Patients with heart failure often develop cardiac arrhythmias. The mechanisms and interrelations linking heart failure and arrhythmias are not fully understood. Historically, research into arrhythmias has been performed on affected individuals or in vivo (animal) models. The latter however is constrained by interspecies variation, demands to reduce animal experiments and cost. Recent developments in in vitro induced pluripotent stem cell technology and in silico modelling have expanded the number of models available for the evaluation of heart failure and arrhythmia. An agnostic approach, combining the modalities discussed here, has the potential to improve our understanding for appraising the pathology and interactions between heart failure and arrhythmia and can provide robust and validated outcomes in a variety of research settings. This review discusses the state of the art models, methodologies and techniques used in the evaluation of heart failure and arrhythmia and will highlight the benefits of using them in combination. Special consideration is paid to assessing the pivotal role calcium handling has in the development of heart failure and arrhythmia.

Activation of cardiac fibroblasts and differentiation to myofibroblasts underlies development of pathological cardiac fibrosis, leading to arrhythmias and heart failure. Myofibroblasts are characterised by increased α-smooth muscle actin (α-SMA) fibre expression, secretion of collagens and changes in proliferation. Transforming growth factor-beta (TGF-β) and increased mechanical stress can initiate myofibroblast activation. Reversibility of the myofibroblast phenotype has been observed in murine cells but has not been explored in human cardiac fibroblasts. In this study, chronically activated adult primary human ventricular cardiac fibroblasts and human induced pluripotent stem cell derived cFbs (hiPSC-cFbs) were used to investigate the potential for reversal of the myofibroblast phenotype using either subculture on soft substrates or TGF-β receptor inhibition. Culture on softer plates (25 or 2 kPa Young’s modulus) did not alter proliferation or reduce expression of α-SMA and collagen 1. Similarly, culture of myofibroblasts in the presence of TGF-β inhibitor did not reverse myofibroblasts back to a quiescent phenotype. Chronically activated hiPSC-cFbs also showed attenuated response to TGF-β receptor inhibition and inability to reverse to quiescent fibroblast phenotype. Our data demonstrate substantial loss of TGF-β signalling plasticity as well as a loss of feedback from the surrounding mechanical environment in chronically activated human myofibroblasts.