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Aims Methods and results Conclusion To evaluate clinical outcomes, echocardiographic features, and the efficacy and safety of sacubitril/valsartan compared to valsartan across age groups in the PARAGON‐HF trial.A total of 4796 participants ≥50 years of age with chronic heart failure (HF) and left ventricular ejection fraction (LVEF) ≥45% were divided into three age groups: <65 years (n = 825), 65–74 years (n = 1772), and ≥75 years (n = 2199). Echocardiograms of 1097 patients were analysed in a standardized fashion at a core imaging laboratory. The primary composite outcome was total HF hospitalizations and cardiovascular (CV) death. Older patients were more likely to experience primary composite outcomes (compared to patients <65 years, adjusted rate ratio [aRR] for ≥75 years: 1.39, 95% confidence interval [CI] 1.21–1.61), total HF hospitalization (aRR 1.27, 95% CI 1.09–1.49), and CV death (adjusted hazard ratio [aHR] 2.04, 95% CI 1.44–2.87). Age did not modify the effect of sacubitril/valsartan compared to valsartan on primary composite endpoint (pinteraction = 0.79) in the overall population or in those with LVEF ≤57%. Older adults randomized to sacubitril/valsartan were more likely to develop hypotension compared to those receiving valsartan (pinteraction = 0.026). Older patients had smaller left ventricular chamber sizes, higher LVEF, and were more likely to have abnormal measures of diastolic function.Older patients with HF with preserved ejection fraction had higher event rates than younger patients, more adverse events overall, and more hypotension when treated with sacubitril/valsartan; however, the treatment benefits of sacubitril/valsartan were retained in older patients. [ABSTRACT FROM AUTHOR]

Background and Aims Accelerated atrial pacing offers potential benefits for patients with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), compared with standard lower-rate pacing. The study investigates the relationship between atrial pacing rate and left-heart filling pressure. Methods Seventy-five consecutive patients undergoing catheter ablation for AF underwent assessment of mean left atrial pressure (mLAP) and atrioventricular (AV) conduction delay (PR interval) in sinus rhythm and accelerated atrial pacing with 10 bpm increments up to Wenckebach block. Computer simulations (CircAdapt) of a virtual HFpEF cohort complemented clinical observations and hypothesized the modulating effects of AV coupling and atrial (dys)function. Results In the study cohort, 49(65%) patients had a high HFpEF likelihood (H2FPEF ≥ 5.0), and 28(37%) an elevated mLAP ≥ 15 mmHg at sinus rhythm. Optimal pacing rates of 100 [70–110]bpm (median [IQR]) significantly reduced mLAP from 12.8 [10.0–17.4]mmHg in sinus rhythm (55 [52–61]bpm) to 10.4 [7.8–14.8]mmHg (P <.001). Conversely, higher pacing rates (130 [110–140]bpm) significantly increased mLAP to 14.7 [11.0–17.8]mmHg (P <.05). PR interval and, hence, AV conduction delay prolonged incrementally with increasing pacing rates. Simulations corroborated these clinical findings, showing mLAP reduction at a moderately increased pacing rate and a subsequent increase at higher rates. Moreover, simulations suggested that mLAP reduction is optimized when AV conduction delay shortens with increasing rate. Conclusions Accelerated pacing acutely reduces left-heart filling pressure in patients undergoing AF catheter ablation and computer simulations with HFpEF features, suggesting it as a potential therapeutic strategy to alleviate congestion symptoms. Virtual HFpEF patient cohorts hypothesize that AV sequential pacing may further optimize this therapy's beneficial effects. [ABSTRACT FROM AUTHOR]

Background: The relationship between serum glucose/potassium ratio (GPR) and the adverse outcomes in patients with heart failure with preserved ejection fraction (HFpEF) has not been completely clarified. Methods: Patients were included from the American cohort of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. The primary endpoint was the composite of cardiovascular mortality, aborted cardiac arrest, and hospitalization for HF. The Cox regression models were applied to calculate the hazard ratio (HR) and 95% confidence interval (CI) to examine the relationship between GPR and prognosis. Restricted cubic spline (RCS) curves were performed to explore the nonlinear relationship between GPR and the primary endpoint. Receiver Operating Characteristic (ROC) curves were constructed, and the areas under the curves (AUCs) for GPR and its components were compared using the DeLong test. Subgroup analysis and interaction effect were also explored. Results: A total of 1749 HFpEF patients were included. During the follow-up, 514 (29.4%) patients reached the primary outcome. An increase in GPR was independently associated with a higher risk in the primary endpoint [Tertile 3 vs. Tertile 1: HR (95% CI), 1.35 (1.07–1.70), P = 0.012] and HF hospitalization [Tertile 3 vs. Tertile 1: HR (95% CI), 1.57 (1.20–2.05), P = 0.001]. RCS curve showed a J-shape trend between GPR and primary endpoint (non-linear P = 0.002). The AUC for GPR was superior to that of the glucose and potassium (De long test P < 0.05). Additionally, the prognostic value of GPR was stronger in patients without diabetes and with less severe heart failure symptoms (P interaction < 0.05). Conclusion: A J-shaped relationship was existed between GPR levels and the primary outcome in HFpEF patients. An increased GPR was an independent predictor of poor prognosis in HFpEF patients, especially in non-diabetic patients and those with less severe heart failure symptoms. [ABSTRACT FROM AUTHOR]

Background: Cardiometabolic heart failure with preserved ejection fraction (HFpEF) is largely driven by obesity-related factors, including adipokines and bioactive peptides primarily secreted by the adipose tissue, such as leptin, adiponectin, and resistin. These molecules link metabolic dysregulation to cardiovascular dysfunction, influencing HFpEF progression and patient outcomes Methods: A comprehensive literature search was conducted in PubMed up to 20 November 2024, using keywords and MeSH terms, such as "HFpEF", "adipokines", "leptin", "adiponectin", and "resistin", yielding 723 results. Boolean operators refined the search, and reference lists of key studies were reviewed. After screening for duplicates and irrelevant studies, 103 articles were included, providing data on adipokines' roles in HFpEF pathophysiology, biomarkers, and therapeutic implications. Results: Both preclinical and clinical studies have demonstrated that adipokines play a role in modulating cardiovascular function, thereby contributing to the development of cardiometabolic HFpEF. Leptin promotes myocardial hypertrophy, fibrosis, endothelial dysfunction, and inflammation, though contradictory evidence suggests potential cardioprotective roles in subgroups like obese African American women. Adiponectin generally offers protective effects but presents a paradox, where elevated levels may correlate with worse outcomes, which may reflect either a compensatory response to cardiac dysfunction or a maladaptive state characterized by adiponectin resistance. Resistin is associated with increased cardiovascular risk through pro-inflammatory and pro-fibrotic effects, though its role in HFpEF requires further clarification. Other adipokines, like retinol-binding protein 4 and omentin-1, have emerged as potential contributors. Despite growing insights, clinical translation remains limited, underscoring a significant gap between experimental evidence and therapeutic application. Conclusions: Future research should focus on targeted interventions that modulate adipokine pathways to potentially improve HFpEF outcomes. Innovative treatment strategies addressing underlying metabolic disturbances and adipokine dysregulation are essential for advancing the management of this challenging condition. [ABSTRACT FROM AUTHOR]

Background: The clinical impact of heart rate (HR) in heart failure with preserved ejection fraction (HFpEF) is a matter of debate. Among those with HFpEF, chronotropic incompetence (CI) has emerged as a pathophysiological mechanism linked to the severity of the disease. In this study, we sought to evaluate whether admission heart rate in acute heart failure differs along left ventricular ejection fraction (LVEF). Methods: We included retrospectively 3,712 consecutive patients admitted for acute heart failure (AHF) in the Cardiology department of a third level center. HR values were assessed at presentation. LVEF was assessed by transthoracic echocardiogram during the index admission and stratified into four categories: reduced ejection fraction ( ≤ 40%), mildly reduced ejection fraction (41–49%), preserved ejection fraction (50–64%) and supranormal ejection fraction ( ≥ 65%). The association between HR and LVEF was assessed by multivariate linear and multinomial regression analyses. Results: The mean age of the sample was 73,9 ± 11.3 years, 1,734 (47,4%) were women, and 1,214 (33,2%), 570 (15,6%), 1,229 (33,6%) and 648 (17,7%) patients showed LVEF ≤ 40%, 41–49%, 50–64%, and ≥65% respectively. The median HR at admission was 95 (IQR 78–120) beats per minute and 1,653 were on atrial fibrillation (45.2%). There was an inverse relationship between HR at admission and LVEF. Lower HR was significantly associated with a higher LVEF in the whole sample (p < 0,001). This inverse relationship was found in sinus rhythm but not in patients with atrial fibrillation. Conclusion: HR at admission for AHF is a predictor of LVEF but only in patients with sinus rhythm. [ABSTRACT FROM AUTHOR]

Objective: People living with HIV have an increased risk of heart failure (HF). There are different subtypes of HF. Knowledge about the factors differentiating HF subtypes in people with HIV is limited but necessary to guide preventive measures and treatment. Methods: A retrospective review of medical records was undertaken in people with HIV aged ≥18 years who received care at the University of Miami/Jackson Memorial HIV Clinic between January 2017 and November 2019 (N = 1166). Patients with an echocardiogram available for review (n = 305) were included. HF was defined as a documented diagnosis of any HF subtype (n = 52). We stratified those with HF by their ejection fraction (EF) into HF with preserved EF (HFpEF), HF with borderline EF, or HF with reduced EF (HFrEF). Results: The prevalence of HF was 4.5%. The cohort included 46.2% females and 75% self‐identified African Americans. Those with HF had a higher prevalence of hypertension, prior myocardial infarction, angina, coronary artery disease, percutaneous coronary intervention, coronary artery bypass grafting, diastolic dysfunction, and left ventricle hypertrophy. People with HIV with HF with borderline EF exhibited more coronary artery disease than those with HFpEF. Conclusions: We characterize HF in people with HIV in South Florida and report the prevalence of HF and HF subtypes. Only a small percentage of patients had echocardiograms performed, suggesting an ongoing need for recognition of the increased risk of HF in people living with HIV, and raising the concern about lack of awareness contributing to underdiagnosis and missed treatment opportunities in this population. [ABSTRACT FROM AUTHOR]

While Reddy proposed the H2FPEF diagnostic algorithm to aid in diagnosing heart failure with preserved ejection fraction (HFpEF), certain parameters like age and obesity are not suitable for Asian population, especially given the increasing incidence of HFpEF in younger individuals. Therefore, this study aimed to develop an easy-to-use nomogram with non-invasive indices that can be used in outpatient clinics in Taiwan to quickly estimate the probability of HFpEF and help decide whether further invasive cardiopulmonary exercise test (CPET) is needed. Outpatients with unexplained dyspnea and fatigue were recruited divided into HFpEF (n = 64) and non-HFpEF (n = 34) groups based on invasive CPET and echocardiography. Multivariate logistic regression analyses identified independent noninvasive variables for developing an HFpEF nomogram. The nomogram's performance was assessed and validated using the concordance index (C-index), area under the curve (AUC), calibration curves, and decision curve analysis. Multivariate logistic regression analyses identified five independent noninvasive variables for developing an HFpEF nomogram, including dyslipidemia (OR = 5.264, p = 0.010), diabetes (OR = 3.929, p = 0.050), left atrial area (OR = 1.130, p = 0.046), hemoglobin <13 g/dL (OR = 5.372, p = 0.010), and NT-proBNP ≥245 pg/mL (OR = 5.108, p = 0.027). The nomogram showed good discriminatory ability (C-index = 0.842) and calibration performance (p = 0.873) and high net benefit (0.1−0.95). Notably, the HFpEF nomogram showed better diagnostic accuracy than the H 2 FPEF score model in predicting Taiwanese HFpEF patients (AUC: 0.873 vs. 0.608, p = 0.0006). The noninvasive HFpEF nomogram provides a preliminary estimation of the probability of HFpEF in Taiwanese outpatients with unexplained dyspnea and fatigue, which may help the decision-making on further invasive CPET. [ABSTRACT FROM AUTHOR]

Aims: Cardiac amyloidosis (CA) is a potentially fatal multisystemic disease that remains significantly underdiagnosed, particularly in the Middle East. This study aims to evaluate the prevalence and clinical characteristics of CA in a high‐risk population at a tertiary centre in Saudi Arabia. Methods: This cross‐sectional, retrospective, single‐centre study was conducted at a tertiary hospital in Riyadh, Saudi Arabia. We reviewed the medical records of heart failure patients seen between August 2018 and July 2022 who exhibited red flags for CA and subsequently underwent CA screening. Red flags that prompted the workup included at least two of the following factors: the presence of unilateral or bilateral carpal tunnel syndrome, a family history of transthyretin amyloid (ATTR) amyloidosis and specific electrocardiographic features (relative/absolute low QRS voltage, pseudoinfarct pattern and atrioventricular/interventricular conduction abnormalities). Echocardiographic red flags included mainly increased wall thickness (≥12 mm), significant diastolic dysfunction, reduced left ventricular (LV) longitudinal function, right ventricular (RV) dysfunction and elevated right atrial (RA)/pulmonary artery (PA) pressure. Cardiac magnetic resonance (CMR) red flags included aspects similar to those in an echocardiogram as well as a subendocardial or transmural late gadolinium enhancement (LGE) pattern. These patients were assessed for CA through technetium‐99m pyrophosphate ([99mTc]Tc‐PYP) bone scintigraphy, serum and urine protein electrophoresis with immunofixation and a serum‐free light chain assay. Results: A total of 177 patients were screened, of which 21.0 (11.9%) patients were diagnosed with transthyretin amyloid CA (ATTR‐CA) and 13 (7.3%) patients were diagnosed with light chain CA (AL‐CA). Compared with patients with negative/equivocal [99mTc]Tc‐PYP scans (grades 0–1), patients with positive [99mTc]Tc‐PYP scans (grades 2–3) were older (78.0 vs. 68.0 years, P < 0.001), had higher levels of troponin (P = 0.003) and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) (P < 0.001), had a higher LV mass index (P < 0.001), displayed a more depressed global longitudinal strain (GLS) (P < 0.001) with a greater prevalence of a relative apical sparing pattern (P < 0.001) and demonstrated a higher incidence of first‐degree atrioventricular block (P = 0.008) and low voltage patterns on electrocardiography (P < 0.001). Patients with ATTR‐CA and AL‐CA were more likely to have a subendocardial or transmural LGE pattern on CMR (P < 0.001) and had a significantly lower overall survival (P < 0.001) when compared with other heart failure aetiologies. Conclusions: This is the first study to describe the clinical characteristics and outcomes of CA in the Middle East and Saudi Arabia. The prevalence of CA among screened heart failure patients here aligns with major international studies, suggesting significant underdiagnosis in the region. Therefore, larger multicentric studies and regional screening programmes are urgently needed to accurately characterize the epidemiology and outcomes of CA in the Middle East. [ABSTRACT FROM AUTHOR]

Aims: Certain critical risk factors of heart failure with preserved ejection fraction (HFpEF) patients were significantly different from those of heart failure with reduced ejection fraction (HFrEF) patients, resulting in the limitations of existing predictive models in real‐world situations. This study aimed to develop a machine learning model for predicting 90 day readmission for HFpEF patients. Methods and Results: Data were extracted from electronic health records from 1 August 2020 to 1 August 2021 and follow‐up records of patients with HFpEF within 3 months after discharge. Feature extraction was performed by univariate analysis combined with the least absolute shrinkage and selection operator (LASSO) algorithms. Machine learning models like eXtreme Gradient Boosting (XGBoost), random forest, neural network and logistic regression were adopted to construct models. The discrimination and calibration of each model were compared, and the Shapley Additive exPlanations (SHAP) method was used to explore the interpretability of the model. The cohort included 746 patients, of whom 103 (13.8%) were readmitted within 90 days. XGBoost owned the best performance [area under the curve (AUC) = 0.896, precision‐recall area under the curve (PR‐AUC) = 0.868, sensitivity = 0.817, specificity = 0.837, balanced accuracy = 0.827]. The Kolmogorov–Smirnov (KS) statistic was 0.694 at 0.468 in the XGBoost model. SHAP identified the top 12 risk features, including activities of daily living (ADL), left atrial dimension (LAD), left ventricular end‐diastolic diameter (LVDD), shortness, nitrates, length of stay, nutritional risk, fall risk, accompanied by other symptoms, educational level, anticoagulants and edema. Conclusions: Our model could help medical agencies achieve the early identification of 90 day readmission risk in HFpEF patients and reveal risk factors that provide valuable insights for treatments. [ABSTRACT FROM AUTHOR]

Aims: Intercellular adhesion molecule‐1 (ICAM‐1) facilitates inflammation via leucocyte recruitment and has been implicated in heart failure with preserved ejection fraction (HFpEF). Approximately 35% of African American individuals carry a copy of an ICAM1 missense variant (rs5491; p.K56M), which is associated with an increased risk of HFpEF. The pathways by which rs5491 increases HFpEF risk are not well defined. We evaluated the circulating immune cell profile of rs5491. Methods: Among African American individuals in the Multi‐Ethnic Study of Atherosclerosis, we evaluated the associations of rs5491 with 29 circulating peripheral blood mononuclear cell subsets. The top immune cells were then related to echocardiographic measures of structure and function. Results: Among 502 individuals with immune cell profiling (mean age 63 years, 51% female), 191 individuals (38%) had at least one copy of rs5491. Each additional rs5491 allele was significantly associated with higher proportions of Tc17 CD8+ cytotoxic T cells (β = 1.34, SE = 0.45, P = 9.5 × 10−5) and Tc2 CD8+ cytotoxic T cells (β = 1.19, SE = 0.44, P = 0.00012). There were no other associations noted between rs5491 and the remaining immune cells. A higher proportion of Tc17 cells was significantly associated with a higher left ventricular ejection fraction, E/e′ average and right ventricular systolic pressure (RVSP), while a higher proportion of Tc2 cells was significantly associated with a higher RVSP. Conclusions: The ICAM1 p.K56M variant (rs5491) carries a distinct and inflammatory T‐cell subset profile. These cytotoxic T cells are in turn associated with alterations in cardiac function and adverse haemodynamics later in life, thus providing insight into pathways by which rs5491 may increase the risk of HFpEF. [ABSTRACT FROM AUTHOR]

Aims: Inflammation accompanies heart failure (HF) and elevated levels of inflammatory biomarkers are linked to new onset of HF. However, whether the prognostic relevance of inflammatory biomarkers is different in HF with reduced (HFrEF) and preserved ejection fraction (HFpEF) is unclear. The aim of the current study is to explore the role of inflammation on the mortality risk in patients with HF. Methods: We analysed interleukin‐6 and hsCRP levels by ELISA and immunonephelometry, respectively, in HFpEF and HFrEF patients referred for coronary angiography and assessed the prognostic value in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Results: HF was present in 1086 patients (N = 506 HFpEF; N = 580 HFrEF; mean age 65 ± 10 years; 28% female). Increasing IL‐6 levels were significantly associated with increased CV mortality in HFpEF [1.5 (95% CI: 1.1–2.2), P = 0.018] but not HFrEF [HR 1.3 (95% CI: 1.0–1.7), P = 0.06] patients. High‐sensitive CRP followed a similar pattern but failed to reach statistical significance after full‐adjustment (HFpEF: HR 1.4 95%C I: 1.0–2.0; P = 0.065; HFrEF HR: 1.0 95% CI: 0.7–1.3; P = 0.800). Interaction analysis in patients stratified by IL‐6 and N terminal pro brain natriuretic peptide (NT‐proBNP) above and below the median revealed a stepwise increase in CV‐mortality in HFpEF (P = 0.036) but not HFrEF patients (P = 0.220). To investigate the relationship between IL‐6 and NT‐proBNP, we assessed the genetic IL6‐Receptor variant p.Asp358Ala (rs2228145) which is linked to impaired IL‐6 receptor signalling. Homozygous carriers with HFpEF but not HFrEF exhibited significantly lower NT‐pro‐BNP levels compared with wildtype carriers (HFpEF 779 pg/mL ± 787 vs. 1180 pg/ mL ± 1532; P = 0.008; HFrEF 2289 pg/ mL ± 3439 vs. 2326 pg/ mL ± 3386; P = 0.94), raising the hypothesis that IL‐6 signalling may play a pathophysiological role in HFpEF. Conclusions: These data suggest a predictive value of elevated IL‐6 for CV‐mortality in HFpEF but not in HFrEF patients. [ABSTRACT FROM AUTHOR]

Aims: The detailed sub‐categories of death and hospitalization, and the impact of comorbidities on cause‐specific outcomes, remain poorly understood in heart failure (HF) with preserved ejection fraction (HFpEF). We sought to evaluate rates and predictors of cardiovascular (CV) and non‐CV outcomes in HFpEF. Methods: The Karolinska–Rennes study was a bi‐national prospective observational study designed to characterize HFpEF (ejection fraction ≥45%). Patients were followed for cause‐specific death and hospitalization. Baseline characteristics were pre‐selected based on clinical relevance and potential eligibility criteria for HFpEF trials. The associations between characteristics and cause‐specific outcomes were assessed with univariable and multivariable Cox regressions. Results: Five hundred thirty‐nine patients [56% females; median (inter‐quartile range) age 79 (72–84) years; NT‐proBNP/BNP 2448 (1290–4790)/429 (229–805) ng/L] were included. Over 1196 patient‐years follow‐up [median (min, max) 744 days (13–1959)], there were 159 (29%) deaths (13 per 100 patient‐years: CV 5.1 per 100, dominated by HF 3.9 per 100; and non‐CV 5.8 per 100, dominated by cancer, 2.3 per 100). There were 723 hospitalizations in 338 patients (63%; 60 per 100 patient‐years: CV 33 per 100, dominated by HF 17 per 100; and non‐CV 27 per 100, dominated by lung disease 5 per 100). Higher age and natriuretic peptides, lower serum natraemia and NYHA class III–IV were independent predictors of CV death; lower serum natraemia, anaemia and stroke of non‐CV death; and anaemia and lower serum natraemia of non‐CV death or hospitalizations. There were no apparent predictors of CV death or hospitalization. Conclusions: In a clinical cohort hospitalized and diagnosed with HFpEF, death and hospitalization rates were roughly similar for CV and non‐CV causes. CV deaths were predicted primarily by severity of HF; non‐CV deaths primarily by anaemia and prior stroke. Lower serum sodium predicted both. Hospitalizations were difficult to predict. [ABSTRACT FROM AUTHOR]

Purpose of review: This review focuses on the association between RA and heart failure, highlighting the role of inflammation and the prevalence of heart failure with preserved ejection fraction (HFpEF) in this population. Recent findings: The incidence of heart failure in RA patients is two to three times higher than in the general population, with inflammation playing a significant role independent of traditional cardiovascular risk factors. HFpEF accounts for about half of heart failure cases and is increasingly recognized in RA patients, although it remains underdiagnosed. Atypical presentations and non-specific symptoms further complicate diagnosis. Early control of inflammation has been shown to reduce the risk of heart failure development and progression, improving both morbidity and mortality outcomes. Summary: Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting approximately 1% of the population, with cardiovascular disease being the leading cause of premature death in these patients. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Uncertainty exists about defining true iron deficiency (ID) in heart failure (HF) patients. We assessed the relationship of different ID definitions with cardiac structure and function, congestion, exercise capacity, and prognosis in HF outpatients.Iron deficiency was defined according to guidelines (G‐ID: ferritin <100 ng/ml or ferritin 100–299 ng/ml with transferrin saturation [TSAT] <20%). Alternative ID definitions based on TSAT (<20%), iron (≤13 μmol/L), and ferritin (<100 or < 300 ng/ml) were explored. Relationships with rest/exercise measures of cardiac function and congestion using ultrasound, effort intolerance and adverse outcome (HF hospitalizations or all‐cause mortality) were assessed. Of 1502 patients (72% with left ventricular ejection fraction [LVEF] ≥50%), 471 (31%) had TSAT <20%, while 728 (48%) had G‐ID. Patients with TSAT <20% or G‐ID had greater left atrial volume but similar LVEF. Lower TSAT, iron and haemoglobin, but not ferritin, were associated with more signs of congestion by ultrasound. After correcting for multiple clinical variables, including haemoglobin, TSAT was directly associated with peak oxygen uptake (standardized coefficient 0.069, p = 0.041), while ferritin was not. There was no interaction with HF phenotype (HF with preserved vs. reduced LVEF). During a median follow‐up of 18 months, TSAT <20% and iron ≤13 μmol/L were associated with worse outcomes in models adjusted for clinical variables, including LVEF and N‐terminal pro‐B‐type natriuretic peptide (hazard ratio 2.48, 95% confidence interval 1.88–3.17 and 1.93, 1.48–2.52, respectively), while G‐ID or ferritin <100 or <300 ng/ml were not.In HF outpatients, TSAT <20% is more consistently associated with congestion by ultrasound and poorer functional capacity than other ID definitions, irrespective of LVEF. TSAT <20% and iron ≤13 μmol/L, but not G‐ID or ferritin‐based ID, predict a worse prognosis in HF outpatients with preserved and reduced LVEF. [ABSTRACT FROM AUTHOR]

Background: Diastolic heart failure (DHF) and type 2 diabetes mellitus (T2DM) often coexist, causing increased mortality rates. Glycaemic variability (GV) exacerbates cardiovascular complications, but its impact on outcomes in patients with DHF and T2DM remains unclear. This study examined the relationships between GV with mortality outcomes, and developed a machine learning (ML) model for long-term mortality in these patients. Methods: Patients with DHF and T2DM were included from the Medical Information Mart for Intensive Care IV, with admissions (2008–2019) as primary analysis cohort and admissions (2020–2022) as external validation cohort. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to evaluate the associations of GV with 90-day, 1-year, and 3-year all-cause mortality. The primary analysis cohort was split into training and internal validation cohorts, then developing ML models for predicting 1-year all-cause mortality in training cohort, which were validated using the internal and external validation cohorts. Results: 2,128 patients with DHF and T2DM were included in primary analysis cohort (meidian age 71.0years [IQR: 62.0–79.0]; 46.9% male), 498 patients with DHF and T2DM were included in the external validation cohort (meidian age 75.0years [IQR: 67.0–81.0]; 54.0% male). Multivariate Cox proportional hazards models showed that high GV tertiles were associated with higher risk of 90-day (T2: HR 1.45, 95%CI 1.09–1.93; T3: HR 1.96, 95%CI 1.48–2.60), 1-year (T2: HR 1.25, 95%CI 1.02–1.53; T3: HR 1.54, 95%CI 1.26–1.89), and 3-year (T2: HR 1.31, 95%CI: 1.10–1.56; T3: HR 1.48, 95%CI 1.23–1.77) all-cause mortality, compared with lowest GV tertile. Chronic kidney disease, creatinine, potassium, haemoglobin, and white blood cell were identified as mediators of GV and 1-year all-cause mortality. Additionally, GV and other clinical features were pre-selected to construct ML models. The random forest model performed best, with AUC (0.770) and G-mean (0.591) in internal validation, with AUC (0.753) and G-mean (0.599) in external validation. Conclusion: GV was determined as an independent risk factor for short-term and long-term all-cause mortality in patients with DHF and T2DM, with a potential intervention threshold around 25.0%. The ML model incorporating GV demonstrated strong predictive performance for 1-year all-cause mortality, highlighting its importance in early risk stratification management of these patients. [ABSTRACT FROM AUTHOR]

Background: The triglyceride-glucose (TyG) index is a surrogate indicator of insulin resistance. Therefore, we aimed to determine the association between TyG index and heart failure (HF) with preserved ejection fraction (HFpEF) in patients with coronary heart disease (CHD) and to explore whether such associations would be modified by different metabolic states. Methods: Among 107,301 CHD patients, 62,794 were included to analyze the relationship between the TyG index and HF. Among them, 8,606 patients who had undergone echocardiography were included to identify different types of HF, including HF with reduced ejection fraction (HFrEF), HF with intermediate-range ejection fraction (HFmrEF), and HFpEF. Among them, 1896 patients were diagnosed with HFpEF. Logistic regression was used to analyze the relationship between the TyG index and HFpEF in CHD patients. In addition, the association between TyG index and HFpEF according to sex, age, blood lipids, and blood pressure was assessed. Results: A baseline analysis of CHD patients divided into four groups according to the tertile level of the TyG index showed significant differences in the related parameters between the groups. In the multi-adjusted models, the TyG index was significantly associated with the risk of HFpEF (odds ratio [OR]: 1.17; 95% confidence interval [CI]: 1.09–1.25). After adjustment for multivariates, TyG index levels for T2 (OR: 1.33; 95% CI: 1.16–1.52) and T3 (OR: 1.52; 95% CI: 1.32–1.74) were associated with increased OR in HFpEF. In addition, the TyG index of CHD patients was significantly associated with HFpEF in older adults aged > 60 years (OR: 1.20; 95% CI: 1.11–1.29), hypertension (OR: 1.27; 95% CI: 1.17–1.37), and dyslipidemia (OR: 1.15; 95% CI: 1.08–1.24). Moreover, the OR (OR: 1.23; 95% CI: 1.11–1.36) in women is higher than in men (OR: 1.17; 95% CI: 1.02–1.22, indicating a stronger association between TyG index and HFpEF in women. Conclusions: Our findings demonstrated a significant association between TyG index and HFpEF in CHD patients. Furthermore, TyG index was independently associated with HFpEF in hypertension, dyslipidemia, and older patients (aged > 60 years). In addition, the association between the TyG index and HFpEF in CHD patients differed according to sex. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (PH-HFpEF) represents a frequent form of PH related to left ventricular dysfunction. The pathophysiology of PH-HFpEF is intricate, and varied and includes vascular, cardiac, and pulmonary factors that contribute synergistically to developing this clinical syndrome. Improved knowledge of the pathophysiology of PH-HFpEF has paved the way for the use of new drugs such as angiotensin receptor neprilysin inhibitors (ARNIs), non-steroidal mineral corticoid receptor antagonist (nsMRA), sodium-glucose cotransporter inhibitors (SGLT2is), levosimendan, and glucagon-like peptide 1 (GLP-1) agonists. ARNIs are a widely used drug for the treatment of PH associated with heart failure with reduced ejection fraction. They have also recently been used in PH-HFpEF patients with hemodynamic benefits that need to be confirmed in future research. Finerenone is an innovative non-steroidal mineralocorticoid receptor antagonist that exhibits notable cardioprotective and renoprotective properties in individuals suffering from chronic diabetic kidney disease. It also enhances outcomes for patients with heart failure, whether they have mildly reduced or preserved ejection fraction. Moreover, in experimental studies, finerenone has been found to lower pulmonary artery pressure, reduce muscularization, and decrease the wall thickness of pulmonary arteries. SGLT2i have revolutionized the treatment of patients with heart failure irrespective of left ventricular ejection fraction, and their treatment is also associated with an improvement in the hemodynamics profile in patients with PH-HFpEF. Levosimendan is a widely used inodilator in the treatment of acute and advanced heart failure. In addition, its use in patients with PH-HFpEF (supported by the positive effects on pulmonary hemodynamics that levosimendan exerts) has recently demonstrated hemodynamic benefit in a small phase 2 study that paved the way for phase 3 studies and the creation of an oral formulation of levosimendan. Finally, GLP1 agonists are a class of drugs that, in preliminary evidence, have shown a positive effect on cardiac hemodynamics, mainly by facilitating left ventricular unloading. These effects, along with the reduction in insulin resistance and weight loss, likely lead to beneficial outcomes for PH-HFpEF patients, especially those with obesity as a comorbidity. [ABSTRACT FROM AUTHOR]

Background: The study aimed to evaluate the changes of left ventricular diastolic function and the improvement of clinical symptoms in hypertrophic cardiomyopathy (HCM) patients with heart failure with preserved ejection fraction (HFpEF) after percutaneous intramyocardial septal radiofrequency ablation (PIMSRA). Methods: This study enrolled 31 adult HCM patients with HFpEF who underwent PIMSRA treatment. Electrocardiogram, imaging, and blood biochemical examinations were performed on these patients during a 6‐month follow‐up. Results: Compared with the baseline, at 6 months after PIMSRA, patients showed significant reductions in peak left ventricular outflow tract pressure gradients (resting gradient: from a mean of 83.24 to 23.40 mmHg, p < 0.001; postexercise gradient: from a mean of 109.70 to 33.39 mmHg, p< 0.001). The interventricular septal thickness reduced from a mean of 22.90 to 17.48 mm, p < 0.001. The E/e' decreased from a median of 18.67 to 11.54, p < 0.001. The 6‐minute walk distance (6MWD) increased from a mean of 359.03 to 435.81 m, p < 0.001. The Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ OS) increased from a mean of 57.57 to 71.93, p < 0.001. The number of HFpEF patients diagnosed according to the European Society of Cardiology's Heart Failure Association HFA‐PEFF score decreased from 31 to 23. None of the patients had new‐onset bundle branch block or complete heart block after PIMSRA. Conclusion: PIMSRA is a safe and effective treatment. It can improve left ventricular diastolic function and quality of life in HCM patients. [ABSTRACT FROM AUTHOR]

Background Growth differentiation factor 15 (GDF-15) holds promise as a novel marker for heart failure. However, current detection methods fall short of meeting essential clinical requirements. Objectives The aim of this investigation was to assess the clinical significance of serum GDF-15 detection through the chemiluminescence method and to enhance its clinical application for predicting and evaluating heart failure in patients. Methods A total of 122 patients were included in the study. Serum GDF-15 levels were assessed using the chemiluminescence method and compared with results for NT-proBNP, N-terminal pro-brain natriuretic peptide (NT-proBNP), growth stimulation expressed gene 2 (ST2), high-sensitivity C-reactive protein (hs-CRP), and left ventricular ejection fraction (LVEF). Additionally, we conducted an analysis to evaluate the correlation between these indicators and heart failure events. Results LVEF, ST2, NT-proBNP, and GDF-15 exhibited significant associations with heart failure. In the multivariate proportional hazard analysis, subsequent to adjusting for the effects of other markers, however, only LVEF and GDF-15 retained their associations with heart failure events. Notably, GDF-15 emerged as the exclusive marker suitable for diagnosing heart failure with preserved ejection fraction. Conclusion The chemiluminescence method proved efficient in the rapid and sensitive detection of GDF-15 in patients with heart failure. Additionally, GDF-15 combined with other markers created a robust multi-index model. This model is valuable for heart failure diagnosis, treatment, and monitoring, with broad clinical applicability. [ABSTRACT FROM AUTHOR]

• Skeletal muscle is displayed and easily quantifiable on standard CMR T1-maps. • High native skeletal muscle T1 times are linked to a more unfavorable prognosis. • Native skeletal muscle T1 time may serve as a risk stratification marker in HFpEF. Heart failure with preserved ejection fraction (HFpEF) is associated with heart failure (HF) hospitalizations and death. Previous studies have shown that altered muscle composition is associated with higher risk of adverse outcome in HFpEF patients. The purpose of our study was to investigate the association between skeletal muscle composition, as measured by skeletal muscle T1-times on cardiac magnetic resonance (CMR) imaging, and adverse outcome. We measured skeletal muscle T1-times of the back muscles on standard CMR images in a prospective cohort of HFpEF patients. Cox regression models were used to test the association of skeletal muscle T1-times and adverse outcome defined as hospitalization for HF and/or cardiovascular death. We included 101 patients (mean age 72±7 years, 71 % female) in our study. The median skeletal muscle T1-times were 842 ms (IQR 806–881 ms). In univariate analysis high muscle T1-time was associated with adverse outcome (HR=1.96 [95 % CI, 1.31–2.94] per every 100 ms increase; p =.001). After adjustment for age, sex, body mass index, left- and right ventricular ejection fraction, N-terminal pro-brain natriuretic peptide and myocardial native T1-times, native skeletal muscle T1-time remained an independent predictor for adverse outcome (HR=1.94 [95 % CI, 1.24–3.03] per every 100 ms increase; p =.004). In patients with HFpEF, high skeletal muscle T1-times on standard CMR scans are associated with higher rates of HF hospitalizations and cardiovascular death. Condensed abstract: Skeletal muscle abnormalities are common in patients with heart failure with preserved ejection fraction (HFpEF). The present study evaluates skeletal muscle composition, as quantified by native skeletal muscle T1-times of the back muscles on standard cardiac magnetic resonance imaging, and assessed the association with adverse outcome, defined as hospitalization for heart failure and/or cardiovascular death. In a prospective cohort of 101 patients with HFpEF, we found that high native skeletal muscle T1-times are associated with an increased risk for adverse outcome. These findings suggest that native skeletal muscle T1-time may serve as marker for improved risk prediction. High skeletal muscle T1-time is associated with highest risk of adverse cardiovascular events including heart failure hospitalizations and cardiovascular death 101 patients with HFpEF underwent CMR for measurement of skeletal muscle T1-time of the back muscles (green arrows on panel 3) using T1-mapping to assess muscle tissue. The right panel shows time-to-event curves of the study cohort for the combined endpoint of HF hospitalizations and/or cardiovascular death, stratified by skeletal muscle T1-time median. Patients with high skeletal muscle T1-time (purple line), suggesting that inflammation and fibrosis are present, had a higher risk for adverse outcome compared to patients with a low skeletal muscle T1-time (blue line). CMR, cardiac magnetic resonance; HF, heart failure; HFpEF, heart failure with preserved ejection fraction. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Hydroxychloroquine (HCQ) reduces cardiovascular events among patients with autoimmune disorders and is being evaluated as a therapeutic option for populations with high‐risk cardiovascular disease. However, recent studies have raised concerns about HCQ use and cardiovascular events. Objective: To assess the association of HCQ initiation with heart failure–related and all‐cause hospitalizations among patients with heart failure and preserved ejection fraction (HFpEF). Methods: We conducted a cohort study of patients aged ≥18 years with diagnosed HFpEF and autoimmune disease using MarketScan Commercial and Medicare Supplemental databases (2007–2019). Patients were required to initiate HCQ after their first HFpEF diagnosis (HCQ users) or not (HCQ nonusers). For the patients in the HCQ users group, the first HCQ prescription date was assigned as the index date. Index date for the HCQ nonuser group was assigned by prescription‐time distribution matching HCQ users, by utilizing the number of days from HFpEF diagnosis to the first HCQ prescription. After 1:≥3 propensity score (PS) matching, Cox proportional hazards regression models were used to compare HF‐related and all‐cause hospitalizations between users and nonusers. Results: After PS matching, 2229 patients (592 HCQ users and 1637 HCQ nonusers) were included. After controlling for covariates, patients who received HCQ had lower risks of HF‐related hospitalization (adjusted hazard ratio, 0.44; 95% CI, 0.24–0.82) and all‐cause hospitalization (adjusted hazard ratio, 0.69; 95% CI, 0.57–0.83) compared with patients not using HCQ. Conclusions: Among patients with HFpEF and autoimmune disease, initiation of HCQ use was associated with a decreased risk of HF‐related and all‐cause hospitalizations. [ABSTRACT FROM AUTHOR]

The concept of quadruple therapy as a "one-size-fit-all" approach is effective among all eligible patients with heart failure with reduced ejection fraction, with consistent and significant clinical benefits including reduced mortality across various subgroups. However, with exception of sodium-glucose cotransporter 2 inhibitors, the consistency of benefit with therapies does not extend to patients with heart failure with preserved ejection fraction. The clinical benefits of other promising medical therapies, such as angiotensin receptor–neprilysin inhibitors, mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, have been demonstrated only in certain phenotypes of the highly heterogenous heart failure with preserved ejection fraction population. This variability can confuse frontline practicing cardiologists, potentially leading to the under-implementation of these medications. Therefore, we propose a simple approach: "targeted" combination therapy. This strategy aims to optimize evidence-based medications in heart failure with preserved ejection fraction by tailoring treatments to specific subgroups within the heart failure with preserved ejection fraction population where significant benefits are most evident. [ABSTRACT FROM AUTHOR]

In heart failure (HF) patients undergoing cardiac surgery, an increased activity of mechanisms related to cardiac remodeling may determine a higher risk of postoperative atrial fibrillation (POAF). Given that atrial fibrillation (AF) has a negative impact on the course and management of HF, including the need for anticoagulation therapy, identifying the factors associated with AF occurrence after cardiac surgery is crucial for the prognosis of these patients. POAF is thought to occur when various clinical and biochemical triggers act on susceptible cardiac tissue (first hit), with oxidative stress and inflammation during cardiopulmonary bypass (CPB) surgery being potential contributing factors (second hit). However, the molecular mechanisms involved in these processes remain poorly characterized. Recent research has shown that patients who later develop POAF often have pre-existing abnormalities in calcium handling and activation of NLRP3-inflammasome signaling in their atrial cardiomyocytes. These molecular changes may make cardiomyocytes more susceptible to spontaneous Ca2+-releases and subsequent arrhythmias, particularly when exposed to inflammatory mediators. Additionally, some clinical studies have linked POAF with elevated preoperative inflammatory markers, but there is a need for further research in order to better understand the impact of CPB surgery on local and systemic inflammation. This knowledge would make it possible to determine whether patients susceptible to POAF have pre-existing inflammatory conditions or cellular electrophysiological factors that make them more prone to developing AF and cardiac remodeling. In this context, the NLRP3 inflammasome, expressed in cardiomyocytes and cardiac fibroblasts, has been identified as playing a key role in the development of HF and AF, making patients with pre-existing HF with reduced ejection fraction (HFrEF) the focus of several clinical studies with interventions that act at this level. On the other hand, HFpEF has been linked to metabolic and non-ischemic risk factors, but more research is needed to better characterize the myocardial remodeling events associated with HFpEF. Therefore, since ventricular remodeling may differ between HFrEF and HFpEF, it is necessary to perform studies in both groups of patients due to their pathophysiological variations. Clinical evidence has shown that pharmacological therapies that are effective for HFrEF may not provide the same anti-remodeling benefits in HFpEF patients, particularly compared to traditional adrenergic and renin–angiotensin–aldosterone system inhibitors. On the other hand, there is growing interest in medications with pleiotropic or antioxidant/anti-inflammatory effects, such as sodium–glucose cotransporter 2 inhibitors (SGLT-2is). These drugs may offer anti-remodeling effects in both HFrEF and HFpEF by inhibiting pro-inflammatory, pro-oxidant, and NLRP3 signaling pathways and their mediators. The anti-inflammatory, antioxidant, and anti-remodeling effects of SGLT-2 i have progressively expanded from HFrEF and HFpEF to other forms of cardiac remodeling. However, these advances in research have not yet encompassed POAF despite its associations with inflammation, oxidative stress, and remodeling. Currently, the direct or indirect effects of NLRP3-dependent pathway inhibition on the occurrence of POAF have not been clinically assessed. However, given that NLRP3 pathway inhibition may also indirectly affect other pathways, such as inhibition of NF-kappaB or inhibition of matrix synthesis, which are strongly linked to POAF and cardiac remodeling, it is reasonable to hypothesize that this type of intervention could play a role in preventing these events. [ABSTRACT FROM AUTHOR]

Despite remarkable progress in therapeutic drugs, morbidity, and mortality for heart failure (HF) remains high in developed countries. HF with preserved ejection fraction (HFpEF) now accounts for around half of all HF cases. It is a heterogeneous disease, with multiple aetiologies, and as such poses a significant diagnostic challenge. Cardiac magnetic resonance (CMR) has become a valuable non-invasive modality to assess cardiac morphology and function, but beyond that, the multi-parametric nature of CMR allows novel approaches to characterize haemodynamics and with magnetic resonance spectroscopy (MRS), the study of metabolism. Furthermore, exercise CMR, when combined with lung water imaging provides an in-depth understanding of the underlying pathophysiological and mechanistic processes in HFpEF. Thus, CMR provides a comprehensive phenotyping tool for HFpEF, which points towards a targeted and personalized therapy with improved diagnostics and prevention. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) constitutes approximately half of the heart failure population, with its prevalence markedly increasing with older age and the presence of cardio-metabolic comorbidities. Although HFpEF is associated with a high symptom- and mortality burden, historically there have been few evidence-based treatment options for patients with HFpEF. Recent randomized clinical trials have expanded evidence on pharmacological treatment options, introducing new agents for managing HFpEF. Given the complex clinical phenotype with pathophysiological heterogeneity and evolving diagnostic standards, the evidence-based management of HFpEF remains challenging for clinicians. This review summarizes the latest evidence from contemporary randomized clinical trials and recent guideline recommendations to provide guidance for the treatment of patients with HFpEF. [ABSTRACT FROM AUTHOR]

Diastolic dysfunction refers to impaired relaxation or filling of the ventricles during the diastolic phase of the cardiac cycle. Left ventricular diastolic dysfunction (LVDD) is common in hypertensive individuals and is associated with increased morbidity and mortality. LVDD serves as a critical precursor to heart failure, particularly heart failure with preserved ejection fraction. The pathophysiology of LVDD in hypertension is complex, involving alterations in cardiac structure and function, neurohormonal activation, and vascular stiffness. While the diagnosis of LVDD relies primarily on echocardiography, management remains challenging due to a lack of specific treatment guidelines for LVDD. This review offers an overview of the pathophysiological mechanisms underlying LVDD in hypertension, diagnostic methods, clinical manifestations, strategies for managing LVDD, and prospects for future research. [ABSTRACT FROM AUTHOR]

Understanding of the pathophysiology of heart failure with preserved ejection fraction (HFpEF) has advanced rapidly over the past two decades. Currently, HFpEF is recognized as a heterogeneous syndrome, and there is a growing movement towards developing personalized treatments based on phenotype-guided strategies. Left ventricular dysfunction is a fundamental pathophysiological abnormality in HFpEF; however, recent evidence also highlights significant roles for the atria, right ventricle, pericardium, and extracardiac contributors. Imaging plays a central role in characterizing these complex and highly integrated domains of pathophysiology. This review focuses on established evidence, recent insights, and the challenges that need to be addressed concerning the pathophysiology of HFpEF, with a focus on imaging-based evaluations and opportunities for further research. [ABSTRACT FROM AUTHOR]

Inflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved heart failure–related symptoms, physical limitations, and exercise function, reduced the levels of C-reactive protein (CRP), a biomarker of inflammation, and reduced body weight in participants with obesity-related HFpEF. However, neither the prevalence nor the clinical characteristics of patients who have various magnitudes of inflammation in the context of obesity-related HFpEF have been well described. Furthermore, whether the beneficial effects of semaglutide on the various HF efficacy endpoints in the STEP-HFpEF Program are modified by the baseline levels of inflammation has not been fully established. Finally, the relationship between weight reduction and changes in CRP across the STEP-HFpEF Program have not been fully defined. This study sought to: 1) evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF that have various levels of inflammation in the STEP-HFpEF Program; 2) determine if the effects of weekly semaglutide 2.4 mg vs placebo across all key outcomes are influenced by baseline levels of inflammation assessed by CRP levels; and 3) determine the relationship between change in CRP and weight loss in the STEP-HFpEF Program. This was a secondary analysis of pooled data from 2 international, double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM). The outcomes were change in the dual primary endpoints (health status [measured by the Kansas City Cardiomyopathy Questionnaire—Clinical Summary Score (KCCQ-CSS)] and body weight) from baseline to 52 weeks according to baseline CRP levels. Additional efficacy endpoints included change in 6-minute walk distance (6MWD), a hierarchical composite endpoint that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6MWD, and levels of CRP in semaglutide- vs placebo-treated patients. Patients were stratified into 3 categories based on baseline CRP levels (<2, ≥2 to <10, and ≥10 mg/L). In total, 1,145 patients were randomized, of which 71% of patients had evidence of inflammation (CRP ≥2 mg/L). At baseline, those with higher levels of inflammation were younger, were more likely to be female, and had higher body mass index, worse health status (KCCQ-CSS), and shorter 6MWD. Semaglutide vs placebo led to reductions in HF-related symptoms and physical limitations as well as body weight, and to improvements in 6MWD and the hierarchical composite endpoint that were consistent across baseline CRP categories (all P interaction nonsignificant). Semaglutide also reduced CRP to a greater extent than placebo regardless of baseline CRP levels (P interaction = 0.32). Change in CRP from baseline to 52 weeks was similar regardless of the magnitude of weight loss (P interaction = 0.91). Inflammation is highly prevalent in obesity-related HFpEF. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced body weight across the categories of baseline CRP. Semaglutide also reduced inflammation, regardless of either baseline CRP or magnitude of weight loss during the trials. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511 ]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM; NCT04916470 ]) [ABSTRACT FROM AUTHOR]

Obesity is a key factor in the development and progression of both heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF). In the STEP-HFpEF Program (comprising the STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes] trials), once-weekly semaglutide 2.4 mg improved HF-related symptoms, physical limitations, and exercise function and reduced body weight in patients with obesity-related HFpEF. Whether the effects of semaglutide in this patient group differ in participants with and without AF (and across various AF types) has not been fully examined. The goals of this study were: 1) to evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF with and without a history of AF; and 2) to determine if the efficacy of semaglutide across all key trial outcomes are influenced by baseline history of AF (and AF types) in the STEP-HFpEF Program. This was a secondary analysis of pooled data from the STEP-HFpEF and STEP-HFpEF DM trials. Patients with heart failure, left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to receive once-weekly semaglutide 2.4 mg or matching placebo for 52 weeks. Dual primary endpoints (change in KCCQ-CSS and percent change in body weight), confirmatory secondary endpoints (change in 6-minute walk distance; hierarchical composite endpoint comprising all-cause death, HF events, thresholds of change in KCCQ-CSS, and 6-minute walk distance; and C-reactive protein [CRP]), and exploratory endpoint (change in N-terminal pro–B-type natriuretic peptide [NT-proBNP]) were examined according to investigator-reported history of AF (yes/no). Responder analyses examined the proportions of patients who experienced a ≥5-, ≥10, ≥15, and ≥20-point improvement in KCCQ-CSS per history of AF. Of the 1,145 participants, 518 (45%) had a history of AF (40% paroxysmal, 24% persistent AF, and 35% permanent AF) and 627 (55%) did not. Participants with (vs without) AF were older, more often male, had higher NT-proBNP levels, included a higher proportion of those with NYHA functional class III symptoms, and used more antithrombotic therapies, beta-blockers, and diuretics. Semaglutide led to larger improvements in KCCQ-CSS (11.5 points [95% CI: 8.3-14.8] vs 4.3 points [95% CI: 1.3-7.2]; P interaction = 0.001) and the hierarchal composite endpoint (win ratio of 2.25 [95% CI: 1.79-2.83] vs 1.30 [95% CI: 1.06-1.59]; P interaction < 0.001) in participants with AF vs without AF, respectively. The proportions of patients receiving semaglutide vs those receiving placebo experiencing ≥5-, ≥10-, ≥15-, and ≥20-point improvement in KCCQ-CSS were also higher in those with (vs without) AF (all P interaction values <0.05). Semaglutide consistently reduced CRP, NT-proBNP, and body weight regardless of AF status (all P interaction values not significant). There were fewer serious adverse events and serious cardiac disorders in participants treated with semaglutide vs placebo irrespective of AF history. In the STEP-HFpEF Program, AF was observed in nearly one-half of patients with obesity-related HFpEF and was associated with several features of more advanced HF. Treatment with semaglutide led to significant improvements in HF-related symptoms, physical limitations, and exercise function, as well as reductions in weight, CRP, and NT-proBNP in people with and without AF and across AF types. The magnitude of semaglutide-mediated improvements in HF-related symptoms and physical limitations was more pronounced in those with AF vs without AF at baseline. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511 ]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM; NCT04916470 ]) [ABSTRACT FROM AUTHOR]

Obesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown. In this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function. Echocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values. Overall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, −6.13 mL; 95% CI: −9.85 to −2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: −1.99 cm2; 95% CI: −3.60 to −0.38 cm2; P = 0.016; EMD in RV end-systolic area: −1.41 cm2; 95% CI: −2.42 to −0.40] cm2; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: −5.63 cm/s; 95% CI: −9.42 to −1.84 cm/s; P = 0.0037), E/A (early/late mitral inflow velocity) ratio (EMD: −0.14; 95% CI: −0.24 to −0.04; P = 0.0075), and E/e′ (early mitral inflow velocity/early diastolic mitral annular velocity) average (EMD: −0.79; 95% CI: −1.60 to 0.01; P = 0.05). These associations were not modified by diabetes or atrial fibrillation status. Semaglutide did not significantly affect left ventricular dimensions, mass, or systolic function. Greater weight loss with semaglutide was associated with greater reduction in LA volume (P interaction = 0.033) but not with changes in E-wave velocity, E/e′ average, or RV end-diastolic area. In the STEP-HFpEF Program echocardiography substudy, semaglutide appeared to improve adverse cardiac remodeling compared with placebo, further suggesting that treatment with semaglutide may be disease modifying among patients with obesity-related HFpEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511 ; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470) [ABSTRACT FROM AUTHOR]

Obesity is an ongoing pandemic and is associated with the development of heart failure (HF), and especially HF with preserved ejection fraction. The definition of obesity is currently based on anthropometric measurements but neglects the location and molecular properties of excess fat. Important depots associated with HF development are subcutaneous adipose tissue and visceral adipose tissue, both located in the abdominal region, and epicardial adipose tissue (EAT) surrounding the myocardium. However, mechanisms linking these different adipose tissue depots to HF development are incompletely understood. EAT in particular is of great interest because of its close proximity to the heart. In this review, we therefore focus on the characteristics of different adipose tissue depots and their response to obesity. In addition, we evaluate how different mechanisms associated with EAT expansion potentially contribute to HF and in particular HF with preserved ejection fraction development. • Obesity is a major contributor to the development of HFpEF, but pathophysiological mechanisms remain elusive. • Fat localization is an important consideration because subcutaneous, visceral, and epicardial adipose tissue respond differently in obesity. • Epicardial adipose tissue potentially contributes to HFpEF development through proinflammatory paracrine effects, lipid infiltration, and pericardial constraint. • Targeting unique properties of different adipose tissues is a potential approach to reduce incident HFpEF. [ABSTRACT FROM AUTHOR]

Objective: To explore the cardiac structural and functional changes in obstructive sleep apnea-hypopnea syndrome (OSAHS) patients with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF). Methods: This retrospective study included 336 OSAHS patients with HFpEF. They were divided into Groups A (without an AF history and no AF episodes during cardiac color ultrasound examination), B (an AF history but no AF episodes), and C (an AF history and AF episodes). They all received cardiac color ultrasound examinations. Cardiac structural and functional changes in ultrasonic cardiograms were compared between the three groups. Results: Compared with Groups A and B, Group C showed increased left atrial diameter (LAD), left atrial volume (LAV), right ventricular diameter at end-diastole (RV-D1), right ventricular diameter at end-systole (RV-D2), right ventricular outflow tract diameter (RVOT2), right atrial diameter at end-diastole (RA-D1), right atrial diameter at end-systole (RA-D2), and right atrial area (RAA) (p < 0.05). Compared with Group A, Group C showed decreased fractional shortening (FS), left ventricular ejection fraction (LVEF), deceleration time (DT), isovolumic relaxation time (IVRT), E/E' ratio, and peak filling velocity (FPV), as well as increased E and E' (p < 0.01). Compared with Group B, Group C showed decreased FS and increased E and FPV (p < 0.01). Conclusion: In OSAHS patients with HFpEF and AF, cardiac remodeling and AF incidence are increased with the severity of OSAHS. OSAHS patients with HFpEF combined with AF have a significantly higher abnormality rate in right heart structural indices rather than left heart, mainly in the right atrium. [ABSTRACT FROM AUTHOR]

Objective To screen out sensitive heart rate variability (HRV) index reflecting left ventricular (LV) stiffness in patients with heart failure with preserved ejection fraction (HFpEF), and to assess its prognostic evaluation value for HFpEF patients. Methods We selected 150 patients with normal LVEF who had undergone 24-hour ambulatory electrocardiography and routine echocardiography examinations. The enrolled patients were divided into normal control group (68 cases) and HFpEF group (82 cases). The receiver operating characteristic curve analysis was used to screen out the sensitive HRV index associated with LV stiffness in HFpEF patients. The primary endpoint events were followed up. Results Among HRV indexes, the area under curve (AUC) of SDANN was the largest in the prediction of HFpEF (AUC = 0. 68, P<0. 01); the cut-off value was 90 ms. SDANN was negatively associated with LV diastolic wall strain. The higher the SDANN was, the higher the LV stiffness was. According to the cut-off value of SDANN, the patients with HFpEF were divided into high-SDANN group (cut-off value≥90 ms, 44 cases) and low-SDANN group (cut-off value<90 ms, 38 cases). In the low-SDANN group, the LV stiffness was lower. The survival curve analysis revealed that in the high-SDANN group the incidence of major adverse cardiac events and total mortality were significantly higher than those in the low-SDANN group (P<0. 05). Conclusion SDANN could be served as a sensitive indicator for making clinical diagnosis and prognostic evaluation among patients with HFpEF. [ABSTRACT FROM AUTHOR]

AIM: To investigate the role and possible mechanisms of disulfiram （DSF） in a rat model of heart failure with preserved ejection fraction （HFpEF） induced by high-fat diet （HFD） and nitric oxide blocker Nω-nitro-L-arginine methyl ester （L-NAME）. METHODS: The HFpEF rat model was constructed using HFD and L-NAME. Sprague-Dawley rats were randomly divided into 3 groups: control group （fed with a normal diet and water）, HFpEF group （fed with HFD and drinking water containing 0. 5 g/L L-NAME）, and DSF+HFpEF group（ treated with DSF in addition to HFD and L-NAME）. After 5 weeks, cardiac function of the rats was examined using echocardiography and exercise test. Myocardial pathological changes were detected using hematoxylin-eosin and wheat germ agglutinin staining, the degree of cardiac fibrosis was assessed using Masson staining, and apoptosis levels were observed using TUNEL staining. Western blot was performed to detect the expression of nucleotide-binding oligomerization domain-like receptor protein 3 （NLRP3）, cleaved caspase-1, gasdermin D N-terminal fragment（ GSDMD-N） in the myocardium, and serum level of N-terminal probrain natriuretic peptide （NT-proBNP）, and interleukin （IL）-1β and IL-18 in the myocardium were detected by ELISA. RESULTS: Compared with control group, the rats in HFpEF group showed increased body weight, systolic blood pressure, diastolic blood pressure, E/E′ ratio, left ventricular anterior wall thickness at diastole and serum NT-proBNP level （P<0. 05）, and decreased E/A ratio and absolute value of global longitudinal strain （GLS; P<0. 05）. In contrast, the rats in DSF+HFpEF group showed decreased body weight, E/E′ ratio, diastolic blood pressure and serum NT-proBNP level （P<0. 05）, and increased E/A ratio and absolute value of GLS （P<0. 05）, with no significant changes in systolic blood pressure, left ventricular posterior wall thickness at diastole and left ventricular ejection fraction （P>0. 05）. The rats in HFpEF group had increased myocardial fibrosis area, cardiomyocyte cross-sectional area, and apoptotic rate compared with control group （P<0. 05）, while these indexes were reduced in DSF+HFpEF group （P<0. 05）. The results of Western blot and ELISA showed that the levels of NLRP3, cleaved caspase-1, GSDMD-N, IL-1β and IL-18 were increased in the myocardium of rats in HFpEF group compared with control group （P<0. 05）, but decreased in DSF+HFpEF group compared with HFpEF group （P<0. 05）. CONCLUSION: Disulfiram improves cardiac function and attenuates myocardial remodeling in HFpEF rats. The mechanism may be related to the modulation of NLRP3/caspase-1/GSDMD signaling pathway and the reduction of myocardial inflammatory response. [ABSTRACT FROM AUTHOR]

Aims Adults with heart failure with preserved ejection fraction (HFpEF) responded more favourably to an exercise intervention compared with those with reduced ejection fraction. This study explores factors that contributed to this response, focusing on the qualitative perceptions of adults with HFpEF enrolled in an exercise intervention. Methods and results This qualitative descriptive study is a secondary analysis of longitudinal interviews collected at 3, 6, 12, and 18 months from participants with HFpEF enrolled in a randomized controlled trial testing an intervention to promote adherence to exercise. We included participants with at least two interviews. Interviews were examined across and within participants and time points using thematic analysis. Analyses included 67 interviews from 21 adults with HFpEF enrolled in the intervention arm. The sample consisted of 52% (11/21) males and over 47% (10/21) non-White participants. Mean age at enrolment was 63.7 ± 9.9 years. We identified four major themes: (1) overcoming negative attitudes, barriers, and injury, (2) motivations to exercise, (3) exercise—the panacea for HFpEF symptoms and quality of life, and (4) advice for others with HFpEF. Conclusion Our findings suggest that for many adults with HFpEF, initial hesitancy, fear, and negative attitudes about exercise can be overcome. Exercise coaching using social cognitive constructs, medical fitness centre memberships, and heart rate self-monitoring are successful strategies of engaging adults with HFpEF in long-term unsupervised exercise training. Registration ClinicalTrials.gov , NCT01658670. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to investigate whether the H2FPEF score, which was developed to improve the diagnosis of heart failure (HF) with preserved ejection fraction, is associated with HF outcomes in patients with hypertrophic cardiomyopathy (HCM). Methods and results: Patients with HCM and preserved left ventricular ejection fraction (LVEF ≥50%) were included from a multicentre registry and the H2FPEF score was calculated. Patients were divided into three groups: low (0–1), intermediate (2–5) and high (6–9) H2FPEF score. The primary combined endpoint was a composite of all‐cause death and HF admissions, while the secondary endpoints were all‐cause death and HF admissions separately. A total of 955 patients were included (age 51 ± 17 years, 310 [32.5%] female). Patients with a high H2FPEF score (n = 105) were more often female, and presented with more symptoms and comorbidities. On echocardiography, patients with a high H2FPEF score had lower LVEF, more impaired diastolic function and more frequently left ventricular outflow tract obstruction. During follow‐up (median 90 months [interquartile range 49–176]), 103 (11%) patients died and 57 (6%) patients had a first HF hospitalization. Event‐free survival rate for the primary combined and secondary endpoints was lower for patients with an intermediate and high H2FPEF score. On multivariate Cox regression analysis, female sex (hazard ratio [HR] 1.670, 95% confidence interval [CI] 1.157–2.410; p = 0.006), Asian ethnicity (HR 6.711, 95% CI 4.076–11.048; p < 0.001), ischaemic heart disease (HR 1.732, 95% CI 1.133–2.650; p = 0.011), left atrial diameter (HR 1.028, 95% CI 1.005–1.051; p = 0.016) and intermediate (HR 2.757, 95% CI 1.612–4.713; p < 0.001) or high H2FPEF score (HR 3.689, 95% CI 1.908–7.134; p < 0.001) were independently associated with the primary combined endpoint. Conclusion: The H2FPEF score is independently associated with HF outcome in patients with HCM and may be considered for risk stratification. [ABSTRACT FROM AUTHOR]

Aims: Atrial fibrillation (AF) is common in heart failure (HF) and negatively impacts outcomes. The role of ablation‐based rhythm control in patients with AF and HF with preserved (HFpEF) or mildly reduced ejection fraction (HFmrEF) is not known. The CABA‐HFPEF‐DZHK27 (CAtheter‐Based Ablation of atrial fibrillation compared to conventional treatment in patients with Heart Failure with Preserved Ejection Fraction) trial will determine whether early catheter ablation for AF can prevent adverse cardiovascular outcomes in patients with HFpEF or HFmrEF. Methods: CABA‐HFPEF‐DZHK27 (NCT05508256) is an investigator‐initiated, prospective, randomized, open, interventional multicentre strategy trial with blinded outcome assessment. Approximately 1548 patients with paroxysmal or persistent AF diagnosed within 24 months prior to enrolment and HFpEF or HFmrEF will be randomized to early catheter ablation within 4 weeks after randomization or to usual care. All patients receive anticoagulation, rate control, and HF management according to current guideline recommendations. Usual care can include rhythm control in symptomatic patients. Patients will be followed until the end of the trial for the primary outcome, a composite of cardiovascular death, stroke, and total unplanned hospitalizations for HF or acute coronary syndrome. The safety outcome comprises complications of catheter ablation and death. The trial is powered for a rate ratio of 0.75 (two‐sided alpha = 0.05, 1‐beta = 0.8). Conclusion: CABA‐HFPEF‐DZHK27 will define the role of systematic and early catheter ablation in patients with AF and HFpEF or HFmrEF. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationship between serum soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK), soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), and carotid atherosclerosis in patients with H-type hypertension complicated by heart failure with preserved ejection fraction (HFpEF). Methods A total of 161 patients with H-type hypertension and HFpEF admitted to Cangzhou Traditional Chinese and Western Medicine Hospital from February 2021 to March 2023 were selected. They were divided into atherosclerosis and non-atherosclerosis groups based on the presence of carotid atherosclerosis. Additionally, 80 healthy volunteers undergoing routine health checks were selected as a control group. Clinical data were collected, and serum levels of sTWEAK and sLOX-1 were measured using enzyme-linked immunosorbent assay (ELISA). The serum levels of sTWEAK and sLOX-1 in patients with H-type hypertension and HFpEF were compared to those in the control group. Multivariate logistic regression analysis was conducted to identify factors influencing carotid atherosclerosis, and receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value of serum sTWEAK and sLOX-1 for carotid atherosclerosis. Results Among the 161 patients, 65 were found to have carotid atherosclerosis, resulting in an incidence rate of 40. 37% (65/161). Significant differences were observed between the two groups regarding age, smoking, and lipid levels (P＜0. 05). Serum sTWEAK levels were lower in both atherosclerosis and non-atherosclerosis groups compared to the control group, while sLOX-1 levels were higher (P＜0. 05). Additionally, sTWEAK levels were lower and sLOX-1 levels were higher in the atherosclerosis group compared to the non-atherosclerosis group (P＜0. 05). Multivariate logistic regression analysis indicated that HDL-C, sTWEAK, age, LDL-C, and sLOX-1 levels were significant factors influencing the occurrence of carotid atherosclerosis (P＜0. 05). The ROC curve analysis revealed that the combined detection of serum sTWEAK and sLOX-1 had an area under the curve (AUC) of 0. 842 for predicting carotid atherosclerosis, demonstrating higher predictive efficacy than either marker alone. Conclusion Decreased serum sTWEAK levels and increased sLOX-1 levels in patients with H-type hypertension complicated by HFpEF are associated with the occurrence of carotid atherosclerosis. The combined measurement of both biomarkers holds predictive value for the onset of carotid atherosclerosis. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is a significant challenge in the field of cardiovascular diseases. Inflammation, myocardial fibrosis, and coronary microcirculation dysfunction are the core pathophysiological mechanisms of HFpEF. As a key part of adaptive immune response, T cell subsets widely participate in the above process through various mechanisms, further aggravating the damage of myocardial structure and function, and ultimately leading to the development of HFpEF. This article provides a comprehensive review on the roles of immunity and inflammation in HFpEF, summarizes the characteristics and functions of different T cell subsets involved in HFpEF, and aims to explore novel biomarkers and potential therapeutic targets by targeting T cell subsets. [ABSTRACT FROM AUTHOR]

Chronic heart failure (CHF) is a complex clinical syndrome, associated with frailty, higher fall rates, and frequent hospitalizations. Heart Failure (HF) and preserved ejection fraction (HFpEF) is defined as a condition where a patient with HF have a diagnosis of left ventricular ejection fraction (LVEF) of ≥ 50%. The risk of HFpEF increases with age and is related to higher non-cardiovascular mortality. The aim of this study was to evaluate static balance and examine the effect of task difficulty on the discriminating power of balance control between patients with HFpEF (Patients with HFpEF) and their healthy controls. Moreover, the associations between static balance parameters, balance confidence, falls, lean muscle mass, and strength were assessed. Seventy two patients with HFpEF (mean age: 66.0 ± 11.6 years) and seventy two age- and gender-matched healthy individuals (mean age: 65.3 ± 9.5 years) participated in this study. Participants underwent a 30 s bilateral stance (BS) test and a 20 s Tandem-Romberg stance (TRS) on a force platform, evaluating the Range and Standard Deviation of Center of Pressure (COP) displacement parameters in both axes. Balance confidence was evaluated by the Activities-Specific Balance Confidence (ABC) Scale, and the number of falls during the last year was recorded. Lower limb strength was measured using an isokinetic dynamometer, isometric leg strength, and a Sit-to-Stand test. Bioelectrical impedance analysis was conducted to assess lean fat mass, lean fat mass index, and lean%. Patients with HFpEF presented with lower static balance in BS and TRS compared to healthy controls (p < 0.05), lower balance confidence by 21.5% (p < 0.05), and a higher incidence of falls by 72.9% (p < 0.05). BS was a better descriptor of the between-group difference. Furthermore, static balance, assessed in controlled lab conditions, was found to have little if no relationship to falls, strength, lean muscle mass, and balance confidence. Although no correlation was noted between the static balance parameters and falls, the fall rate was related to balance confidence, age, muscle strength, and lean fat. [ABSTRACT FROM AUTHOR]

Background: The pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF) is suggested to be influenced by inflammation. Leukocyte indices, including the neutrophil–lymphocyte ratio (NLR), the monocyte–lymphocyte ratio (MLR), and the pan-immune inflammation value (PIV), can be utilized as biomarkers of systemic inflammation. Their prognostic utility is yet to be fully understood. Methods: Between December 2010 and May 2023, patients presenting to a tertiary referral center for HFpEF were included into a prospective registry. The association of the NLR, MLR, and PIV with the composite endpoint of all-cause mortality and HF-related hospitalization was tested utilizing Cox regression analysis. Results: In total, 479 patients (median 74.3, interquartile range (IQR): 69.22–78.3 years, 27.8% male) were included. Patients were observed for 43 (IQR: 11–70) months, during which a total of 267 (55.7%) patients met the primary endpoint. In a univariate Cox regression analysis, an above-the-median NLR implied a hazard ratio (HR) of 1.76 (95%-confidence interval (CI): 1.38–2.24, p < 0.001), an MLR of 1.46 (95%-CI: 1.14–1.86, p = 0.003), and a PIV of 1.67, 95%-CI: 1.30–2.13, p < 0.001) for the composite endpoint. After adjustment in a step-wise model, the NLR (HR: 1.81, 95%-CI: 1.22–2.69, p = 0.003), the MLR (HR: 1.57, 95%-CI: 1.06–2.34, p = 0.026), and the PIV (HR: 1.64, 95%-CI: 1.10–2.46, p = 0.015) remained significantly associated with the combined endpoint. Conclusions: The NLR, the MLR, and the PIV are simple biomarkers independently associated with outcomes in patients with HFpEF. [ABSTRACT FROM AUTHOR]

Morphological and structural remodeling of the heart, including cardiac hypertrophy and fibrosis, has been considered as a therapeutic target for heart failure for approximately three decades. Groundbreaking heart failure medications demonstrating reverse remodeling effects have contributed significantly to medical advancements. However, nearly 50% of heart failure patients still exhibit drug resistance, posing a challenge to the healthcare system. Recently, characteristics of heart failure resistant to ARBs and β-blockers have been defined, highlighting preserved systolic function despite impaired diastolic function, leading to the classification of heart failure with preserved ejection fraction (HFpEF). The pathogenesis and aetiology of HFpEF may be related to metabolic abnormalities, as evidenced by its mimicry through endothelial dysfunction and excessive intake of high-fat diets. Our recent findings indicate a significant involvement of mitochondrial hyper-fission in the progression of heart failure. This mitochondrial pathological remodeling is associated with redox imbalance, especially hydrogen sulphide accumulation due to abnormal electron leak in myocardium. In this review, we also introduce a novel therapeutic strategy for heart failure from the current perspective of mitochondrial redox-metabolic remodeling. [ABSTRACT FROM AUTHOR]

Background: The triglyceride-glucose (TyG) index is regarded as an independent predictor of cardiovascular disease consequences and a reliable surrogate measure of insulin resistance (IR). However, the correlation analysis between triglyceride glucose index and heart failure with preserved ejection fraction in patients with essential hypertension remains unknown. Methods: A single-center, retrospective study was conducted with patients diagnosed with essential hypertension at the First Affiliated Hospital of Xinjiang Medical University, from December 2018 to September 2020. Participants were selected based on specific inclusion and exclusion criteria, with their clinical data and laboratory tests collected. The study employed Spearman's correlation analysis, logistic regression models, restricted cubic spline plots, and receiver operating characteristic (ROC) curves to investigate the relationships between the TyG index and HFpEF. Results: Out of 1,602 enrolled hypertensive patients, 992 were included in the analysis after applying exclusion criteria. Patients were categorized into tertiles based on the TyG index, which showed that patients in the highest tertile had characteristics associated with a higher risk of HFpEF, including age, body mass index (BMI), systolic blood pressure (SBP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and left ventricular mass index (LVMI). A significant, independent association between the TyG index and HFpEF was confirmed, with an odds ratio (OR) of 5.127 (95% CI [3.894–6.856]). Furthermore, an S-shaped nonlinear relationship was observed between the TyG index and the incidence of HFpEF (nonlinear p < 0.001). TyG index (AUC: 0.824, 95% CI [0.795–0.854]), NT-proBNP (AUC: 0.840, 95% CI [0.816–0.864]), and LVMI (AUC: 0.847, 95% CI [0.820–0.875]) showed good predictive ability for HFpEF. In addition, the TyG+LVMI combination demonstrated the strongest predictive ability (AUC: 0.907, 95% CI [0.887–0.927]). Conclusion: The study underscores a significant association between IR, as indicated by the TyG index, and the development of HFpEF in hypertensive patients. It highlights the critical role of metabolic dysfunction in the pathophysiology of HFpEF, advocating for a broader perspective on cardiovascular risk management. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of heart failure with preserved ejection fraction (HFpEF) is continuously rising and predominantly affects older women often hypertensive and/or obese or diabetic. Indeed, there is evidence on sex differences in the development of HF. Hence, we studied cardiovascular performance dependent on sex and age as well as pathomechanisms on a cellular and molecular level. Methods: We studied 15-week- and 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked blood pressure and cardiac function via echocardiography. After sacrificing the 1-year survivors we studied vascular smooth muscle and endothelial function. Isolated single skinned cardiomyocytes were used to determine passive stiffness and Ca2+-dependent force. In addition, Western blots were applied to analyse the phosphorylation status of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII as well as their expression. Protein kinase activity assays were used to measure activities of CaMKII, PKG and angiotensin-converting enzyme (ACE). Results: TG male rats showed significantly higher mortality at 1 year than females or WT male rats. Left ventricular (LV) ejection fraction was specifically reduced in male, but not in female TG rats, while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte function showing different response to acetylcholine and Ca2+-sensitivity of force production, respectively cardiomyocyte functional changes were associated with altered phosphorylation states of cardiac myosin binding protein C and cardiac troponin I phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in TG animals. On a molecular level titin phosphorylation pattern was altered, though alterations were sex-specific. Thus, also the reduction of PKG expression and activity was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored by PKG and CaMKII treatments in both TG sexes. Conclusion: Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male TG rats in contrast to female TG rats was observed as well as reduced LV systolic function, whereas females mainly developed HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired titin function contributes to a sex-specific molecular mechanism. The functional derangements of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems. [ABSTRACT FROM AUTHOR]

Aims: Anaemia has been reported as poor predictor in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to evaluate the impact of changes in haemoglobin (Hb) from discharge to 1 year after discharge on the prognosis using a lower cut‐off value of Hb than the World Health Organization (WHO) criteria. Methods and results: First, 547 HFpEF cases were divided into two groups, Hb < 11.0 g/dL (n = 218) and Hb ≥ 11.0 g/dL (n = 329), according to Hb at discharge, and further were divided according to Hb 1 year after discharge into Hb < 11.0 g/dL (G1, n = 113), Hb ≥ 11.0 g/dL (G2, n = 105), Hb < 11.0 g/dL (G3, n = 66), and Hb ≥ 11.0 g/dL (G4, n = 263), respectively. Major adverse cardiovascular events (MACE) was defined as composite of all‐cause death and heart failure readmission after a visit 1 year after discharge. The cut‐off value of Hb was analysed by the receiver operating characteristics curve that predicts MACE. We examined the incidence rate of MACE between G4 and other subgroups and verified predictors of improving or worsening anaemia and covarying factors with change in Hb. In multivariate Cox proportional hazard model, MACE was significantly higher in G3 with worsening anaemia from Hb ≥ 11.0 g/dL to <11.0 g/dL than G4 with persistently Hb ≥ 11 g/dL (adjusted hazard ratio (HR): 3.14 [95% confidence interval (CI), 1.76–5.60], P < 0.001). MACE was not significantly different between G2 with improving anaemia from Hb < 11.0 g/dL to ≥ 11.0 g/dL and G4 (adjusted HR: 1.37 [95% CI, 0.68–2.75], P = 0.38). In multivariate logistic regression analysis, independent predictors of improving anaemia were male [odds ratio (OR): 0.45], chronic obstructive pulmonary disease (OR: 10.3), prior heart failure hospitalization (OR: 0.38), and estimated glomerular filtration rate (OR: 1.04). Independent predictors of worsening anaemia were age (OR: 1.07), body mass index (BMI) (OR: 0.86), clinical frailty scale score (OR: 1.29), Hb at discharge (OR: 0.63), and use of angiotensin‐converting‐enzyme inhibitor or angiotensin II receptor blocker (OR: 2.76). In multivariate linear regression analysis, covarying factors with change in Hb were BMI (β = −0.098), serum albumin (β = 0.411), and total cholesterol (β = 0.179). Conclusions: Change in haemoglobin after discharge using a lower cut‐off value than WHO criteria has prognostic impact in patients with HFpEF. [ABSTRACT FROM AUTHOR]

Aims: Heart failure with preserved ejection fraction (HFpEF) is associated with an array of central and peripheral haemodynamic and metabolic changes. The exact pathogenesis of exercise limitation in HFpEF remains uncertain. Our aim was to compare lactate accumulation and central haemodynamic responses to exercise in patients with HFpEF, non‐cardiac dyspnoea (NCD), and healthy volunteers. Methods and results: Right heart catheterization with mixed venous blood gas and lactate measurements was performed at rest and during symptom‐limited supine exercise. Multivariable analyses were conducted to determine the relationship between haemodynamic and biochemical parameters and their association with exercise capacity. Of 362 subjects, 198 (55%) had HFpEF, 103 (28%) had NCD, and 61 (17%) were healthy volunteers. This included 139 (70%) females with HFpEF, 77 (75%) in NCD (P = 0.41 HFpEF vs. NCD), and 31 (51%) in healthy volunteers (P < 0.001 HFpEF vs. volunteers). The median age was 71 (65, 75) years in HFpEF, 66 (57, 72) years in NCD, and 49 (38, 65) years in healthy volunteers (HFpEF vs. NCD or volunteer, both P < 0.001). Peak workload was lower in HFpEF compared with healthy volunteers [52 W (interquartile range 31–73), 150 W (125–175), P < 0.001], but not NCD [53 W (33, 75), P = 0.85]. Exercise lactate indexed to workload was higher in HFpEF at 0.08 mmol/L/W (0.05–0.11), 0.06 mmol/L/W (0.05–0.08; P = 0.016) in NCD, and 0.04 mmol/L/W (0.03–0.05; P < 0.001) in volunteers. Exercise cardiac index was 4.5 L/min/m2 (3.7–5.5) in HFpEF, 5.2 L/min/m2 (4.3–6.2; P < 0.001) in NCD, and 9.1 L/min/m2 (8.0–9.9; P < 0.001) in volunteers. Oxygen delivery in HFpEF was lower at 1553 mL/min (1175–1986) vs. 1758 mL/min (1361–2282; P = 0.024) in NCD and 3117 mL/min (2667–3502; P < 0.001) in the volunteer group during exercise. Predictors of higher exercise lactate levels in HFpEF following adjustment included female sex and chronic kidney disease (both P < 0.001). Conclusions: HFpEF is associated with reduced exercise capacity secondary to both central and peripheral factors that alter oxygen utilization. This results in hyperlactataemia. In HFpEF, plasma lactate responses to exercise may be a marker of haemodynamic and cardiometabolic derangements and represent an important target for future potential therapies. [ABSTRACT FROM AUTHOR]

Aims: Clinical trials in heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) commonly have detailed eligibility criteria. This may contribute to challenges with efficient enrolment and questions regarding the generalizability of trial findings. Methods and results: Patients with HFmrEF/HFpEF from a large US healthcare system were identified through a computable phenotype applied in linked imaging and electronic health record databases. We evaluated shared eligibility criteria from five recent/ongoing HFmrEF/HFpEF trials (PARAGON‐HF, EMPEROR‐Preserved, DELIVER, FINE‐ARTS, and SPIRRIT‐HFpEF) and compared clinical and echocardiographic features as well as outcomes between trial‐eligible and trial‐ineligible patients. Among 5552 patients with HFpEF/HFmrEF, 792 (14%) were eligible for trial consideration, having met all criteria assessed. Causes of ineligibility included lack of recent loop diuretics (37%), significant pulmonary disease (24%), reduced estimated glomerular filtration rate (17%), recent stroke/transient ischaemic attack (13%), or low natriuretic peptides (12%); 53% of ineligible patients had >1 reason for exclusion. Compared with eligible patients, ineligible patients were younger (age 71 vs. 75 years, P < 0.001) with higher rates of coronary artery disease (66% vs. 59%, P < 0.001) and peripheral vascular disease (40% vs. 33%, P < 0.001), but less mitral regurgitation, lower E/e′ ratio, and smaller left atrial sizes. Both eligible and ineligible patients demonstrated high rates of structural heart disease consistent with HFpEF [elevated left atrial size or left ventricular (LV) hypertrophy/increased LV mass], although this was slightly higher among eligible patients (95% vs. 92%, P = 0.001). The two cohorts demonstrated similar LV global longitudinal strain along with a similar prevalence of atrial fibrillation/flutter, hypertension, and obesity. Ineligible patients had similar all‐cause mortality (33% vs. 33% at 3 years) to those eligible but lower rates of heart failure hospitalization (20% vs. 28% at 3 years, P < 0.001). Conclusions: Among patients with HFmrEF/HFpEF from a large health system, approximately one in seven were eligible for major trials based on key criteria applied through a clinical computable phenotype. These findings highlight the large proportion of patients with HFmrEF/HFpEF ineligible for contemporary trials for whom the generalizability of trial findings may be questioned and further investigation would be beneficial. [ABSTRACT FROM AUTHOR]

Aims: The molecular signatures in epicardial adipose tissue (EAT) that contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF) are poorly characterized. In this study, we sought to elucidate molecular signatures including genetic transcripts and long non‐coding RNAs (lncRNAs) in EAT that might modulate HFpEF development. Methods: RNA sequencing (RNA‐seq) was performed to identify differentially expressed lncRNAs and mRNAs in EAT samples from patients with HFpEF (n = 5) and without HF (control, n = 5) who underwent coronary artery bypass grafting. The sequencing results were validated using quantitative real‐time PCR (qRT‐PCR). Bioinformatics analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) of differentially expressed RNAs was performed to predict enriched functions. Results: HFpEF patients had higher EAT thickness and NT‐proBNP levels than the control group. A total of 64 471 transcripts were detected including 35 395 protein‐coding sequences, corresponding to 16 854 genes in EAT. RNA‐seq identified a total of 741 dysregulated mRNA transcripts (394 up‐regulated and 347 down‐regulated) and 334 differentially expressed lncRNA transcripts (222 up‐regulated and 112 down‐regulated) in the HFpEF group compared with the control group (P < 0.05). qRT‐PCR analysis confirmed that two lncRNAs ENST00000561775 (P = 0.0194) and ENST00000519093 (P = 0.027) and an mRNA POSTN (P = 0.003) were differentially expressed. Functional enrichment analysis of the differentially expressed mRNAs suggested their potential roles in immune response involving cytokine interaction and chemokine signalling. Conclusions: We are the first group to report on the lncRNA and mRNA landscape in EAT in HFpEF patients. Our study suggests the possible role of lncRNAs in EAT. [ABSTRACT FROM AUTHOR]

Abstract Aims The detailed sub‐categories of death and hospitalization, and the impact of comorbidities on cause‐specific outcomes, remain poorly understood in heart failure (HF) with preserved ejection fraction (HFpEF). We sought to evaluate rates and predictors of cardiovascular (CV) and non‐CV outcomes in HFpEF. Methods The Karolinska–Rennes study was a bi‐national prospective observational study designed to characterize HFpEF (ejection fraction ≥45%). Patients were followed for cause‐specific death and hospitalization. Baseline characteristics were pre‐selected based on clinical relevance and potential eligibility criteria for HFpEF trials. The associations between characteristics and cause‐specific outcomes were assessed with univariable and multivariable Cox regressions. Results Five hundred thirty‐nine patients [56% females; median (inter‐quartile range) age 79 (72–84) years; NT‐proBNP/BNP 2448 (1290–4790)/429 (229–805) ng/L] were included. Over 1196 patient‐years follow‐up [median (min, max) 744 days (13–1959)], there were 159 (29%) deaths (13 per 100 patient‐years: CV 5.1 per 100, dominated by HF 3.9 per 100; and non‐CV 5.8 per 100, dominated by cancer, 2.3 per 100). There were 723 hospitalizations in 338 patients (63%; 60 per 100 patient‐years: CV 33 per 100, dominated by HF 17 per 100; and non‐CV 27 per 100, dominated by lung disease 5 per 100). Higher age and natriuretic peptides, lower serum natraemia and NYHA class III–IV were independent predictors of CV death; lower serum natraemia, anaemia and stroke of non‐CV death; and anaemia and lower serum natraemia of non‐CV death or hospitalizations. There were no apparent predictors of CV death or hospitalization. Conclusions In a clinical cohort hospitalized and diagnosed with HFpEF, death and hospitalization rates were roughly similar for CV and non‐CV causes. CV deaths were predicted primarily by severity of HF; non‐CV deaths primarily by anaemia and prior stroke. Lower serum sodium predicted both. Hospitalizations were difficult to predict.