Characterization of a robust mouse model for heart failure with preserved ejection fraction
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE221502 | GEO | 2023/06/07
REPOSITORIES: GEO
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Project description:As patients with heart failure with preserved ejection fraction (HFpEF) present with multiple comorbidities, we hypothesized, that metabolic syndrome in aging animals could lead to the development of diastolic dysfunction and HFpEF. HFpEF is a common complex morbid syndrome for which there are currently little evidence-based therapies. Obesity-prone rats were exposed to high-fat diet and compared to obesity-resistant rats fed with standard chow. Phenotyping of metabolic syndrome, associated with echocardiographic and cardiac hemodynamic measurements, was performed after 4 and 12 months. Blood and myocardial tissue sampling were performed for pathobiological evaluation. High-fat diet in obesity-prone rats elicited metabolic syndrome, characterized by increased body and abdominal fat weights, glucose intolerance and hyperlipidemia, as well as increased left ventricular (LV) systolic pressure (after 12 months). This was associated with LV diastolic dysfunction (assessed by increased LV end-diastolic pressure) and pulmonary hypertension (assessed by increased right ventricular systolic pressure). Echocardiography revealed significant concentric LV hypertrophy, while LV ejection fraction was preserved. LV remodeling was associated with cardiomyocyte hypertrophy, as well as myocardial and perivascular fibrosis. Circulating levels of soluble ST2 markedly increased in rats with HFpEF, while plasma NT-proBNP levels decreased. RNA-sequencing analysis identified clusters of genes implicated in fatty acid metabolism and calcium-dependent contraction as upregulated pathways in the myocardium of rats with HFpEF. High-fat diet during 12 months in obesity-prone rats led to the development of a relevant preclinical model of HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.
2022-02-02 | GSE189190 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats) or cardiometabolic syndrome (in ZSF1 obese rats). Mechanistically, this effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics, as evidenced by cardiac trasncriptome and metabolome analyses. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium ATPase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans.
2021-02-11 | GSE163665 | GEO
Project description:Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic cardiomyocyte-fibroblast communication can be corrected, constituting a novel therapeutic strategy for HFpEF.
2024-11-17 | GSE240403 | GEO
Project description:Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic cardiomyocyte-fibroblast communication can be corrected, constituting a novel therapeutic strategy for HFpEF.
2024-11-17 | GSE240400 | GEO
Project description:Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic cardiomyocyte-fibroblast communication can be corrected, constituting a novel therapeutic strategy for HFpEF.
2024-11-17 | GSE240401 | GEO
Project description:BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of heart failure patients. Clinically, HFpEF prevalence show age and gender biases. Although the majority of HFpEF patients are elderly, there is an emergence of young HFpEF patients. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. METHODS AND RESULTS: HFpEF dietary regimen (HFD + L-NAME) was used to induce HFpEF in wildtype and telomerase RNA knockout mice (mTRG2 and mTRG3), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in mTRG2 (at 6-weeks) and mTRG3 (at 4-weeks) compared to wildtype (8-weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial-specific p53 knockout animals, we demonstrate that p53 is necessary for the development of HFpEF. CONCLUSIONS: Here we demonstrate that p53 activation is critical for the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 prevents HFpEF upon HFD + L-NAME challenge.
2022-07-06 | GSE195482 | GEO
Project description:Aims: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like Glucagon Like Peptide Receptor Agonist (GLP-1RA) and Sodium Glucose Transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide and a SGLT2i dapagliflozin. Methods&Results: Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high fat diet (HFD) for 12 weeks. After 8 weeks HFD, Angiotensin-II (ANGII), was administered for 4 weeks via osmotic mini-pumps. HFD+ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling and metabolic dysregulation with inflammation. The multiple-hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement lung congestion, and elevated blood pressures. Treatment with liraglutide attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapagliflozin treatment improved glucose handling, but had mild effects on the HFpEF phenotype. Conclusions: We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for treatment of HFpEF.
2020-09-16 | GSE153923 | GEO
Project description:Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 (Angptl4) next to basement membrane compounds, such as collagen IV (Col4a1). Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ with estimated fibroblast target genes including Col4a1 and Angptl4. Treatment with recombinant ANGPTL4 ameliorated the murine HFpEF phenotype and diastolic dysfunction by reducing collagen IV deposition from fibroblasts in vivo and in vitro. In line, ANGPTL4, was elevated in plasma samples of HFpEF patients and particularly high levels associated with a preserved global longitudinal strain. Taken together, our study provides a comprehensive characterization of molecular fibroblast activation patterns in murine HFpEF, as well as the identification of Angiopoietin-like 4 as central mechanistic regulator with protective effects.
2024-08-28 | GSE275031 | GEO
Project description:Heart failure affects 2–3% of adult Western population. Prevalence of heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) increases. Studies suggest HFpEF patients to have altered myocardial structure and functional changes such as incomplete relaxation and increased cardiac stiffness. We hypothesised that patients undergoing elective coronary bypass surgery (CABG) with HFpEF characteristics will show distinctive gene expression compared to patients with normal LV physiology. Myocardial biopsies for mRNA expression analysis were obtained from sixteen patients with LV ejection fraction ≥ 45%. Five out of 16 patients (31%) had echocardiographic characteristics and increased NTproBNP levels indicative of HFpEF and this group was used as HFpEF proxy, while 11 patients had Normal LV physiology. Utilising principal component analysis, the gene expression data clustered into two groups, corresponding to HFpEF proxy and Normal physiology, and 743 differentially expressed genes were identified. The associated top biological functions were cardiac muscle contraction, oxidative phosphorylation, cellular remodelling and matrix organisation. Our results also indicate that upstream regulatory events, including inhibition of transcription factors STAT4, SRF and TP53, and activation of transcription repressors HEY2 and KDM5A, could provide explanatory mechanisms to observed gene expression differences and ultimately cardiac dysfunction in the HFpEF proxy group. <br> Sequencing data from clinical patients fall under GDPR regulations of sharing of personal data and will be made available through EGA-SE.
2019-03-02 | E-MTAB-7454 | biostudies-arrayexpress
Project description:Phosphorylation of sarcomeric proteins has been implicated in heart failure with preserved ejection fraction (HFpEF); such changes may contribute to diastolic dysfunction by altering contractility, cardiac stiffness, Ca2+-sensitivity and mechanosensing. Treatment with cardiosphere-derived cells (CDCs) restores normal diastolic function, attenuates fibrosis and inflammation, and improves survival in a rat HFpEF model. Here, we quantified the phosphorylation changes that underlie HFpEF and those reversed by CDC therapy, with a focus on the sarcomeric subproteome.
2022-04-23 | PXD025555 | Pride