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CSAHi study: Evaluation of MED64 multi-electrode array in combination with human iPS cell-derived cardiomyocytes to predict drug-induced QT prolongation and arrhythmia
384
Abstracts
0162 Assessment of drug-induced QT prolongation using human iPS cell-derived mature cardiomyocytes Yasunari Kandaa, Min Lib, Takashi Ashiharac, Yuko Sekinoa, Tetsushi Furukawab, Junko Kurokawab a Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan b Department of Bio-informational Pharmacology, Tokyo Medical and Dental University, Medical Research Institute, Tokyo, Japan c Department of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan
The comprehensive in vitro proarrhythmia assay (CiPA) initiative proposes a paradigm shift in cardiac safety assessment relying on the comprehensive mechanistic understanding of TdP. In the studies presented we utilized hiPSC-derived Cor.4U cardiomyocytes to compare the effects of dofetilide, E-4031, flecainide, moxifloxacin, ranolazine, quinidine, nifedipine, verapamil, TTX, and ATX II reference compounds in either manual patch clamp and microelectrode array (MEA) recordings with HTS compatible fluorescent calcium and voltage sensitive dye assays. The results nicely reveal that hiPSC-derived Cor.4U cardiomyocytes are suitable in either of these assays for CiPA.
doi:10.1016/j.vascn.2016.02.160 Drug-induced arrhythmias have been a major reason for drug attrition. Since current non-clinical QT prolongation testing is not enough to predict drug-induced proarrhythmia, human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) might be a powerful tool for cardiac drug safety testing as a human cell model. Our patch-clamp technique revealed that hiPS-CMs exhibited diverse shapes of spontaneous action potentials (APs) with relatively depolarized maximum diastolic potential (MDP), suggesting an immature differentiation state of the hiPS-CMs. We then generated electrophysiological mature hiPS-CMs by overexpressing of gene X into hiPS-CMs and characterized the utility for evaluation of drug effects on cardiac repolarization process. The viral transduction of gene X made hiPS-CMs quiescent in several iPS/ES cell lines. The gene X-transduced iPS-CMs had a more hyperpolarized MDP and were excitable with electrical field stimulation. The hERG blocker E4031 prolonged AP durations in gene X-transduced iPS-CM and FP durations of hiPS-CM 2D sheets in a dose-dependent manner. Furthermore, we performed mathematical simulation to understand our pharmacological data using hiPSC-derived mature cardiomyocytes. These data suggest that the mature hiPS-CMs are a good model for QT prolongation. Thus, our novel approach would provide new insights into the evaluation of cardiac safety of QT-prolonging drugs in iPS-CMs. doi:10.1016/j.vascn.2016.02.159
0163 Human iPSC-derived Cor.4U cardiomyocytes as a predictive tool for different comprehensive in vitro proarrhythmia assay endpoints Ralf Kettenhofena, Anika Duenbostella, Greg Luermanb, Ping Lic, Yimei Yuec, Jared Bronsonc, Hirofumi Horaid, Jean Marc D'Angeloe, Thomas Niedereichholzf, John Ken Gibsona a
Axiogenesis AG, Cologne, Germany Axiogenesis Inc., Plymouth Meeting, PA, USA c Ionic Transport Assays Inc., St. Louis, MO, USA d Hamamatsu Photonics, Hamamatsu, Japan e Hamamatsu Photonics, Massy, France f Hamamatsu Photonics, Herrsching, Germany b
The current assessment of the clinical potential of drug candidates to induce life threatening Torsade-des-Pointes arrhythmias (TdP) as described in the ICHS7B and E14 guidelines is primarily based on hERG block and QT prolongation as surrogate markers for proarrhythmia. These methods largely eliminated new drugs with unanticipated proarrhythmic potentials from entering the market but eventually led to a stop of the development of potentially valuable drug candidates.
0164 CSAHi study: Evaluation of MED64 multi-electrode array in combination with human iPS cell-derived cardiomyocytes to predict drug-induced QT prolongation and arrhythmia Takashi Kitaguchia,c, Yuta Moriyamab,c, Norimasa Miyamotoa,d, Tomohiko Taniguchib,d, Atsuko Ojimab,d, Hiroyuki Andoa,e, Takaaki Udab,e, Koji Otabeb,f, Masao Oguchib,f, Shigekazu Shimizub,g, Hiroyuki Saitob,g, Maya Moritab,h, Atsushi Toratanib,i, Mahoko Asayamab,i, Wataru Yamamotob,j, Emi Matsumotob,j, Daisuke Sajib,k, Hiroki Ohnakab,k, Ikumi Washiob,l, Masakazu Ishimurab,m a Japan Pharmaceutical Manufacturers Association (JPMA) Drug Evaluation Committee Non-Clinical Evaluation Expert Committee, TF2/Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Tokyo, Japan b Consortium for Safety Assessment using Human iPS Cells (CSAHi), Tokyo, Japan c Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan d Eisai Co., Ltd., Ibaraki, Japan e Ono Pharmaceutical Co., Ltd., Fukui, Japan f Ina Research Inc., Nagano, Japan g CMIC BIORESEARCH CENTER Co., Ltd., Yamanashi, Japan h Takeda Pharmaceutical Company Limited, Kanagawa, Japan i Mitsubishi Tanabe Pharma Corporation, Chiba/Saitama, Japan j Teijin Pharma Limited, Tokyo, Japan k NISSEI BILIS Co., Ltd., Shiga, Japan l Nippon Boehringer Ingelheim Co., Ltd., Hyogo, Japan m Kaken Pharmaceutical Co., Ltd., Kyoto, Japan
Introduction: Drug-induced QT prolongation is a major safety issue during drug development, because it may lead to lethal ventricular arrhythmias. In this study, we evaluated the utility of multi-electrode arrays (MEA) with human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to predict drug-induced QT prolongation and arrhythmia in multiple pharmaceutical companies and research institutes. Methods: Eleven facilities evaluated the effects of reference drugs under the same experimental conditions using a MED64 MEA system with commercially available hiPS-CMs (iCell® cardiomyocytes). Field potential duration (FPD), beat rate, FPD corrected by Fridericia's formula (FPDc), concentrations inducing 10% FPDc prolongation (FPDc10), and incidence of early afterdepolarization (EAD) or triggered activity (TA)-like waveform were assessed. Results and conclusion: The CSAHi reached a consensus that MEA using hiPS-CMs can detect 1) the response to various cardiac ion channel and receptor, 2) EAD and/or TA-like waveforms, which might correlate with clinical arrhythmia, and 3) the effects of drugs within acceptable range of inter-facility variability and
Abstracts
reproducibility. Additionally, MEA with hiPS-CMs can detect clinical QT prolongation and/or arrhythmogenic liability more sensitively as compared to existing in vitro and ex vivo assays. Therefore our results indicate that MEA with hiPS-CMs can be a novel and generalized platform to predict drug-induced QT prolongation and arrhythmia in human. doi:10.1016/j.vascn.2016.02.161
0165 An in vitro assessment of delayed HDAC inhibitor-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes Ivan Kopljar, Eddy Vlaminckx, Hua Rong Lu, David Gallacher Janssen Pharmaceutica, Beerse, Belgium Histone deacetylases (HDAC) are enzymes involved in the epigenetic regulation of gene transcription and are promising targets to treat various cancers. Unfortunately, the therapeutic potential of HDAC inhibitors is hampered by reports of various cardiotoxicities in clinical studies (i.e. atrial fibrillations, long QT and torsade de pointes). However, the underlying molecular mechanism remains poorly understood and cardiotoxicity is difficult to detect in early stages of pre-clinical safety pharmacology due to the delayed onset of effects. In this study, we evaluated whether human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are suitable as a translational model for HDAC inhibitor-mediated cardiotoxicity in humans. We investigated the long-term (84 h) effects of 5 HDAC inhibitors (Dacinostat, Panobinostat, Vorinostat, Entinostat and Tubastatin-A) on the beating properties of hiPS-CMs using an impedance-based functional assay. HDAC inhibitors did not show acute effects but instead developed delayed cardiotoxicity with an onset after ±12 h. HDAC inhibitors decreased in a concentrationdependent manner the beat rate and amplitude of contractions, and caused arrhythmia-‘like’ events (sustained contractions, fibrillations). There was a good correlation between the side effects on hiPS-CM function and the incidence of cardiac adverse effects (based on free plasma Cmax) observed with different HDAC inhibitors in the clinic. Next, we identified changes in transcriptional expression in hiPS-CMs identifying several genes/pathways that might be linked to HDAC inhibitor-mediated cardiotoxicity. Our findings suggest that hiPS-CMs have a potential value in the detection of HDAC inhibitormediated delayed cardiotoxicity in humans. doi:10.1016/j.vascn.2016.02.162
0166 CSAHi study: Usability assessment of multi-electrode array in combination with human iPS cell-derived cardiomyocytes for prediction of drug-induced QT prolongation and arrhythmia — Multi Channel Systems (MEA60 and MEA2100) Takeshi Kunimatsua,b, Yumiko Nozakia, Yayoi Hondaa, Hitoshi Watanabea, Atsuhiro Yamanishib,c, Hisashi Nogawac, Hiroko Endoc, Shota Saikib,d, Chiho Nagasawab,e, Chiaki Nakamorie, Chiaki Nakayamae, Hiroshi Iwasakie, Etsushi Takahashib,f, Kaori Miyamotof, Kaoru Morimuraf, Kohji Tanakab,g, Shinobu Suzukib,g, Ikumi Washiog a Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co. Ltd., Osaka, Japan
385
b
Japan Pharmaceutical Manufacturers Association (JPMA), Drug Evaluation Committee Non-Clinical Evaluation Expert Committee, TF2/Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Tokyo, Japan c Toxicology Research Laboratory, Kyorin Pharmaceutical Co. Ltd., Tochigi, Japan d Research Laboratory for Development, Shionogi & Co., Ltd., Osaka, Japan e Research Center, Taisho Pharmaceutical Co., Ltd., Saitama, Japan f Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan g Nippon Boehringer Ingelheim Co., Ltd., Hyogo, Japan To predict drug-induced QT prolongation and Torsade de Pointes (TdP) in clinical practice, both in vitro and in vivo non-clinical assessments are recommended under ICH S7B guideline. Inhibition of hERG channel is one of the critical events leading to QT prolongation and thus has been a standard surrogate marker. However, proarrhythmia is known to be evoked by various causes including mutual action on ion channels other than hERG channel, and interspecies variation prevents reliable link to clinical relevance. Japan Pharmaceutical Manufacturers Association has created a consortium for drug safety assessment using Human iPS Cells (CSAHi)' in an effort to establish a novel test system that would enable better prediction of drug-induced proarrhythmia/QT prolongation. Six Japanese pharmaceutical companies belonged to the CSAHi assessed the effects of about 40 reference compounds on beat rate, FPDc and FPDc10 using a multi-electrode array (MEA) manufactured by Multi Channel Systems in human iPS cell-derived Cardiomyocytes (hiPS-CMs) based on an optimized standard protocol. We introduce the entire results of hiPS-CMs using MEA system in CSAHi study and compare with in vitro and in vivo assessment of cardiovascular events. doi:10.1016/j.vascn.2016.02.163
0167 Could in vitro animal assays be replaced by human stem cell-based assays for drug-induced cardiac risks: Beyond QT-prolongation/CIPA? Hua Rong Lu, An Hermans, Ivan Kopljar, Jutta Rohrbacher, Ard Teisman, David J. Gallacher Global Safety Pharmacology, Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are increasingly used as a new source of cardiac cells for drug safety assessment. Indeed, attention to this field has increased in response to the FDA/HESI's CiPA proposal on July 2013. We investigated the effects of 20 reference compounds (with different mechanisms of action, mostly known to have cardiac effects) in different stem cellbased technologies, including a high content screen (HCS)-Ca2 + transient measurement, Multi-electrode Array (MEA) and fluorescence-optical action potential measurement. For these 20 drugs we compared the stem cell-based technologies with the in vitro-isolated rabbit wedge model and the isolated guinea-pig right atrium model. In addition, we investigated the drug-induced acute and delayed effects in an impedance-based assay (xCELLigence) using hiPS-CMs. Our data suggested that 1). Using hiPS-CMs with HCS screen technologies (Ca2 + transients and Optical AP) could be suitable to detect drug-induced QTprolongation, shortening, and increase in beat rate; 2). The xCELLigence technology could be used to detect drug-induced delayed cardiac effects in vitro. However, due to the current nature of hiPS-CMs (i.e. immature, in 2D and lack of supporting/connections with fibroblasts, neuronal- and
Abstracts
0162 Assessment of drug-induced QT prolongation using human iPS cell-derived mature cardiomyocytes Yasunari Kandaa, Min Lib, Takashi Ashiharac, Yuko Sekinoa, Tetsushi Furukawab, Junko Kurokawab a Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan b Department of Bio-informational Pharmacology, Tokyo Medical and Dental University, Medical Research Institute, Tokyo, Japan c Department of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan
The comprehensive in vitro proarrhythmia assay (CiPA) initiative proposes a paradigm shift in cardiac safety assessment relying on the comprehensive mechanistic understanding of TdP. In the studies presented we utilized hiPSC-derived Cor.4U cardiomyocytes to compare the effects of dofetilide, E-4031, flecainide, moxifloxacin, ranolazine, quinidine, nifedipine, verapamil, TTX, and ATX II reference compounds in either manual patch clamp and microelectrode array (MEA) recordings with HTS compatible fluorescent calcium and voltage sensitive dye assays. The results nicely reveal that hiPSC-derived Cor.4U cardiomyocytes are suitable in either of these assays for CiPA.
doi:10.1016/j.vascn.2016.02.160 Drug-induced arrhythmias have been a major reason for drug attrition. Since current non-clinical QT prolongation testing is not enough to predict drug-induced proarrhythmia, human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) might be a powerful tool for cardiac drug safety testing as a human cell model. Our patch-clamp technique revealed that hiPS-CMs exhibited diverse shapes of spontaneous action potentials (APs) with relatively depolarized maximum diastolic potential (MDP), suggesting an immature differentiation state of the hiPS-CMs. We then generated electrophysiological mature hiPS-CMs by overexpressing of gene X into hiPS-CMs and characterized the utility for evaluation of drug effects on cardiac repolarization process. The viral transduction of gene X made hiPS-CMs quiescent in several iPS/ES cell lines. The gene X-transduced iPS-CMs had a more hyperpolarized MDP and were excitable with electrical field stimulation. The hERG blocker E4031 prolonged AP durations in gene X-transduced iPS-CM and FP durations of hiPS-CM 2D sheets in a dose-dependent manner. Furthermore, we performed mathematical simulation to understand our pharmacological data using hiPSC-derived mature cardiomyocytes. These data suggest that the mature hiPS-CMs are a good model for QT prolongation. Thus, our novel approach would provide new insights into the evaluation of cardiac safety of QT-prolonging drugs in iPS-CMs. doi:10.1016/j.vascn.2016.02.159
0163 Human iPSC-derived Cor.4U cardiomyocytes as a predictive tool for different comprehensive in vitro proarrhythmia assay endpoints Ralf Kettenhofena, Anika Duenbostella, Greg Luermanb, Ping Lic, Yimei Yuec, Jared Bronsonc, Hirofumi Horaid, Jean Marc D'Angeloe, Thomas Niedereichholzf, John Ken Gibsona a
Axiogenesis AG, Cologne, Germany Axiogenesis Inc., Plymouth Meeting, PA, USA c Ionic Transport Assays Inc., St. Louis, MO, USA d Hamamatsu Photonics, Hamamatsu, Japan e Hamamatsu Photonics, Massy, France f Hamamatsu Photonics, Herrsching, Germany b
The current assessment of the clinical potential of drug candidates to induce life threatening Torsade-des-Pointes arrhythmias (TdP) as described in the ICHS7B and E14 guidelines is primarily based on hERG block and QT prolongation as surrogate markers for proarrhythmia. These methods largely eliminated new drugs with unanticipated proarrhythmic potentials from entering the market but eventually led to a stop of the development of potentially valuable drug candidates.
0164 CSAHi study: Evaluation of MED64 multi-electrode array in combination with human iPS cell-derived cardiomyocytes to predict drug-induced QT prolongation and arrhythmia Takashi Kitaguchia,c, Yuta Moriyamab,c, Norimasa Miyamotoa,d, Tomohiko Taniguchib,d, Atsuko Ojimab,d, Hiroyuki Andoa,e, Takaaki Udab,e, Koji Otabeb,f, Masao Oguchib,f, Shigekazu Shimizub,g, Hiroyuki Saitob,g, Maya Moritab,h, Atsushi Toratanib,i, Mahoko Asayamab,i, Wataru Yamamotob,j, Emi Matsumotob,j, Daisuke Sajib,k, Hiroki Ohnakab,k, Ikumi Washiob,l, Masakazu Ishimurab,m a Japan Pharmaceutical Manufacturers Association (JPMA) Drug Evaluation Committee Non-Clinical Evaluation Expert Committee, TF2/Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Tokyo, Japan b Consortium for Safety Assessment using Human iPS Cells (CSAHi), Tokyo, Japan c Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan d Eisai Co., Ltd., Ibaraki, Japan e Ono Pharmaceutical Co., Ltd., Fukui, Japan f Ina Research Inc., Nagano, Japan g CMIC BIORESEARCH CENTER Co., Ltd., Yamanashi, Japan h Takeda Pharmaceutical Company Limited, Kanagawa, Japan i Mitsubishi Tanabe Pharma Corporation, Chiba/Saitama, Japan j Teijin Pharma Limited, Tokyo, Japan k NISSEI BILIS Co., Ltd., Shiga, Japan l Nippon Boehringer Ingelheim Co., Ltd., Hyogo, Japan m Kaken Pharmaceutical Co., Ltd., Kyoto, Japan
Introduction: Drug-induced QT prolongation is a major safety issue during drug development, because it may lead to lethal ventricular arrhythmias. In this study, we evaluated the utility of multi-electrode arrays (MEA) with human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) to predict drug-induced QT prolongation and arrhythmia in multiple pharmaceutical companies and research institutes. Methods: Eleven facilities evaluated the effects of reference drugs under the same experimental conditions using a MED64 MEA system with commercially available hiPS-CMs (iCell® cardiomyocytes). Field potential duration (FPD), beat rate, FPD corrected by Fridericia's formula (FPDc), concentrations inducing 10% FPDc prolongation (FPDc10), and incidence of early afterdepolarization (EAD) or triggered activity (TA)-like waveform were assessed. Results and conclusion: The CSAHi reached a consensus that MEA using hiPS-CMs can detect 1) the response to various cardiac ion channel and receptor, 2) EAD and/or TA-like waveforms, which might correlate with clinical arrhythmia, and 3) the effects of drugs within acceptable range of inter-facility variability and
Abstracts
reproducibility. Additionally, MEA with hiPS-CMs can detect clinical QT prolongation and/or arrhythmogenic liability more sensitively as compared to existing in vitro and ex vivo assays. Therefore our results indicate that MEA with hiPS-CMs can be a novel and generalized platform to predict drug-induced QT prolongation and arrhythmia in human. doi:10.1016/j.vascn.2016.02.161
0165 An in vitro assessment of delayed HDAC inhibitor-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes Ivan Kopljar, Eddy Vlaminckx, Hua Rong Lu, David Gallacher Janssen Pharmaceutica, Beerse, Belgium Histone deacetylases (HDAC) are enzymes involved in the epigenetic regulation of gene transcription and are promising targets to treat various cancers. Unfortunately, the therapeutic potential of HDAC inhibitors is hampered by reports of various cardiotoxicities in clinical studies (i.e. atrial fibrillations, long QT and torsade de pointes). However, the underlying molecular mechanism remains poorly understood and cardiotoxicity is difficult to detect in early stages of pre-clinical safety pharmacology due to the delayed onset of effects. In this study, we evaluated whether human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are suitable as a translational model for HDAC inhibitor-mediated cardiotoxicity in humans. We investigated the long-term (84 h) effects of 5 HDAC inhibitors (Dacinostat, Panobinostat, Vorinostat, Entinostat and Tubastatin-A) on the beating properties of hiPS-CMs using an impedance-based functional assay. HDAC inhibitors did not show acute effects but instead developed delayed cardiotoxicity with an onset after ±12 h. HDAC inhibitors decreased in a concentrationdependent manner the beat rate and amplitude of contractions, and caused arrhythmia-‘like’ events (sustained contractions, fibrillations). There was a good correlation between the side effects on hiPS-CM function and the incidence of cardiac adverse effects (based on free plasma Cmax) observed with different HDAC inhibitors in the clinic. Next, we identified changes in transcriptional expression in hiPS-CMs identifying several genes/pathways that might be linked to HDAC inhibitor-mediated cardiotoxicity. Our findings suggest that hiPS-CMs have a potential value in the detection of HDAC inhibitormediated delayed cardiotoxicity in humans. doi:10.1016/j.vascn.2016.02.162
0166 CSAHi study: Usability assessment of multi-electrode array in combination with human iPS cell-derived cardiomyocytes for prediction of drug-induced QT prolongation and arrhythmia — Multi Channel Systems (MEA60 and MEA2100) Takeshi Kunimatsua,b, Yumiko Nozakia, Yayoi Hondaa, Hitoshi Watanabea, Atsuhiro Yamanishib,c, Hisashi Nogawac, Hiroko Endoc, Shota Saikib,d, Chiho Nagasawab,e, Chiaki Nakamorie, Chiaki Nakayamae, Hiroshi Iwasakie, Etsushi Takahashib,f, Kaori Miyamotof, Kaoru Morimuraf, Kohji Tanakab,g, Shinobu Suzukib,g, Ikumi Washiog a Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co. Ltd., Osaka, Japan
385
b
Japan Pharmaceutical Manufacturers Association (JPMA), Drug Evaluation Committee Non-Clinical Evaluation Expert Committee, TF2/Consortium for Safety Assessment using Human iPS Cells (CSAHi): HEART team, Tokyo, Japan c Toxicology Research Laboratory, Kyorin Pharmaceutical Co. Ltd., Tochigi, Japan d Research Laboratory for Development, Shionogi & Co., Ltd., Osaka, Japan e Research Center, Taisho Pharmaceutical Co., Ltd., Saitama, Japan f Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan g Nippon Boehringer Ingelheim Co., Ltd., Hyogo, Japan To predict drug-induced QT prolongation and Torsade de Pointes (TdP) in clinical practice, both in vitro and in vivo non-clinical assessments are recommended under ICH S7B guideline. Inhibition of hERG channel is one of the critical events leading to QT prolongation and thus has been a standard surrogate marker. However, proarrhythmia is known to be evoked by various causes including mutual action on ion channels other than hERG channel, and interspecies variation prevents reliable link to clinical relevance. Japan Pharmaceutical Manufacturers Association has created a consortium for drug safety assessment using Human iPS Cells (CSAHi)' in an effort to establish a novel test system that would enable better prediction of drug-induced proarrhythmia/QT prolongation. Six Japanese pharmaceutical companies belonged to the CSAHi assessed the effects of about 40 reference compounds on beat rate, FPDc and FPDc10 using a multi-electrode array (MEA) manufactured by Multi Channel Systems in human iPS cell-derived Cardiomyocytes (hiPS-CMs) based on an optimized standard protocol. We introduce the entire results of hiPS-CMs using MEA system in CSAHi study and compare with in vitro and in vivo assessment of cardiovascular events. doi:10.1016/j.vascn.2016.02.163
0167 Could in vitro animal assays be replaced by human stem cell-based assays for drug-induced cardiac risks: Beyond QT-prolongation/CIPA? Hua Rong Lu, An Hermans, Ivan Kopljar, Jutta Rohrbacher, Ard Teisman, David J. Gallacher Global Safety Pharmacology, Discovery Sciences, Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are increasingly used as a new source of cardiac cells for drug safety assessment. Indeed, attention to this field has increased in response to the FDA/HESI's CiPA proposal on July 2013. We investigated the effects of 20 reference compounds (with different mechanisms of action, mostly known to have cardiac effects) in different stem cellbased technologies, including a high content screen (HCS)-Ca2 + transient measurement, Multi-electrode Array (MEA) and fluorescence-optical action potential measurement. For these 20 drugs we compared the stem cell-based technologies with the in vitro-isolated rabbit wedge model and the isolated guinea-pig right atrium model. In addition, we investigated the drug-induced acute and delayed effects in an impedance-based assay (xCELLigence) using hiPS-CMs. Our data suggested that 1). Using hiPS-CMs with HCS screen technologies (Ca2 + transients and Optical AP) could be suitable to detect drug-induced QTprolongation, shortening, and increase in beat rate; 2). The xCELLigence technology could be used to detect drug-induced delayed cardiac effects in vitro. However, due to the current nature of hiPS-CMs (i.e. immature, in 2D and lack of supporting/connections with fibroblasts, neuronal- and