ABSTRACT: Background: Heart failure with reduced ejection fraction (HFrEF) constitutes half of all heart failure cases and remains a major clinical and public health problem.
Project description:Females with heart failure and reduced ejection fraction (HFrEF) have greater physical limitations and a lower quality of life compared to males, however, the role of non-cardiac mechanisms remains poorly resolved. We hypothesized that differences in skeletal muscle pathology between males and females with HFrEF may explain clinical heterogeneity. In this study, we performed an unbiased RNA sequencing of 5 male controls, 5 female controls, 6 male HFrEF patients, and 5 female HFrEF patients.
Project description:Background: Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all heart failure but has few effective therapies. Recent human myocardial transcriptomics and metabolomics have revealed major differences between HFpEF, HF with reduced EF (HFrEF), and controls. How this translates at the protein level is currently unknown. Methods: Myocardial tissue from patients with HFpEF and non-failing donor controls was analyzed by data-dependent (DDA, n=10 HFpEF, n=9 controls) and data-independent (DIA, n=44 HFpEF, n=5 controls) mass spectrometry-based proteomics. Previously reported myocardial proteomic data from end-stage HFrEF and controls were also used. Differential protein expression analysis, machine learning and pathway enrichment were integrated with clinical characteristics and myocardial transcriptomics. Results: DDA-MS proteomics identified 88 significantly upregulated and 248 down-regulated proteins in HFpEF vs controls, out of 1996 identified proteins. Principal component analysis of DDA-MS proteomics found HFpEF was separated into 2 sub-groups: one being similar to controls the other quite disparate. Top proteins contributing to the separation of HFpEF subgroups were enriched in actin/myosin binding, regulation of DNA replication/repair, transcription, and translation. Downregulated proteins in HFpEF vs controls were enriched in pathways related to ribosome structure, transmembrane transporters, metabolic enzymes, and oxidative phosphorylation (OxPhos) proteins. Enriched pathways for proteins upregulated in HFpEF related to actin and phospholipid binding, growth factor signaling, kinase regulation, and glycolysis. Ingenuity pathway analysis predicted downregulation of protein translation, mitochondrial function, and glucose and fat metabolism in HFpEF. OxPhos gene (increased) versus protein (decreased) expression was discordant in HFpEF. The second DIA proteomic analysis also yielded two HFpEF sub-groups; the one most different from controls also having reduced OxPhos and protein translation pathways. A higher proportion of these patients also had severe obesity. Conclusions: Integrative proteomics, transcriptomics, and pathway analysis supports a translational defect particularly involving mitochondrial, ribosomal and protein translation proteins in HFpEF. Patients with more distinct proteomic signatures from control were more often very obese. The results support therapeutic efforts targeting metabolism, mitochondrial function, and protein translation in this subgroup.
Project description:Background: Heart failure with preserved ejection fraction (HFpEF) constitutes more than half of all heart failure but has few effective therapies. Recent human myocardial transcriptomics and metabolomics have revealed major differences between HFpEF, HF with reduced EF (HFrEF), and controls. How this translates at the protein level is currently unknown. Methods: Myocardial tissue from patients with HFpEF and non-failing donor controls was analyzed by data-dependent (DDA, n=10 HFpEF, n=9 controls) and data-independent (DIA, n=44 HFpEF, n=5 controls) mass spectrometry-based proteomics. Previously reported myocardial proteomic data from end-stage HFrEF and controls were also used. Differential protein expression analysis, machine learning and pathway enrichment were integrated with clinical characteristics and myocardial transcriptomics. Results: DDA-MS proteomics identified 88 significantly upregulated and 248 down-regulated proteins in HFpEF vs controls, out of 1996 identified proteins. Principal component analysis of DDA-MS proteomics found HFpEF was separated into 2 sub-groups: one being similar to controls the other quite disparate. Top proteins contributing to the separation of HFpEF subgroups were enriched in actin/myosin binding, regulation of DNA replication/repair, transcription, and translation. Downregulated proteins in HFpEF vs controls were enriched in pathways related to ribosome structure, transmembrane transporters, metabolic enzymes, and oxidative phosphorylation (OxPhos) proteins. Enriched pathways for proteins upregulated in HFpEF related to actin and phospholipid binding, growth factor signaling, kinase regulation, and glycolysis. Ingenuity pathway analysis predicted downregulation of protein translation, mitochondrial function, and glucose and fat metabolism in HFpEF. OxPhos gene (increased) versus protein (decreased) expression was discordant in HFpEF. The second DIA proteomic analysis also yielded two HFpEF sub-groups; the one most different from controls also having reduced OxPhos and protein translation pathways. A higher proportion of these patients also had severe obesity. Conclusions: Integrative proteomics, transcriptomics, and pathway analysis supports a translational defect particularly involving mitochondrial, ribosomal and protein translation proteins in HFpEF. Patients with more distinct proteomic signatures from control were more often very obese. The results support therapeutic efforts targeting metabolism, mitochondrial function, and protein translation in this subgroup.
Project description:In this study, we compared the expression profiles of circulating miRNAs in blood samples from controls and patients with heart ailment. Subject with no past history of heart failure/disease are considered as controls. The patients were classified according to the percentage of left ventricular ejection fraction. Patients were grouped as heart failure with reduced (hfREF) and preserved (hfPEF) left ventricular ejection fraction. Employing miRNA microarray, we identified 'signature miRNAs' in peripheral blood samples that distinguished Heart failure from the non-heart failure controls, as well as those of hfREF and hfPEF groups.
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.
Project description:Heart failure with reduced ejection fraction (HFrEF) constitutes 50% of HF hospitalizations and is characterized by high rates of mortality. To explore the underlying mechanisms of HFrEF etiology and progression, we studied the molecular and cellular differences in four chambers of non-failing (NF, n=10) and HFrEF (n=12) human hearts. This study contributes to a growing body of knowledge describing chamber-specific heart transcriptomics and revealed genes and pathways that are associated with heart failure pathophysiology, which may aid in therapeutic target discovery.
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.
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.
Project description:This research aimed to identify protein biomarkers of right ventricular dysfunction in patients with advanced heart failure with reduced ejection fraction (HFrEF). Samples of myocardium from both, right and left ventricles (RV, LV) were obtained from 10 HFrEF patients with right ventricular dysfunction (RVD), 10 HFrEF patients without RVD (noRVD) undergoing heart transplantation, and 10 non-failing unused donor hearts (Control). Tissue samples were homogenized and extracted using mild Triton X-100 detergent and processed by SP3 extraction to remove the detergent prior the analysis, (LFQ) proteomic analysis identified a total of 4 032 proteins in the left ventricle and 3 788 proteins in the right ventricle.
Project description:Heart failure with reduced ejection fraction (HFrEF) remains a major therapeutic challenge. Bcl2-associated transcription factor 1 (Bclaf1) is implicated in RNA splicing and cardiac disease, but its role in HFrEF pathogenesis is unknown. Here, we demonstrate that Bclaf1 expression is elevated in human HFrEF myocardium and in murine pressure-overload models. Cardiac-specific Bclaf1 overexpression drives pathological hypertrophy and systolic dysfunction, whereas its genetic knockout or AAV9-mediated knockdown attenuates these phenotypes. Mechanistically, Bclaf1 interacts with the splicing factor Srsf2 to bind and enhance the splicing efficiency of Hand2 pre-mRNA, leading to increased mature Hand2 levels and maladaptive remodeling. Inhibition of either Bclaf1 or Hand2 rescues cardiac function and structure in experimental HFrEF. Our work defines a novel Bclaf1/Srsf2/Hand2 splicing axis as a critical driver of HFrEF and reveals a promising therapeutic target for heart failure.