title: 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.
authors.affiliation: Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8563, Japan. ; UT-Heart Inc., 3-25-8 Nozawa, Setagaya-ku, Tokyo 154-0003, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Okada
authors.affiliation: Global CV Assessment, Eisai Co. Ltd., Tokodai 5-1-3, Tsukua-shi, Ibaraki 300-2635, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshinaga
authors.affiliation: Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kurokawa
authors.affiliation: Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8563, Japan. ; UT-Heart Inc., 3-25-8 Nozawa, Setagaya-ku, Tokyo 154-0003, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Washio
authors.affiliation: Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Global CV Assessment, Eisai Co. Ltd., Tokodai 5-1-3, Tsukua-shi, Ibaraki 300-2635, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sawada
authors.affiliation: Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8563, Japan. ; UT-Heart Inc., 3-25-8 Nozawa, Setagaya-ku, Tokyo 154-0003, Japan.
authors.forename: Seiryo
authors.initials: S
authors.lastname: Sugiura
authors.affiliation: Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8563, Japan. ; UT-Heart Inc., 3-25-8 Nozawa, Setagaya-ku, Tokyo 154-0003, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hisada
keywords: Cardiotoxicity; Heart Simulator; Torsade de pointes; drug screening; finite element method