{
  "abstract": "Background Pre-clinical studies on contractility offer valuable mechanistic insights into cardiovascular diseases/conditions such as heart failure (HF) and drug-induced cardiotoxicity. Traditional methods often rely on unloaded isometric twitches, which fail to mimic the heart‘s dynamic movements. In-vivo contractility is characterised by four distinct phases, as shown by pressure-volume (PV) loops: isovolumic contraction, ejection, isovolumic relaxation, and diastolic filling. We have pioneered extensive development of a novel high-content ‘work-loop’ (WL) contractility assay using rat and human heart papillary/trabeculae tissue and cardiomyocyte preparations. 1–4 The cardiac WL mimics the cardiac length change cycle providing realistic evaluation of in-vivo ‘like’ myocardial contractile mechanics. We investigated the feasibility of using refined human engineered heart tissue (hEHT)5 in our novel research platform, capable of generating cardiac WLs which accurately reflect the cardiac cycle, in addition to evaluation of clinically relevant inotropic drug responses.Methods Refined 3D hEHTs with defined iPSC-generated cardiomyocytes and quiescent fibroblasts were generated as described previously. 5 The refined hEHTs were superfused and electrically stimulated, and biomechanical preload/afterload parameters were optimised. Active WLs were undertaken and clinically relevant mechanical characteristics of the refined EHT assessed (e.g. power output (PO); developed force (DF)). The refined hEHTs were also perfused in the absence or presence of relevant positive and negative inotropic agents. Macroscopic and molecular biomarker assessments of control and drug treated refined hEHTs were also undertaken following mechanical characterisation.Results The refined hEHT produced robust and enhanced developed force responses compared to other studies reporting hEHT force-length data. The refined hEHT WL platform was able to perform clinically relevant mechanical ‘cardiac cycle’ characteristics, in addition to significant responses to a range of positive and negative inotropes (e.g. PO and DF). Cardiac biomarkers were expressed by the refined hEHTs, including the presence of contractile muscle protein F-actin, observed as regular striated patterns in the hEHTs using Phalloidin.Conclusion We describe the characterisation of a clinically relevant refined hEHT WL platform which mimics the cardiac cycle and enables mechanical assessment of the refined hEHTs in response to drugs. The novel refined hEHT WL platform has the potential to accelerate and enhance the progression of hEHT research in relation to patient-specific drug screening, regenerative medicine and drug discovery applications.References Gharanei, et al. J Pharm Tox Meth. 2017;88(Part 2):227.Fletcher, et al. Sci Rep. 2020;10(1):5258.Tran, et al. J Cardio Transl Res. 2024;17(2):275–286.Linekar, et al. Heart 2024;110:A268-A269.Cumberland, et al. F1000Res. 2024;12:1224.",
  "authors": [
    {
      "affiliations": [
        "Centre for Health and Life Sciences, Coventry University, Coventry, CV1 5FB, UK",
        "InoCardia Ltd, TechnoCentre, Puma Way, Coventry, CV1 2TT, UK"
      ],
      "name": "Adam Linekar"
    },
    {
      "affiliations": [
        "Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT"
      ],
      "name": "Sean Benson"
    },
    {
      "affiliations": [
        "Centre for Health and Life Sciences, Coventry University, Coventry, CV1 5FB, UK"
      ],
      "name": "Mike Dodd"
    },
    {
      "affiliations": [
        "Centre for Health and Life Sciences, Coventry University, Coventry, CV1 5FB, UK"
      ],
      "name": "Hardip Sandhu"
    },
    {
      "affiliations": [
        "InoCardia Ltd, TechnoCentre, Puma Way, Coventry, CV1 2TT, UK"
      ],
      "name": "Ben Gowland"
    },
    {
      "affiliations": [
        "Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT"
      ],
      "name": "Davor Pavlovic"
    },
    {
      "affiliations": [
        "Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham, UK, B15 2TT"
      ],
      "name": "Katja Gehmlich"
    },
    {
      "affiliations": [
        "Centre for Health and Life Sciences, Coventry University, Coventry, CV1 5FB, UK",
        "InoCardia Ltd, TechnoCentre, Puma Way, Coventry, CV1 2TT, UK"
      ],
      "name": "Helen Maddock"
    }
  ],
  "title": "BS28 Mimicking the cardiac cycle: mechanical characterisation of the novel refined human engineered heart tissue using the work-loop platform",
  "uid": "9b1416e7-46f8-5df7-816f-c255cbf2c7ed"
}