{
  "abstract": "Background Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia globally, affecting 1 in 45 individuals in the UK, and is a leading arrhythmic cause of heart failure, stroke, and premature mortality. The cost of AF treatment is around £1.7 billion annually (1% of NHS expenditure) and expected to rise to 2-4% over the next decade. AF therapies are limited to medication therapy aimed to relieving symptoms, or ablation, which is associated with high recurrence rate of 30-50% within 1 year after index procedure due to underlying structural remodelling within the atria. There is strong unmet clinical need to identify new drug targets to mitigate structural remodelling in AF, of which IL6 and IL11 have been suggested as regulators of cardiac fibrosis pathways in animal studies respectively which are here investigated for the case of human atrial fibrillation.Methods Myocardial-secreted (coronary sinus, CS) and circulating (peripheral venous, PV) blood from 97 patients in AF or non-AF controls undergoing cardiac procedures, were collected. Serum IL11 and 6 levels were measured by ELISA for pre- and post-ablation, and at 3- and 12-month follow-ups. Human atrial tissue (left atrial, LA) biopsies from 20 cardiac surgery patients in sinus rhythm (SR) or with persistent AF (AF) were used for human fibroblast isolation (standard enzymatic digestion protocol). Cells were cultured to passage 3-4. Gene and protein expression of IL11 and its receptor (IL11RA) or IL6 and IL6R were assessed by qPCR and western blot.Results Baseline characteristics of study participants are show in table 1. IL11 protein levels in circulating (PV, p=0.034) and myocardium-derived (CS, p=0.024) serum were significantly elevated AF patients compared to non-AF controls (figure 1A-B). Baseline PV IL11 levels correlated with markers of structural remodeling such as LA dimension (figure 1C), p=0.04, and age, a risk factor of AF development (figure 1D, p=0.04). IL6 levels, however were only elevated in short-lived paroxysmal (pxAF) (p=0.03) and post-cardiac surgery postoperative AF (poAF) cohorts (p=0.04), but not persistent AF (persAF) (figure 1E-G). At 12months follow-up, serum IL11 and IL6 were significantly lower in those with no AF relapse (figure 1H-I). From an in vitro cellular level, human left atrial fibroblast (hAFB) IL11 mRNA expression is significantly upregulated in persistent AF patients (p=0.019), while they were negligible in control patients in sinus rhythm (SR) (figure 1J). Immunoblotting revealed protein expression of IL11 was elevated within the human left atrium (figure 1K-L) in AF. Stimulation of hAFBs with IL11 at 10-50ng/ml range showed elevated profibrotic gene expression such as Col1A1 and TGFb1 (p=0.04, p=0.03 respectively), and Collagen-1 protein expression in fibroblasts (figure 1M).Conclusions Our results indicate for the first time that myocardial and circulating IL11 and IL6 levels are associated with AF disease, and higher levels are associated with AF-recurrence post AF ablation. While elevation of IL6 is observed in short-term AF subtypes (in paroxysmal and post-operative AF), IL11 increases in a long-standing persistent AF (persAF), and positively correlates with atrial structural remodelling. Moreover, AF is associated with enhanced human atrial fibroblast IL11 signalling at a gene transcription and protein level. The data suggest that targeting IL11/IL6 signalling may represent a novel strategy to mitigate atrial fibrosis and improve outcomes in AF. Future experiments assesses impact of IL11/6 signalling inhibitors (e.g. LASN01 or tocilizumab) in hAFbs in context of AF to dampen pro-fibrotic phenotypes of hAFbs.Funding This study is funded and supported by the British Heart Foundation Clinical Research Training Fellowship (BHF FS/CRTF/20/24786).Ethical Approval 18/SC/0304, 18/SC/0404.References Elliott AD, Middeldorp ME, Van Gelder IC, et al. Epidemiology and modifiable risk factors for atrial fibrillation. Nat Rev Cardiol 2023;20:404–417. https://doi.org/10.1038/s41569-022-00820-8Cook SA. Understanding interleukin 11 as a disease gene and therapeutic target. Biochem J. 2023;480(23):1987–2008. https://doi.org/10.1042/BCJ20220160. PMID: 38054591; PMCID: PMC10754292.",
  "authors": [
    {
      "affiliations": [
        "Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom",
        "Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom"
      ],
      "name": "Chenhan Sam Ma"
    },
    {
      "affiliations": [
        "Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom"
      ],
      "name": "Chi Him Kendrick Yiu"
    },
    {
      "affiliations": [
        "Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom"
      ],
      "name": "Aaron Johnston"
    },
    {
      "affiliations": [
        "Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom"
      ],
      "name": "Lucia M Moreira"
    },
    {
      "affiliations": [
        "Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom"
      ],
      "name": "Lorena Perez Carrillo"
    },
    {
      "affiliations": [
        "Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom"
      ],
      "name": "Kim Rajappan"
    },
    {
      "affiliations": [
        "Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom",
        "Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom"
      ],
      "name": "Timothy Betts"
    },
    {
      "affiliations": [
        "Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom"
      ],
      "name": "Matthew Ginks"
    },
    {
      "affiliations": [
        "Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom"
      ],
      "name": "Michala Pedersen"
    },
    {
      "affiliations": [
        "Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom"
      ],
      "name": "Rohan Wijesurendra"
    },
    {
      "affiliations": [
        "Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom"
      ],
      "name": "Rana Sayeed"
    },
    {
      "affiliations": [
        "Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom",
        "Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom"
      ],
      "name": "George Krasopoulos"
    },
    {
      "affiliations": [
        "Imperial College London, London, United Kingdom"
      ],
      "name": "Stuart Cook"
    },
    {
      "affiliations": [
        "Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom",
        "Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom"
      ],
      "name": "Robin Choudhury"
    },
    {
      "affiliations": [
        "Division of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom"
      ],
      "name": "Svetlana Reilly"
    }
  ],
  "title": "414 Investigating the role of interleukin-11 (IL11) with interleukin-6 (IL6) in patients with atrial fibrillation",
  "uid": "de000b2d-008e-53b3-b607-6a79823d95a0"
}