Heart Failure With Preserved Ejection Fraction Patients Research Articles

HEART FAILURE AND ITS PHENOTYPES IN THE REAL WORLD: DATA FROM THE CARDIOVASCULAR OBSERVATORY OF FRIULI–VENEZIA GIULIA

Abstract Introduction Heart Failure (HF) is a disease with high mortality and morbidity burden. Guidelines classify HF according the ejection fraction (EF) in three phenotypes. HF with preserved ejection fraction (HFpEF) is the most prevalent in the real world for increasing in life expectancy and the presence of many comorbidities. Aim Knowing and analysing the epidemiology and clinic features of HF to create the most appropriate diagnostic–therapeutic pathways. The Cardiovascular Observatory of Friuli–Venezia Giulia (CVOFVG), which allows this analysis, is a powerful tool for clinical governance. Results In Friuli Venezia Giulia, at 1st January 2023, 21.212 alive patients had a HF diagnosis (1.78% prevalence). Considering the different phenotypes, in the real world, from 2018 to 2023, the most prevalent patients had EF > 40% (in 2022: HFpEF 55%, HFmrEF 9% and HFimpEF 20%). In our registry patients with HFpEF are older (mean age 80±10 yrs vs 79±11 yrs in HFmrEF vs 76±11 yrs in HFrEF), mostly women (52% vs 38% in HFmrEF, vs 27% in HFrEF), with many cardiovascular (CV) diseases, such as atrial fibrillation (57% vs 53% in HFmrEF vs 49% in HFrEF) and non CV as obesity and chronic obstructive pulmonary disease. As expected, ischemic heart disease is prevalent in HFrEF in 59% vs 38% in HFpEF. In the CVOFVG, in 2022 the hospitalization rate was 1260/100000 inhabitants (262 for HF hospitalization, 188 for CV causes, 808 for non CV disease). HFrEF has a higher incidence of HF hospitalization (54.3 on 166.2/100.000 totals). Furthermore, HFpEF because of its high prevalence, has a higher rate of CV and HF hospitalization than HFrEF (77.8 vs 54.3/100.000 inhabitants for year, 929 hospitalization vs 646). The mortality in one year is higher in HFrEF and HFmrEF vs HFpEF and above all HFimpEF. Drug prescription was different from clinical trial: in 2022, 72.2% of HFrEF patients received renin angiotensin system inhibitors (RASi), 89.2% beta blockers (BB), 62.6% mineralocorticoid receptor antagonist (MRA) and 44% SGLT2–inibitors (SGLT2–I). Same prescription for RASi, BB, MRA was in HFimpEF and HFmrEF, less for HFpEF. Conclusions The patients’ complexity, their increasing number, the new drugs for HFpEF lead to create multidisciplinary pathways, above all for HFpEF patients who are frequently visited by General Physicians, Internal Physicians and Geriatrics, to select the most complex case where a therapeutic intervention can be efficacy.

Safety and Efficacy of Anti-Hypertensive Medications in Patients with Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-analysis.

Hypertension (HTN) is a co-morbidity that is commonly associated with heart failure with preserved ejection fraction (HFpEF). However, it remains unclear whether treatment of hypertension in HFpEF patients is associated with improved cardiovascular outcomes. The purpose of this meta-analysis is to evaluate the association of anti-hypertensive medical therapy with cardiovascular outcomes in patients with HFpEF. We performed a database search for studies reporting on the association of anti-hypertensive medications with cardiovascular outcomes and safety endpoints in patients with HFpEF. The databases searched include OVID Medline, Web of Science, and Embase. The primary endpoint was all-cause mortality. Secondary endpoints include cardiovascular (CV) mortality, worsening heart failure (HF), CV hospitalization, composite major adverse cardiovascular events (MACE), hyperkalemia, worsening renal function, and hypotension. A total of 12 studies with 14062 HFpEF participants (7010 treated with medical therapy versus 7052 treated with placebo) met inclusion criteria. Use of anti-hypertensive medications was not associated with lower all-cause mortality, CV mortality or CV hospitalization compared to treatment with placebo (OR 1.02, 95% CI 0.77-1.35; p=0.9, OR 0.88, 95% CI 0.73-1.06; p=0.19, OR 0.99, 95% CI 0.87-1.12; p=0.83, OR 0.90, 95% CI 0.79-1.03; p=0.11). Anti-hypertensive medications were not associated with lower risk of subsequent acute myocardial infarction (AMI) (OR 0.53, 95% CI 0.07-3.73; p=0.5). Use of anti-hypertensive medications was associated with a statistically significant lower risk of MACE (OR 0.90, 95% CI 0.83-0.98; p=0.02). While treatment with anti-hypertensive medications was not associated with lower risk of all-cause mortality, their use may be associated with reduce risk of adverse cardiovascular outcomes in patients with HFpEF regardless of whether they have HTN. Additional high quality studies are required to clarify this association and determine the effect based on specific classes of medications.

Empagliflozin inhibits increased Na influx in atrial cardiomyocytes of patients with HFpEF.

Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality. Importantly, atrial remodelling and atrial fibrillation are frequently observed in HFpEF. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently been shown to improve clinical outcomes in HFpEF, and post-hoc analyses suggest atrial anti-arrhythmic effects. We tested if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx, which is known to cause atrial arrhythmias, and if that is responsive to treatment with the SGTL2i empagliflozin. Cardiomyocytes were isolated from atrial biopsies of 124 patients (82 with HFpEF) undergoing elective cardiac surgery. Na influx was measured with the Na-dye Asante Natrium Green-2 AM (ANG-2). Compared to patients without heart failure (NF), Na influx was doubled in HFpEF patients (NF vs. HFpEF: 0.21 ± 0.02 vs. 0.38 ± 0.04 mmol/L/min (N = 7 vs. 18); P = 0.0078). Moreover, late INa (measured via whole-cell patch clamp) was significantly increased in HFpEF compared to NF. Western blot and HDAC4 pulldown assay indicated a significant increase in CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation in HFpEF compared to NF, whereas NaV1.5 protein and mRNA abundance remained unchanged. Consistently, increased Na influx was significantly reduced by treatment not only with the CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP), late INa inhibitor tetrodotoxin (TTX) but also with sodium/hydrogen exchanger 1 (NHE1) inhibitor cariporide. Importantly, empagliflozin abolished both increased Na influx and late INa in HFpEF. Multivariate linear regression analysis, adjusting for important clinical confounders, revealed HFpEF to be an independent predictor for changes in Na handling in atrial cardiomyocytes. We show for the first time increased Na influx in human atrial cardiomyocytes from HFpEF patients, partly due to increased late INa and enhanced NHE1-mediated Na influx. Empagliflozin inhibits Na influx and late INa, which could contribute to anti-arrhythmic effects in patients with HFpEF.

Clinical characteristics and atrial fibrillation management in hospitalized patients with heart failure with reduced versus preserved ejection fraction

Abstract Funding Acknowledgements None. Background Non-valvular atrial fibrillation (NVAF) and heart failure (HF) frequently coexist. AF management in HF is currently changing with increasing role of rhythm control. Data about clinical characteristics and AF management in hospitalized patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) are lacking. The purpose of the study was to assess the clinical characteristics and AF management in hospitalized patients with NVAF and HFrEF and compare them to those of NVAF and HFpEF. Methods Consecutive NVAF patients hospitalized with HF decompensation between January 2020 and May 2022 were retrospectively evaluated. Patients were divided into two groups: HFrEF and HFpEF (defined as left ventricular ejection fraction > 40%). Clinical characteristics and AF treatment strategy in both groups were studied and compared. Numerical data are expressed as median (interquartile range). P<0.05 was considered significant. Results In a total of 388 AF-HF patients (age 73.5 years [66-82], 59.3% males), 147 (37.9%) had reduced ejection fraction. Patients with HFrEF compared to those with HFpEF were younger (69.3 vs 74.7 years; P < 0.001), more often male and with a higher rate of NYHA classes III-IV (73.9% vs 63.5%; P < 0.05), N-terminal pro-B-type natriuretic peptide level (2658.5 pg/ml vs 1799.1 pg/ml; p<0.001), sum of B-lines by lung ultrasound (35.2 vs 28.9; P<0.05) and prevalence of non-paroxysmal forms of AF (70.4% vs 50.4%; p < 0.05). Patients with HFrEF had a higher burden of coronary artery disease, chronic kidney disease and prior stroke (31.7% vs 19.2%, 83.9% vs 69.0, 18.5% vs 9.7%, respectively; p< 0.05 for all) than HFpEF patients. Patients with HFpEF were more likely than those with HFrEF to have diabetes mellitus (25.9% vs 37.1%; p< 0.05) The subgroup of patients with HFrEF compared to those with HFpEF had higher bleeding risk (HAS-BLED ≥3 in 32.1% vs 20.4%, P<0.05) due to more frequent abnormal renal/liver function, concomitant antithrombotic treatment/alcohol, prior stroke (24.7% vs 10.6%, 28.4% vs 16.8%, 18.5% vs 9.7%, respectively; P<0.05 for all) but lower thromboembolic risk according to CHA 2 DS 2 -VASc (4.0 vs 4.4; p < 0.05). Oral anticoagulants (OAC) were administered in 88% of patients on discharge. Patterns of anticoagulation administration didn’t differ between the two groups. Patients with HFrEF were less likely to receive first-line rhythm control for AF compared to HFpEF patients (36.1% vs 68.1%; p<0.05). Conclusion Hospitalized patients with NVAF and HFrEF compared to those with HFpEF were younger, with greater severity of HF, higher burden of comorbidities and bleeding risk and slightly lower thromboembolic risk. Despite different clinical characteristics, OAC administration patterns were similar and OAC prescription rate was not optimal in both groups. There is a need for improvement of guideline adherence to first-line rhythm control strategy in AF and HFrEF.

Diagnostic and prognostic value of an ejection fraction adjusted for myocardial remodeling.

Ejection fraction (EF) is widely used to evaluate heart function during heart failure (HF) due to its simplicity compared but it may misrepresent cardiac function during ventricular hypertrophy, especially in heart failure with preserved EF (HFpEF). To resolve this shortcoming, we evaluate a correction factor to EF, which is equivalent to computing EF at the mid-wall layer (without the need for mid-layer identification) rather than at the endocardial surface, and thus better complements other complex metrics. The retrospective cohort data was studied, consisting of 2,752 individuals (56.5% male, age 69.3 ± 16.4 years) admitted with a request of a troponin test and undergoing echocardiography as part of their clinical assessment across three centres. Cox-proportional regression models were constructed to compare the adjusted EF (EFa) to EF in evaluating risk of heart failure admissions. Comparing HFpEF patients to non-HF cases, there was no significant difference in EF (62.3 ± 7.6% vs. 64.2 ± 6.2%, p = 0.79), but there was a significant difference in EFa (56.6 ± 6.4% vs. 61.8 ± 9.9%, p = 0.0007). Both low EF and low EFa were associated with a high HF readmission risk. However, in the cohort with a normal EF (EF ≥ 50%), models using EFa were significantly more associative with HF readmissions within 3 years, where the leave one out cross validation ROC analysis showed a 18.6% reduction in errors, and Net Classification Index (NRI) analysis showed that risk increment classification of events increased by 12.2%, while risk decrement classification of non-events decreased by 16.6%. EFa is associated with HF readmission in patients with a normal EF.

Beta blockers are associated with lower all-cause mortality among HFpEF patients.

The evidence regarding beta blocker (BB) benefit in heart failure with preserved ejection fraction (HFpEF) remains inconclusive, leading to consideration of BB withdrawal in this population. In this study, we retrospectively analyzed the association of BB on all-cause mortality in HFpEF patients. This is a single-center retrospective cohort study of 20,206 patients with left ventricular ejection fraction (EF) ≥ 50% who were hospitalized with decompensated HF between January 2011 and March 2020. Survival is reported at 30days, 1year, and 3years. A secondary analysis comparing mortality for patients on BB with additional indications including hypertension (HTN), coronary artery disease (CAD), and atrial fibrillation (AF) was completed. Mortality was compared between patients on BB and additional therapies of spironolactone or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs). BB showed lower all-cause mortality at 30days, 1year, and 3years (p < 0.0001). This association with lower all-cause mortality was validated by a supplementary propensity score-matched analysis. At 3years, there was significant mortality reduction with addition of BB to either spironolactone (p = 0.0359) or ACEi/ARBs (p < 0.0001). In a large single-center retrospective registry, BB use was associated with lower mortality in HFpEF patients with a recent decompensated HF hospitalization. The mortality benefit persisted in those treated with spironolactone or ACEi/ARBs, and in those with AF. This provocative data further highlights the uncertainty of the benefit of BB use in this cohort and calls for re-consideration of BB withdrawal, especially in those tolerating it well, without conclusive, large, and randomized trials showing lack of benefit or harm.

Pulmonary Function Abnormalities in Heart Failure Subtypes: Impact of Upper Body Adiposity

Study objective: Heart failure (HF) syndrome is associated with pulmonary system abnormalities that have a direct impact on mortality. Heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are distinct subtypes of HF with different pathophysiologies, clinical presentations, and treatment approaches. Obesity is highly prevalent in HFpEF and significantly contributes to its development. Importantly, obesity and high abdominal adiposity can have significant effects on pulmonary function. Therefore, HFpEF patients may have more pronounced pulmonary function impairment than HFrEF patients in part due to higher prevalence of upper body adiposity. Hypothesis: We hypothesized that lung volumes would be lower in patients with HFpEF compared to those with HFrEF and CTL. Further, we hypothesized that higher upper body adiposity (measured as trunk fat by dual-energy X-ray absorptiometry) would be associated with lower lung volumes in patients with HFpEF. Methods: HFpEF patients (n=26), HFrEF patients (n=26) and CTL (n=36) performed pulmonary function tests according to ATS/ERS guidelines. Total lung capacity (TLC), residual volume (RV), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) were measured and absolute and % predicted values are reported. Dual-energy X-ray absorptiometry scans quantified % trunk fat. Absolute lung volumes were compared across groups using ANCOVA with age as a covariate and % predicted lung volumes were compared using one-way ANOVA. Results: HFpEF patients were older than HFrEF patients and CTL (HFpEF: 71±9 vs. HFrEF: 65±9 vs. CTL: 63±11 yrs, both p&lt;0.05) while no differences were present among groups for sex, height, or BMI (all, p&gt;0.05). HFpEF patients had higher % trunk fat than CTL (p&lt;0.01), while no differences were present between HFrEF and HFpEF or CTL (p&gt;0.05) (HFpEF: 46±11 vs. HFrEF: 42±8 vs. CTL: 38±11%). HFpEF patients had lower FVC (HFpEF: 3.0±0.7 vs. HFrEF: 3.7±1.0 vs. CTL: 3.8±0.8 L), FEV1 (HFpEF: 2.3±0.5 vs. HFrEF: 2.8±0.8 vs. CTL: 2.9±0.6 L), TLC (HFpEF: 5.5±1.3 vs. HFrEF: 6.3±1.4 vs. CTL: 6.4±1.1 L), and % predicted TLC than CTL (all, p&lt;0.05). HFpEF and HFrEF patients had lower % predicted FVC and % predicted FEV1 than CTL (p&lt;0.05). All other pulmonary function parameters were not different among groups (p&gt;0.05). There was a negative relationship between % trunk fat and TLC for HFpEF patients (r= -0.51, p&lt;0.05). There were negative relationships between % trunk fat and FVC for CTL (r= -0.37) and HFpEF patients (r= -0.50) (both, p&lt;0.05), with statistically different y-intercepts (p&lt;0.01). There were no other significant relationships (all, p&gt;0.05). Conclusion: These findings demonstrate that patients with HF have smaller lung volumes than CTL. Further, our findings suggest that upper body adiposity may be an important contributing factor to these pulmonary system abnormalities in HFpEF. None. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Comparison of clinical characteristics and prognostic factors in patients with heart failure with preserved ejection fraction with and without renal dysfunction.

Heart failure with preserved ejection fraction (HFpEF) with renal dysfunction (RD) is considered to be a specific phenotype of HFpEF. This study aimed to compare the clinical characteristics and prognostic factors for in-hospital mortality between HFpEF-diagnosed patients with and without RD. This multicenter retrospective study included 5867 consecutive patients with acute HFpEF. RD was defined by an estimated glomerular filtration rate (eGFR) of <60 mL/min per 1.73 m2. Kaplan-Meier survival curves and log-rank tests were used to compare the in-hospital mortality between the groups. Univariable and multivariable Cox regression analyses were performed to identify significant prognostic factors. Across the study cohort, 68% of patients had RD. In-hospital mortality was significantly higher in HFpEF patients with RD than in those without RD. The comorbidities and laboratory data differed significantly between the groups. Independent prognostic factors for in-hospital mortality in the HFpEF patients with RD were age (hazard ratio [HR], 1.039), systolic blood pressure (HR, 0.991), eGFR (HR, 0.981), C-reactive protein (CRP; HR, 1.028), diuretics (HR, 0.374), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACE-I/ARBs; HR, 0.680), and beta-blockers (HR, 0.662). In HFpEF patients without RD, age (HR, 1.039), systolic blood pressure (HR, 0.979), and ACE-I/ARBs (HR, 0.373) were independent prognostic factors. Significant differences in the clinical characteristics and prognostic factors, such as CRP and beta-blockers, were observed between the HFpEF patients with and without RD. These results have implications for future research and may help guide individualized patient management strategies.

Evaluation of renal sodium handling in heart failure with preserved ejection fraction: A pilot study.

The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo-responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B-type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank-sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo-responsiveness to NPs.

AORTIC STENOSIS AND HEART FAILURE: DIFFERENCES AND SIMILARITIES BEYOND PRESERVED EJECTION FRACTION

Objective: Degenerative aortic stenosis (AS) is highly prevalent in Western countries and shows a strong association with age and other cardiovascular risk factors such as arterial hypertension, diabetes mellitus, dyslipidaemia, and visceral obesity. The same risk factors are involved in the development of heart failure with preserved ejection fraction (HFpEF). Notwithstanding several similarities, patients with AS and preserved left ventricular ejection fraction (ASpEF) are not considered to actually have HFpEF. We sought to investigate the haemodynamic and metabolic features of patients with ASpEF both at rest and during physical effort and highlight similarities and differences with HFpEF. Design and method: We enrolled 148 patients with HFpEF, 150 with ASpEF (with at least moderate aortic transvalvular gradient), and 80 age- and sex-matched healthy controls. All patients received a comprehensive laboratory evaluation, a resting echocardiographic examination, and a combined cardiopulmonary-echocardiographic stress test. Patients with ASpEF who fulfilled the criteria for transcatheter aortic valve replacement (n=125) underwent cardiac computed tomography to measure aortic valve calcium score and volume. Results: Serum levels of N-terminal prohormone of brain natriuretic peptide were similar between HFpEF and ASpEF patients after excluding subjects with atrial fibrillation. As a marker of deregulated inflammation, epicardial adipose tissue (EAT) thickness was significantly greater in ASpEF than HFpEF and controls and was inversely related to peak oxygen consumption (VO2) in all subgroups (Figure). Furthermore, all patients showed a significant impairment in peak VO2 caused by a reduction in bith cardiac output (CO) and peripheral arteriovenous oxygen difference (AVO2diff). HFpEF patients displayed increased arterial stiffness, worse left ventricular-arterial coupling, and worse left atrial function. On the other hand, patients with ASpEF showed worse right ventricular-pulmonary arterial coupling. In ASpEF, disease severity, evaluated by aortic transvalvular peak velocity, mean gradient at rest and peak exercise, and aortic valve calcium score and volume, was directly related to EAT thickness. Conclusions: ASpEF shows substantial similarities to HFpEF. ASpEF could represent a separate phenotype in the spectrum of HFpEF; further and larger studies should investigate this hypothesis to give further insight into the pathophysiology of ASpEF.

Estimated pulse wave velocity predicts mortality in patients with heart failure with preserved ejection fraction

ObjectiveEstimated pulse wave velocity (ePWV), a newly established arterial stiffness (AS) parameter, predicts the development of cardiovascular disease (CVD) and death in the general population or in patients with CVD risk factors. However, whether ePWV is associated with adverse outcomes in heart failure with preserved ejection fraction (HFpEF) patients remains unknown. Our study aimed to evaluate the prognostic value of ePWV on clinical outcomes in HFpEF. Methods and ResultsWe analyzed HFpEF participants from the Americas in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial with available baseline data (n = 1764). Cox proportional hazard model was used to explore the prognostic value of ePWV on long-term clinical outcomes (all-cause mortality, cardiovascular mortality, all-cause hospitalization, and heart failure hospitalization). Each ePWV increase by 1 m/s increased the risk for all-cause death by 16% (HR:1.16; 95% CI:1.10–1.23; P < 0.001) and CVD mortality by 13% (HR:1.13; 95% CI:1.04–1.21; P = 0.002) after adjusting for confounders. Patients were then grouped into 4 quartiles of ePWV. Our study indicated that the highest ePWV quartile (ePWV ≥ 12.806 m/s) was associated with increased risk of all-cause mortality (HR: 1.96; 95% CI: 1.43–2.69; P < 0.001) and CVD mortality (HR: 1.72; 95% CI: 1.16–2.56; P = 0.008) after adjusting for potential confounders. ConclusionThese results suggested ePWV is independently associated with increased all-cause mortality and CVD mortality in HFpEF patients, indicating ePWV is an appropriate predictor of prognosis in patients with HFpEF.

Efficacy and safety of semaglutide in patients with heart failure with preserved ejection fraction and obesity.

Semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, has shown promise in weight management and cardiovascular outcomes in other populations. This study aimed to evaluate the efficacy of semaglutide in heart failure with preserved ejection fraction(HFpEF) patients with obesity. A retrospective study analyzed 318 patients with HFpEF, of which 104 received semaglutide and 214 received placebo. Primary endpoints included evaluating changes in exercise capacity and weight management. Semaglutide treatment led to significant improvements in the primary endpoints. Patients in the semaglutide group demonstrated substantial enhancements in exercise capacity, as measured by the 6-min walk distance, compared to the placebo group (mean difference 15.1 meters, 95% CI 5.8 to 24.4, p = 0.002). Additionally, semaglutide resulted in substantial weight loss compared to placebo (mean difference -2.9%, 95% CI -4.1--1.7, p = 0.001). Several secondary endpoints, including reductions in C-reactive protein levels and improvements in other clinical parameters, further supported the efficacy of semaglutide. Adverse events were generally well-tolerated, with no unexpected safety concerns. Semaglutide demonstrated significant clinical benefits in HFpEF patients with obesity, as evidenced by improved symptoms, physical function, and weight reduction.

New Mechanisms to Prevent Heart Failure with Preserved Ejection Fraction Using Glucagon-like Peptide-1 Receptor Agonism (GLP-1 RA) in Metabolic Syndrome and in Type 2 Diabetes: A Review.

This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of β-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans.

Transthyretin amyloid cardiomyopathy among patients with heart failure and preserved ejection fraction: the AMY score.

Transthyretin 'wild-type' amyloid cardiomyopathy (ATTRwt-CM) is a differential diagnosis of heart failure with preserved ejection fraction (HFpEF). The clinical work-up for ATTRwt-CM is challenging. Considering a combination of clinical variables specific for ATTRwt-CM might aid in identifying patients at risk. Sixty patients (78±6years, 8% female) were diagnosed with ATTRwt-CM by endomyocardial biopsy. Preserved ejection fraction (LVEF >45%) was present in 41 of the patients. Those were 1:1 propensity score age- and sex-matched to a cohort of patients with HFpEF. ATTRwt-CM patients had less obesity (P=0.01) and higher septal thickness (IVSd, P<0.01) as well as more diastolic dysfunction (E/e', P<0.01). On multivariable regression IVSd>14mm, E/e'>14 and absence of obesity (P>0.01 for all) were identified as predictors for ATTRwt-CM. A weighted point-based score was derived with IVSd>14mm=1 point; absence of obesity=2 points; and E/e'>14=3 points. Area under the curve (AUC) for the summation score was 0.91 (0.84-0.97, P<0.01) and a score of more than 3 points predicted ATTRwt-CM with good sensitivity (78%) and specificity (90%). The score was validated in an external cohort of 142 patients with ATTRwt-CM and 419 HFpEF patients showing sufficient accuracy (AUC 0.91, 0.88-0.94, P<0.01). A value greater than 3 points demonstrated a high sensitivity (93%) and a negative predictive value of 97%. A score based on basic clinical and echocardiographic features helps to distinguish ATTRwt-CM from typical HFpEF. This could facilitate the diagnostic work-up for these patients and enable earlier disease screening on a large scale.

Applicability of H2FPEF and HFA-PEFF Scores in Chinese Patients Suffering From Heart Failure With Preserved Ejection Fraction and Heart Failure With Preserved Ejection Fraction Complicated With Atrial Fibrillation

Objective To analyze the diagnostic values of H2FPEF and HFA-PEFF scores for heart failure with preserved ejection fraction (HFpEF) and HFpEF complicated with atrial fibrillation (HFpEF-AF) in Chinese patients and explore the related factors. Methods A cross-sectional study was conducted.A total of 835 consecutive HFpEF patients treated in the Department of Geriatric Cardiology,the First Hospital of Lanzhou University from 2009 to 2020 were selected and assigned to a HFpEF-AF group (n=267) and a HFpEF group (n=568) according to the presence of AF or not.HFA-PEFF and H2FPEF scores were used for retrospective diagnosis and the diagnostic consistency of the two scores was assessed.One hundred and thirty-six healthy volunteers with age and sex matching the patients during the same period were selected as healthy controls.The receiver operating characteristic (ROC) curves were established for H2FPEF and HFA-PEFF scores in diagnosing HFpEF-AF and HFpEF,on the basis of which the diagnostic performance of the two scores was evaluated. Results There was no difference in the HFA-PEFF score between the two groups (P=0.070).However,the HFpEF-AF group had higher mean H2FPEF score and higher proportion of patients with the score no less than 6 than the HFpEF group (P<0.001).According to the ROC curves,HFA-PEFF and H2FPEF scores demonstrated high performance in diagnosing all HFpEF patients,with the area under the curve (AUC) of 0.892 and 0.922 and the optimal cut-offs of 4 and 4,respectively.The HFA-PEFF score showed similar performance in diagnosing HFpEF and HFpEF-AF,with the AUC of 0.899 and 0.911,respectively.The H2FPEF score had higher performance in diagnosing HFpEF-AF (AUC of approximately 1.000) and low performance in diagnosing HFpEF (AUC of 0.885). Conclusions The HFA-PEFF score is applicable in the diagnosis of both HFpEF and HFpEF-AF.The H2FPEF score may underestimate HFpEF in Chinese patients,and its applicability in the Chinese patients with HFpEF alone remains to be investigated.

A Murine Model of Hyperlipidemia-Induced Heart Failure with Preserved Ejection Fraction.

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) driven by lipotoxicity is incompletely understood. Given the urgent need for animal models that accurately mimic cardio-metabolic HFpEF, a hyperlipidemia-induced murine model was developed by reverse engineering phenotypes seen in HFpEF patients. This model aimed to investigate HFpEF, focusing on the interplay between lipotoxicity and metabolic syndrome. Hyperlipidemia was induced in wild-type (WT) mice on a 129J strain background through bi-weekly intraperitoneal injections of poloxamer-407 (P-407), a block co-polymer that blocks lipoprotein lipase, combined with a single intravenous injection of adeno-associated virus 9-cardiac troponin T-low-density lipoprotein receptor (AAV9-cTnT-LDLR). Extensive assessments were conducted between 4 and 8 weeks post-treatment, including echocardiography, blood pressure recording, whole-body plethysmography, echocardiography (ECG) telemetry, activity wheel monitoring (AWM), and biochemical and histological analyses. The LDLR/P-407 mice exhibited distinctive features at four weeks, including diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness. Notably, blood pressure and renal function remained within normal ranges. Additionally, ECG and AWM revealed heart blocks and reduced activity, respectively. Diastolic function deteriorated at eight weeks, accompanied by a significant decline in respiratory rates. Further investigation into the double treatment model revealed elevated fibrosis, wet/dry lung ratios, and heart weight/body weight ratios. The LDLR/P-407 mice exhibited xanthelasmas, ascites, and cardiac ischemia. Interestingly, sudden deaths occurred between 6 and 12 weeks post-treatment. The murine HFpEF model offers a valuable and promising experimental resource for elucidating the intricacies of metabolic syndrome contributing to diastolic dysfunction within the context of lipotoxicity-mediated HFpEF.

Prognostic value of measurement of myocardial extracellular volume using dual-energy CT in heart failure with preserved ejection fraction

Diffuse myocardial fibrosis is associated with adverse outcomes in heart failure with preserved ejection fraction (HFpEF). Dual-energy CT (DECT) can noninvasively assess myocardial fibrosis by quantification of extracellular volume (ECV) fraction. This study evaluated the association between ECV measured by DECT and clinical outcomes in patients with HFpEF. 125 hospitalized HFpEF patients were enrolled in this retrospective cohort study. ECV was measured using DECT with late iodine enhancement. The composite endpoint was defined as HFpEF hospitalization and all-cause mortality during the follow-up. During the median follow-up of 10.4 months, 34 patients (27.20%) experienced the composite outcomes, including 5 deaths; and 29 HFpEF hospitalizations. The higher DECT-ECV group had higher rates of composite outcomes than the low ECV group (log-rank X2 = 6.818, P = 0.033). In multivariate Cox regression analysis, the ECV (HR 1.17, 95% CI 1.06–1.30, P = 0.001) and NT-pro BNP (HR 2.83, 95% CI 1.16–6.88, P = 0.022) were independent risk factors for the adverse outcomes. Myocardial ECV measured using DECT was an independent risk factor for adverse outcomes in patients with HFpEF.

Retinal Vascular Changes in Heart Failure with Preserved Ejection Fraction Using Optical Coherence Tomography Angiography.

Background: Systemic microvascular regression and dysfunction are considered important underlying mechanisms in heart failure with preserved ejection fraction (HFpEF), but retinal changes are unknown. Methods: This prospective study aimed to investigate whether retinal microvascular and structural parameters assessed using optical coherence tomography angiography (OCT-A) differ between patients with HFpEF and control individuals (i.e., capillary vessel density, thickness of retina layers). We also aimed to assess the associations of retinal parameters with clinical and echocardiographic parameters in HFpEF. HFpEF patients, but not controls, underwent echocardiography. Macula-centered 6 × 6 mm volume scans were computed of both eyes. Results: Twenty-two HFpEF patients and 24 controls without known HFpEF were evaluated, with an age of 74 [68-80] vs. 68 [58-77] years (p = 0.027), and 73% vs. 42% females (p = 0.034), respectively. HFpEF patients showed vascular degeneration compared to controls, depicted by lower macular vessel density (p < 0.001) and macular ganglion cell-inner plexiform layer thickness (p = 0.025), and a trend towards lower total retinal volume (p = 0.050) on OCT-A. In HFpEF, a lower total retinal volume was associated with markers of diastolic dysfunction (septal e', septal and average E/e': R2 = 0.38, 0.36, 0.25, respectively; all p < 0.05), even after adjustment for age, sex, diabetes mellitus, or atrial fibrillation. Conclusions: Patients with HFpEF showed clear levels of retinal vascular changes compared to control individuals, and retinal alterations appeared to be associated with markers of more severe diastolic dysfunction in HFpEF. OCT-A may therefore be a promising technique for monitoring systemic microvascular regression and cardiac diastolic dysfunction.

Impact of heart rate changes during hospitalization on outcome in heart failure with preserved ejection fraction.

The benefits of lowering heart rate (HR) in heart failure (HF) with preserved ejection fraction (HFpEF) patients are still a matter of debate. This study aimed to investigate the relationship between changes in HR during hospitalization and cardiovascular (CV) events and all-cause death in hospitalized HFpEF patients. Hospitalized HF patients between January 2017 and December 2021 were consecutively enrolled in a national, multicentred, and prospective registry database, the China Cardiovascular Association Database-HF Center Registry. HF patients with a left ventricular ejection fraction of ≥50% were defined as HFpEF patients. The study analysed admission/discharge HR, change in HR during hospitalization (∆HR), and ∆HR ratio (∆HR/admission HR). The patients were categorized into three groups: no HR dropping group (ΔHR ratio>0.0%), moderate HR dropping group (-15%<ΔHR ratio≤0.0%), and excessive HR dropping group (ΔHR ratio≤-15%). All patients were followed up for 12months. The primary endpoint was CV events (CV death or HF rehospitalization). The secondary endpoint was all-cause death. A total of 19510 HFpEF patients (9750 males, mean age 71.9±12.2years) were included, with 4575 in the no HR dropping group, 8434 in the moderate HR dropping group, and 6501 in the excessive HR dropping group. Excessive HR dropping during hospitalization was significantly associated with an increased risk of CV events (17.1%) compared with the no HR dropping group (14.5%, P<0.001) or the moderate HR dropping group (14.0%, P<0.001), although all-cause mortality was similar among the three groups. After adjusting for multiple confounding factors, excessive HR dropping remained an independent predictor of increased CV event risk [hazard ratio 1.197, 95% confidence interval (CI) 1.078-1.328]. Subgroup analysis revealed that the prognostic impact of excessive HR dropping on increased CV event risk remained in the subgroups of older age, New York Heart Association class IV, ischaemic HF, higher left ventricular ejection fraction, absence of chronic kidney disease, and use of beta-blockers or ivabradine. Independent determinants associated with excessive HR dropping during admission included use of beta-blockers [odds ratio (OR) 1.683, 95% CI 1.558-1.819], lower discharge diastolic blood pressure (OR 0.988, 95% CI 0.985-0.991), no pacemaker (OR 0.501, 95% CI 0.416-0.603), coexisting atrial fibrillation or atrial flutter (OR 1.327, 95% CI 1.218-1.445), and use of digoxin (OR 1.340, 95% CI 1.213-1.480). In hospitalized HFpEF patients, excessive HR dropping during hospitalization is associated with an increased risk of CV death or HF rehospitalization. These findings highlight the importance of HR monitoring and avoiding excessively slowing down HR in hospitalized HFpEF patients to reduce the risk of CV events.

HBI-8000 improves heart failure with preserved ejection fraction via the TGF-β1/MAPK signalling pathway.

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of total heart failure patients and is characterized by peripheral circulation, cardiac remodelling and comorbidities (such as advanced age, obesity, hypertension and diabetes) with limited treatment options. Chidamide (HBI-8000) is a domestically produced benzamide-based histone deacetylase isoform-selective inhibitor used for the treatment of relapsed refractory peripheral T-cell lymphomas. Based on our invivo studies, we propose that HBI-8000 exerts its therapeutic effects by inhibiting myocardial fibrosis and myocardial hypertrophy in HFpEF patients. At the cellular level, we found that HBI-8000 inhibits AngII-induced proliferation and activation of CFs and downregulates the expression of fibrosis-related factors. In addition, we observed that the HFpEF group and AngII stimulation significantly increased the expression of TGF-β1 as well as phosphorylated p38MAPK, JNK and ERK, whereas the expression of the above factors was significantly reduced after HBI-8000 treatment. Activation of the TGF-β1/MAPK pathway promotes the development of fibrotic remodelling, and pretreatment with SB203580 (p38MAPK inhibitor) reverses this pathological change. In conclusion, our data suggest that HBI-8000 inhibits fibrosis by modulating the TGF-β1/MAPK pathway thereby improving HFpEF. Therefore, HBI-8000 may become a new hope for the treatment of HFpEF patients.