{
  "abstract": "Background Type 2 diabetes (T2D) promotes the development of diabetic cardiomyopathy (dbCM), characterised by diastolic dysfunction, adverse ventricular remodelling, and impaired myocardial energetics. Chronic metabolic overload in T2D drives mitochondrial dysfunction and low-grade inflammation, yet the molecular pathways linking metabolic stress and cardiac dysfunction remain poorly defined. The NLRP3 inflammasome is activated by hyperglycaemia, hyperlipidaemia and mitochondrial injury, making it a potential link between metabolic stress and dbCM. We hypothesise that T2D-induced NLRP3 signalling contributes to maladaptive cardiometabolic remodelling.Methods We integrated population-scale human genetic analysis (UK Biobank) with experimental models to define the role of NLRP3 signalling in cardiac function and metabolism. In UK Biobank participants with cardiac MRI (n=64,679) we tested associations between pathogenic variants in inflammasome- and mitochondrial-related genes and left ventricular (LV) phenotypes in the general population and individuals with T2D. Mechanistic studies used global NLRP3 knockout mice (NLRP3 -/-, B6.129S6-Nlrp3tm1Bhk/J) and C57BL/6J controls under basal conditions and following T2D induction using high-fat diet combined with low-dose anomer-equilibrated streptozotocin. Cardiac function was assessed by echocardiography, myocardial metabolism by targeted LC-MS/MS, and myocardial stress tolerance using ex vivo ischaemia-reperfusion.Results In the general population pathogenic variants in NLRP3-inflammasome and mitochondrial regulatory genes were associated with adverse LV remodelling and myocardial performance. In individuals with T2D, NLRP3 variants were associated with increased indexed LV end-diastolic volume, consistent with adverse chamber remodelling, while variants in downstream inflammasome and mitochondrial pathways were linked to impaired myocardial contractility and altered LV geometry.In NLRP3-/- mice under basal conditions cardiac function was preserved however LC-MS/MS analysis revealed a distinct myocardial metabolic state, demonstrating that NLRP3 signalling contributes to cardiometabolic regulation. Following induction of T2D, NLRP3 deficiency profoundly altered diabetes-associated metabolic remodelling and reduced myocardial tolerance to ischaemia-reperfusion injury, indicating that chronic, global loss of NLRP3 disrupts adaptive metabolic stress responses in the diabetic heart.Conclusions Our findings highlight a context-dependent role for inflammasome signalling. While dysregulated NLRP3 signalling in diabetes associates with adverse cardiac remodelling in humans, complete lifelong absence of NLRP3 reveals a requirement for inflammasome signalling in myocardial metabolic adaptation under stress. Together, these data position NLRP3 as a stress-responsive regulator in cardiometabolic stress signalling and provide a mechanistic framework linking metabolic overload to dbCM.",
  "authors": [
    {
      "affiliations": [
        "William Harvey Research Institute, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Megan Young"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Hannah Nicholls"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Sanushi Dambure"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Zenouska Ramchunder"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Emina ND Mody"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Fenn Cullen"
    },
    {
      "affiliations": [
        "University College London, London, United Kingdom"
      ],
      "name": "Sian M Henson"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Nay Aung"
    },
    {
      "affiliations": [
        "Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland"
      ],
      "name": "Luke AJ O’Neill"
    },
    {
      "affiliations": [
        "William Harvey Research Institute, Queen Mary University of London, London, United Kingdom"
      ],
      "name": "Dunja Aksentijevic"
    }
  ],
  "title": "559 NLRP3 signalling links diabetic metabolic stress to cardiac metabolic remodelling",
  "uid": "3a392e60-83aa-50ff-83fe-dcebb652a09b"
}