Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2DM with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2DM and HFpEF remain unknown. METHODS: A total of 24 patients with T2DM and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period. RESULTS: During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P<0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, -2 to 0) and at peak exercise by 5 mm Hg (95% CI, -9 to -1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise (P<0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs. CONCLUSIONS: In patients with T2DM and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2DM and HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05236335.

Ferric carboxymaltose and exercise capacity in heart failure with preserved ejection fraction and iron deficiency: the FAIR-HFpEF trial.

BACKGROUND AND AIMS: Evidence is lacking that correcting iron deficiency (ID) has clinically important benefits for patients with heart failure with preserved ejection fraction (HFpEF). METHODS: FAIR-HFpEF was a multicentre, randomized, double-blind trial designed to compare intravenous ferric carboxymaltose (FCM) with placebo (saline) in 200 patients with symptomatic HFpEF and ID (serum ferritin < 100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation < 20%). The primary endpoint was change in 6-min walking test distance (6MWTD) from baseline to week 24. Secondary endpoints included changes in New York Heart Association class, patient global assessment, and health-related quality of life (QoL). RESULTS: The trial was stopped because of slow recruitment after 39 patients had been included (median age 80 years, 62% women). The change in 6MWTD from baseline to week 24 was greater for those assigned to FCM compared to placebo [least square mean difference 49 m, 95% confidence interval (CI) 5-93; P = .029]. Changes in secondary endpoints were not significantly different between groups. The total number of adverse events (76 vs. 114) and serious adverse events (5 vs. 19; rate ratio 0.27, 95% CI 0.07-0.96; P = .043) was lower with FCM than placebo. CONCLUSIONS: In patients with HFpEF and markers of ID, intravenous FCM improved 6MWTD and was associated with fewer serious adverse events. However, the trial lacked sufficient power to identify or refute effects on symptoms or QoL. The potential benefits of intravenous iron in HFpEF with ID should be investigated further in a larger cohort.

Semaglutide and Diuretic Use in Obesity-Related Heart Failure with Preserved Ejection Fraction: A Pooled Analysis of the STEP-HFpEF and STEP-HFpEF-DM trials.

BACKGROUND AND AIMS: In the STEP-HFpEF trial program, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. METHODS: In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n=1145), which randomized participants with HFpEF and body mass index ≥30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. RESULTS: At baseline, across no diuretic (n=220), non-loop diuretic only (n=223), and loop diuretic (<40 [n=219], 40 [n=309], and >40 [n=174] mg/day furosemide-equivalents) groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from -8.8% [95% CI -10.3, -6.3] to -6.9% [95% CI -9.1, -4.7] from no diuretics to the highest loop diuretic dose category; interaction P=0.39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P=0.042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6-min walk distance) across diuretic subgroups (interaction P=0.24-0.92). Safety also favored semaglutide versus placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P<0.0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P<0.001 for both) from baseline to 52 weeks. CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide versus placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. CLINICALTRIALS.GOV REGISTRATION: NCT04788511 and NCT04916470.

Renal Denervation to Treat Heart Failure.

Heart failure (HF) is a global pandemic with a poor prognosis after hospitalization. Despite HF syndrome complexities, evidence of significant sympathetic overactivity in the manifestation and progression of HF is universally accepted. Confirmation of this dogma is observed in guideline-directed use of neurohormonal pharmacotherapies as a standard of care in HF. Despite reductions in morbidity and mortality, a growing patient population is resistant to these medications, while off-target side effects lead to dismal patient adherence to lifelong drug regimens. Novel therapeutic strategies, devoid of these limitations, are necessary to attenuate the progression of HF pathophysiology while continuing to reduce morbidity and mortality. Renal denervation is an endovascular procedure, whereby the ablation of renal nerves results in reduced renal afferent and efferent sympathetic nerve activity in the kidney and globally. In this review, we discuss the current state of preclinical and clinical research related to renal sympathetic denervation to treat HF.

Elevated ITGA1 levels in type 2 diabetes: implications for cardiac function impairment.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus is known to contribute to the development of heart failure with preserved ejection fraction (HFpEF). However, identifying HFpEF in individuals with type 2 diabetes early on is often challenging due to a limited array of biomarkers. This study aims to investigate specific biomarkers associated with the progression of HFpEF in individuals with type 2 diabetes, for the purpose of enabling early detection and more effective management strategies. METHODS: Blood samples were collected from individuals with type 2 diabetes, both with and without HFpEF, for proteomic analysis. Plasma integrin α1 (ITGA1) levels were measured and compared between the two groups. Participants were further categorised based on ITGA1 levels and underwent detailed transthoracic echocardiography at baseline and during a median follow-up period of 30 months. Multivariable linear and Cox regression analyses were conducted separately to assess the associations between plasma ITGA1 levels and changes in echocardiography indicators and re-hospitalisation risk. Additionally, proteomic data for the individuals' left ventricles, from ProteomeXchange database, were analysed to uncover mechanisms underlying the change in ITGA1 levels in HFpEF. RESULTS: Individuals with type 2 diabetes and HFpEF showed significantly higher plasma ITGA1 levels than the individuals with type 2 diabetes without HFpEF. These elevated ITGA1 levels were associated with left ventricular remodelling and impaired diastolic function. Furthermore, during a median follow-up of 30 months, multivariable analysis revealed that elevated ITGA1 levels independently correlated with deterioration of both diastolic and systolic cardiac functions. Additionally, higher baseline plasma ITGA1 levels independently predicted re-hospitalisation risk (HR 2.331 [95% CI 1.387, 3.917], p=0.001). Proteomic analysis of left ventricular myocardial tissue provided insights into the impact of increased ITGA1 levels on cardiac fibrosis-related pathways and the contribution made by these changes to the development and progression of HFpEF. CONCLUSIONS/INTERPRETATION: ITGA1 serves as a biomarker for monitoring cardiac structural and functional damage, can be used to accurately diagnose the presence of HFpEF, and can be used to predict potential deterioration in cardiac structure and function as well as re-hospitalisation for individuals with type 2 diabetes. Its measurement holds promise for facilitating risk stratification and early intervention to mitigate the adverse cardiovascular effects associated with diabetes. DATA AVAILABILITY: The proteomic data of left ventricular myocardial tissue from individuals with type 2 diabetes, encompassing both those with and without HFpEF, is available from the ProteomeXchange database at http://proteomecentral.proteomexchange.org .

HBI-8000 improves heart failure with preserved ejection fraction via the TGF-ß1/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 in vivo 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-ß1 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-ß1/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-ß1/MAPK pathway thereby improving HFpEF. Therefore, HBI-8000 may become a new hope for the treatment of HFpEF patients.

The total xanthones extracted from Gentianella acuta alleviates HFpEF by activating the IRE1α/Xbp1s pathway.

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by pulmonary and systemic congestion resulting from left ventricular diastolic dysfunction and increased filling pressure. Currently, however, there is no evidence on effective pharmacotherapy for HFpEF. In this study, we aimed to investigate the therapeutic effect of total xanthones extracted from Gentianella acuta (TXG) on HFpEF by establishing an high-fat diet (HFD) + L-NAME-induced mouse model. Echocardiography was employed to assess the impact of TXG on the cardiac function in HFpEF mice. Haematoxylin and eosin staining, wheat germ agglutinin staining, and Masson's trichrome staining were utilized to observe the histopathological changes following TXG treatment. The results demonstrated that TXG alleviated HFpEF by reducing the expressions of genes associated with myocardial hypertrophy, fibrosis and apoptosis. Furthermore, TXG improved cardiomyocyte apoptosis by inhibiting the expression of apoptosis-related proteins. Mechanistic investigations revealed that TXG could activate the inositol-requiring enzyme 1α (IRE1α)/X-box-binding protein 1 (Xbp1s) signalling pathway, but the knockdown of IRE1α using the IRE1α inhibitor STF083010 or siRNA-IRE1α impaired the ability of TXG to ameliorate cardiac remodelling in HFpEF models. In conclusion, TXG alleviates myocardial hypertrophy, fibrosis and apoptosis through the activation of the IRE1α/Xbp1s signalling pathway, suggesting its potential beneficial effects on HFpEF patients.

Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The human heart primarily metabolizes fatty acids, and this decreases as alternative fuel use rises in heart failure with reduced ejection fraction (HFrEF). Patients with severe obesity and diabetes are thought to have increased myocardial fatty acid metabolism, but whether this is found in those who also have heart failure with preserved ejection fraction (HFpEF) is unknown. METHODS: Plasma and endomyocardial biopsies were obtained from HFpEF (n=38), HFrEF (n=30), and nonfailing donor controls (n=20). Quantitative targeted metabolomics measured organic acids, amino acids, and acylcarnitines in myocardium (72 metabolites) and plasma (69 metabolites). The results were integrated with reported RNA sequencing data. Metabolomics were analyzed using agnostic clustering tools, Kruskal-Wallis test with Dunn test, and machine learning. RESULTS: Agnostic clustering of myocardial but not plasma metabolites separated disease groups. Despite more obesity and diabetes in HFpEF versus HFrEF (body mass index, 39.8 kg/m2 versus 26.1 kg/m2; diabetes, 70% versus 30%; both P<0.0001), medium- and long-chain acylcarnitines (mostly metabolites of fatty acid oxidation) were markedly lower in myocardium from both heart failure groups versus control. In contrast, plasma levels were no different or higher than control. Gene expression linked to fatty acid metabolism was generally lower in HFpEF versus control. Myocardial pyruvate was higher in HFpEF whereas the tricarboxylic acid cycle intermediates succinate and fumarate were lower, as were several genes controlling glucose metabolism. Non-branched-chain and branched-chain amino acids (BCAA) were highest in HFpEF myocardium, yet downstream BCAA metabolites and genes controlling BCAA metabolism were lower. Ketone levels were higher in myocardium and plasma of patients with HFrEF but not HFpEF. HFpEF metabolomic-derived subgroups were differentiated by only a few differences in BCAA metabolites. CONCLUSIONS: Despite marked obesity and diabetes, HFpEF myocardium exhibited lower fatty acid metabolites compared with HFrEF. Ketones and metabolites of the tricarboxylic acid cycle and BCAA were also lower in HFpEF, suggesting insufficient use of alternative fuels. These differences were not detectable in plasma and challenge conventional views of myocardial fuel use in HFpEF with marked diabetes and obesity and suggest substantial fuel inflexibility in this syndrome.

Simple model of pulmonary hypertension secondary to left heart pressure overload induced by partial intravascular occlusion of the ascending aorta.

Pulmonary hypertension is a group of diseases characterized by elevated pulmonary artery pressure and pulmonary vascular resistance with significant morbidity and mortality. The most prevalent type is pulmonary hypertension secondary to left heart disease (PH-LHD). The available experimental models of PH-LHD use partial pulmonary clamping by technically nontrivial open-chest surgery with lengthy recovery. We present a simple model in which the reduction of the cross-sectional area of the ascending aorta is achieved not by external clamping but by partial intravascular obstruction without opening the chest. In anesthetized rats, a blind polyethylene tubing was advanced from the right carotid artery to just above the aortic valve. The procedure is quick and easy to learn. Three weeks after the procedure, left heart pressure overload was confirmed by measuring left ventricular end-diastolic pressure by puncture (1.3 ± 0.2 vs. 0.4 ± 0.3 mmHg in controls, mean ± SD, P < 0.0001). The presence of pulmonary hypertension was documented by measuring pulmonary artery pressure by catheterization (22.3 ± 2.3 vs. 16.9 ± 2.7 mmHg, P = 0.0282) and by detecting right ventricular hypertrophy and increased muscularization of peripheral pulmonary vessels. Contributions of a precapillary vascular segment and vasoconstriction to the increased pulmonary vascular resistance were demonstrated, respectively, by arterial occlusion technique and by normalization of resistance by a vasodilator, sodium nitroprusside, in isolated lungs. These changes were comparable, but not additive, to those induced by an established pulmonary hypertension model, chronic hypoxic exposure. Intravascular partial aortic obstruction offers an easy model of pulmonary hypertension induced by left heart disease that has a vasoconstrictor and precapillary component.NEW & NOTEWORTHY We present a new, simple model of a clinically important type of pulmonary hypertension, that induced by left heart failure. Left ventricular pressure overload is induced in rats by inserting a blinded cannula into the ascending aorta via carotid artery access. This partial intravascular aortic obstruction, which does not require opening of the chest and prolonged recovery, causes pulmonary hypertension, which has a precapillary and vasoconstrictor as well as a vascular remodeling component.

Heart Failure with Preserved Ejection Fraction: Mechanisms and Treatment Strategies.

Approximately half of all patients with heart failure (HF) have a preserved ejection fraction, and the prevalence is growing rapidly given the aging population in many countries and the rising prevalence of obesity, diabetes, and hypertension. Functional capacity and quality of life are severely impaired in heart failure with preserved ejection fraction (HFpEF), and morbidity and mortality are high. In striking contrast to HF with reduced ejection fraction, there are few effective treatments currently identified for HFpEF, and these are limited to decongestion by diuretics, promotion of a healthy active lifestyle, and management of comorbidities. Improved phenotyping of subgroups within the overall HFpEF population might enhance individualization of treatment. This review focuses on the current understanding of the pathophysiologic mechanisms underlying HFpEF and treatment strategies for this complex syndrome.

Hospitalization after hydroxychloroquine initiation in patients with heart failure with preserved ejection fraction and autoimmune disease.

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.

Inhibition of ferroptosis reverses heart failure with preserved ejection fraction in mice.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of heart failure cases. The molecular mechanisms by which HFpEF leads to impaired diastolic function of the heart have not been clarified, nor have the drugs that target the clinical symptoms of HFpEF patients. METHODS: HFpEF chip data (GSE180065) was downloaded from the National Center for Biotechnology Information (NCBI) database. Differentially expressed genes (DEGs) were filtered by the limma package in R and processed for GO and KEGG pathway analyses. Then, ferroptosis-related genes in HFpEF were identified by taking the intersection between DEGs and ferroptosis-related genes. CytoHubba and MCODE were used to screen ferroptosis-related hub DEGs in the protein-protein interaction (PPI) network. Establishment of a mouse HFpEF model to validate the transcript levels of ferroptosis-related hub DEGs and ferroptosis-related phenotypes. Transcript levels of ferroptosis-related hub DEGs and HFpEF phenotypic changes in the hearts of HFpEF mice were further examined after the use of ferroptosis inhibitors. RESULTS: GO and KEGG enrichment analyses suggested that the DEGs in HFpEF were significantly enriched in ferroptosis-related pathways. A total of 24 ferroptosis-related DEGs were identified between the ferroptosis gene dataset and the DEGs. The established PPI network was further analyzed by CytoHubba and MCODE modules, and 11 ferroptosis-related hub DEGs in HFpEF were obtained. In animal experiments, HFpEF mice showed significant abnormal activation of ferroptosis. The expression trends of the 11 hub DEGs associated with ferroptosis, except for Cdh1, were consistent with the results of the bioinformatics analysis. Inhibition of ferroptosis alters the transcript levels of 11 ferroptosis-related hub DEGs and ameliorates HFpEF phenotypes. CONCLUSIONS: The present study contributes to a deeper understanding of the specific mechanisms by which ferroptosis is involved in the development of HFpEF and suggests that inhibition of ferroptosis may mitigate the progression of HFpEF. In addition, eleven hub genes were recognized as potential drug binding targets.

Characterizing heart failure and its subtypes in people living with HIV.

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.

The Effectiveness of Lifestyle Interventions in Heart Failure With Preserved Ejection Fraction: A Systematic Review and Network Meta-Analysis.

OBJECTIVES: To perform a network meta-analysis to determine the effectiveness of lifestyle interventions in exercise tolerance and quality of life (QoL) in people with HFpEF. METHODS: Ten databases were searched for randomized controlled trials that evaluated a diet and/or exercise intervention in people with heart failure with preserved ejection fraction until May 2022. The co-primary outcomes were peak oxygen uptake (V̇O2peak) and Quality of Life as assessed by the Minnesota Living with Heart Failure Questionnaire (MLHFQ). We synthesized data using network meta-analysis. RESULTS: We identified 13 trials, including a total of 869 participants, and we incorporated 6 different interventions. Improvements in V̇O2peak compared to controls were seen for all exercise interventions (2.88 [95% CI: 1.36; 4.39] mL/kg/min) for high-intensity interval training (HIIT); 2.37 [95% CI: 1.02; 3.71] mL/kg/min for low-intensity exercise (LIT) combined with a hypocaloric diet; 2.05 [95% CI: 0.81; 3.29] mL/kg/min for moderate-intensity continuous training (MICT); 1.94 [95% CI: 0.59; 3.29] mL/kg/min for LIT; 1.85 [95% CI: 0.27; 3.44] mL/kg/min for MICT combined with resistance training) but not a hypocaloric diet alone (1.26 [95%CI: -0.08; 2.61] mL/kg/min). Only HIIT (-14.45 [95%CI: -24.81; -4.10] points) and LIT (95% CI: -11.05 [-20.55; -1.54] mL/kg/min) significantly improved MLHFQ scores. Network meta-analysis indicated that HIIT was the most effective intervention for improving both V̇O2peak (mean improvement 2.88 [95% CI: 1.36; 4.39] mL/kg/min, follow-up range, 4 weeks-3 years) and QoL (-14.45 [95% CI: -24.81; -4.10] points, follow-up range, 12-26 weeks) compared to usual care. CONCLUSIONS: This network meta-analysis indicates that HIIT is the most effective lifestyle intervention studied to improve exercise capacity and QoL, with mean improvements exceeding the minimum clinically meaningful thresholds. HIIT is likely to be an underused management strategy in HFpEF, but further studies are needed to confirm long-term improvements in symptoms and clinical outcomes.

Myeloperoxidase Inhibition in Heart Failure With Preserved or Mildly Reduced Ejection Fraction: SATELLITE Trial Results.

BACKGROUND: Inflammation is a key driver of heart failure with preserved left ventricular ejection fraction. AZD4831 inhibits extracellular myeloperoxidase, decreases inflammation, and improves microvascular function in preclinical disease models. METHODS AND RESULTS: In this double-blind phase 2a study (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure [SATELLITE]; NCT03756285), patients with symptomatic heart failure, left ventricular ejection fraction of ≥40%, and elevated B-type natriuretic peptides were randomized 2:1 to once-daily oral AZD4831 5 mg or placebo for 90 days. We aimed to assess target engagement (primary end point: myeloperoxidase specific activity) and safety of AZD4831. Owing to coronavirus disease 2019, the study was terminated early after randomizing 41 patients (median age 74.0 years, 53.7% male). Myeloperoxidase activity was decreased by more than 50% from baseline to day 30 and day 90 in the AZD4831 group, with a placebo-adjusted decreased of 75% (95% confidence interval, 48, 88, nominal P < .001). No improvements were noted in secondary or exploratory end points, apart from a trend in Kansas City Cardiomyopathy Questionnaire overall summary score. No deaths or treatment-related serious adverse events occurred. AZD4831 treatment-related adverse events were generalized maculopapular rash, pruritus, and diarrhea (all n = 1). CONCLUSIONS: AZD4831 inhibited myeloperoxidase and was well tolerated in patients with heart failure and left ventricular ejection fraction of 40% or greater. Efficacy findings were exploratory owing to early termination, but warrant further clinical investigation of AZD4831. LAY SUMMARY: Few treatments are available for patients with the forms of heart failure known as heart failure with preserved or mildly reduced ejection fraction. Current treatments do not target inflammation, which may play an important role in this condition. We tested a new drug called AZD4831 (mitiperstat), which decreases inflammation by inhibiting the enzyme myeloperoxidase. Among the 41 patients in our clinical trial, AZD4831 had a good safety profile and inhibited myeloperoxidase by the expected amount. Results mean we can conduct further trials to see whether AZD4831 decreases the symptoms of heart failure and improves patients' ability to participate in physical exercise.

Diagnosis of heart failure with preserved ejection fraction: a systematic narrative review of the evidence.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a common condition in clinical practice, affecting more than half of patients with HF. HFpEF is associated with morbidity and mortality and with considerable healthcare resource utilization and costs. Therefore, early diagnosis is crucial to facilitate prompt management, particularly initiation of sodium-glucose co-transporter 2 inhibitors. Although European guidelines define HFpEF as the presence of symptoms with or without signs of HF, left ventricular EF ≥ 50%, and objective evidence of cardiac structural and/or functional abnormalities, together with elevated natriuretic peptide levels, the diagnosis of HFpEF remains challenging. First, there is no clear consensus on how HFpEF should be defined. Furthermore, diagnostic tools, such as natriuretic peptide levels and resting echocardiogram findings, are significantly limited in the diagnosis of HFpEF. As a result, some patients are overdiagnosed (i.e., elderly people with comorbidities that mimic HF), although in other cases, HFpEF is overlooked. In this manuscript, we perform a systematic narrative review of the diagnostic approach to patients with HFpEF. We also propose a comprehensible algorithm that can be easily applied in daily clinical practice and could prove useful for confirming or ruling out a diagnosis of HFpEF.

Anti-obesity medications in the management of heart failure with preserved ejection fraction: available evidence and next STEPS.

Obesity is associated with an increased risk of incident heart failure with preserved ejection fraction (HFpEF) and, among patients with existing heart failure, is associated with worse quality of life, higher symptom burden, and more HF hospitalizations. Anti-obesity medication (AOM) semaglutide has been shown to be efficacious at both causing intentional weight loss and improving HF symptom burden, with some evidence to suggest that HF clinical events may also be reduced. Additional ongoing trials of AOM in patients with cardiovascular disease, including HFpEF, will further improve insight into the potential role of managing obesity to improve HF status among patients with HFpEF and obesity.

The prevalence of coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF): a systematic review and meta-analysis.

To date, studies on the prevalence of coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF) have not been summarized and analyzed as a whole. We conducted this systematic review and meta-analysis to assess the prevalence of CMD in patients with HFpEF. The PubMed, Cochrane, and Embase databases were searched from dates of inception until May 1, 2023. The primary outcome was the prevalence of CMD in patients with HFpEF, and values of CMD prevalence were pooled using a random-effects model. In total, 10 studies involving 1267 patients, including 822 with HFpEF and 445 without HFpEF, were included. The pooled prevalence of CMD in patients with HFpEF was 71% (95% CI, 0.63-0.79). In the subgroup analysis, the prevalence of CMD was 79% (95% CI, 0.71-0.87) by invasive measurement and 66% (95% CI, 0.54-0.77) by noninvasive measurement and 67% (95% CI, 0.52-0.82) with CFR < 2.0 and 75.0% (95% CI, 0.71-0.79) with CFR < 2.5. The prevalence of endothelium-independent CMD and endothelium-dependent CMD was 62% (95% CI, 0.53-0.72) and 50% (95% CI, 0.19-0.81), respectively. The prevalence of CMD was 74% (95% CI = 0.69-0.79) and 66% (95% CI = 0.41-0.90) in prospective and retrospective studies, respectively. Compared with the control group, patients with HFpEF had a significantly lower CFR (MD = - 1.28, 95% CI = - 1.82 to - 0.74, P < 0.01) and a higher prevalence of CMD (RR = 2.21, 95% CI = 1.52 to 3.20, P < 0.01). Qualitative analysis demonstrated that CMD might be associated with poor clinical outcomes in patients with HFpEF. In conclusion, this is the first systematic review and meta-analysis of all studies reporting the prevalence of CMD in patients with HFpEF. Our study demonstrates that CMD is common in patients with HFpEF and might be associated with poor clinical outcomes in these patients. Clinicians should attach importance to CMD in the diagnosis and treatment of HFpEF. The number of studies in this field is relatively small. Therefore, more high-quality studies are needed to explore the diagnostic and prognostic value of CMD and the potential role of CMD as a therapeutic target in patients with HFpEF.

Advance in the pharmacological and comorbidities management of heart failure with preserved ejection fraction: evidence from clinical trials.

The prevalence of heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of the total heart failure population, and with the aging of the population and the increasing prevalence of hypertension, obesity, and type 2 diabetes (T2DM), the incidence of HFpEF continues to rise and has become the most common subtype of heart failure. Compared with heart failure with reduced ejection fraction, HFpEF has a more complex pathophysiology and is more often associated with hypertension, T2DM, obesity, atrial fibrillation, renal insufficiency, pulmonary hypertension, obstructive sleep apnea, and other comorbidities. HFpEF has generally been considered a syndrome with high phenotypic heterogeneity, and no effective treatments have been shown to reduce mortality to date. Diuretics and comorbidity management are traditional treatments for HFpEF; however, they are mostly empirical due to a lack of clinical evidence in the setting of HFpEF. With the EMPEROR-Preserved and DELIVER results, sodium-glucose cotransporter 2 inhibitors become the first evidence-based therapies to reduce rehospitalization for heart failure. Subgroup analyses of the PARAGON-HF, TOPCAT, and CHARM-Preserved trials suggest that angiotensin receptor-neprilysin inhibitors, spironolactone, and angiotensin II receptor blockers may be beneficial in patients at the lower end of the ejection fraction spectrum. Other potential pharmacotherapies represented by non-steroidal mineralocorticoid receptor antagonists finerenone and antifibrotic agent pirfenidone also hold promise for the treatment of HFpEF. This article intends to review the clinical evidence on current pharmacotherapies of HFpEF, as well as the comorbidities management of atrial fibrillation, hypertension, T2DM, obesity, pulmonary hypertension, renal insufficiency, obstructive sleep apnea, and iron deficiency, to optimize the clinical management of HFpEF.

Large animal models to study effectiveness of therapy devices in the treatment of heart failure with preserved ejection fraction (HFpEF).

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.