Action potential-based MEA platform for in vitro screening of drug-induced cardiotoxicity using human iPSCs and rat neonatal myocytes.

Drug-induced cardiotoxicity poses a negative impact on public health and drug development. Cardiac safety pharmacology issues urged for the preclinical assessment of drug-induced ventricular arrhythmia leading to the design of several in vitro electrophysiological screening assays. In general, patch clamp systems allow for intracellular recordings, while multi-electrode array (MEA) technology detect extracellular activity. Here, we demonstrate a complementary metal oxide semiconductor (CMOS)-based MEA system as a reliable platform for non-invasive, long-term intracellular recording of cardiac action potentials at high resolution. Quinidine (8 concentrations from 10 ^-7 to 2.10 ^-5 M) and verapamil (7 concentrations from 10 ^-11 to 10 ^-5 M) were tested for dose-dependent responses in a network of cardiomyocytes. Electrophysiological parameters, such as the action potential duration (APD), rates of depolarization and repolarization and beating frequency were assessed. In hiPSC, quinidine prolonged APD with EC ₅₀ of 2.2·10 ^-6 M. Further analysis indicated a multifactorial action potential prolongation by quinidine: (1) decreasing fast repolarization with IC ₅₀ of 1.1·10 ^-6 M; (2) reducing maximum upstroke velocity with IC ₅₀ of 2.6·10 ^-6 M; and (3) suppressing spontaneous activity with EC ₅₀ of 3.8·10 ^-6 M. In rat neonatal cardiomyocytes, verapamil blocked spontaneous activity with EC ₅₀ of 5.3·10 ^-8 M and prolonged the APD with EC ₅₀ of 2.5·10 ^-8 M. Verapamil reduced rates of fast depolarization and repolarization with IC ₅₀ s of 1.8 and 2.2·10 ^-7 M, respectively. In conclusion, the proposed action potential-based MEA platform offers high quality and stable long-term recordings with high information content allowing to characterize multi-ion channel blocking drugs. We anticipate application of the system as a screening platform to efficiently and cost-effectively test drugs for cardiac safety.
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