{
  "abstract": "Background Chronic kidney disease-associated cardiomyopathy (CKD-CM) begins early during renal dysfunction and is characterised by diffuse myocardial fibrosis, diastolic impairment, atrial dilatation and increased arrhythmogenic risk, long before overt ventricular hypertrophy develops. Clinical studies demonstrate that interstitial fibrosis, atrial dysfunction and electrophysiological abnormalities emerge from eGFR ≈60 mL/min/1.73 m 2 and progressively worsen as CKD advances. However, the earliest mechanistic drivers, particularly atrial electrophysiological remodelling, remain poorly defined. Sodium–glucose cotransporter-2 inhibitors (SGLT2i) have shown substantial cardioprotective benefit across CKD and heart failure phenotypes, but their effects on the initial stages of CKD-CM are not well understood.Methods Female C57BL/6J mice were either fed a 0.15% adenine-containing diet (n=18) or control chow (n=15) for 7 weeks. A further group of adenine-fed mice received dapagliflozin (3 mg/kg/day) via drinking water during the last 4 weeks of the study (n=12). Renal dysfunction was assessed via serum blood urea nitrogen (BUN) and creatinine concentrations, kidney weight normalised to bodyweight, and histological quantification of renal fibrosis (Picrosirius red staining). Cardiac structure and function were assessed using electrocardiography (ECG) and transthoracic echocardiography. Systemic inflammation was investigated via a multiplex plasma proteomic panel of 43 cytokines with absolute concentrations (Olink). Blood pressure, bodyweight and water intake were monitored throughout. Atrial electrophysiology was assessed ex vivo by optical mapping using voltage-sensitive Di-4-ANEPPS.Results Adenine-fed mice showed impaired renal function, demonstrated by elevated serum BUN (p≤0.0001) and creatinine concentrations (p≤0.0001), decreased kidney weight (p≤0.01) and a substantial increase in renal interstitial fibrosis (p≤0.0001), compared to controls. Dapagliflozin attenuated serum BUN (p≤0.01) and creatinine (p≤0.01) but did not reverse renal fibrosis. Despite preserved LV mass and wall thickness across groups, adenine-fed mice showed significant electrophysiological alterations, including bradycardia (p≤0.01), PR prolongation (p≤0.05) and shortened P-wave duration (p≤0.01), indicative of atrial and AV nodal electrical remodelling. Several circulating inflammatory cytokines (e.g. TNF, IL-6, IL-10, IL-17A) were substantially elevated in CKD and were attenuated by SGLT2i treatment. Importantly, blood pressure did not differ between groups, indicating that changes were independent of blood pressure. Optical mapping demonstrated significantly shortened atrial APD 80 in adenine-fed mice, not rescued by SGLT2 inhibition, whereas SGLT2i unexpectedly increased atrial conduction velocity.Conclusion Early CKD-associated cardiomyopathy induces selective atrial electrophysiological remodelling and systemic inflammation in the absence of overt structural cardiac hypertrophy, consistent with the early CKD-CM phenotype described clinically. SGLT2 inhibition attenuates systemic inflammation and some ECG abnormalities but does not reverse APD shortening, suggesting that electrophysiological remodelling is an early and partially SGLT2 inhibition-resistant component of CKD-CM. This model provides a robust platform for dissecting the mechanisms by which early renal dysfunction promotes atrial arrhythmogenesis and for evaluating emerging cardioprotective interventions.",
  "authors": [
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom"
      ],
      "name": "Abbie Hayes"
    },
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom"
      ],
      "name": "Katie Tompkins"
    },
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom"
      ],
      "name": "Joanne Mitchell"
    },
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom"
      ],
      "name": "Olivia Baines"
    },
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom"
      ],
      "name": "Rina Sha"
    },
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom"
      ],
      "name": "Sophie Broadway-Stringer"
    },
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom"
      ],
      "name": "Michael Sagmeister"
    },
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom"
      ],
      "name": "Jonathan Townend"
    },
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom"
      ],
      "name": "Charles Ferro"
    },
    {
      "affiliations": [
        "Leicester University, Leicester, United Kingdom"
      ],
      "name": "Andre Ng"
    },
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom"
      ],
      "name": "Katja Gehmlich"
    },
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom"
      ],
      "name": "Rowan Hardy"
    },
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom",
        "Warwick University, Warwick, United Kingdom"
      ],
      "name": "Christopher O’Shea"
    },
    {
      "affiliations": [
        "Birmingham University, Birmingham, United Kingdom"
      ],
      "name": "Davor Pavlovic"
    }
  ],
  "title": "132 Atrial electrophysiological remodelling precedes structural disease in early CKD-CM: therapeutic modulation with SGLT2 inhibition",
  "uid": "3450a898-a47d-55c1-9b4b-cc802c63e607"
}