Cardiotoxicity screening: a review of rapid-throughput in vitro approaches

Abstract

Cardiac toxicity represents one of the leading causes of drug failure along different stages of drug development. Multiple very successful pharmaceuticals had to be pulled from the market or labeled with strict usage warnings due to adverse cardiac effects. In order to protect clinical trial participants and patients, the International Conference on Harmonization published guidelines to recommend that all new drugs to be tested preclinically for hERG (Kv11.1) channel sensitivity before submitting for regulatory reviews. However, extensive studies have demonstrated that measurement of hERG activity has limitations due to the multiple molecular targets of drug compound through which it may mitigate or abolish a potential arrhythmia, and therefore, a model measuring multiple ion channel effects is likely to be more predictive. Several phenotypic rapid-throughput methods have been developed to predict the potential cardiac toxic compounds in the early stages of drug development using embryonic stem cells- or human induced pluripotent stem cell-derived cardiomyocytes. These rapid-throughput methods include microelectrode array-based field potential assay, impedance-based or Ca(2+) dynamics-based cardiomyocytes contractility assays. This review aims to discuss advantages and limitations of these phenotypic assays for cardiac toxicity assessment.

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

“…Electrical signals resembling the QT interval of the ECG and defined field potentials can be recorded through extracellular‐ (Harris et al , 2013; Nozaki et al , 2014; Clements, 2016) or intracellular‐ (Fendyur and Spira, 2012; Spira and Hai, 2013) electrodes using multi electrode arrays (MEAs). Some medium‐throughput MEA platforms also allow contractions (displacement) to be measured through impedance (Li et al , 2016; Obergrussberger et al , 2016), generating highly reproducible results (Lu et al , 2015). In some cases, it can be valuable to electrically ‘pace’ CMs so that their beating rate (defined RR‐like interval because it reflects the analogue ECG parameter) is standardized and constant rather than irregular, as often occurs if beating is spontaneous.…”

Modification of distinct ion channels differentially modulates Ca2+ dynamics in primary cultured rat ventricular cardiomyocytes

“…Verapamil is an anti-hypertension drug used in the clinic. Although verapamil is a potent hERG channel blocker, no evidence exists that verapamil can produce LQT syndrome21. We demonstrate that verapamil has no effect on inducing SCO bursts although it decreases SCO frequency.…”

“…LTCCs are directly pertinent to the intracellular Ca 2+ dynamics and are also responsible for the repolarization of the action potentials (APs)21. Activation of LTCC by Bay K 8644 produced irregularity on the SCO pattern with the occurrence of SCO bursts accompanied with increased amplitude and longer FWHM (Fig.…”

“…VGSCs are responsible for the AP generation which is required for the rhythmic cardiomyocyte contraction for cardiomyocytes21. We therefore examined the influence of both VGSC agonist, veratridine and the blocker, tetrodotoxin (TTX) on the SCOs.…”

“…Kvs are responsible for the repolarization of the AP21. 4-aminopyridine (4-AP) is a universal Kv channel blocker24.…”