Microelectrode arrays: from electrophysiology to integrated cancer treatment induced cardiotoxicity assessment

With ongoing and fast paced progress in cancer chemotherapy and immunotherapy, cancer survival rates have been steadily increased. However, cancer patients, especially in the paediatric and geriatric population are faced with a high risk of cardiotoxicity. This resulted in the emergence of the field of cardio-oncology, and more recently, precision cardio-oncology. A major concern in this context is the development of arrhythmias and contraction dysregulation. These adverse effects can be investigated in vitro . In the case of arrhythmia, the Comprehensive in vitro Proarrhythmia Assay (CiPA), established in 2013, provides a framework for evaluating proarrhythmic risk with improved specificity and sensitivity compared to traditional assays. CiPA outlines guidelines for preclinical assessment of drug-induced arrhythmia, incorporating a combination of in vitro , in silico , and clinical approaches applicable to a broad range of pharmaceutical compounds, including chemotherapeutics. The recommended in vitro methods under CiPA are transmembrane potential measurement techniques such as patch clamp and automated patch clamp, microelectrode arrays, impedance measurement and the use voltage sensing optical assays (VSOs) such as voltage indicator dyes and genetically encoded voltage indicators (GECIs). CiPA also recommends interfacing these in vitro methods with human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) to increase physiological relevance. Currently, there are neither guidelines in place for the in vitro assessment of cancer treatment induced arrhythmia (CTIA) or contraction dysregulation, nor any standardized protocols for evaluating cardiotoxicity resulting from cell-based cancer therapies. In this paper we review current in vitro approaches for the assessing of cardiotoxic effects of cancer treatments. Putting the focus in the state-of the art use of micro-electrode arrays (MEA) as a novel approach capable of simultaneously monitoring electrophysiological activity, contractile behaviour, and morphological changes induced by chemotherapeutic and immunotherapeutic agents.