In vitro models of proarrhythmia

Abstract

Proarrhythmia models use electrophysiological markers to predict the risk of torsade de pointes (TdP) in patients. The set of variables used by each model to predict the torsadogenic propensity of a drug has been reported to correlate with clinical outcome; however, these reports should be interpreted cautiously as no model has been independently assessed. Each model is discussed along with its merits and shortcomings; none, as yet, having shown a predictive value that makes it clearly superior to the others. As predictive as these models may become, extrapolation of results directly to the clinic must be exercised with caution. The use of in silico models, from subcellular to whole system, is rapidly beginning to form the first line of screening activity in many drug discovery programmes, indicating that biological experimentation may become secondary to analysis by simulation. In vitro proarrhythmia models challenge current perceptions of appropriate surrogates for TdP in man and question existing non-clinical strategies for assessing proarrhythmic risk. The rapid emergence of such models, compounded by the lack of a clear understanding of the key proarrhythmic mechanisms has resulted in a regulatory reluctance to embrace such models. The wider acceptance of proarrhythmia models is likely to occur when there is a clear understanding and agreement on the key proarrhythmia mechanisms. With greater acceptance and ongoing improvements, these models have the potential to unravel the complex mechanisms underlying TdP.

hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment

“…Further experimental and review studies are required to analyze the propensity of drugs to induce TdP in respect not only of their IC 50 values, but also unbinding kinetics, mode of action (trapped vs. untrapped) and action on other ion channels (counter-balancing effects). 31,32 Such a reference set of highly characterized compounds that show differing propensities to cardiac toxicity would be a valuable resource to the cardiac community.…”

Engineered heart tissues and induced pluripotent stem cells: Macro- and microstructures for disease modeling, drug screening, and translational studies

“…The existing preclinical testing paradigm relies heavily on the use of in vitro cell lines such as Chinese hamster ovary (CHO) and human embryonic kidney 293 (HEK293) cells overexpressing the human ether-à-go-go-related gene (hERG) channels, ex vivo tissue preparations such as isolated arterially perfused left ventricular rabbit wedge preparations, and in vivo studies such as chronic dog atrioventricular (AV) block models [10]. However, there are several challenges with these models, including their high costs and their poor predictive capacity owing to inter-species differences in cardiac electrophysiology and human biology[14, 15]. In addition, CHO and HEK293 cells are not ideal models for cardiotoxicity because ectopic expression of a cardiac ion channel does not always recapitulate function in human cardiomyocytes [16].…”

Assessment of beating parameters in human induced pluripotent stem cells enables quantitative in vitro screening for cardiotoxicity

“…Sensitive in vitro assays that can provide early detection of cardiovascular side effects have been the focus of toxicology research for several decades (Lawrence et al , 2008). Specifically, new cell models that better represent the in vivo environment, as well as new phenotypic readouts that are related to myocardial performance, are needed to develop a sensitive, specific, and predictive assay.…”