{
  "abstract": "Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome associated with ageing, obesity and impaired nitric oxide signalling. Preclinical models often do not capture the sex-specific and cardiometabolic features observed in patients. We hypothesised that biological sex and the degree of nitric oxide synthase (NOS) inhibition would influence development of HFpEF-like versus HFrEF-like phenotypes. Methods and Results: Male and female C57BL/6J mice (>24 weeks) were exposed to a high-fat diet (HFD) combined with low-dose (0.3 g/L; female only) or high-dose (0.5 g/L; male and female) NOS inhibition using N({omega})-nitro-L-arginine methyl ester (L-NAME) for 15 weeks. Female mice receiving low-dose L-NAME+HFD developed a HFpEF-like phenotype characterised by impaired diastolic function, exercise intolerance and preserved systolic function. Increasing NOS inhibition did not worsen diastolic dysfunction but induced inflammatory and stress-associated transcriptional pathways in female hearts. In contrast, male mice given high-dose L-NAME+HFD developed hypertension, elevated ventricular pressures and impaired systolic function, consistent with a HFrEF-like phenotype. Despite different cardiac phenotypes, circulating lipidomic profiling revealed broadly conserved sphingolipid and phospholipid remodelling, with sex-specific regulation of phosphatidylinositol and lysophosphatidylcholine species. Transcriptomic analyses identified shared regulation of extracellular matrix, calcium-handling and metabolic pathways, whereas greater NOS inhibition was associated with transcriptional signatures related to inflammatory signalling, cellular stress responses and mitochondrial homeostasis. Conclusions: Cardiometabolic stress does not produce a uniform HF phenotype. Instead, biological sex and the degree of NOS inhibition direct distinct functional and molecular remodelling trajectories, identifying HFpEF-like dysfunction as one of several potential cardiac responses to cardiometabolic injury.",
  "abstract_shown": true,
  "affiliations": [
    "Baker Heart and Diabetes Institute"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "name": "J. M. Sun"
    },
    {
      "name": "A. T. Riquileme"
    },
    {
      "name": "J. Hor"
    },
    {
      "name": "D. G. Donner"
    },
    {
      "name": "H. Kiriazis"
    },
    {
      "name": "S. M. Walker"
    },
    {
      "name": "S. Bond"
    },
    {
      "name": "N. A. Mellet"
    },
    {
      "name": "P. J. Meikle"
    },
    {
      "name": "A. C. Parslow"
    },
    {
      "name": "M. L. Huang"
    },
    {
      "name": "M. Kanki"
    },
    {
      "name": "B. G. Drew"
    },
    {
      "name": "Y. K. Tham"
    },
    {
      "name": "J. R. McMullen"
    },
    {
      "affs": [
        0
      ],
      "name": "M. J. Young"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/14p4teq4qyzts.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.28.747952",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.28.747952v1.full",
  "id": "14p4teq4qyzts",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.28.747952v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "pathology"
    ],
    [
      "openalex",
      "2705|Cardiovascular Function and Risk Factors"
    ]
  ],
  "openalex": "W7208748675",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.28.747952v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/14p4teq4qyzts.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:14Z",
      "native_id": "10.64898/2026.08.28.747952",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.28.747952v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2705|Cardiovascular Function and Risk Factors",
      "subfield": "cardiovascular"
    }
  ],
  "title": "Nitric oxide synthase inhibition and biological sex define different cardiac responses to cardiometabolic stress in older mice.",
  "title_text": "Nitric oxide synthase inhibition and biological sex define different cardiac responses to cardiometabolic stress in older mice.",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:14Z",
  "url": "https://research.draconitic.com/paper/14p4teq4qyzts",
  "venue": "bioRxiv",
  "versions": []
}