Search Results (452)

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome requiring invasive and/or exercise stress testing for diagnosis, in contrast with the homogeneous nature of HF with reduced EF (HFrEF). We previously demonstrated that acoustic cardiography (AC), combined with advanced signal analysis, can non-invasively estimate left ventricular (LV) functional indices in an experimental swine model of HFrEF. Objectives: To evaluate whether AC-derived features capture stress-dependent LV functional changes, supporting phenotypic differentiation between porcine models of HFpEF, HFrEF, and Control conditions. Methods: Synchronized invasive LV-pressure and non-invasive ECG, pulse oximetry, and AC signals were collected from 12 anesthetized, closed-chest Göttingen minipigs (Control, n = 3; HFrEF, n = 5; HFpEF, n = 4). Through signal analysis, we derived time and frequency features from the non-invasive signals to predict, using our AI model, the invasively measured LV functional indices. Atrial pacing was performed up to 160 bpm as a controlled heart-rate stress paradigm. Two AI modeling strategies were employed: a standard 80/20 train/test ratio, and a leave-one-animal-out (i.e., 1 animal per health status) to assess generalizability. Results: Standard blind testing achieved >95% accuracy in phenotype classification with <3% relative error for predicted LV indices. The leave-one-animal-out classification performance remained robust (79–95% accuracy), supporting translational potential despite inter-animal variability. Notably, HFpEF animals exhibited greater variability in AC-features across increasing heart rates compared to Control and HFrEF. Conclusions: AC-based modelling offers a rapid, non-invasive approach for assessing LV function. Our methodology may complement existing diagnostic tools, particularly for conditions like HFpEF, but warrants further validation in clinical populations. Full article

Background: Breast cancer patients are exposed to cardiovascular complications related to both pre-existing cardiovascular risk factors and cardiotoxic cancer therapies. Heart failure with preserved ejection fraction (HFpEF) is an emerging and often under-recognized condition in this population, potentially present before treatment initiation and further influenced by oncologic therapies. This study aimed to characterize baseline HFpEF probability and its longitudinal evolution using validated scoring systems in a real-world cardio-oncology cohort. Methods: We retrospectively evaluated 145 women with breast cancer undergoing baseline cardio-oncology assessment before initiation of potentially cardiotoxic therapies. HFpEF probability was estimated using three validated algorithms (H₂FPEF, ABA, and HFA-PEFF). A subgroup of 89 patients underwent exploratory reassessment after 12 ± 3 months to investigate longitudinal changes in HFpEF probability according to treatment. Results: At baseline, HFpEF probability varied substantially according to the scoring system applied, with 14.8–41.5% of patients classified as having intermediate-to-high probability. Agreement among the three algorithms was limited, particularly between HFA-PEFF and H₂FPEF/ABA scores. Exploratory longitudinal analyses showed no significant changes in HFpEF probability categories during follow-up. Conclusions: HFpEF probability assessment in breast cancer patients showed substantial baseline heterogeneity across validated scoring systems, with clinically relevant differences in risk classification and limited inter-score agreement. These findings provide novel insights into an underexplored cardio-oncology phenotype and suggest that currently available HFpEF scoring systems may not be directly interchangeable in this clinical setting. Prospective studies including provocative testing are needed to determine the clinical relevance of HFpEF probability scores in breast cancer patients. Full article

Background: Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure (HF) cases and remains diagnostically challenging due to nonspecific symptoms and a lack of accessible noninvasive screening tools, leading to widespread underdiagnosis and delayed treatment. The electrocardiogram (ECG) is a low-cost, widely available tool that reflects myocardial electrical remodeling. We previously developed and externally validated an ECG-based artificial intelligence (ECG-AI) model capable of classifying ECGs into four categories: reduced ejection fraction (rEF), mid-range ejection fraction (mEF), HFpEF, and controls. In this study, we evaluate the ability of this ECG-AI model to predict future HFpEF diagnosis using real-world data from a large integrated health system. Methods: We applied the validated ECG-AI model to an independent cohort of 7713 patients from Wake Forest Baptist Health (WFBH), using one ECG per patient recorded before the clinical diagnosis of HFpEF. Model discrimination was evaluated across multiple prediction windows from six months up to ten years before diagnosis using the area under the receiver operating characteristic curve (AUC), with comparisons performed using DeLong’s test. Performance was also compared head-to-head with the H2FPEF score, a validated clinical score for HFpEF, in the subset of patients with complete data for score calculation. ECG-AI outputs were stratified into quartiles and evaluated using Kaplan–Meier survival analysis and multivariable Cox proportional hazards regression adjusted for demographics and major comorbidities. Results: Of the 7713 patients, 283 (3.7%) were subsequently diagnosed with HFpEF. The ECG-AI model achieved an AUC of 0.79 (95% CI, 0.72–0.86) using ECGs recorded within six months before diagnosis. Discrimination remained stable across prediction windows extending up to ten years before diagnosis (AUC range, 0.78–0.80; all DeLong p > 0.01 vs. the six-month window). Compared with the H2FPEF score, ECG-AI demonstrated superior discrimination, improving the AUC by 0.06–0.07 across the evaluated prediction windows. Patients in the highest ECG-AI risk quartile had an unadjusted hazard ratio (HR) of 11.18 (95% CI, 7.27–17.21; C-index, 0.75) and an adjusted HR of 6.60 (95% CI, 4.24–10.28; C-index, 0.82). Adding clinical covariates to ECG-AI improved the C-index by 0.07 and 0.09 for the five- and ten-year prediction windows, respectively. Conclusions: An independently validated ECG-AI model predicted incident HFpEF up to ten years before clinical diagnosis and outperformed the H2FPEF score using ECG alone, indicating that ECG-derived signatures precede clinical recognition of the syndrome. ECG-AI shows promise as a prognostic, risk-stratification tool to prioritize further evaluation; prospective validation and single-lead assessment are needed before screening or wearable deployment. Full article

Background: Brown adipose tissue (BAT) is increasingly recognized as an endocrine organ that releases bioactive factors (batokines) with cardioprotective properties. Activation of BAT is primarily mediated by the β3-adrenergic receptor (β3-AR). Here, we investigated whether pharmacological activation of β3-AR using mirabegron modulates cardiac remodelling in a murine model of heart failure with preserved ejection fraction (HFpEF) induced by metabolic and hypertensive stress (MHS). Methods: Male and female C57BL/6J mice were exposed to MHS (angiotensin II + high-fat diet) for 28 days, with or without mirabegron treatment (2 mg/kg/day). Cardiac structure and function were assessed by echocardiography, and molecular and histological analyses were performed on cardiac and BATs. Results: Mirabegron attenuated several features of cardiac remodelling in males, including cardiac hypertrophy, left atrial enlargement, and left ventricular dilation. These effects were associated with reduced expression of genes related to hypertrophy and fibrosis. In contrast, it was shown that females exhibited a less pronounced response pattern. BAT mass and thermogenic gene expression (Ucp1) increased more markedly in males than in females, suggesting differential BAT responsiveness between sexes. Conclusions: β3-AR activation is associated with sex-dependent cardiac responses in this HFpEF model, with more pronounced protective effects in males. These findings are consistent with a potential contribution of BAT activation to cardiac remodelling, although causality was not directly demonstrated in the present study. Full article

Heart failure (HF) classification is still primarily based on left ventricular ejection fraction, even though this parameter only partially reflects the biological mechanisms determining disease progression and therapeutic response. The aim of this review was to present a conceptual interpretive framework that analyzes the HFrEF (heart failure with reduced ejection fraction) and HFmrEF (heart failure with mildly reduced ejection fraction) phenotypes through the lens of the network organization of pathophysiological processes. This review integrates data on molecular and cellular mechanisms, clinical phenotypes, clinical trial results, and therapeutic recommendations. Particular attention was paid to the concepts of network coherence, pathway dominance, and the relationship between the disease’s biological architecture and treatment response. The proposed conceptual framework suggests that HFrEF is more often characterized by a relatively coherent pathophysiological architecture, in which neurohormonal activation, disturbances in calcium metabolism, mitochondrial dysfunction, and extracellular matrix remodeling constitute mutually reinforcing processes. HFmrEF, on the other hand, is presented as a heterogeneous category, encompassing patients with partial improvement of previous systolic dysfunction, patients progressing towards HFrEF, and HFpEF (heart failure with preserved ejection fraction)—like phenotypes associated with inflammation, endothelial dysfunction, microcirculatory disturbances, and metabolic dysregulation. In this approach, therapeutic response depends on whether the targeted pathway occupies a central position in the disease network. This review proposes a hypothesis-generating conceptual framework that complements, rather than replaces, the current ejection fraction-based classification of heart failure. Although the proposed framework requires prospective validation, it may facilitate a more mechanistic interpretation of HF phenotypes, support future biologically informed therapeutic strategies, and stimulate the design of mechanistically oriented clinical studies. Full article

Chronic obstructive pulmonary disease (COPD) frequently occurs alongside heart failure (HF), including heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), creating a diagnostic dilemma due to overlapping clinical manifestations such as exertional dyspnea and reduced exercise tolerance. Static diagnostic modalities are often insufficient to distinguish these entities or their overlapping syndromes (HFrEF-COPD and HFpEF-COPD). Cardiopulmonary exercise testing (CPET) uniquely provides a dynamic, integrated assessment of the respiratory, cardiovascular, and peripheral muscle systems during incremental exercise, enabling quantitative characterization of the pathophysiological mechanisms underlying exercise limitation. This review comprehensively summarizes the characteristic CPET profiles of isolated HFrEF, isolated HFpEF, isolated COPD, HFrEF-COPD, and HFpEF-COPD. Integration of CPET parameters with pulmonary function testing results in a comprehensive assessment of the cardiopulmonary system, facilitating accurate diagnosis and prognostic stratification in this complex patient population. Finally, we address current limitations in standardization and outline future directions for advancing precision medicine in this complex clinical landscape. Full article

Heart failure with preserved ejection fraction (HFpEF) is an increasingly common form of heart failure (HF) that is best understood as a systemic, multiorgan syndrome rather than a disease of left-ventricular filling alone. This review has three specific aims: first, to synthesize genetic and molecular pathways that are most relevant to non-ischemic HFpEF; second, to distinguish HFpEF-enriched mechanisms from evidence extrapolated from ischemic cardiomyopathy or HFrEF; and third, to consider translational implications for populations with high consanguinity, including the Kingdom of Saudi Arabia. The available evidence indicates that chronic inflammatory signaling involving CCL2, CCL5, TLR3, PTGS2/COX-2, IL-6/JAK/STAT3, NF-kB, and NLRP3 acts upstream of endothelial dysfunction, nitric-oxide/cGMP/PKG impairment, mitochondrial reactive oxygen species generation, and fibroblast activation. Extracellular-matrix regulators including ASPN, COL1A1, and MMP2 then amplify collagen deposition and myocardial stiffness, whereas mitochondrial genes and proteins such as ATP5C1 contribute to impaired oxidative phosphorylation, reduced ATP reserve, defective fatty-acid oxidation, and blunted mitophagy. Protein-quality-control pathways involving HSP90AA1, CCT2/CCT5, PSMA3, and stress-responsive STAT3 further link metabolic stress to proteotoxic injury. Epigenetic mechanisms, including DNA methylation and microRNAs such as miR-155, miR-1297, and miR-4649-3p, add a regulatory layer that may improve risk stratification but remains insufficiently validated for routine clinical use. In high-consanguinity settings, recessive cardiomyopathy variants can cluster in families and contribute to earlier NIHF presentations; however, population-level HFpEF-specific variant frequencies remain limited, and findings from HFrEF or dilated cardiomyopathy should be interpreted as candidate pathway evidence rather than definitive HFpEF markers. Translationally, SGLT2 inhibitors, mineralocorticoid-receptor antagonism, biomarker panels, and structured genetic evaluation provide the most clinically actionable bridge from molecular mechanisms to precision HFpEF care. Full article

Background: Heart failure with supranormal ejection fraction (HFsnEF) has recently emerged as a distinct phenotype within the preserved ejection fraction spectrum. However, its clinical profile, underlying mechanisms, and prognostic significance remain incompletely understood. Methods: A systematic review was conducted according to PRISMA recommendations. PubMed, Scopus, and EMBASE were searched from inception to May 2026 for studies investigating HFsnEF. Demographic, clinical, laboratory, echocardiographic, prognostic, and therapeutic data were extracted. Weighted descriptive analyses were performed to compare HFsnEF and conventional heart failure with preserved ejection fraction (HFpEF) populations. Random-effects meta-analyses of study-specific event rates were conducted for all-cause mortality and for the composite endpoint of cardiovascular death or heart failure hospitalization. Results: Fourteen studies involving 17,158 HFpEF patients and 7493 HFsnEF patients were included. Compared with HFpEF, HFsnEF patients exhibited broadly similar clinical, laboratory, haemodynamic, and treatment profiles, with a higher prevalence of women and a lower prevalence of coronary artery disease representing the most consistent clinical differences. Conventional laboratory parameters and natriuretic peptide concentrations showed substantial overlap between groups. Echocardiographically, HFsnEF was characterized by significantly smaller left ventricular end-systolic dimensions and volumes and higher ejection fraction despite similar stroke volume and cardiac output. Mechanistic studies further demonstrated significantly higher end-systolic elastance and lower ventriculo-arterial coupling ratios despite comparable arterial elastance, supporting the presence of distinct ventricular–vascular mechanical properties. Prognostic analyses consistently identified HFsnEF as a phenotype associated with adverse clinical outcomes. Pooled event-rate analyses demonstrated significantly higher rates of both all-cause mortality and the composite endpoint of cardiovascular death or heart failure hospitalization in HFsnEF compared with HFpEF. Emerging evidence also suggests a potential benefit of sodium–glucose cotransporter-2 inhibitors in this population. Conclusions: HFsnEF appears to represent a distinct and potentially high-risk phenotype within the preserved ejection fraction spectrum. Its characteristic structural, haemodynamic, and prognostic features challenge the traditional assumption that progressively higher ejection fraction necessarily reflects better cardiovascular health. Further prospective studies incorporating advanced imaging and haemodynamic assessment are needed to refine its pathophysiological characterization and therapeutic management. Full article

Background: Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) usually coexist and are related to increased morbidity and mortality. Cardiovascular benefits have been demonstrated by drugs such as sodium-glucose cotransporter-2 inhibitors (SGLT2i) and GLP-1 receptor agonists including the dual GIP/GLP-1 receptor agonist tirzepatide (collectively, incretin-based therapies); however, their relative effectiveness in patients with concomitant AF and HFpEF remains undefined. Methods: We conducted a retrospective, propensity score-matched cohort study utilizing the TriNetX Global Collaborative Network. Adults with AF or atrial flutter with a diagnosis of HFpEF who initiated incretin-based therapies (GLP-1 receptor agonists or dual GLP-1/GIP receptor agonists) or SGLT2i were included; index medication was required to be initiated within 30 days of a qualifying AF/HFpEF diagnosis. 1:1 matching was performed based on baseline medications, demographics, and comorbidities. Co-primary outcomes were all-cause mortality, inpatient visits, and emergency department (ED) visits at 1 year. Secondary outcomes included myocardial infarction, ischemic stroke, acute kidney injury, transient ischemic attack, major adverse cardiovascular events (MACE; all-cause mortality/MI/stroke composite), and AF-related procedures. Agent-specific subgroup analyses were performed for semaglutide and tirzepatide separately. Sensitivity analyses were conducted at 6 months and 2 years. Results: 7624 patients were included in each cohort after matching (mean age: 70.8 years; 52% women). At 1 year, incretin-based therapy was associated with lower all-cause mortality (5.3% vs. 7.3%, HR 0.721, 95% CI 0.634–0.820; p < 0.001), fewer inpatient visits (30.0% vs. 37.4%, HR 0.743, 95% CI 0.702–0.787; p < 0.001), and no statistically significant difference in ED visits (27.0% vs. 28.0%; HR 0.946, 95% CI 0.888–1.007; p = 0.081) compared with SGLT2i. Incretin-based therapy was also associated with lower risk of MACE (HR 0.709), acute kidney injury (HR 0.751), myocardial infarction (HR 0.583), catheter ablation (HR 0.685), and electrical cardioversion (HR 0.472). No significant differences were observed in ischemic stroke or transient ischemic attack. These findings were broadly consistent at 6-month and 2-year follow-up, and directionally consistent in agent-specific subgroup analyses of semaglutide and tirzepatide. Conclusions: In this large propensity-matched cohort of patients with AF and HFpEF, initiation of incretin-based therapy (GLP-1 receptor agonists or dual GLP-1/GIP receptor agonists) was associated with lower all-cause mortality, fewer inpatient visits, and reduced cardiovascular events compared with SGLT2i. These findings, while subject to observational limitations, suggest potential benefits of incretin-based therapy in this high-risk population and support the need for prospective comparative trials. Full article

Background/Objectives: Heart failure (HF) classification based on left ventricular ejection fraction (LVEF) provides an incomplete representation of disease complexity, as it does not fully integrate functional impairment, structural remodeling, and clinical severity within a unified framework. Although N-terminal pro-B-type natriuretic peptide (NT-proBNP) is widely used for diagnosis and risk stratification, prior studies have primarily evaluated its role in isolation or within individual HF phenotypes, leaving its phenotype-specific distribution and integrative capacity across the HF spectrum insufficiently defined. This study aimed to address this gap by systematically evaluating NT-proBNP across HF phenotypes and assessing its potential as an integrative biomarker linking ventricular dysfunction, structural remodeling, and clinical severity. Methods: A cross-sectional study was conducted including 125 participants, comprising 65 clinically stable HF patients and 60 age- and sex-matched controls. HF patients were stratified according to LVEF into HF with reduced EF (HFrEF) (n = 28), (HFmrEF) (n = 20), and HF with preserved EF (HFpEF) (n = 17). Serum NT-proBNP concentrations were measured using a standardized electrochemiluminescence immunoassay. Clinical and echocardiographic parameters, including LVEF, left ventricular end diastolic diameter (LVEDD), left atrial diameter (LAD), and New York Heart Association (NYHA) functional class, were recorded and analyzed. Results: NT-proBNP levels were significantly higher in HF patients compared with controls (1845 ± 620 vs. 95.7 ± 40.5 pg/mL; p < 0.001) and demonstrated a clear stepwise increase across phenotypes (HFrEF: 2850.6 ± 710.4; HFmrEF: 1620.8 ± 480.2; HFpEF: 920.9 ± 310.3 pg/mL; p < 0.001). NT-proBNP showed a strong inverse correlation with LVEF (r = −0.68, p < 0.001) and significant positive correlations with LVEDD (r = 0.61, p < 0.001) and LAD (r = 0.57, p < 0.001). Higher levels were associated with more advanced NYHA functional class (III–IV vs. II: 2510 ± 680 vs. 980 ± 340 pg/mL; p < 0.001). ROC analysis demonstrated robust discriminatory performance across HF phenotypes, with the highest accuracy observed in HFrEF. Conclusions: NT-proBNP exhibits a phenotype-dependent gradient and consistently reflects ventricular dysfunction, adverse structural remodeling, and clinical severity across the HF spectrum. These findings support its role as an integrative biomarker that captures the multidimensional nature of HF, with potential implications for phenotype-based risk stratification and more precise clinical decision making. Full article

Hypertension is among the most important modifiable risk factors associated with heart failure with preserved ejection fraction (HFpEF) development and progression, yet guideline-directed blood pressure (BP) targets (<130/80 mmHg) and sodium–glucose co-transporter 2 inhibitor (SGLT2i) therapies lack dedicated randomized controlled trials (RCTs) in this specific group of patients. This narrative review synthesizes 2024 ESC/ESH and 2025 JSH meta-analyses, discussing the proposed pathophysiological framework linking hypertension-associated remodeling with HFpEF. Post hoc analyses from landmark trials (EMPEROR-Preserved, DELIVER) demonstrate consistent heart failure (HF) event reductions with SGLT2i (pooled HR 0.79, 95% CI 0.67–0.93), complemented by modest systolic BP lowering (−2.3 mmHg) and biomarker insights. Soluble ST2 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) may contribute to risk stratification in HFpEF populations when interpreted in conjuction with imaging findings and clinical context; however, neither biomarker is specific for hypertension-mediated remodeling. Critical evidence gaps persist: heterogeneous BP thresholds across international guidelines, limited device therapy data (renal denervation showing −8.5 mmHg sustained reduction), and real-world implementation barriers among elderly/comorbid Europeans (adherence < 50%, polypharmacy risks). Hellenic HF Registry data highlight frailty prevalence (68% in patients > 75 years) complicating aggressive BP management. The review addresses phenotype-specific challenges through precision medicine approaches incorporating phenomapping and multi-biomarker panels (NRI 0.28 improvement). We advocate for dedicated HFpEF RCTs evaluating intensive vs. standard BP targets, SGLT2i sequencing with antihypertensives, and European real-world registries to bridge the translational gap. These strategies aim to transform guideline recommendations into optimized, patient-centered care for the rapidly expanding hypertensive HFpEF population. Full article

Background: Heart failure (HF) is a major public health problem and a paradigmatic condition for sex differences in cardiovascular disease. However, national population-based evidence describing these differences remains limited. We aimed to provide the first nationwide sex-stratified epidemiologic characterization of HF in Spain, quantifying incidence, prevalence, and clinical characteristics across age groups and left ventricular ejection fraction (LVEF) categories. Methods: We conducted a retrospective population-based study using the BIG-PAC database, integrating electronic health records from primary and hospital care covering approximately 1.8 million individuals across seven Spanish autonomous communities. Adult patients with incident HF between 2013 and 2019 were identified. HF phenotypes were classified according to LVEF as reduced (HFrEF ≤40%), mildly reduced (HFmrEF 41–49%), preserved (HFpEF ≥50%), or unknown (HFuEF). Incidence rates per 1000 person-years and prevalence were estimated and stratified by sex and LVEF phenotype. Results: In total, 19,961 incident HF cases were identified. Overall HF incidence was 3.23 per 1000 person-years and was similar in women and men (p = 0.697). HF prevalence was 2.34% and higher in men than in women (2.67% vs. 2.06%; p < 0.001). Women were older and more frequently presented with HFpEF (38%), whereas HFrEF predominated in men (53%); notably, HFrEF still accounted for approximately one third of HF cases among women. Once stratified by LVEF phenotype, clinical characteristics were broadly similar between sexes. Conclusions: While HF incidence was similar in women and men, substantial sex differences in prevalence, age, and phenotype distribution were identified, establishing the first nationwide epidemiological framework to inform sex-aware HF prevention and healthcare planning in Spain. Full article

Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly prevalent and now recognized as a systemic syndrome with diverse clinical phenotypes and multiorgan involvement. The predominant clinical phenotype has evolved from patients with isolated hypertensive heart disease to individuals with cardiometabolic (CM) abnormalities [obesity, insulin resistance, increased waist circumference (a surrogate for visceral adiposity), dyslipidemia, type 2 diabetes, and hypertension] that result in metabolic alterations leading to CM-HFpEF. Indeed, CM-HFpEF and metabolic dysfunction-associated fatty liver disease are recognized as two sides of the same coin. Chronic systemic inflammation is a defining pathophysiologic feature of CM-HFpEF, with visceral adipose tissue serving as a central driver. In this regard, lifestyle changes, including diet and exercise, are crucial for managing HFpEF. Several recent studies have shown that exercise training (aerobic and resistance combined) with or without calorie restriction is an effective therapeutic management strategy for improving exercise capacity, physical function, and quality of life in patients with clinically stable HFpEF. Also, the pharmacologic interventions that have proven beneficial in HFpEF so far (sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists) are effective due to their metabolic protective effects. In this review, we outline the current available evidence on lifestyle interventions in HFpEF management and therapeutics, discussing their modalities and potential mechanisms. Full article

Background: The clinical impact of oral semaglutide on cardiac biomarkers in real-world patients with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM) remains unclear. We evaluated whether initiation of oral semaglutide was associated with a reduction in B-type natriuretic peptide (BNP) levels and explored factors associated with this response. Methods: We retrospectively enrolled 27 patients with HFpEF who initiated oral semaglutide for T2DM management at a single academic center. Clinical data were collected at three time points: three months before treatment initiation (pre-treatment period), at initiation (baseline), and three months after semaglutide initiation (on-treatment period). The primary outcome was the change in the common logarithm of BNP levels (log BNP) during the on-treatment versus pre-treatment period. Results: Median age was 67 (59, 78) years and 21 (77.8%) were men. Log BNP remained stable during the pre-treatment period (p = 0.34) but decreased significantly during the on-treatment period (p < 0.001). The reduction in log BNP during the on-treatment period was significantly greater than during the pre-treatment period (mean difference −0.35, 95% confidence interval −0.44 to −0.11, p < 0.001). Concomitant reductions were observed in HbA1c, body weight, C-reactive protein, left atrial volume index, and left ventricular mass index. Changes in C-reactive protein levels were significantly correlated with those in log BNP (r = 0.46, p = 0.015). Conclusions: In patients with HFpEF and T2DM, three-month oral semaglutide therapy was associated with reductions in BNP, as well as improvements in glycemic control, systemic inflammation, left atrial volume index, and left ventricular mass index. Full article

Heart failure with preserved ejection fraction (HFpEF) represents a complex syndrome strongly associated with aging, characterized by diastolic dysfunction, myocardial stiffness, and chronic low-grade inflammation. Cellular senescence and the ensuing senescence-associated secretory phenotype (SASP) significantly contribute to the pathogenesis and progression of HFpEF. This review examines the biological properties of SASP and its mechanistic roles in driving myocardial fibrosis, microvascular dysfunction, and cardiomyocyte injury. We synthesize evidence from preclinical and clinical studies demonstrating how SASP factors orchestrate HFpEF pathophysiology. The therapeutic potential of targeting SASP pathways is critically evaluated, including senolytic agents that eliminate senescent cells and senomorphic compounds that inhibit SASP factor secretion. Finally, we identify key translational barriers, such as limited tissue specificity in senolytic delivery and inadequate SASP biomarkers for treatment monitoring, while outlining future research directions to advance novel therapeutic development for this increasingly prevalent condition. Full article