B. AMUZESCU*,**#, R. AIRINI*,**, LOREDANA GHICA*, F.B. EPUREANU*,**, A.F. DEFTU*,**, DANIELA MARCELA CUCU*,**, VIOLETA PAULA RISTOIU*,**, D.F.MIHĂILESCU*, BEATRICE MIHAELA RADU*,**#
*Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, 91–95 Splaiul Independenței, Bucharest 050095, Romania
**Life, Environmental and Earth Sciences Division, Research Institute of the University of Bucharest (ICUB), 91–95 Splaiul Independenţei, Bucharest 050095, Romania
This minireview summarizes the evolution of experimental techniques in cardiomyocyte electrophysiology over the last 70 years and progressive development of cardiomyocyte electrophysiology computational models. We emphasize the relationship between hERG (the human Ether-à-go-go-Related Gene) ion channels’ susceptibility to block by pharmacological compounds and drug-induced arrhythmias, particularly Torsades-de-Pointes, and expose the already classical clinical and non-clinical, in vitro and in vivo assays used for cardiac safety testing, included in the S7B and E14 guidelines, constituting the so-called “hERG-centric” paradigm. We further present several in-depth studies that pointed out the limitations of this paradigm, and the requirement for a modern in vitro mechanistic approach, combining experimental and in silico (modeling) methods, constituting the novel Cardiac in vitro Pro-arrhythmia Assay (CiPA) paradigm. We review the most relevant achievements during the past three years in implementing CiPA as a new guideline, the various approaches tested by researchers, particularly for evidencing proarrhythmogenic events like early or delayed afterdepolarizations in human induced pluripotent stem cell-derived cardiomyocyte preparations. We conclude that automated patch-clamp methods, especially those using the third generation CytoPatch™ platforms based on the patented Cytocentering® technology, allow development of complex assays combining all three stages of the CiPA approach in a single experiment, leading to advanced testing methods that will transform CiPA into a robust, highly reliable and reproducible standard for the pharmacological industry.
Key words: cardiomyocyte, human induced pluripotent stem cell-derived cardiomyocyte, hERG, early afterdepolarization, Torsades-de-Pointes, drug-induced arrhythmia, cardiac safety drug testing, Comprehensive in vitro Proarrhythmia Assay (CiPA), automated patch-clamp.
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