Cardiopulmonary Phenotyping of Sex-Based Differences in a Feline Model of HFpEF
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ABSTRACT:
ORGANISM(S): Felis catus
PROVIDER: GSE184328 | GEO | 2022/09/16
REPOSITORIES: GEO
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Project description:Heart Failure with preserved Ejection Fraction (HFpEF) is a major global health problem but there are no effective therapies. The aim of this study was to assess the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian (feline) pressure overload model with HFpEF features. Male domestic short hair cats (n=26, aged 2mo), underwent either a sham procedure (n=5) or aortic constriction (n=21) using a pre-shaped band, resulting in slow-progressive pressure overload during subsequent growth. Two-months post-banding, banded cats were treated daily with either 10mg/kg suberoylanilide hydroxamic acid (b+SAHA) (n=8), an FDA approved pan-HDAC inhibitor, or vehicle (b+veh) (n=8) for 2 months. Echocardiography at 4-months post-banding revealed that b+SAHA animals had a significant reduction in left ventricular hypertrophy (LVH) and LA size vs b+veh animals. Invasively measured left ventricular end-diastolic pressure (LVEDP) and mean pulmonary arterial pressure (mPAP) were significantly elevated in b+veh and significantly reduced by b+SAHA. SAHA speeded ex-vivo myofibril relaxation independent of LVH and this effect correlated with in-vivo indices of LV relaxation. Furthermore, SAHA preserved lung structure, improved lung compliance and oxygenation, reflected by a decrease in alveolar-capillary wall thickness, alveolar-arterial oxygen gradient (A-aDO2), and intrapulmonary shunt. SAHA also reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar-capillary stress failure. Acetylation proteomics revealed that SAHA altered protein acetylation in cat hearts, including histones, many mitochondrial metabolic enzymes involved in electron transport chain, TCA cycle, malate aspartate shuttle and beta oxidation, as well as cytoskeletal proteins important for muscle function. These results suggest that acetylation defects in hypertrophic stress states can be reversed by HDAC inhibitors and may be useful to improve cardiac structure and function in HFpEF patients.
2021-09-08 | PXD013663 | Pride
Project description:In this study the authors used systems biology to define progressive changes in metabolism and transcription in a large animal model of heart failure with preserved ejection fraction (HFpEF). Transcriptomic analysis of cardiac tissue, 1 month post-banding, revealed loss of electron transport chain components, and this was supported by changes in metabolism and mitochondrial function, altogether signifying alterations in oxidative metabolism. Established HFpEF, 4 months post-banding, resulted in changes in intermediary metabolism with normalized mitochondrial function. Mitochondrial dysfunction and energetic deficiencies were noted in skeletal muscle at early and late phases of disease, suggesting cardiac-derived signaling contributes to peripheral tissue maladaptation in HFpEF. Collectively, these results provide insights into the cellular biology underlying HFpEF progression.
2021-09-01 | GSE181184 | 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: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:Heart failure (HF) impacts 2-3% of adults in the West, with prevalence rising with age. This condition, leading to high mortality and morbidity, increasingly involves HF with preserved left ventricular (LV) ejection fraction (HFpEF) in the aging population, having a similar stable prognosis as HF with reduced LVEF (HFrEF). However, HFpEF lacks many evidence-based therapies, partly due to its distinct pathophysiology compared to HFrEF. Molecularly, heart failure shows distinct gene expression changes, indicative of varying diseases. Prior research, including our early report from the CABG-PREFERS study, shows gene expression differences in HFpEF and normal hearts, although studies are limited. Both HFpEF and HFrEF patients exhibit altered LV myocardial structure and function, often affecting the right ventricle (RV) secondarily. In the CABG-PREFERS sub-study, part of the PREFERS programme, we classified patients by LVEF, structural abnormalities, diastolic dysfunction, and NT-proBNP levels into HFpEF physiology, HFrEF physiology, and normal LV function groups. Our hypothesis suggests gene expression and transcriptomic variations between LV and RV, and between HFpEF, HFrEF, and normal LV function, providing insights into different HF phenotypes and guiding future therapies.
2024-02-28 | E-MTAB-13553 | biostudies-arrayexpress
Project description:Heart failure (HF) with preserved ejection fraction (HFpEF) is rising, whose morbidity, mortality and healthcare costs are similar to HF with reduced ejection fraction (HFrEF). Although substantial molecular pathways lead to the changes in organ and tissue levels, there are still lack of successful treatments for HFpEF given the complexity molecular networks remaining unknown. Here we report that the significantly changed genes of HFpEF rats associates positively with inflammatory processes and immune responses while negatively with calcium ion transport into cytosol. GSEA analysis shows several KEGG pathways are significantly enriched in HFpEF rats including p53 signaling pathway, Toll like receptor signaling pathway and so on. Our study provides new insights into HFpEF pathogenesis and a new therapeutic against HFpEF.
2019-02-05 | GSE126062 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) is a complex, heterogeneous disease involving multiple cellular lineages and mechanisms. Here, we aimed to characterize the cellular heterogeneity and potential mechanisms of HFpEF at single-cell resolution.
2023-09-01 | GSE236585 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) is a complex, heterogeneous disease involving multiple cellular lineages and mechanisms. Here, we aimed to characterize the cellular heterogeneity and potential mechanisms of HFpEF at single-cell resolution.
2023-09-01 | GSE236584 | GEO
Project description:Background: Heart failure with preserved ejection fraction (HFpEF) has become a major public health problem with a morbidity and mortality similar to heart failure with reduced ejection fraction (HFrEF). Recently, it has been proved epicardial adipose tissue (EAT) played an important role in the pathogenesis of HFpEF, however the underlying mechanisms are not yet fully elucidated. This study attempted to describe comprehensive proteomic analysis of EAT in HFpEF patients and non-HF patients as controls, and identify local candidate molecules characterizing EAT in HFpEF patients. EAT samples were collected from patients undergoing heart surgery in two groups. Proteins was identified in liquid chromatography-tandem mass spectrometry (LC-MS/MS) experiments. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was conducted and protein-protein interaction network was constructed with Cytoscape software. A total of 2416 proteins were identified in LC-MS/MS experiments and 2349 proteins were quantified. Amongst them, totally 96 significant proteins (including 71 upregulated proteins in abundance and 25 downregulated proteins) were differently expressed between HFpEF and non-HF group. GO-enrichment, KEGG pathway analysis and interaction network construction showed these differentially expressed proteins were predominantly involved in HFpEF-related processes including lipid metabolic disorder, inflammation and mitochondrial dysfunction including FABP5, CD36, CFB, ADSL, POSTN, TRAP1 et al., which might contribute to the pathogenesis of HFpEF. In conclusion, this is the first demonstration to describe the parts of EAT proteome in HFpEF patients. Our findings provide a comprehensive understanding for linking EAT to the pathogenesis of HFpEF, which may offer new insights into the treatment of HFpEF targeting on EAT.
2023-01-30 | PXD028158 | Pride
Project description:PBMCs were isolated from normal CKD patient, end-stage renal disease patients without HF (ESRD), ESRD patients with HFpEF, and heart failure with reduced ejection fraction (HFrEF). The difference expression genes (DEGs) in PBMCs among different groups were compared using microarray.
2023-12-30 | E-MTAB-13612 | biostudies-arrayexpress