Heart Failure With Preserved Ejection Fraction Phenotypes Research Articles

Empagliflozin and liraglutide ameliorate HFpEF in mice via augmenting the Erbb4 signaling pathway.

Heart failure with preserved ejection fraction (HFpEF) is closely associated with metabolic derangement. Sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) exert anti-HFpEF effects, but the underlying mechanisms remain unclear. In this study, we explored the anti-HFpEF effects of empagliflozin and liraglutide and the underlying molecular mechanisms in a mouse model of HFpEF. This model was established by high-fat diet (HFD) feedingplus Nω-nitro-L-arginine methyl ester (L-NAME) treatment. The mice were treated with empagliflozin (20 mg·kg-1·d-1, i.g.) or liraglutide (0.3 mg·kg-1·d-1, i.p.) or their combination for 4 weeks. At the end of the experimental protocol, cardiac function was measured using ultrasound, then mice were euthanized and heart, liver, and kidney tissues were collected. Nuclei were isolated from frozen mouse ventricular tissue for single-nucleus RNA-sequencing (snRNA-seq). We showed that administration of empagliflozin or liraglutide alone or in combination significantly improved diastolic function, ameliorated cardiomyocyte hypertrophy and cardiac fibrosis, as well as exercise tolerance but no synergism was observed in the combination group. Furthermore, empagliflozin and/or liraglutide lowered body weight, improved glucose metabolism, lowered blood pressure, and improved liver and kidney function. After the withdrawal of empagliflozin or liraglutide for 1 week, these beneficial effects tended to diminish. The snRNA-seq analysis revealed a subcluster of myocytes, in which Erbb4 expression was down-regulated under HFpEF conditions, and restored by empagliflozin or liraglutide. Pseudo-time trajectory analysis and cell-to-cell communication studies confirmed that the Erbb4 pathway was a prominent pathway essential for both drug actions. In the HFpEF mouse model, both empagliflozin and liraglutide reversed Erbb4 down-regulation. In rat h9c2 cells, we showed that palmitic acid- or high glucose-induced changes in PKCα and/or ERK1/2 phosphorylation at least in part through Erbb4. Collectively, the single-cell atlas reveals the anti-HFpEF mechanism of empagliflozin and liraglutide, suggesting that Erbb4 pathway represents a new therapeutic target for HFpEF. Effects and mechanisms of action of empagliflozin and liraglutide in HFpEF mice. HFpEF was induced with a high-fat diet and L-NAME for 15 weeks, and treatment with empagliflozin and liraglutide improved the HFpEF phenotype. Single nucleus RNA sequencing (snRNA-seq) was used to reveal the underlying mechanism of action of empagliflozin and liraglutide.

Long-term outcomes prediction in diabetic heart failure with preserved ejection fraction by cardiac MRI.

We aimed to explore imaging features including tissue characterization and myocardial deformation in diabetic heart failure with preserved ejection fraction (HFpEF)patients by magnetic resonance imaging (MRI) and investigate its prognostic value for adverse outcomes. Patients with HFpEF who underwent cardiac MRI between January 2010 and December 2016 were enrolled. Feature-tracking (FT) analysis and myocardial fibrosis were assessed by cardiac MRI. Cox proportional regression analysis was performed to determine the association between MRI variables and primary outcomes. Primary outcomes were all-cause death or heart failure hospitalization during the follow-up period. Of the 335 enrolled patients with HFpEF, 191 had diabetes mellitus (DM) (mean age: 58.7years ± 10.8; 137 men). During a median follow-up of 10.2years, 91 diabetic HFpEF and 56 non-diabetic HFpEF patients experienced primary outcomes. DM was a significant predictor of worse prognosis in HFpEF. In diabetic HFpEF, the addition of conventional imaging variables (left ventricular ejection fraction, left atrial volume index, extent of late gadolinium enhancement (LGE)) and global longitudinal strain (GLS) resulted in a significant increase in the area under the receiver operating characteristic curve (from 0.693 to 0.760, p < 0.05). After adjustment for multiple clinical and imaging variables, each 1% worsening in GLS was associated with a 9.8% increased risk of adverse events (p = 0.004). Diabetic HFpEF is characterized by more severely impaired strains and myocardial fibrosis, which is identified as a high-risk HFpEF phenotype. In diabetic HFpEF, comprehensive cardiac MRI provides incremental value in predicting prognosis. Particularly, MRI-FT measurement of GLS is an independent predictor of adverse outcome in diabetic HFpEF. Our findings suggested that MRI-derived variables, especially global longitudinal strain, played a crucial role in risk stratification and predicting worse prognosis in diabetic heart failure with preserved ejection fraction, which could assist in identifying high-risk patients and guiding therapeutic decision-making. • Limited data are available on the cardiac MRI features of diabetic heart failure with preserved ejection fraction, including myocardial deformation and tissue characterization, as well as their incremental prognostic value. • Diabetic heart failure with preserved ejection fraction patients was characterized by more impaired strains and myocardial fibrosis. Comprehensive MRI, including tissue characterization and global longitudinal strain, provided incremental value for risk prediction. • MRI served as a valuable tool for identifying high-risk patients and guiding clinical management in diabetic heart failure with preserved ejection fraction.

AdipoRon ameliorates the progression of heart failure with preserved ejection fraction via mitigating lipid accumulation and fibrosis

IntroductionObesity and imbalance in lipid homeostasis contribute greatly to heart failure with preserved ejection fraction (HFpEF), the dominant form of heart failure. Few effective therapies exist to control metabolic alterations and lipid homeostasis. ObjectivesWe aimed to investigate the cardioprotective roles of AdipoRon, the adiponectin receptor agonist, in regulating lipid accumulation in the two-hit HFpEF model. MethodsHFpEF mouse model was induced using 60 % high-fat diet plus L-NAME drinking water. Then, AdipoRon (50 mg/kg) or vehicle were administered by gavage to the two-hit HFpEF mouse model once daily for 4 weeks. Cardiac function was evaluated using echocardiography, and Postmortem analysis included RNA-sequencing, untargeted metabolomics, transmission electron microscopy and molecular biology methods. ResultsOur study presents the pioneering evidence that AdipoR was downregulated and impaired fatty acid oxidation in the myocardia of HFpEF mice, which was associated with lipid metabolism as indicated by untargeted metabolomics. AdipoRon, orally active synthetic adiponectin receptor agonist, could upregulate AdipoR1/2 (independently of adiponectin) and reduce lipid droplet accumulation, and alleviate fibrosis to restore HFpEF phenotypes. Finally, AdipoRon primarily exerted its effects through restoring the balance of myocardial fatty acid intake, transport, and oxidation via the downstream AMPKα or PPARα signaling pathways. The protective effects of AdipoRon in HFpEF mice were reversed by compound C and GW6471, inhibitors of AMPKα and PPARα, respectively. ConclusionsAdipoRon ameliorated the HFpEF phenotype by promoting myocardial fatty acid oxidation, decreasing fatty acid transport, and inhibiting fibrosis via the upregulation of AdipoR and the activation of AdipoR1/AMPKα and AdipoR2/PPARα-related downstream pathways. These findings underscore the therapeutic potential of AdipoRon in HFpEF. Importantly, all these parameters get restored in the context of continued mechanical and metabolic stressors associated with HFpEF.

Single-Cell RNA Sequencing Reveals Metabolic Stress-Dependent Activation of Cardiac Macrophages in a Model of Dyslipidemia-Induced Diastolic Dysfunction.

Metabolic distress is often associated with heart failure with preserved ejection fraction (HFpEF) and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities with HFpEF. How metabolic changes affect myocardial inflammation in the context of HFpEF is not known. We found that ApoE knockout mice fed a Western diet recapitulate many features of HFpEF. Single-cell RNA sequencing was used for expression analysis of CD45+ cardiac cells to evaluate the involvement of inflammation in diastolic dysfunction. We focused bioinformatics analysis on macrophages, obtaining high-resolution identification of subsets of these cells in the heart, enabling us to study the outcomes of metabolic distress on the cardiac macrophage infiltrate and to identify a macrophage-to-cardiomyocyte regulatory axis. To test whether a clinically relevant sodium glucose cotransporter-2 inhibitor could ameliorate the cardiac immune infiltrate profile in our model, mice were randomized to receive the sodium glucose cotransporter-2 inhibitor dapagliflozin or vehicle for 8 weeks. ApoE knockout mice fed a Western diet presented with reduced diastolic function, reduced exercise tolerance, and increased pulmonary congestion associated with cardiac lipid overload and reduced polyunsaturated fatty acids. The main immune cell types infiltrating the heart included 4 subpopulations of resident and monocyte-derived macrophages, determining a proinflammatory profile exclusively in ApoE knockout- Western diet mice. Lipid overload had a direct effect on inflammatory gene activation in macrophages, mediated through endoplasmic reticulum stress pathways. Investigation of the macrophage-to-cardiomyocyte regulatory axis revealed the potential effects on cardiomyocytes of multiple inflammatory cytokines secreted by macrophages, affecting pathways such as hypertrophy, fibrosis, and autophagy. Finally, we describe an anti-inflammatory effect of sodium glucose cotransporter-2 inhibitor in this model. Using single-cell RNA sequencing , in a model of diastolic dysfunction driven by hyperlipidemia, we have determined the effects of metabolic distress on cardiac inflammatory cells, in particular on macrophages, and suggest sodium glucose cotransporter-2 inhibitors as potential therapeutic agents for the targeting of a specific phenotype of HFpEF.

Remodelling of cAMP dynamics within the SERCA2a microdomain in heart failure with preserved ejection fraction caused by obesity and type 2 diabetes.

Despite massive efforts, we remain far behind in our attempts to identify effective therapies to treat heart failure with preserved ejection fraction (HFpEF). Diastolic function is critically regulated by sarcoplasmic/endoplasmic reticulum (SR) calcium ATPase 2a (SERCA2a), which forms a functional cardiomyocyte (CM) microdomain where 3',5'-cyclic adenosine monophosphate (cAMP) produced upon β-adrenergic receptor (β-AR) stimulation leads to phospholamban (PLN) phosphorylation and facilitated Ca2+ re-uptake. To visualize real-time cAMP dynamics in the direct vicinity of SERCA2a in healthy and diseased myocytes, we generated a novel mouse model on the leprdb background that stably expresses the Epac1-PLN Förster resonance energy transfer biosensor. Mice homozygous for the leprdb mutation (db/db) developed obesity and type 2 diabetes and presented with a HFpEF phenotype, evident by mild left ventricular hypertrophy and elevated left atria filling pressures. Live cell imaging uncovered a substantial β2-AR subtype stimulated cAMP response within the PLN/SERCA2a microdomain of db/db but not healthy control (db/+) CMs, which was accompanied by increased PLN phosphorylation and accelerated calcium re-uptake. Importantly, db/db CMs also exhibited a desensitization of β1-AR stimulated cAMP pools within the PLN/SERCA2a microdomain, which was accompanied by a blunted lusitropic effect, suggesting that the increased β2-AR control is an intrinsic compensatory mechanism to maintain PLN/SERCA2a-mediated calcium dynamics and cardiac relaxation. Mechanistically, this was due to a local loss of cAMP-degrading phosphodiesterase 4 associated specifically with the PLN/SERCA2a complex. These newly identified alterations of cAMP dynamics at the subcellular level in HFpEF should provide mechanistic understanding of microdomain remodelling and pave the way towards new therapies.

Insights into the Interaction of Heart Failure with Preserved Ejection Fraction and Sleep-Disordered Breathing.

Heart failure with preserved ejection fraction (HFpEF) is emerging as a widespread disease with global socioeconomic impact. Patients with HFpEF show a dramatically increased morbidity and mortality, and, unfortunately, specific treatment options are limited. This is due to the various etiologies that promote HFpEF development. Indeed, cluster analyses with common HFpEF comorbidities revealed the existence of several HFpEF phenotypes. One especially frequent, yet underappreciated, comorbidity is sleep-disordered breathing (SDB), which is closely intertwined with the development and progression of the "obese HFpEF phenotype". The following review article aims to provide an overview of the common HFpEF etiologies and phenotypes, especially in the context of SDB. As general HFpEF therapies are often not successful, patient- and phenotype-individualized therapeutic strategies are warranted. Therefore, for the "obese HFpEF phenotype", a better understanding of the mechanistic parallels between both HFpEF and SDB is required, which may help to identify potential phenotype-individualized therapeutic strategies. Novel technologies like single-cell transcriptomics or CRISPR-Cas9 gene editing further broaden the groundwork for deeper insights into pathomechanisms and precision medicine.

Pathophysiological insights into machine-learning-based subphenotypes of acute heart failure with preserved ejection fraction: a biomarker analysis of PURSUIT-HFpEF registry

Abstract Background Our understanding of heart failure with preserved ejection fraction (HFpEF) has evolved from mere left ventricular diastolic dysfunction to a multiorgan disease. Purpose This study aimed to investigate the heterogeneous pathophysiology of the several phenotypes of HFpEF with multiple biomarker data. Methods This study is a post-hoc analysis of the PURSUIT-HFpEF study (N=1,231), an ongoing, prospective, multi-referral center, observational study of acute decompensated HFpEF [UMIN000021831]. In this registry, there is a pre-defined sub-cohort in which we perform multi-biomarker tests (N=212). We applied the machine-learning-based clustering model that we have previously established to the sub-cohort and classified them into 4 phenotypes: phenotype 1 labeled as "rhythm trouble" (n=69), phenotype 2 "ventricular-arterial uncoupling" (n=49), phenotype 3 "low output and systemic congestion" (n=41), and phenotype 4 "systemic failure" (n=53). Characteristics of biomarker tests in each phenotype were evaluated. Results The phenotype 2 characterized by hypertension and cardiac hypertrophy showed the highest value of N-terminal pro-brain natriuretic peptide (NT-proBNP), IL-16, high-sensitive C-reactive protein (CRP), tumor necrosis factor (TNF)-α, growth differentiation factor (GDF)-15, troponin T, and cystatin C, whereas the phenotype 1 presented the lowest value of these markers. The phenotype 3 showed the second highest value of GDF-15 and cystatin C. The phenotype 4 presented a low NT-proBNP value and a relatively high GDF-15. Conclusions The specific characteristics of biomarkers in each phenotype confirmed the validity of the machine learning model-based classification. The contribution of inflammation to the pathogenesis considerably differed in different HFpEF phenotypes. Systemic inflammation substantially contributes to the pathophysiology of the classical HFpEF phenotype with cardiac hypertrophy.

Transcriptional regulation of macrophage inflammation in the heart failure with preserved ejection fraction: a translational study

Abstract Background/Introduction Inflammatory response is a key player in heart failure with preserved ejection fraction (HFpEF) but the underlying mechanisms are poorly understood (1). Recent studies have shown a critical involvement of cardiac macrophage recruitment and activation in myocardial remodelling (2,3). Purpose here we sought to determine the role of macrophage inflammation in experimental and human HFpEF. Methods We employed a translational approach combining human and murine LV myocardial tissue, FACS analysis of cardiac immune cells, in vitro experiments in primary macrophages and cardiac cells as well as ex vivo functional analyses in LV tissues. Human LV myocardial samples were used to evaluate the pro-inflammatory activity of macrophages in the HFpEF myocardium. Induction of HFpEF in mice was done through a validated mouse model combining metabolic (high-fat diet) and hemodynamic stress (L-NAME). Cardiac function was investigated by high resolution ultrasound imaging (Vevo3100) and the LV myocardial samples were used to study the macrophage polarization and their inflammatory activity. Based on interrogation of available RNA-seq datasets –showing the transcriptional repressor NCOR1 as a relevant signature in macrophages during cardiac inflammation, we generated myeloid cell-specific NCOR1 knockout (Ncor1-KO) transgenic mice to investigate the in vivo effects of NCOR1 deletion on the HFpEF phenotype. In vitro experiments included RAW 264.7 cells polarization through a metabolic stress model via palmitic acid (PA) and the assessment of macrophage phenotype switching in the presence or the absence of NCOR1. To study the crosstalk of macrophages with the surrounding cardiac cells, cardiomyocytes (H9c2) and endothelial cells (HAECS) were exposed to conditioned media from cultured RAW. Afterwards, cellular function and the pro-inflammatory cytokine levels were investigated. Results The expression of macrophage markers in human LV specimens showed an increase in pro-inflammatory macrophages (M1) and a decrease in regulatory macrophages (M2) as compared to age-matched control mice. HFpEF mice showed increased expression of vascular adhesion molecules (ICAM1, ICAM2, E-selectin) and a significant recruitment of M1 macrophages to the myocardium. Of interest, cardiac function and myocardial inflammation (TNF-a, IL6, IL-1b) were significantly reduced in Ncor1-KO mice. In vitro assays showed that stimulation of macrophages with PA induced M1 type switch and increased NCOR1, TNF-a, IL-6, and IL-1b levels, whereas NCOR1 depletion prevented detrimental changes of macrophage secretome (Fig.2). Conclusion NCOR1 is a crucial co-regulator of immune response and macrophage inflammation in the heart. Our findings pave the way for mechanism-based therapies to prevent HFpEF development.

Abstract 15172: P21 Activated Kinase 2 Mediates Cardioprotection in Heart Failure With Preserved Ejection Fraction by Modulating Endoplasmic Reticulum Stress Response

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a type of heart failure characterised by diastolic dysfunction but normal systolic function. Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of HFpEF. Previous studies have reported that P21 activated kinase 2 (Pak2) confers cardioprotection against the endoplasmic reticulum stress response. Hypothesis: Pak2 protein can potentially alleviate the adverse effects of maladaptive ER stress in HFpEF. Methods: The HFpEF model was developed by feeding C57/BL6N male mice with a high-fat diet (HFD) and a constitutive nitric oxide inhibitor, L-NAME, in drinking water for 15 weeks. Cardiac function was assessed by echocardiography and hemodynamics. Heart and lung structure was detected by H&amp;E staining and Masson staining. Electron microscopy, immunoblotting, and RNA sequencing were used to investigate the ER structure and function. Cardiomyocyte-specific Pak2 knockout (Pak2 CKO ) mice and adeno-associated virus (AAV) 9 for Pak2 overexpression were used to investigate the role of Pak2 in the heart. Results: After 15 weeks of feeding, mice on the HFD+L-NAME diet developed an HFpEF phenotype, as indicated by cardiac hypertrophy, impaired diastolic function but preserved systolic function, and pulmonary remodelling. The ER structure and the IRE1/XBP1s pathway were impaired in the cardiomyocytes of HFD+L-NAME mice. Pak2CKO mice exhibited the HFpEF phenotype at 10 weeks. In addition, Pak2 overexpression prevented diastolic dysfunction after 15 weeks and preserved the activation of the IRE1/XBP1s pathway under stress conditions. Conclusions: HFD + L-NAME diet for 15 weeks recapitulated the features of HFpEF in mice. Pak2 plays a protective role in HFpEF progression by modulating the cardiomyocyte ER stress response through the IRE1/XBP1s signaling pathway.

Abstract 18614: Growth Hormone Releasing Hormone Agonists Reverse the Cardiometabolic Heart Failure With Preserved Ejection Fraction Phenotype via the Hypoxia-Inducible Factor 1 Alpha

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) treatment is limited due in large part to lack of understanding of the underlying mechanisms involved. Recently, we showed that growth hormone-releasing hormone-agonist (GHRH-agonist) has cardioprotective effects in a cardiometabolic HFpEF model; however, the mechanism of these therapeutic effects is still unclear. Here, we hypothesize that the anti-HFpEF properties of GHRH-receptor activation are mediated by hypoxia-induced factor (HIF)-1α pathway. Methods: Wild-type (WT) and HIF-1α cardiomyocyte knockout (HIF-1α CM KO) mice received a high-fat diet (HFD) plus the nitric oxide synthase inhibitor (L-NAME) for 9 weeks. After 5 weeks of HFD+L-NAME regimen, animals receive daily injections of GHRH-agonist, MR-356, or placebo during a 4-week period. Control animals received no HFD+L-NAME or MR-356 treatment. Echocardiography, blood pressure, glucose tolerance test, and hemodynamic measurements were evaluated. Results: The HFD+L-NAME diet produced a HFpEF phenotype, which was reversed in mice with intact HIF-1α treated with MR-356 (Figure 1 A-E). In contrast, following cardiac-specific deletion of HIF-1α CM , MR-356 no longer reversed (A) the elevated isovolumetric relaxation time (IVRT), (B) increased E/E’ ratio and (C) reduced global longitudinal strain (GLS). EF was preserved (D) while the slope of the end-diastolic pressure-volume relationship (EDPVR, E) was increased in the placebo group and restored by MR-356 in WT mice but not HIF-1α CM KO mice. Figure 1F shows representative pressure-volume loops from WT placebo, HIF-1α CM treated with placebo or MR-356. Conclusions: Our findings show that cardiac-specific HIF-1α deletion blocks cardioprotective effects of MR-356 suggesting that HIF-1α is necessary for its anti-HFpEF effects.

Abstract 15000: Renal Denervation Improves Cardiac Function and Mitigates Pathophysiological Changes in a Novel Murine Model of Heart Failure With Preserved Ejection Fraction

Introduction: Heart Failure with Preserved Ejection Fraction (HFpEF) is a multifaceted disease, intricately linked with sympathetic nervous system activation. Despite advancements, therapeutic options for HFpEF remain constrained, largely due to a dearth of fitting preclinical models. Renal denervation (RDN), an emerging intervention, holds potential in attenuating sympathetic activity and ameliorating HFpEF high-risk factors such as hypertension and insulin resistance. Aims: our study is designed to establish a multifactorial HFpEF mouse model and assess the therapeutic implications of RDN. Methods: Aged 12-month-old male C57BL/6N mice were exposed to a high-fat diet (60% calories from lard) and L-NAME (0.5 g/L in drinking water) over a 5-week period to generate a multi-hit HFpEF model. The efficacy of the model was assessed through a range of methods, encompassing echocardiography, histology, exercise exhaustion tests, serum NT-proBNP measurements, and intraperitoneal glucose tolerance tests. Upon successful model establishment, mice were randomized to receive either bilateral renal denervation or a sham operation. The subsequent impact of RDN on the aforementioned parameters was then evaluated. Results: In C57BL/6N mice, a cardiometabolic HFpEF phenotype was effectively induced through a multi-hit approach encompassing a high-fat diet, L-NAME administration, and aging. This potent combination triggered obesity and glucose intolerance, culminating in the emergence of characteristic HFpEF features such as cardiac hypertrophy, fibrosis, preserved fractional shortening with impaired deformation, atrial enlargement, lung congestion, hypertension and decreased exercise endurance. Intervention with RDN mitigated this cardiometabolic dysregulation and enhanced cardiac function, as demonstrated by reductions in cardiac hypertrophy, myocardial fibrosis, atrial weight, NT-proBNP levels, lung congestion, and improved exercise endurance. Conclusions: Our study suggests that RDN effectively mitigates cardiac function and structure in a multi-hit HFpEF mouse model, indicating its potential as a promising therapeutic strategy for HFpEF.

Semaglutide in Patients With Obesity and Heart Failure Across Mildly Reduced or Preserved Ejection Fraction.

Many therapies for heart failure (HF) have shown differential impact across the spectrum of left ventricular ejection fraction (LVEF). In this prespecified analysis, the authors assessed the effects of semaglutide across the baseline LVEF strata in patients with the obesity phenotype of HF with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) trial. STEP-HFpEF randomized 529 patients (263 semaglutide; 266 placebo). For this prespecified analysis, patients were categorized into 3 groups based on LVEF: 45% to 49% (n=85), 50% to 59% (n=215), and≥60% (n=229). At 52weeks, semaglutide improved the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (estimated treatment difference: EF [ejection fraction] 45%-49%: 5.0 points [95%CI:-2.7 to 12.8 points], EF 50%-59%: 9.8 points [95%CI: 5.0 to 14.6 points], and EF≥60%: 7.4 points [95%CI: 2.8 to 12.0 points]; P interaction=0.56) and body weight (EF: 45%-49%:-7.6 [95%CI:-10.7 to-4.4], EF 50%-59%:-10.6 [95%CI:-12.6 to-8.6] and EF≥60%:-11.9 [95%CI:-13.8 to-9.9]; P interaction=0.08), to a similar extent across LVEF categories. Likewise, LVEF did not influence the benefit of semaglutide on confirmatory secondary endpoints: 6-minute walk distance (P interaction=0.19), hierarchal composite endpoint (P interaction=0.43), and high-sensitivity C-reactive protein (P interaction=0.26); or exploratory endpoint of N-terminal pro-brain natriuretic peptide (Pinteraction=0.96). Semaglutide was well-tolerated across LVEF categories. In patients with HFpEF and obesity, semaglutide 2.4mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight to a similar extent across LVEF categories. These data support treatment with semaglutide in patients with the obesity phenotype of HFpEF regardless of LVEF. (Research Study to Investigate How Well Semaglutide Works in People Living With HeartFailure and Obesity [STEP-HFpEF]; NCT04788511).

Left Atrial Decompression With the HeartMate3 in Heart Failure With Preserved Ejection Fraction: Virtual Fitting and Hemodynamic Analysis.

Effective treatment of heart failure with preserved ejection fraction (HFpEF) remains an unmet medical need. Although left atrial decompression using mechanical circulatory support devices was previously suggested, the heterogeneous HFpEF population and the lack of tailored devices have prevented the translation into clinical practice. This study aimed to evaluate the feasibility of left atrial decompression in HFpEF patients with a HeartMate 3 (HM3, Abbott Inc, Chicago, USA) in silico and in vitro . Anatomic compatibility of the HM3 pump was assessed by virtual device implantation into the left atrium through the left atrial appendage (LAA) and left atrial posterior wall (LAPW) of 10 HFpEF patients. Further, the efficacy of left atrial decompression was investigated experimentally in a hybrid mock loop, replicating the hemodynamics of an HFpEF phenotype at rest and exercise conditions. Virtual implantation without substantial intersection with surrounding tissues was accomplished through the LAA in 90% and 100% through the LAPW. Hemodynamic analysis in resting conditions demonstrated normalization of left atrial pressures without backflow at a pump speed of around 5400 rpm, whereas a range of 6400-7400 rpm was required during exercise. Therefore, left atrial decompression with the HM3 may be feasible in terms of anatomic compatibility and hemodynamic efficacy.

Pathophysiological insights into machine learning-based subphenotypes of acute heart failure with preserved ejection fraction

ObjectiveThe heterogeneous pathophysiology of the diverse heart failure with preserved ejection fraction (HFpEF) phenotypes needs to be examined. We aim to assess differences in the biomarkers among the phenotypes of...

Abstract 079: Multi-omics Analyses Identify Galectin-1 As A Potential Novel Mediator Of Heart Failure With Preserved Ejection Fraction In Mice And Humans

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome where patients present with symptoms of volume overload despite having a normal systolic function. HFpEF is associated with elevation of inflammatory biomarkers, but the precise pathways leading to cardiac dysfunction is not known. In a deoxycorticosterone acetate (DOCA)-salt model of hypertension and HFpEF, we performed CITE-Seq analysis on total leukocytes isolated from the heart, which revealed significant differential gene expression primarily in the myeloid population. We took the top 20 genes that were differentially expressed between myeloid cells from DOCA-salt vs sham treated mice and performed a genetic analysis called PrediXcan in Vanderbilt’s DNA databank, BioVU. Of these, the gene encoding galectin 1, Lgals1 , had the lowest p-value (0.02) and highest beta coefficient (0.32) corresponding to an odds ratio for HFpEF of 1.38. The role of galectin-1 in heart failure is unknown. We hypothesized that Lgals1 exacerbates HFpEF. We found that siRNA knockdown of Lgals1 in bone marrow derived macrophages stimulated with lipoprotein saccharide and IFNγ; expressed significantly more inflammatory genes including IL-1α; (p&lt;0.0001), IL-6 (p=0.0219), iNOS (p=0.043), and TNF-α; (p=0.0031) using a 2-way ANOVA followed by Sidak’s multiple comparison test. Next, we explored the role of Lgals1 in the pathophysiology of HFpEF using Lgals1-/- mice. Surprisingly, Lgals1-/- mice did not show a significant difference in HFpEF phenotype (blood pressure, exercise tolerance, echocardiography, heart weight, or pulmonary congestion) after DOCA-salt treatment compared to littermate Lgals1+/+ controls in either males or females (p &gt; 0.05 using Student’s t-test, n=10-12). One hypothesis for this negative result is that Lgals1 is ubiquitously expressed, and a total body knockout may have compensatory mechanisms. We subsequently created Lgals1 floxed mice and ongoing studies will determine the effect of macrophage specific deletion of galectin-1 on HFpEF. In conclusion, while multi-omics approaches in mice and humans identify galectin-1 as a novel mediator of HFpEF, further studies are needed to determine its role as a potential therapeutic target.

Development of heart failure with preserved ejection fraction is independent of eosinophils in a preclinical model.

The increasing burden of heart failure with preserved ejection fraction (HFpEF) has become a global health problem. HFpEF is characterized by systematic inflammation, cardiac metabolic remodeling, and fibrosis. Eosinophils act as an essential but generally overlooked subgroup of white blood cells, which participate in cardiac fibrosis, as reported in several recent studies. Herein, we explored the role of eosinophils in a "two-hit" preclinical HFpEF model. The peripheral eosinophil counts were comparable between the normal chow and HFpEF mice. Deficiency of eosinophils failed to alter the phenotype of HFpEF. Conclusively, the development of HFpEF is independent of eosinophils in terms of the functional, biochemical, and histological results.

Animal models of heart failure with preserved ejection fraction (HFpEF): from metabolic pathobiology to drug discovery.

Heart failure (HF) with preserved ejection fraction (HFpEF) is currently a preeminent challenge for cardiovascular medicine. It has a poor prognosis, increasing mortality, and is escalating in prevalence worldwide. Despite accounting for over 50% of all HF patients, the mechanistic underpinnings driving HFpEF are poorly understood, thus impeding the discovery and development of mechanism-based therapies. HFpEF is a disease syndrome driven by diverse comorbidities, including hypertension, diabetes and obesity, pulmonary hypertension, aging, and atrial fibrillation. There is a lack of high-fidelity animal models that faithfully recapitulate the HFpEF phenotype, owing primarily to the disease heterogeneity, which has hampered our understanding of the complex pathophysiology of HFpEF. This review provides an updated overview of the currently available animal models of HFpEF and discusses their characteristics from the perspective of energy metabolism. Interventional strategies for efficiently utilizing energy substrates in preclinical HFpEF models are also discussed.

Dapagliflozin Attenuates Heart Failure With Preserved Ejection Fraction Remodeling and Dysfunction by Elevating β-Hydroxybutyrate-activated Citrate Synthase.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, accounting for 50% of all heart failure patients, and is associated with significant mortality. Sodium-glucose cotransporter subtype inhibitor (SGLT2i) is recommended in the AHA and ESC guidelines for the treatment of HFpEF, but the mechanism of SGLT2i to prevent and treat cardiac remodeling and dysfunction is currently unknown, hindering the understanding of the pathophysiology of HFpEF and the development of novel therapeutics. HFpEF model was induced by a high-fat diet (60% calories from lard) + N [w] -nitro- l -arginine methyl ester ( l -NAME-0.5 g/L) (2 Hit) in male Sprague Dawley rats to effectively recapture the myriad phenotype of HFpEF. This study's results showed that administration of dapagliflozin (DAPA, SGLT2 inhibitor) significantly limited the 2-Hit-induced cardiomyocyte hypertrophy, apoptosis, inflammation, oxidative stress, and fibrosis. It also improved cardiac diastolic and systolic dysfunction in a late-stage progression of HFpEF. Mechanistically, DAPA influences energy metabolism associated with fatty acid intake and mitochondrial dysfunction in HFpEF by increasing β-hydroxybutyric acid (β-OHB) levels, directing the activation of citrate synthase, reducing acetyl coenzyme A (acetyl-CoA) pools, modulating adenosine 5'-triphosphate production, and increasing the expression of mitochondrial oxidative phosphorylation system complexes I-V. In addition, following clinical DAPA therapy, the blood levels of β-OHB and citrate synthase increased and the levels of acetyl-CoA in the blood of HFpEF patients decreased. SGLT2i plays a beneficial role in the prevention and treatment of cardiac remodeling and dysfunction in HFpEF model by attenuating cardiometabolic dysregulation.

Abstract P2091: Histone Deacetylase 6 (HDAC6) Inhibitor Improves Stress-Induced Cardiomyocyte Restructuring in Heart Failure with Preserved Ejection Fraction (HFpEF) in a Multimodal Manner Based on Single Nucleus RNA-seq (snRNA-seq) Analyses

In the high fat diet (HFD)/L-NAME mouse model of HFpEF, Ranjbarvaziri et al from Tenaya Therapeutics have previously shown that pharmacological inhibition of HDAC6 improves functional and structural cardiac metrics, together with improved oxidative phosphorylation, improved contraction, and reduced fibrosis. Tissue level as well as single cell level transcriptional studies of control, HFD + L-NAME HFpEF, and HFD + L-NAME HFpEF treated with either HDAC6 inhibitor TYA-018 or SGLT2 inhibitor empagliflozin, demonstrated extensive reversal of disease phenotypes in mice treated with TYA-018. Based on snRNA-Seq analyses, we report characterization of cardiomyocyte (CM) subtypes in HFpEF that establish specific and substantial cell-cell interactions with their surrounding fibroblasts and endothelial cells. These interactions initiate CM-subtype-specific signaling cascades, leading to emergence of ‘stressed’ hypoxic CM and hypercontractile CM subtypes. We show that these cell types increase in the HFpEF disease state. The proportion of ‘stressed’ CMs at tissue level corresponds to the worsening cardiac functional measures, and their composing fractions in left ventricle tissue decline and normalize after TYA-018 treatment. These findings suggest HDAC6 inhibition may regulate undesirable HFpEF phenotype characteristics such as dysregulated metabolism, fibrosis and hypertrophy, and also present detailed cell-level evidence of HDAC6 inhibition’s favorable effects in metabolic syndrome.

Abstract P2085: Growth Hormone Releasing Hormone Agonist Counteracts The Cardiometabolic Heart Failure With Preserved Ejection Fraction Phenotype In Vivo Via The Hypoxia Inducible Factor 1 Alpha

Heart failure (HF) with preserved ejection fraction (HFpEF) treatment is limited due in large part to a lack of understanding of the underlying mechanisms. Recently, we showed that growth hormone-releasing hormone-agonist (GHRH-agonist) has cardioprotective effects in a murine model of cardiometabolic HFpEF; however, the mechanism of these therapeutic effects is still unclear. Here, we hypothesize that the therapeutic effects of GHRH-agonist in HFpEF are mediated by GHRH-receptor activation of the hypoxia-induced factor (HIF)-1α pathway. Methods: Wild-type (WT) and HIF-1α cardiomyocyte knockout (HIF-1α CM KO) mice were fed a high-fat diet (HFD) plus the nitric oxide synthase inhibitor (L-NAME) for 9 weeks. After 5 weeks of HFD+L-NAME regimen, animals received daily injections of placebo or the GHRH-agonist, MR-356, for the remaining 4-week period. Control animals received no HFD+L-NAME or MR-356 treatment. Echocardiography, blood pressure, glucose tolerance test, and hemodynamic measurements were evaluated. Results: The HFD+L-NAME diet produced a HFpEF phenotype, which was reversed in mice with intact HIF-1α treated with MR-356. In contrast, in mice with a cardiac-specific deletion of HIF-1α CM , MR-356 treatment failed to reverse the elevated relative wall thickness in diastole (RWTd), increased E/E’ ratio and reduced global longitudinal strain (GLS). The slope of end-diastolic pressure-volume relationship (EDPVR) was increased in the placebo group and restored by MR-356 in WT mice but not HIF-1α CM KO mice, while EF was preserved. Conclusion: Our findings suggest that HIF-1α is necessary for the cardioprotective and anti-HFpEF effects MR-356.