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Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator.

ABSTRACT: To save time and cost for drug discovery, a paradigm shift in cardiotoxicity testing is required. We introduce a novel screening system for drug-induced arrhythmogenic risk that combines in vitro pharmacological assays and a multiscale heart simulator. For 12 drugs reported to have varying cardiotoxicity risks, dose-inhibition curves were determined for six ion channels using automated patch clamp systems. By manipulating the channel models implemented in a heart simulator consisting of more than 20 million myocyte models, we simulated a standard electrocardiogram (ECG) under various doses of drugs. When the drug concentrations were increased from therapeutic levels, each drug induced a concentration-dependent characteristic type of ventricular arrhythmia, whereas no arrhythmias were observed at any dose with drugs known to be safe. We have shown that our system combining in vitro and in silico technologies can predict drug-induced arrhythmogenic risk reliably and efficiently.

SUBMITTER: Okada J 

PROVIDER: S-EPMC4640654 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator.

Okada Jun-Ichi J   Yoshinaga Takashi T   Kurokawa Junko J   Washio Takumi T   Furukawa Tetsushi T   Sawada Kohei K   Sugiura Seiryo S   Hisada Toshiaki T  

Science advances 20150501 4

To save time and cost for drug discovery, a paradigm shift in cardiotoxicity testing is required. We introduce a novel screening system for drug-induced arrhythmogenic risk that combines in vitro pharmacological assays and a multiscale heart simulator. For 12 drugs reported to have varying cardiotoxicity risks, dose-inhibition curves were determined for six ion channels using automated patch clamp systems. By manipulating the channel models implemented in a heart simulator consisting of more tha  ...[more]

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