bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2026–05–17
two papers selected by
Kyle McCommis, Saint Louis University
  1. Single Cell Analysis of Human Heart Failure With Preserved Ejection Fraction.
  2. A Translational Model of MASLD-Associated HFpEF Defines Mitochondrial Dysfunction and Cardiac Plasticity During Disease Progression and Regression.
  1. Circ Res. 2026 May 15.
    Single Cell Analysis of Human Heart Failure With Preserved Ejection Fraction.
    Virginia S Hahn, Mark Chaffin, Bridget Simonson, Sydney C Jenkin, Abigail S Mulligan, Malihe Rezaee, Kenneth C Bedi, Kenneth B Margulies, Carla A Klattenhoff, Kavita Sharma, David A Kass, Patrick T Ellinor.
       BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a poorly understood, multisystem disease with high morbidity and mortality. To improve understanding of its pathobiology, we analyzed single-nucleus RNA sequencing in human HFpEF myocardium versus controls.
    METHODS: Septal myocardial biopsies from 19 HFpEF and 24 nonfailing controls were analyzed using the 10× Genomics Chromium platform, with nuclei isolated from combined samples (6 patients/pool). Genotype-based demultiplexing was performed with souporcell, and gene expression was quantified with CellRanger and CellBender. After quality control, nuclei were annotated by cell types, and differential expression was performed between HFpEF versus controls using limma-voom. Functional analysis was performed using Gene Set Enrichment Analysis. Data were compared with prior single-nucleus RNA sequencing in dilated cardiomyopathy versus controls.
    RESULTS: We successfully demultiplexed pooled myocardial biopsies, assigning >70% of nuclei to individuals. After quality control, we recovered 48 886 nuclei and identified 14 cell types. Many differentially expressed genes across cell types were detected in HFpEF versus controls (fibroblasts, 5905; cardiomyocytes, 5159; endothelial cells, 2143; pericytes, 1812; and macrophages, 1405). Enriched pathways common to multiple cell types included immune activation, transcription/translation, metabolism, and protein quality control. They were particularly shared between cardiomyocytes and fibroblasts. Vascular smooth muscle cells had a more synthetic, proliferative phenotype. Immune cell analyses suggested enhanced T-cell activation and reduced macrophage clearance programs. Comparative analysis between HFpEF and dilated cardiomyopathy identified transcriptional differences primarily in cardiomyocytes. Two of 3 cardiomyocyte differential expression genes unique to HFpEF were validated to have concordant protein expression changes in HFpEF (MAP2K6 and PLPP3).
    CONCLUSIONS: Our findings reveal a distinct, cell-type-specific transcriptomic landscape in the human HFpEF myocardium. While HFpEF and dilated cardiomyopathy share significant molecular pathways across most cell types, the profound divergence within cardiomyocytes suggests a unique pathological driver for HFpEF. These signatures may provide a high-resolution roadmap for identifying precision therapeutic targets in HFpEF.
    Keywords:  cardiomyopathy, dilated; heart failure; metabolism; myocytes, cardiac; single-cell analysis
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327433
  2. bioRxiv. 2026 Feb 28. pii: 2026.02.26.708088. [Epub ahead of print]
    A Translational Model of MASLD-Associated HFpEF Defines Mitochondrial Dysfunction and Cardiac Plasticity During Disease Progression and Regression.
    Souradipta Ganguly, Betul Gunes, Yusu Gu, Jorge Suarez, Gautam Gupta, Kei Ishizuka, Rabi Murad, Tatiana Kisseleva, Wolfgang Dillmann, Kirk Peterson, Eric Adler, David A Brenner, Debanjan Dhar.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are strongly linked to heart failure with preserved ejection fraction (HFpEF), yet the mechanisms underlying this association remain unclear because robust integrative preclinical models are lacking and the liver and heart are rarely studied as a coordinated system. Here we show that Alms1 -/- (Foz/Foz) mice fed a Western diet develop MASH with advanced liver fibrosis accompanied by a HFpEF phenotype characterized by left ventricular hypertrophy, impaired cardiomyocyte contractility, reduced β-adrenergic reserve, elevated BNP, and increased mortality despite ejection fraction >50. Liver fibrosis emerged as a strong predictor of cardiac dysfunction. Remarkably, dietary reversal restored hepatic architecture, normalized cardiac function, and improved survival, revealing marked plasticity of the liver-heart axis. Mechanistic analyses revealed coordinated mitochondrial dysfunction, altered substrate utilization, and extracellular matrix remodeling in the left ventricle, with strong concordance to human HFpEF transcriptomic signatures. Ultrastructural studies confirmed mitochondrial injury and sarcomeric disorganization, linking metabolic failure to impaired cardiomyocyte performance. Together, these findings identify mitochondrial dysfunction as a central mediator of MASLD-associated HFpEF and establish the Foz/Foz model as a powerful platform for dissecting liver-to-heart signaling pathways and testing mechanism-based therapeutic strategies.
    STRUCTURED ABSTRACT: Background: Metabolic dysfunction associated steatotic liver disease (MASLD) and its advanced form, MASH, are closely linked to heart failure with preserved ejection fraction (HFpEF). However, the mechanisms driving MASLD-associated HFpEF and its reversibility remain poorly understood, largely due to the lack of robust preclinical models. Here, we established a translational model of MASLD-associated HFpEF and applied functional and transcriptomic analyses of the left ventricle (LV) to define the mechanisms underlying cardiac dysfunction and its reversibility.Methods: Alms1 -/- (Foz/Foz) mice and wild-type littermates were fed normal chow (NC) or Western diet (WD) for up to 34w. Reversibility was modeled by switching WD-fed Foz/Foz mice at 12w back to NC for 12w. Cardiac assessment included echocardiography, invasive hemodynamics with dobutamine stimulation, histopathology, electron microscopy and isolated cardiomyocyte contractility. LV transcriptomes were profiled by bulk RNA sequencing and analyzed by differential expression and pathway enrichment. Result: Foz/Foz mice on WD for 24w developed metabolic syndrome and MASH with advanced liver fibrosis. Cardiac phenotyping showed LV hypertrophy, impaired cardiomyocyte contractility, reduced β-adrenergic reserve, elevated plasma BNP, and increased mortality while the ejection fraction was preserved (>50%), consistent with HFpEF. Liver fibrosis was a strong predictor of HFpEF. Switching WD-fed Foz/Foz mice at 12w to normal chow diet reversed hepatic fibrosis, restored LV function, and reduced mortality, demonstrating plasticity of the liver-heart axis. LV transcriptome during disease progression and regression revealed mitochondrial dysfunction, altered substrate utilization, extracellular matrix remodeling, and metabolic stress as central drivers of HFpEF, with strong overlap to human HFpEF signatures. Cardiac electron microscopy revealed swollen mitochondria with disrupted cristae, which normalized following dietary intervention.Conclusions: Mitochondrial dysfunction and fibroinflammatory remodeling are central mediators of MASLD-associated HFpEF. Reversal of hepatic and cardiac phenotypes with dietary intervention, together with elucidation of underlying pathways, establish the Foz/Foz model as a robust translational platform for mechanistic and therapeutic discovery targeting the liver-heart axis.
    DOI:  https://doi.org/10.64898/2026.02.26.708088
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