{
  "abstract": "Introduction Chronic kidney disease (CKD) represents a significant global health burden, affecting over 840million people, with cardiovascular disease (CVD) being the leading cause of mortality in this population. CKD induces a distinct cardiac phenotype, characterised by extensive structural, metabolic and functional remodeling, leading to heart failure with preserved ejection fraction (HFpEF). However, the molecular mechanisms that drive the progression of cardiac dysfunction in CKD remain to be fully elucidated.Methods We utilised a 5/6 nephrectomy model of CKD in rats to examine longitudinal changes in the cardiac transcriptome in CKD-HFpEF. Cardiac tissue harvested at experimental endpoint (4- and 12-weeks post-CKD induction) were snap frozen and processed for bulk-RNA sequencing using DNBSEQ technology (BGI Biotech, Hong Kong). Differentially expressed genes (DEGs) and associated pathways were analysed in RStudio (v4.4.2) using DESeq2 with a multifactorial design incorporating time (4 vs 12 weeks), condition (CKD vs Sham), and their interaction (~time+condition+time:condition) (padj < 0.05 and log 2FC ≥ 1). The ComplexUpset R package was used to visualise overlap of DEGs across conditions and time points. Gene set enrichment analysis was performed using clusterProfiler (p-value<0.1). Integrative causal network analysis of 1H-NMR metabolomics and transcriptomic data was performed using cosmosR package (padj < 0.05, log2FC ≥ 1).Results At early-stage CKD-HFpEF (4-weeks), SDC1 was upregulated and associated with fibrotic and inflammatory signalling, while CYP2E1 and HAMP were downregulated, indicative of suppressed oxidative metabolism and iron dysregulation. Causal network analysis identified intermediate pathways linking metabolic and transcriptomic changes. Metabolic remodelling of ATP and acetate influences EGFR, MAPK1/3 and PRKCA related signalling pathways which converge on transcription factors STAT3 and CEBPA that regulate the expression of DEGs identified. In more advanced 12-week CKD-HFpEF, 46 DEGs were identified, which were implicated in suppression of mitochondrial oxidative phosphorylation, ribosomal processes, and ATP synthesis. Causal network structure mirrored that observed at 4-weeks but with greater network complexity and depth, consistent with progressive amplification of metabolic–signalling interactions. Progression from 4- to 12-week CKD-HFpEF resulted in 86 age-independent, stage specific DEGs. The identified gene set is enriched in pathways activating cell adhesion, cytoskeletal organisation, and protein kinase activity, alongside suppressing mitochondrial oxidative phosphorylation, ATP synthesis, and ribosomal functions.Conclusions These findings indicate that CKD-associated HFpEF arises from early metabolic– transcriptional dysregulation that progressively suppresses mitochondrial and translational function through conserved ATP- and acetate-linked EGFR–MAPK–PRKCA signalling converging on STAT3, CEBPA, and PPARα.",
  "authors": [
    {
      "affiliations": [
        "William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Sanushi Dambure"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Megan Young"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Fenn Cullen"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Claudia Cabrera"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Nay Aung"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Dunja Aksentijevic"
    }
  ],
  "title": "469 Progressive metabolic and transcriptional remodeling in CKD-associated HFpEF",
  "uid": "c2069ac8-1e6e-5e4a-9e0f-b5c0f931c5bf"
}