Explore the vast range of titles available.

the use of a structured approach by HF specialist nurse using prompt of an ABCDEF mnemonic to guide management of multimorbidity in HFpEF clinics and compare this with standard care (without prompt by a mnemonic).MethodsThis was a retrospective analysis of a prospective cohort study of 75 patients with recent decompensated HFpEF within 30 days,ResultsThe mean age was comparable between the 2 cohorts. There was also no significant difference in terms of co-morbidities. 30-day all-cause re-admissions showed a trend towards being lower in the mnemonic cohortUse of a structured mnemonic approach to manage multimorbidity appears to be an easy intervention to apply in HFpEF clinics.Conflict of InterestNone

IntroductionLeft ventricular ejection fraction (LVEF) has well-known limitations including modest reproducibility, load dependence, and representation of the percentage change in left ventricular (LV) volume rather than myocardial contractility. Although diastolic dysfunction has been proposed as a key mechanism underpinning the pathophysiology of heart failure with a preserved ejection fraction (HFpEF) the presence of subtle or concomitant systolic dysfunction has previously been suggested. We aimed to assess the prognostic value of systolic blood pressure: indexed left ventricular end-systolic volume ratio, or ‘cardiac contractility index’ (CCI).MethodsIn a prospective, observational cohort study LVEF and CCI were measured in 728 unselected individuals with newly diagnosed chronic heart failure. We divided patients into tertiles of LVEF and CCI, and also divided those with heart failure with reduced ejection fraction (HFrEF) or HFpEF by the median value of CCI (4.43mmHg/ml/m2) into four groups. Unadjusted and adjusted Poisson regression models were used to determine mortality rates for CCI and LVEF as continuous variables.ResultsThere was a modest, positive correlation between LVEF and CCI (r=0.70 [0.66-0.74], R2 0.49; p<0.0001), although the latter was distributed widely for any given value of LVEF, especially for those with HFpEF (Figure 1). We observed distinct clinical characteristics across tertiles of both LVEF and CCI, with an inverse relationship with conventional markers of risk including N-terminal B-type natriuretic peptide (p<0.001 in both comparisons) (Table 1). During 5.9 (2.9-9.0) years of follow up 491 (67.4%) patients died. There was a clear relationship between tertiles of CCI and all-cause mortality risk (p<0.001), which was less evident when patients were divided by LVEF. When modelled as continuous variables there was a curvi-linear relationship between all-cause mortality rates and CCI, but the relationship between LVEF and mortality risk was more complex, with no clear association across a wide range from 25-55%. In models including relevant covariates, the association between LVEF and mortality was no longer evident except for those with LVEF 60% (relative to 50%) but remained evident for all specified values of CCI (Table 1). Patients with HFpEF and CCI below the median value had distinct clinical characteristics (Table 2), and all-cause mortality risk ~40% higher than those with CCI above median (p<0.001), similar to those with HFrEF (Figure 2).ConclusionsCCI is a non-invasive, relatively afterload independent measure left ventricular contractility which provided additional prognostic information beyond conventional assessment by LVEF. These data could help refine the inclusion criteria of future randomised controlled trials, and its simplicity means CCI could be easily applied to existing datasets in order to identify who may have derived benefits from pharmacological therapies.Abstract 132 Table 1Unadjusted and adjusted poisson regression analyses Cardiac contractility index LVEF Unadjusted IRR (95% CI) Adjusted IRR (95% CI ) Adjusted IRR (95% CI ) Age (per year)1.06 (1.05-1.07)1.06 (1.04-1.07)1.06 (1.04-1.07)Male1.19 (0.99-1.42)1.08 (0.87-1.35)1.15 (0.93-1.43)Ischaemic heart disease1.05 (0.87-1.28)0.94 (0.76-1.17)0.96 (0.77-1.19)Diabetes mellitus1.09 (0.89-1.32)1.21 (0.98-1.50)1.22 (1.00-1.51)Hypertension1.00 (0.83-1.21)1.07 (0.87-1.32)1.05 (0.85-1.30)SBP (per mmHg)1.00 (0.99-1.00)1.00 (1.00-1.00)1.00 (0.99-1.00)HR (per beat/min)1.01 (1.00-1.01)1.01 (1.00-1.01)1.01 (1.00-1.01)log10 haemoglobin (per g/L)0.32 (0.17-0.61)0.87 (0.35-2.19)0.62 (0.25-1.51)Log10 creatinine (per μmol/L)6.61 (3.74-11.67)1.59 (0.78-3.23)1.58 (0.77-3.24)Log10 albumin0.00 (0.00-0.01)0.01 (0.00-0.16)0.01 (0.00-0.14)Log10 NTpro-BNP2.19 (1.85-2.59)1.29 (1.02-1.62)1.37 (1.09-1.72)Cardiac contractility index (mmHg/ml/m2) 21.56 (1.26-1.93)1.34 (1.03-1.75)- 41.07 (1.01-1.13)1.06 (1.00-1.13)- 4.431.001.00- 60.78 (0.67-0.92)0.78 (0.66-0.93)- 80.54 (0.39-0.74)0.61 (0.43-0.85)-LVEF (%) 201.69 (1.24-2.29)-1.27 (0.89-1.80) 301.19 (0.98-1.45)-1.01 (0.80-1.28) 400.95 (0.79-1.13)-0.89 (0.73-1.09) 501.00-1.00 600.66 (0.52-0.84)-0.69 (0.54-0.88)Abstract 132 Table 2Clinical characteristics of patients with HFrEF and HFpEF divided by median cardiac contractility index All patients (n=728) HFrEF HFpEF Low CCI (n=232) High CCI (n=61) Low CCI (n=132) High CCI (n=303) Age (years)82.6 ± 9.281.1 ± 10.3# 83.2 ± 8.583.9 ± 8.4# 83.1 ± 8.4Male sex [n(%)]330 (45.3)151 (65.1)*# 23 (37.7)*64 (48.5)*# 92 (30.4)*NYHA Class III/IV [n(%)]328 (45.1)95 (40.9)18 (29.5)55 (41.7)160 (52.8)IHD [n(%)]210 (28.8)87 (37.5)# 25 (41.0)# 33 (25.0)# 65 (21.5)# Hypertension [n(%)]490 (67.3)123 (53.0)*# 42 (68.9)*94 (71.2)# 231 (76.2)Atrial fibrillation [n(%)]263 (36.1)81 (34.9)20 (32.8)57 (43.2)105 (34.7)SBP (mmHg)140.3 ± 22.9131.6 ± 22.8*149.0 ± 20.5*133.8 ± 20.0*148.0 ± 21.4*Heart rate (beats/min)76.0 ± 16.978.7 ± 19.7# 79.5 ± 19.3# 74.4 ± 15.5# 73.8 ± 14.3# LVEF (%)48.2 ± 11.634.6 ± 9.6*# 45.0 ± 4.1*# 54.2 ± 3.5*# 56.6 ± 3.8*# CCI (mmHg/ml/m2)4.55 ± 1.922.64 ± 0.88*# 5.31 ± 0.77*# 3.69 ± 0.56*# 6.24 ± 1.37*# NT-proBNP (pg/mL)1066 (503.5-2570)2235 (788-5052)*# 813 (450-1810)*1153 (503-2353)*# 761 (401-1409)* *represents p<0.05 between cardiac contractility index categories within HFrEF and HFpEF groups. #represents p<0.05 between HFrEF and HFpEF within cardiac contractility index groups.Abstract 132 Figure 1Abstract 132 Figure 2Conflict of InterestSpeaker's fees, Honoraria and non-financial support from AstraZeneca.

Background Heart failure with preserved ejection fraction (HFpEF) presents significant therapeutic challenges, particularly exacerbated by comorbidities such as hypertension and diabetes. The modulation of the Renin–Angiotensin–Aldosterone System is critical in managing HFpEF progression. Esaxerenone (ESAX), a selective mineralocorticoid receptor antagonist, may offer benefits in managing HFpEF continuum due to its unique mechanism. Methods Conducted at Odawara Municipal Hospital, this single‐center, prospective, observational study involved hypertensive adult outpatients diagnosed with either type 2 diabetes mellitus or chronic kidney disease. Patients were categorized into HFpEF and pre‐HFpEF groups based on established criteria. The study primarily assessed changes in blood pressure and cardiac function (through NT‐proBNP levels and echocardiography), along with secondary outcomes including aortic stiffness and oxidative stress over a 24‐week period. Results Both HFpEF and pre‐HFpEF patients exhibited significant reductions in blood pressure, with no significant differences between the patients. HFpEF patients experienced decreases in NT‐proBNP levels and oxidative stress similar to those in pre‐HFpEF patients. Notably, pre‐HFpEF patients demonstrated more pronounced improvements in cardiac function, particularly in the E/e' ratio and global longitudinal strain, compared to HFpEF patients. Additionally, 30% of pre‐HFpEF patients had improved to stage A, suggesting potential for early intervention. Conclusions ESAX appears to be effective in managing the heart failure continuum, particularly benefiting pre‐HFpEF patients. Its impacts suggest the potential benefits of early intervention in decelerating disease progression and potentially preventing the new onset of HFpEF, highlighting the importance of targeted therapies at early stages of heart failure. Study Overview: Prospective study on Esaxerenone in HFpEF with 67 patients showing improvements in blood pressure, aortic stiffness, and especially cardiac function in pre‐stage patients. Safety was comparable to prior reports. Conclusion: Esaxerenone is effective in HFpEF treatment, particularly promising for early intervention.

Heart failure with preserved ejection fraction (HFpEF) represents a significant and growing clinical challenge. Initially, for an extended period, HFpEF was simply considered as a subset of heart failure, manifesting as haemodynamic disorders such as hypertension, myocardial hypertrophy, and diastolic dysfunction. However, the rising prevalence of obesity and diabetes has reshaped the HFpEF phenotype, with nearly 45% of cases coexisting with diabetes. Currently, it is recognized as a multi-system disorder that involves the heart, liver, kidneys, skeletal muscle, adipose tissue, along with immune and inflammatory signaling pathways. In this review, we summarize the landscape of metabolic rewiring and the crosstalk between the heart and other organs/systems (e.g., adipose, gut, liver and hematopoiesis system) in diabetic HFpEF for the first instance. A diverse array of metabolites and cytokines play pivotal roles in this intricate crosstalk process, with metabolic rewiring, chronic inflammatory responses, immune dysregulation, endothelial dysfunction, and myocardial fibrosis identified as the central mechanisms at the heart of this complex interplay. The liver-heart axis links nonalcoholic steatohepatitis and HFpEF through shared lipid accumulation, inflammation, and fibrosis pathways, while the gut-heart axis involves dysbiosis-driven metabolites (e.g., trimethylamine N-oxide, indole-3-propionic acid and short-chain fatty acids) impacting cardiac function and inflammation. Adipose-heart crosstalk highlights epicardial adipose tissue as a source of local inflammation and mechanical stress, whereas the hematopoietic system contributes via immune cell activation and cytokine release. We contend that, based on the viewpoints expounded in this review, breaking this inter-organ/system vicious cycle is the linchpin of treating diabetic HFpEF. Graphical abstract Research insights What is currently known about this topic? Diabetic patients with HFpEF are younger and more obese than their non-diabetic counterparts, and often have a higher rate of hospitalization and poorer prognosis. What is the key research question? What are the characteristics and mechanisms of diabetic HFpEF? What is new? This study describes the key cellular mechanisms of this inter-organ crosstalk in diabetic HFpEF. We also discuss the mediators of this crosstalk, such as circulating metabolites, cytokines and other factors, which are either directly released into the circulation or transported by exosomes to their target tissue. How might this study influence clinical practice? Findings could lead to personalized treatment strategies for diabetic HFpEF.

Chronic kidney disease (CKD) is associated with a high burden of cardiovascular remodeling and increased risk of heart failure with preserved ejection fraction (HFpEF). However, the interpretation of natriuretic peptide-based HFpEF diagnostic remains challenging in CKD populations, where structural cardiac abnormalities and elevated NT-proBNP levels frequently coexist. We conducted a cross-sectional study including ambulatory patients with CKD stages G3-G4 and NYHA II dyspnea. Clinical, metabolic, vascular, and echocardiographic assessments were performed. HFpEF was assessed using a modified HFA-PEFF-based approach derived from the ESC-recommended diagnostic algorithm. We evaluated the impact of NT-proBNP thresholds on HFpEF classification and explored the relationship between NT-proBNP, echocardiographic diastolic dysfunction, and structural cardiac abnormalities. The cohort displayed a high cardiometabolic burden (74.9%), and structural cardiac abnormalities were highly prevalent. Using a modified HFA-PEFF diagnostic algorithm, HFpEF was identified in 52.9% of patients. However, when the biomarker domain was excluded, 86.7% of patients remained within the intermediate-probability range. In an exploratory analysis, a cutoff of 700 pg/mL was identified as the cohort-adapted threshold with the best diagnostic balance and identified 19.8% patients as having HFpEF. Patients with CKD G3-G4 exhibited substantial structural and functional cardiovascular abnormalities despite no prior diagnosis of heart failure. HFpEF classification varied according to the NT-proBNP threshold applied, while NT-proBNP demonstrated limited discriminatory performance for echocardiographic diastolic dysfunction. These findings support the need for more refined and CKD-sensitive approaches for HFpEF characterization in this population.

IntroductionHeart Failure with preserved Ejection Fraction (HFpEF) affects over 50% of patients with HF, majority of whom are females with conditions such as hypertension, obesity and diabetes. Our in vivo animal models of these conditions show increased fibrosis and oxidized Calcium-calmodulin dependent protein kinase II (CaMKII) activity. At the cellular level, mitochondrial health is known to be implicated in HF, and our in vitro models have signified the impact of female cardiac fibroblasts (CFs) on altered calcium (Ca2+) signalling in cardiac myocytes (CMs), during co-culture. However, knowledge on the characteristics of CFs in HFpEF still remains obscure. Here, we investigated altered Ca2+ signalling, mitochondrial Reactive Oxygen Species (ROS) production, and the therapeutic potential of inhibiting CaMKII activity in CFs, during hyperglycaemia and hypertension.MethodsAdult human CFs (Promocell) sourced from both female and male donors were cultured under hyperglycaemic (22 mM Glucose), hypertensive (200nM Angiotensin II) or HFpEF-like (hyperglycaemic plus hypertensive) conditions, in the absence or presence of a CaMKII inhibitor (5µM KN93), for 48 hours. Following pathological conditioning of CFs, cells were loaded with Cal520AM calcium indicator or MitoSOX red mitochondrial superoxide indicator. Live cell fluorescence imaging was utilised to assess Ca2+ activity and mitochondrial ROS production in CFs.ResultsFemale CFs treated under hyperglycaemic conditions showed a greater Endothelin-1-induced Ca2+ transient amplitude (ΔF/F0) relative to control and hypertensive conditioning [Control: 0.184±0.008; Diabetes: 0.305±0.026; Hypertension: 0.208±0.030; HFpEF: 0.241±0.008, n=4passages]. Mitochondrial superoxide (AU) levels were elevated only in female CFs, in both hyperglycaemic and hypertensive conditions [Control: 18.0±2.0; Diabetes: 36.7±3.4; Hypertension: 29.5±4.5; HFpEF: 22.7±2.0, n=4passages]. These alterations in Ca2+ transient amplitude and superoxide production were impeded by the presence of KN93 [Ca2+ Transient Amplitude- Control: 0.197±0.020; Diabetes: 0.167±0.022; Hypertension: 0.199±0.037; HFpEF: 0.205±0.023, Mitochondrial superoxide- Control: 16.6±2.4; Diabetes: 14.7±2.6; Hypertension: 13.3±1.1; HFpEF: 18.1±2.6, [n=4passages].ConclusionsThese results indicate CaMKII is important in mitochondrial oxidative stress in female CFs, in hyperglycaemic and hypertensive conditions. Further work is needed to investigate the importance of these processes in the development of fibrosis in HFpEF.Abstract BS42 Figure 1Endothelin-1-induced calcium transient amplitude in female CFs. * p<0.05 and ** p<0.01Abstract BS42 Figure 2Mitochondrial superoxide production in female CFs. * p<0.05, ** p<0.01 and *** p<0.001Conflict of InterestNone

Heart failure with preserved ejection fraction (HFpEF) represents nearly half of all heart failure cases globally. The increased prevalence of cardiometabolic disease, driven by unhealthy lifestyles, has led to a growing population of people developing the so called “cardiometabolic HFpEF (cmHFpEF)” phenotype. This condition represents an end stage cardiometabolic phenotype which results from the clustering of metabolic stress (obesity), hemodynamic stress (hypertension), immune activation, and systemic inflammation. This form of HFpEF is preceded by a “metabolic cardiomyopathy” phenotype, characterized by myocardial metabolic remodeling, rewiring of lipid metabolism, and inflammation eventually fostering left ventricular hypertrophy, diastolic dysfunction and atrial dilatation. Recent work over the last years has unveiled the molecular cues underpinning cmHFpEF pathogenesis thus contributing to the identification of novel therapeutic approaches to treat this complex syndrome. The present review provides an overview of recent advances in cmHFpEF biology and pathophysiology with particular emphasis on the following aspects: (i) metabolic alterations associated with cmHFpEF; (ii) changes of the immune landscape; (iii) microvascular dysfunction; (iv) inflammation; (v) chromatin remodeling. Additionally, we will discuss potential mechanisms-based therapeutic strategies to tackle this growing health concern.

Cardiac fibrosis is central to the pathology of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). Irrespective of the underlying profibrotic condition (e.g. ageing, diabetes, hypertension), maladaptive cardiac fibrosis is defined by the transformation of resident fibroblasts to matrix‐secreting myofibroblasts. Numerous profibrotic factors have been identified at the molecular level (e.g. TGFβ, IL11, AngII), which activate gene expression programs for myofibroblast activation. A number of existing HF therapies indirectly target fibrotic pathways; however, despite multiple clinical trials in HFpEF, a specific clinically effective antifibrotic therapy remains elusive. Therapeutic inhibition of TGFβ, the master‐regulator of fibrosis, has unfortunately proven toxic and ineffective in clinical trials to date, and new approaches are needed. In this review, we discuss the pathophysiology and clinical implications of interstitial fibrosis in HFpEF. We provide an overview of trials targeting fibrosis in HFpEF to date and discuss the promise of potential new therapeutic approaches and targets in the context of underlying molecular mechanisms. Graphical Abstract This review discusses recent advances in novel therapeutic approaches against cardiac fibrosis in heart failure with preserved ejection fraction and their underlying molecular mechanisms.

Our understanding of the complex pathophysiology of Heart failure with preserved ejection fraction (HFpEF) is limited by the lack of a robust in vivo model. Existing in-vivo models attempt to reproduce the four main phenotypes of HFpEF; ageing, obesity, diabetes mellitus and hypertension. To date, there is no in vivo model that represents all the haemodynamic characteristics of HFpEF, and only a few have proven to be reliable for the preclinical evaluation of potentially new therapeutic targets. HFpEF accounts for 50% of all the heart failure cases and its incidence is on the rise, posing a huge economic burden on the health system. Patients with HFpEF have limited therapeutic options available. The inadequate effectiveness of current pharmaceutical therapeutics for HFpEF has prompted the development of device-based treatments that target the hemodynamic changes to reduce the symptoms of HFpEF. However, despite the potential of device-based solutions to treat HFpEF, most of these therapies are still in the developmental stage and a relevant HFpEF in vivo model will surely expedite their development process. This review article outlines the major limitations of the current large in-vivo models in use while discussing how these designs have helped in the development of therapy devices for the treatment of HFpEF.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are emerging as a new treatment strategy for heart failure with reduced ejection fraction (HFrEF) and—depending on the wistfully awaited results of two clinical trials (DELIVER and EMPEROR-Preserved)—may be the first drug class to improve cardiovascular outcomes in patients suffering from heart failure with preserved ejection fraction (HFpEF). Proposed mechanisms of action of this class of drugs are diverse and include metabolic and hemodynamic effects as well as effects on inflammation, neurohumoral activation, and intracellular ion homeostasis. In this review we focus on the growing body of evidence for SGLT2i-mediated effects on cardiac intracellular Na+ as an upstream mechanism. Therefore, we will first give a short overview of physiological cardiomyocyte Na+ handling and its deterioration in heart failure. On this basis we discuss the salutary effects of SGLT2i on Na+ homeostasis by influencing NHE1 activity, late INa as well as CaMKII activity. Finally, we highlight the potential relevance of these effects for systolic and diastolic dysfunction as well as arrhythmogenesis.