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Project description:Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates the efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6's role in HFpEF due to their shared mechanisms of inflammation and metabolism. Here, we show that inhibiting HDAC6 with TYA-018 effectively reverses established heart failure and its associated symptoms in male HFpEF mouse models. Additionally, in male mice lacking Hdac6 gene, HFpEF progression is delayed and they are resistant to TYA-018's effects. The efficacy of TYA-018 is comparable to a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the combination shows enhanced effects. Mechanistically, TYA-018 restores gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. Furthermore, TYA-018 also inhibits activation of human cardiac fibroblasts and enhances mitochondrial respiratory capacity in cardiomyocytes. In this work, our findings show that HDAC6 impacts on heart pathophysiology and is a promising target for HFpEF treatment.
| S-EPMC10897156 | biostudies-literature
Project description:Targeting HDAC6 to treat heart failure with preserved ejection fraction (HFpEF)
| PRJNA1048993 | ENA
Project description: Not available
| S-EPMC11464698 | biostudies-literature
Project description:Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates the efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6’s role in HFpEF due to their shared mechanisms of inflammation and metabolism. Here, we show that inhibiting HDAC6 with TYA-018 effectively reverses established heart failure and its associated symptoms in HFpEF mouse models. Additionally, in mice lacking the Hdac6 gene, HFpEF progression is delayed and they are resistant to TYA-018’s effects. The efficacy of TYA-018 is comparable to a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and their combination shows enhanced effects. Mechanistically, TYA-018 restores gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. Furthermore, TYA-018 also inhibits activation of human cardiac fibroblasts and enhances mitochondrial respiratory capacity in cardiomyocytes. In this work, our findings show that HDAC6 impacts heart pathophysiology and is a promising target for HFpEF treatment.
2024-01-17 | PXD048363 | Pride
Project description:Heart failure with preserved ejection fraction (HFpEF) is a major unmet medical need that is characterized by the presence of multiple cardiovascular and non-cardiovascular comorbidities. Foremost among these comorbidities are obesity and diabetes, which are not only risk factors for the development of HFpEF, but worsen symptoms and outcome. Coronary microvascular inflammation with endothelial dysfunction is a common denominator among HFpEF, obesity, and diabetes that likely explains at least in part the etiology of HFpEF and its synergistic relationship with obesity and diabetes. Thus, pharmacological strategies to supplement nitric oxide and subsequent cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling may have therapeutic promise. Other potential approaches include exercise and lifestyle modifications, as well as targeting endothelial cell mineralocorticoid receptors, non-coding RNAs, sodium glucose transporter 2 inhibitors, and enhancers of natriuretic peptide protective NO-independent cGMP-initiated and alternative signaling, such as LCZ696 and phosphodiesterase-9 inhibitors. Additionally, understanding the role of adipokines in HFpEF may lead to new treatments. Identifying novel drug targets based on the shared underlying microvascular disease process may improve the quality of life and lifespan of those afflicted with both HFpEF and obesity or diabetes, or even prevent its occurrence.
| S-EPMC5512012 | biostudies-other
Project description:Although the prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, evidence-based therapies for HFpEF remain limited, likely due to an incomplete understanding of this disease. This study sought to identify the cardiac-specific features of protein and phosphoprotein changes in a murine model of HFpEF using mass spectrometry. HFpEF mice demonstrated moderate hypertension, left ventricle (LV) hypertrophy, lung congestion and diastolic dysfunction. Proteomics analysis of the LV tissue showed that 897 proteins were differentially expressed between HFpEF and Sham mice. We observed abundant changes in sarcomeric proteins, mitochondrial-related proteins, and NAD-dependent protein deacetylase sirtuin-3 (SIRT3). Upregulated pathways by GSEA analysis were related to immune modulation and muscle contraction, while downregulated pathways were predominantly related to mitochondrial metabolism. Western blot analysis validated SIRT3 downregulated cardiac expression in HFpEF vs. Sham (0.8 ± 0.0 vs. 1.0 ± 0.0; P < 0.001). Phosphoproteomics analysis showed that 72 phosphosites were differentially regulated between HFpEF and Sham LV. Aberrant phosphorylation patterns mostly occurred in sarcomere proteins and nuclear-localized proteins associated with contractile dysfunction and cardiac hypertrophy. Seven aberrant phosphosites were observed at the z-disk binding region of titin. Additional agarose gel analysis showed that while total titin cardiac expression remained unaltered, its stiffer N2B isoform was significantly increased in HFpEF vs. Sham (0.144 ± 0.01 vs. 0.127 ± 0.01; P < 0.05). In summary, this study demonstrates marked changes in proteins related to mitochondrial metabolism and the cardiac contractile apparatus in HFpEF. We propose that SIRT3 may play a role in perpetuating these changes and may be a target for drug development in HFpEF.
| S-EPMC9452734 | biostudies-literature
Project description:Diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF) is characterised by increased left ventricular stiffness and impaired active relaxation. Underpinning pathomechanisms are incompletely understood. Cardiac hypertrophy and end stage heart disease are associated with alterations in the cardiac microtubule (MT) network. Increased amounts and modifications of α-tubulin associate with myocardial stiffness. MT alterations in HFpEF have not been analysed yet. Using ZSF1 obese rats (O-ZSF1), a validated HFpEF model, we characterised MT-modifying enzymes, quantity and tyrosination/detyrosination pattern of α-tubulin at 20 and 32 weeks of age. In the left ventricle of O-ZSF1, α-tubulin concentration (20 weeks: 1.5-fold, p = 0.019; 32 weeks: 1.7-fold, p = 0.042) and detyrosination levels (20 weeks: 1.4-fold, p = 0.013; 32 weeks: 1.3-fold, p = 0.074) were increased compared to lean ZSF1 rats. Tyrosination/α-tubulin ratio was lower in O-ZSF1 (20 weeks: 0.8-fold, p = 0.020; 32 weeks: 0.7-fold, p = 0.052). Expression of α-tubulin modifying enzymes was comparable. These results reveal new alterations in the left ventricle in HFpEF that are detectable during early (20 weeks) and late (32 weeks) progression. We suppose that these alterations contribute to diastolic dysfunction in HFpEF and that reestablishment of MT homeostasis might represent a new target for pharmacological interventions.
| S-EPMC9492725 | biostudies-literature
Project description:Heart failure with preserved ejection fraction (HFpEF) is a heterogenous clinical syndrome characterized by diastolic dysfunction, concentric cardiac left ventricular (LV) hypertrophy, and myocardial fibrosis with preserved systolic function. However, the underlying mechanisms of HFpEF are not clear. We hypothesize that an enhanced central sympathetic drive is sufficient to induce LV dysfunction and HFpEF in rats. Male Sprague-Dawley rats were subjected to central infusion of either saline controls (saline) or angiotensin II (Ang II, 20 ng/min, i.c.v) via osmotic mini-pumps for 14 days to elicit enhanced sympathetic drive. Echocardiography and invasive cardiac catheterization were used to measure systolic and diastolic functions. Mean arterial pressure, heart rate, left ventricular end-diastolic pressure (LVEDP), and ± dP/dt changes in responses to isoproterenol (0.5 μg/kg, iv) were measured. Central infusion of Ang II resulted in increased sympatho-excitation with a consequent increase in blood pressure. Although the ejection fraction was comparable between the groups, there was a decrease in the E/A ratio (saline: 1.5 ± 0.2 vs Ang II: 1.2 ± 0.1). LVEDP was significantly increased in the Ang II-treated group (saline: 1.8 ± 0.2 vs Ang II: 4.6 ± 0.5). The increase in +dP/dt to isoproterenol was not significantly different between the groups, but the response in -dP/dt was significantly lower in Ang II-infused rats (saline: 11,765 ± 708 mmHg/s vs Ang II: 8,581 ± 661). Ang II-infused rats demonstrated an increased heart to body weight ratio, cardiomyocyte hypertrophy, and fibrosis. There were elevated levels of atrial natriuretic peptide and interleukin-6 in the Ang II-infused group. In conclusion, central infusion of Ang II in rats induces sympatho-excitation with concurrent diastolic dysfunction, pathological cardiac concentric hypertrophy, and cardiac fibrosis. This novel model of centrally mediated sympatho-excitation demonstrates characteristic diastolic dysfunction in rats, representing a potentially useful preclinical murine model of HFpEF to investigate various altered underlying mechanisms during HFpEF in future studies.
| S-EPMC10758618 | biostudies-literature
Project description:Background and aimsPatients with heart failure with preserved ejection fraction (HFpEF) tend to have low resting and exercise heart rates. Phosphodiesterase-3 (PDE-3) inhibitors improve heart rates, haemodynamics and symptoms in patients with HFpEF. Cilostazol is an oral PDE-3 inhibitor used in peripheral artery disease. This study thought to evaluate the short-term effects of cilostazol on health status, N-terminal brain natriuretic peptide (NT-proBNP) levels and mechanisms of action.MethodsThe effect of cilostazol was evaluated in 23 patients with HFpEF in a randomized placebo controlled multiple crossover trial (CLIP-HFpEF). Participants received placebo or cilostazol for 1 week followed by three crossovers to the alternate assignment at weeks 2, 3 and 4. The primary endpoint was the Kansas City Cardiomyopathy Questionnaire (KCCQ-12) overall summary score obtained at the end of each treatment period. NT-proBNP was the secondary endpoint. In an exploratory mechanistic analysis, pulmonary artery (PA) pressures and heart rates were followed amongst the five participants with implanted pressure monitors.ResultsCilostazol improved the KCCQ score by 4.8 points (95% confidence interval, 2.0-7.7, P = 0.003). NT-proBNP levels were 448 (154-1056) pg/mL on placebo and 375 (68-974) pg/mL on cilostazol (P = 0.006). In patients with PA pressure monitors, diastolic pressure was 20.5 (18.7-23.0) mmHg on placebo and 18.0 (17.0-20.0) mmHg on cilostazol, an effect linked to higher heart rates (P < 0.001).ConclusionsAmongst patients with HFpEF, short-term treatment with cilostazol leads to improvements in health status and NT-proBNP when compared with placebo. These effects are likely conveyed by a heart rate-dependent reduction in cardiac filling pressures.Trial registrationClinicalTrials.gov Identifier: NCT05126836.
| S-EPMC11911562 | biostudies-literature
Project description:ObjectivesTo develop and compare prediction models for 30-day and 1-year mortality in Heart failure with preserved ejection fraction (HFpEF) using EHR data, utilizing both traditional and machine learning (ML) techniques.BackgroundHFpEF represents 1 in 2 heart failure patients. Predictive models in HFpEF, specifically those derived from electronic health record (EHR) data, are less established.MethodsUsing MIMIC-IV EHR data from 2008-2019, patients aged ≥ 18 years admitted with a primary diagnosis of HFpEF were identified using ICD-9 and 10 codes. Demographics, vital signs, prior diagnoses, and lab data were extracted. Data was partitioned into 80% training, 20% test sets. Prediction models from seven model classes (Support Vector Classifier (SVC), Logistic Regression, Lasso Regression, Elastic Net, Random Forest, Histogram-based Gradient Boosting Classifier (HGBC), and XGBoost) were developed using various imputation and oversampling techniques with 5-fold cross-validation. Model performance was compared using several metrics, and individual feature importance assessed using SHapley Additive exPlanations (SHAP) analysis.ResultsAmong 3910 hospitalizations for HFpEF, 30-day mortality was 6.3%, and 1-year mortality was 29.2%. Logistic regression performed well for 30-day mortality (Area Under the Receiver operating characteristic curve (AUC) 0.83), whereas Random Forest (AUC 0.79) and HGBC (AUC 0.78) for 1-year mortality. Age and NT-proBNP were the strongest predictors in SHAP analyses for both outcomes.ConclusionModels derived from EHR data can predict mortality after HFpEF hospitalization with comparable performance to models derived from registry or trial data, highlighting the potential for clinical implementation.
| S-EPMC11527066 | biostudies-literature