Acute heart failure (AHF) is commonly regarded as a worsening stage of chronic heart failure (CHF), yet the hemodynamic transition to decompensation remains incompletely defined. This study evaluated whether a noninvasive physiology-guided approach based on venous return (VR)-cardiac output (CO) balance can provide a framework to characterize transitional circulatory states preceding overt AHF. A total of 193 patients with CHF, hypertensive heart disease, or AHF were analyzed. Mean circulatory filling pressure and right atrial pressure were estimated noninvasively using inferior vena cava diameter indexed to body surface area (IVC/BSA) and extracellular-to-total body water ratio (ECW/TBW), respectively. VR-CO imbalance was quantified using a composite mismatch index. The distribution of VR-CO mismatch demonstrated a bimodal pattern on Gaussian mixture modeling, with two components (means ± SD: 2.25 ± 0.96 and 5.25 ± 2.61). All overt AHF cases were localized within the higher-mismatch component. Intermediate states exhibited increasing mismatch while maintaining relatively preserved forward flow, consistent with buffered circulatory states. A subset of patients exhibited marked hemodynamic mismatch without clinical congestion, representing a highly buffered pre-decompensated state. AHF may represent a failure of circulatory compensation in which venous-return loading exceeds the capacity of forward flow. A noninvasive VR-CO framework reveals a continuum from compensated to buffered to overtly decompensated states and identifies a previously unrecognized highly buffered state preceding clinical deterioration. This physiology-guided approach may enable earlier detection of circulatory instability and provide a quantitative framework for risk stratification and therapeutic monitoring.

To define incident heart failure (HF) risk in ischaemic stroke/TIA survivors. The secondary aims were to define the association of HF with all-cause mortality in stroke survivors and to describe their cardiac magnetic resonance (CMR) findings. This was a prospective cohort study using the UK Biobank (UKBB) cohort of individuals aged 40 to 69-years-old. We excluded individuals with prior HF and stratified them by history of ischaemic stroke/TIA. The main outcome was incident HF as defined by hospital admissions coded for heart failure. Secondary outcomes were all-cause mortality, myocardial infarction and CMR findings. We included 405,406 individuals (age 56.5 years, 45.6% males). Over 13.7 years, 15,565 individuals experienced incident HF. Stroke survivors had an overall HR of 3.6 (95% confidence interval 3.3 to 3.8, p<0.0001) for HF hospitalization and an adjusted HR of 1.4 (95% confidence interval 1.3 to 1.5, p<0.0001). The risk of HF hospitalization was greater than the risk of myocardial infarction (12.6% vs 5.4%). Stroke survivors with HF had a lower LVEF and higher LV mass than those without HF. Incident HF in stroke survivors was associated with a HR of 1.8 (95% confidence interval 1.6 to 1.9, p<0.0001) for mortality. Incident HF is common in stroke survivors and strongly associates with mortality. The risk of HF varies greatly depending on underlying risk factors. Exploratory analyses suggest that stroke survivors with HF may have a lower ejection fraction phenotype. Future trials of HF preventive therapy in high-risk stroke survivors are warranted.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are currently recommended as one of the four pillars of treatment in heart failure (HF) with reduced ejection fraction (HFrEF). Following the approval of dapagliflozin in 2020, real-world data are relevant for the medical community and payers. This study aimed to characterize the patient population with dapagliflozin initiated for HFrEF in clinical practice in 9 countries from Central Eastern Europe and the Baltic Area (CEE-BA). EVOLUTION-HF CEE-BA is a multicentre, multi-country, observational, longitudinal study conducted in 102 centres in Bulgaria, Croatia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, and Slovenia. All treatment decisions were at the discretion of the patient's healthcare providers, based on the locally approved product information and routine clinical practice. Patients with type 1 diabetes, prior treatment with dapagliflozin or other SGLT2i, and initiation of dapagliflozin outside the approved HFrEF indication were excluded. The baseline period covered 12 months prior to dapagliflozin initiation, with prospective follow-up continuing up to 12 months or until loss to follow-up, death, or study discontinuation, whichever occurred first. Descriptive statistics and Kaplan-Meier methods were used. A total of 1131 patients with HFrEF were included in the full analysis set. Ischaemic aetiology was present in 52% of patients. The mean left ventricular ejection fraction was 32%. The most frequent comorbidities were atrial fibrillation (46%), type 2 diabetes (37%), and chronic kidney disease (29%). At the time of dapagliflozin initiation, 93% of patients received any combination of a renin-angiotensin-aldosterone system inhibitor (RAASi), beta-blocker (BB), or mineralocorticoid receptor antagonists (MRA). Of all patients, 60% received concomitantly all three classes plus dapagliflozin for their HFrEF. Except for dapagliflozin, which was administered as 10 mg/day, optimal doses were recorded for 14% for any RAASi, 17% for BB, and 25% for MRA. At 6- and 12-month follow-up, maintenance of dapagliflozin treatment was recorded in 95% and 96% of patients, respectively. The real-world median time to discontinuation of dapagliflozin has not been reached. The percentage of patients receiving all four classes recommended in HFrEF remained stable over the study period. Adverse events were reported spontaneously, as in routine clinical practice in each centre. This large non-interventional study provides a contemporary perspective of the treatments used in HFrEF over 1-year follow-up. Despite high dapagliflozin persistence rates, a low proportion of patients received complete guideline-directed medical therapy in optimal doses. Improvement of HF management decisions across the CEE-BA region is warranted.

Myocardial fibrosis (MF) represents a key player in transition to heart failure in aortic stenosis (AS), and AS patients with high baseline MF are at increased risk to die within 12 months after transcatheter aortic valve implantation (TAVI). Therefore, the objective of the Reduce-MFA DZHK25 trial is to assess the impact of anti-fibrotic therapy on regression of AS-induced MF after TAVI in patients with high baseline fibrotic burden. Key secondary objectives include reverse LV remodelling, symptomatic improvement, and reduction of mortality and cardiac hospitalizations. Reduce-MFA represents a national, prospective, randomized, parallel group, controlled, open-label interventional multi-centre trial with blinded outcome assessment (PROBE design) enrolling patients with severe AS scheduled for TAVI. The anti-fibrotic principles employed are spironolactone and low-dose dihydralazine (epigenetic reactivation of anti-fibrotic genes). Baseline burden and course of MF are assessed by cardiac MRI (CMR). Since CMR-derived extracellular volume fraction (ECV%) ≥ 25.9% emerged as independent mortality predictor, only patients above this cut-off are randomized into three parallel groups: (i) Standard of Care alone, (ii) + spironolactone, (iii) + spironolactone + low-dose dihydralazine, each for 12 months. To assess MF regression, CMR is repeated after 12 months. MF is assessed by quantification of the ECV-derived LV matrix volume using T1 mapping. Additionally, measures of heart failure (Kansas City Cardiomyopathies Quality of Life Questionnaire, 6MWT, NT-proBNP, NYHA class) and reverse cardiac remodelling are evaluated at 6 and 12 months. Mortality and cardiac hospitalizations are recorded. The recruitment was recently completed with 384 enrolled and 153 randomized patients. The study findings have the potential to inform the development of a novel adjuvant therapy to improve the prognosis of specific AS patients.

Early identification of patients with cardiogenic shock (CS) who will require temporary mechanical circulatory support (MCS) remains challenging. Right ventricular (RV) dysfunction is common in CS and affects hemodynamic stability. RV free wall longitudinal strain (RV FWLS) is a sensitive marker of myocardial dysfunction, but its role in predicting MCS escalation in CS remains unclear. In this single-center retrospective study, patients admitted with CS between January 2023 and December 2025 were screened. Inclusion required transthoracic echocardiography within 24 hours of CS diagnosis and prior to MCS implantation. RV FWLS was measured using commercially available software. Primary outcome was temporary MCS implantation during hospitalization. Secondary outcomes included in-hospital mortality and intensive care and hospital length of stay. Ninety-two patients were included; 31 (34%) required temporary MCS. Severe RV FWLS impairment (<11%) was strongly associated with temporary MCS use (OR 10.49, 95% CI 3.72-29.59). Tricuspid annular plane systolic excursion and fractional area change were not significantly associated with temporary MCS. Severe RV FWLS was linked to longer intensive care stay (21 vs 8 days, p=0.003) and hospital stay (25 vs 14 days, p=0.003), but not mortality. RV FWLS demonstrated moderate discrimination (AUC 0.74), improving with left ventricular ejection fraction (LVEF) and SOFA score (AUC 0.82). A CART-derived algorithm using RV FWLS, SOFA score, and LVEF stratified patients into distinct risk groups with 78% overall accuracy and 95% specificity. Integration of RV FWLS with clinical parameters may improve early risk stratification in CS.

Normothermic ex vivo heart perfusion (NEVHP) allows functional assessment and preservation of donor hearts, but the biological responses occurring during perfusion are not well characterized. This pilot study evaluated the feasibility of sequential biomarker monitoring during human cardiac NEVHP and described inflammatory, endothelial, and hemostatic responses over time. This single-center, prospective, observational pilot study included five consecutive donor hearts preserved with the TransMedics Organ Care System (OCS) at the University Hospital of Rennes between March 2021 and January 2023. OCS use was indicated for expected cold ischemia >4 hours or surgical complexity. Perfusate samples were collected after priming (T0), at 10 minutes (T1), 60 minutes (T2), and before cooling (T3). Cytokines, chemokines, endothelial markers, and hemostatic factors were quantified by multiplex immunoassay and ELISA. Data were analyzed using linear mixed-effects models and expressed as fold-change versus T0. Donor median age was 44 years (IQR 36-50) and 60% male. All grafts were transplanted. Recipient mean age was 53±9 years and 20% female. Two of five (40%) developed severe primary graft dysfunction. Sequential sampling was successful in all perfusions. Inflammatory mediators rose during perfusion: at T3 versus T0, IL-8 increased 11.5-fold (95% CI 6.5-20.1), bFGF 8.4-fold (6.7-10.5), IL-6 4.5-fold (2.4-8.2), and MCP-1/CCL2 4.1-fold (2.6-6.6). IL-10 and TNF-α showed smaller increases (2.0- and 1.6-fold). Leukocyte counts remained stable (0.57×109/L at T0; fold-change 0.9). Endothelial markers showed activation without evidence of injury. Angiopoietin-2 increased 1.6-fold (1.2-2.1) and VEGF 2.0-fold (1.2-3.5), while angiopoietin-1, syndecan-1, soluble E-selectin, thrombomodulin, VEGFR2, PlGF, and vWF:Ag showed minimal or inconsistent changes. These trajectories are consistent with endothelial activation in the absence of glycocalyx shedding or structural disruption. Despite high heparin levels (median 6.9 IU/mL), low-grade hemostatic activation occurred. D-dimer increased 1.9-fold (1.3-2.7), fibrin monomer 2.2-fold (1.2-3.9), and soluble P-selectin 1.5-fold (1.1-2.0). Platelet counts declined to 0.8 (0.7-0.9) relative to baseline. Hematocrit decreased slightly (15.5% to 14.6%, fold-change 0.94), consistent with mild hemodilution. Sequential biomarker monitoring during NEVHP was feasible and demonstrated inflammatory, endothelial, and hemostatic changes. These biological patterns require confirmation in larger cohorts, as potential tools for graft assessment and optimization of perfusion circuits and perfusate composition.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve cardiovascular outcomes in obesity and HFpEF; however, their safety and efficacy in heart failure with reduced ejection fraction (HFrEF) remain uncertain. We sought to evaluate the efficacy and safety of GLP-1 RAs in patients with HFrEF. We conducted a multicenter retrospective cohort study of adult patients with HFrEF (LVEF ≤40%) between 2021 and 2024. Patients receiving semaglutide, tirzepatide, or liraglutide were compared with GLP-1RA-naïve patients. Propensity score matching (PSM) (1:1; caliper 0.1) was conducted to balance demographics, comorbidities, LVEF, BMI, HbA1c, and guideline-directed medical therapy. Primary outcomes were 1-year all-cause mortality and acute decompensated HF (ADHF) hospitalizations. Secondary outcomes included new ACS, stroke/TIA, AF/flutter, and VT/VF events. A total of 127,021 patients met inclusion criteria. After PSM, 2,550 patients (n=1,275 per group) were analyzed (mean age 61.5 ±13 years, 33.5% female, 66% White, mean HbA1c 8.1 ±2.1%, mean LVEF 30 ±8.7%, mean BMI 34.5 ±8.4 kg/m2). Patients prescribed GLP-1 RAs had a lower risk of all-cause mortality (7.1% vs 10.2% OR: 0.68, 95% CI: 0.51-0.90; p=0.006). Time-to-event analysis was also consistent (matched HR: 0.54 [95% CI: 0.41-0.7]; p<0.0001). Patients in the GLP-1 RA group also had a lower risk of ADHF (27.7% vs 32.8% OR: 0.79 [95% CI: 0.66-0.93]; p=0.005). New onset ACS, stroke/TIA, AF/flutter, and VT/VF events were similar in both groups. In this real-world cohort, GLP-1RA therapy in HFrEF was associated with reduced mortality and ADHF without an increase in arrhythmic events. Prospective randomized trials are needed to validate these findings.

The traditional, hospitalization-centric composite endpoint of cardiovascular (CV) death or time-to-first heart failure (HF) hospitalization is increasingly misaligned with contemporary HF care and, as evidence-based therapies lower event rates over time, requires larger trials with longer follow-up. Improved survival, modern ambulatory pathways mean that a larger share of worsening HF is treated outside the hospital and that patients may experience recurrent worsening HF episodes. Relying on time-to-first hospitalization alone can therefore miss clinically relevant morbidity; recurrent-event approaches can offer additional power mainly when risk heterogeneity is high and treatment discontinuation after a first event is infrequent. To address this gap, we propose a standardized, adjudicated definition of worsening HF events informed by published consensus definitions, expanded to capture ambulatory events across care settings. Building on this definition, we recommend hierarchical primary endpoints that prioritize all-cause death with CV death evaluated as a secondary mortality outcome when prespecified and adjudicated, while robustly measuring morbidity through total adjudicated worsening HF events (first and recurrent), with validated patient-reported outcomes as additional hierarchical levels. We outline operational considerations for event capture and adjudication, including prioritized composite analytic approaches, and highlight safeguards to mitigate ascertainment bias and dilution by more subjectively defined events. Adoption of worsening HF -based hierarchical endpoints can better reflect the total disease burden, improve statistical power, and enhance interpretability across evolving care models.

To compare long-term outcomes of patients with Takotsubo syndrome (TTS) and heart failure (HF). This retrospective observational study used the TriNetX global federated research network. Adult patients (≥18 years) discharged with a diagnosis of TTS (ICD-10-CM I51.81) or HF (I50.x) between 2018 and 2022 were identified. Primary outcomes were 3-year risk of all-cause death, major adverse cardiovascular events (MACE; myocardial infarction or ischaemic stroke), and acute HF. Secondary outcomes included myocardial infarction, ischaemic stroke, ventricular arrhythmias (ventricular tachycardia), malignant arrhythmias (ventricular fibrillation or cardiac arrest), and new-onset atrial fibrillation (AF). Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) before and after 1:1 propensity score matching (PSM). Subgroup analyses were performed by HF phenotype, age (≥65 vs <65 years), and mental health status. The study included 2240 patients with TTS (mean age 62.6 ± 17.3 years; 73.7% female) and 265 564 patients with HF (69.3 ± 14.7 years; 45.8% female). After PSM, TTS was associated with a lower risk of acute HF (HR 0.622, 95% CI 0.539-0.717), ventricular arrhythmias (HR 0.637, 95% CI 0.441-0.919), malignant arrhythmias (HR 0.656, 95% CI 0.571-0.754), new-onset AF (HR 0.672, 95% CI 0.517-0.875), and myocardial infarction (HR 0.818, 95% CI 0.687-0.974), with no significant differences in the remaining outcomes. Differences were greater when TTS was compared with heart failure with reduced ejection fraction. TTS is associated with lower risk of adverse events than HF. Further research is needed on mental health in its pathogenesis and prognosis.

Patients with heart failure and preserved ejection fraction (HFpEF) experience significant exercise intolerance, yet its underlying mechanisms remain poorly defined and are multifactorial. Iron deficiency (ID) occurs frequently in HFpEF and may contribute to exercise impairment. This study evaluated mitochondrial oxidative muscle metabolism in HFpEF using in vivo 31phosphorus magnetic resonance spectroscopy (31P-MRS) employing two exercise protocols, and assessed whether ID influences exercise energetics. In this parallel analysis of prospective studies at two sites, patients with HFpEF and control individuals performed either isometric exercise (isolated leg protocol) or dynamic exercise (cardiopulmonary protocol) with concomitant phosphocreatine recovery assessment using in vivo 31P-MRS. Associations between clinical factors and oxidative metabolism were evaluated. ID was defined as ferritin <100 µg/L, or ferritin 100-299 µg/L with transferrin saturation <20%. Fifty-eight patients with HFpEF and 16 controls performed isometric exercise (n = 46 HFpEF; n = 16 control) or cardiopulmonary exercise (n = 12 HFpEF). Phosphocreatine recovery halftime after isometric exercise was prolonged in patients versus controls [27 (23-32) vs 24 (19-28) seconds, respectively; P = .03]. Phosphocreatine recovery halftime after dynamic exercise in patients was 39 (27-57) seconds. Both cohorts consisted of patients with and without ID (n = 19 and 27, and n = 6 and 6, respectively), who had comparable exercise and oxidative muscle capacity (all P > .42). High-sensitive C-reactive protein was associated with prolonged phosphocreatine recovery halftime (P =. 01). Patients with HFpEF exhibit impaired whole-muscle oxidative capacity of skeletal muscle, as shown by two different 31P-MRS protocols with upper leg measurements, independent of ID status. NTR6605, NTR7297 (https://onderzoekmetmensen.nl/nl/trial/55673); NCT05750940 (https://clinicaltrials.gov/study/NCT05750940).