002), whereas no difference was observed between ST and non-ST segment elevation AMI. CONCLUSIONS:In this large, real-world cohort, both HF and AMI were associated with an increased incidence of cancer, particularly haematologic malignancies. HF was associated with a greater excess risk than AMI. These findings are hypothesis-generating and warrant further investigation.

AIMS:The pathogenesis of pulmonary hypertension associated with heart failure (PH-HF) is partially understood. To advance knowledge in this regard, the investigator-initiated, public-funded, prospective, translational stuDy to dISseCt remOdeling of capillaries and Veins in pulmonary hypErtension associated with heaRt failure (DISCOVER PH-HF) will assess biomarkers of PH-HF in pulmonary capillary and venous (PCV) and peripheral venous blood taken during right heart catheterization (RHC). This report presents the design of DISCOVER PH-HF and the baseline characteristics of the included patients. METHODS:DISCOVER PH-HF enrolled heart failure patients scheduled for transcatheter edge-to-edge repair (TEER) of severe mitral regurgitation. PCV and peripheral venous whole blood was collected during RHC within 48 h before mitral regurgitation (MR)-TEER, and processed into plasma/serum aliquots and peripheral blood mononuclear cell (PBMC) pellets. Then, the samples were centralized to a core biobank. Follow-up entails visits at 90 ± 10 and 180 ± 10 days and - optionally - a second RHC with collection of PCV and peripheral venous blood within 30 days from the second follow-up evaluation. A proteomic analysis of part of the PCV and peripheral plasma is already planned. RESULTS:Seven patients without pulmonary hypertension at RHC, 12 patients with isolated postcapillary pulmonary hypertension, and 18 patients with combined postcapillary and precapillary pulmonary hypertension were recruited, leading to a total of 148 PCV and 148 peripheral plasma aliquots, 111 PCV and 111 peripheral serum aliquots, and 37 PBMC pellets. CONCLUSION:DISCOVER PH-HF has generated a limited-size, but unique biobank of RHC-derived PCV and peripheral venous blood samples and PBMCs, linked to clinical and hemodynamic phenotyping, which will allow the exploration of biomarkers of PH-HF and its subtypes.

Altered cardiac and systemic metabolism is a hallmark of heart failure (HF). In the failing heart, cardiomyocytes develop alterations in substrate preference, mitochondrial oxidative metabolism, and the shuttling of high-energy phosphates from mitochondria to the cytosol that compromise energetic efficiency and contribute to disease progression. At the systemic level, neurohormonal activation plays a dominant role in HF with reduced ejection fraction, whereas HF with preserved ejection fraction is shaped by the clustering of multiple comorbidities, such as diabetes, obesity and hypertension, which disrupt the physiological crosstalk between the heart and metabolically active organs. This review provides a perspective on cardiac metabolism in HF. We delineate the specific alterations in substrate metabolism that characterize HF with reduced ejection fraction versus HF with preserved ejection fraction, examine the impact of interorgan communication on myocardial function, and highlight how the benefits of emerging HF therapies, including sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, may be mediated, at least in part, through the restoration of metabolic homeostasis.

AIM:To assess the impact of hyperkalemia on the optimization of heart failure therapy and clinical outcomes in a specialized tertiary care center. METHODS:We retrospectively analyzed data from 690 heart failure patients, categorized into hyperkalemia and no-hyperkalemia groups based on the occurrence of serum potassium greater than 5 mEq/l at any time during follow-up. Baseline characteristics and long-term therapy patterns were compared. Predictors of hyperkalemia were evaluated through logistic regression analysis. Survival outcomes were assessed using Kaplan-Meier curves and Cox proportional hazards models. Four sensitivity analyses were performed, considering moderate hyperkalemia (K ≥ 5.5 mEq/l), propensity score-matched cohorts, heart failure with reduced ejection fraction (HFrEF), and HFrEF population after the approval of sacubitril/valsartan in Italy. RESULTS:Hyperkalemia occurred in 16% of patients and was associated with chronic kidney disease and lower ejection fraction. Baseline use of renin-angiotensin-aldosterone system inhibitors (RAASi), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) was similar between groups, with consistent prescription patterns during follow-up. Approximately 75% of patients in both groups maintained stable RAASi therapy, defined as continuous treatment throughout follow-up. Survival curves showed no significant difference between hyperkalemia and no-hyperkalemia patients. However, those maintaining or initiating RAASi therapy had significantly better long-term survival, regardless of hyperkalemia status. Hyperkalemia was not an independent predictor of mortality [hazard ratio 1.04, 95% confidence interval (CI) 0.72-1.52, P = 0.83], while consistent RAASi use was strongly protective (hazard ratio 0.48, 95% CI 0.33-0.71, P < 0.001). Similar results were observed for secondary endpoints, as well as across all sensitivity analyses. CONCLUSION:In a structured heart failure outpatient setting, hyperkalemia is not an insurmountable barrier to maintaining guideline-directed therapy. Continued RAASi use confers significant prognostic benefit, highlighting the importance of specialized follow-up.