Comprehensive Cardiac Safety Assessment using hiPS-cardiomyocytes (Consortium for Safety Assessment using Human iPS Cells: CSAHi)

Author(s): Kiyoshi Takasuna*, Katsuyuki Kazusa, Tomohiro Hayakawa

Journal Name: Current Pharmaceutical Biotechnology

Volume 21 , Issue 9 , 2020


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Graphical Abstract:


Abstract:

Current cardiac safety assessment platforms (in vitro hERG-centric, APD, and/or in vivo animal QT assays) are not fully predictive of drug-induced Torsades de Pointes (TdP) and do not address other mechanism-based arrhythmia, including ventricular tachycardia or ventricular fibrillation, or cardiac safety liabilities such as contractile and structural cardiotoxicity which are another growing safety concerns. We organized the Consortium for Safety Assessment using Human iPS cells (CSAHi; http://csahi.org/en/) in 2013, based on the Japan Pharmaceutical Manufacturers Association (JPMA), to verify the application of human iPS/ES cell-derived cardiomyocytes for drug safety evaluation. The CSAHi HEART team focused on comprehensive screening strategies to predict a diverse range of cardiotoxicities using recently introduced platforms such as the Multi-Electrode Array (MEA), cellular impedance, Motion Field Imaging (MFI), and optical imaging of Ca transient to identify strengths and weaknesses of each platform. Our study showed that hiPS-CMs used in these platforms could detect pharmacological responses that were more relevant to humans compared to existing hERG, APD, or Langendorff (MAPD/contraction) assays. Further, MEA and other methods such as impedance, MFI, and Ca transient assays provided paradigm changes of platforms for predicting drug-induced QT risk and/or arrhythmia or contractile dysfunctions. In contrast, since discordances such as overestimation (false positive) of arrhythmogenicity, oversight, or opposite conclusions in positive inotropic and negative chronotropic activities to some compounds were also confirmed, possibly due to their functional immaturity of hiPS-CMs, hiPS-CMs should be used in these platforms for cardiac safety assessment based upon their advantages and disadvantages.

Keywords: hiPS, cardiomyocyte, MEA, impedance, motion field imaging, Ca transient, CSAHi.

[1]
Chi, K.R. Revolution dawning in cardiotoxicity testing. Nat. Rev. Drug Discov., 2013, 12(8), 565-567.
[http://dx.doi.org/10.1038/nrd4083] [PMID: 23903208]
[2]
Laverty, H.; Benson, C.; Cartwright, E.; Cross, M.; Garland, C.; Hammond, T.; Holloway, C.; McMahon, N.; Milligan, J.; Park, B.; Pirmohamed, M.; Pollard, C.; Radford, J.; Roome, N.; Sager, P.; Singh, S.; Suter, T.; Suter, W.; Trafford, A.; Volders, P.; Wallis, R.; Weaver, R.; York, M.; Valentin, J. How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines? Br. J. Pharmacol., 2011, 163(4), 675-693.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01255.x] [PMID: 21306581]
[3]
Stockbridge, N.; Morganroth, J.; Shah, R.R.; Garnett, C. Dealing with global safety issues: was the response to QT-liability of non cardiac drugs well-coordinated? Drug Saf., 2013, 36(3), 167-182.
[http://dx.doi.org/10.1007/s40264-013-0016-z] [PMID: 23417505]
[4]
Bass, A.S.; Darpo, B.; Breidenbach, A.; Bruse, K.; Feldman, H.S.; Garnes, D.; Hammond, T.; Haverkamp, W.; January, C.; Koerner, J.; Lawrence, C.; Leishman, D.; Roden, D.; Valentin, J.P.; Vos, M.A.; Zhou, Y.Y.; Karluss, T.; Sager, P. International Life Sciences Institute (Health and Environmental Sciences Institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes. Br. J. Pharmacol., 2008, 154(7), 1491-1501.
[http://dx.doi.org/10.1038/bjp.2008.279] [PMID: 18663380]
[5]
Sager, P.T.; Gintant, G.; Turner, J.R.; Pettit, S.; Stockbridge, N. Rechanneling the cardiac proarrhythmia safety paradigm: A meeting report from the Cardiac Safety Research Consortium. Am. Heart J., 2014, 167(3), 292-300.
[http://dx.doi.org/10.1016/j.ahj.2013.11.004] [PMID: 24576511]
[6]
Takasuna, K.; Chiba, K.; Manabe, S. Preclinical QT risk assessment in pharmaceutical companies. Issues of current QT risk assessment. Biomol. Ther. (Seoul), 2009, 17, 1-11.
[http://dx.doi.org/10.4062/biomolther.2009.17.1.1]
[7]
Johannesen, L.; Vicente, J.; Mason, J.W.; Sanabria, C.; Waite-Labott, K.; Hong, M.; Guo, P.; Lin, J.; Sørensen, J.S.; Galeotti, L.; Florian, J.; Ugander, M.; Stockbridge, N.; Strauss, D.G. Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil. Clin. Pharmacol. Ther., 2014, 96(5), 549-558.
[http://dx.doi.org/10.1038/clpt.2014.155] [PMID: 25054430]
[8]
Fermini, B.; Hancox, J.C.; Abi-Gerges, N.; Bridgland-Taylor, M.; Chaudhary, K.W.; Colatsky, T.; Correll, K.; Crumb, W.; Damiano, B.; Erdemli, G.; Gintant, G.; Imredy, J.; Koerner, J.; Kramer, J.; Levesque, P.; Li, Z.; Lindqvist, A.; Obejero-Paz, C.A.; Rampe, D.; Sawada, K.; Strauss, D.G.; Vandenberg, J.I. A new perspective in the field of cardiac safety testing through the comprehensive in vitro proarrhythmia assay paradigm. J. Biomol. Screen., 2016, 21(1), 1-11.
[http://dx.doi.org/10.1177/1087057115594589] [PMID: 26170255]
[9]
Colatsky, T.; Fermini, B.; Gintant, G.; Pierson, J.B.; Sager, P.; Sekino, Y.; Strauss, D.G.; Stockbridge, N. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative - Update on progress. J. Pharmacol. Toxicol. Methods, 2016, 81, 15-20.
[http://dx.doi.org/10.1016/j.vascn.2016.06.002] [PMID: 27282641]
[10]
Takasuna, K.; Asakura, K.; Araki, S.; Ando, H.; Kazusa, K.; Kitaguchi, T.; Kunimatsu, T.; Suzuki, S.; Miyamoto, N. Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of CSAHi HEART initiative. J. Pharmacol. Toxicol. Methods, 2017, 83, 42-54.
[http://dx.doi.org/10.1016/j.vascn.2016.09.004] [PMID: 27646297]
[11]
Braam, S.R.; Tertoolen, L.; van de Stolpe, A.; Meyer, T.; Passier, R.; Mummery, C.L. Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes. Stem Cell Res. (Amst.), 2010, 4(2), 107-116.
[http://dx.doi.org/10.1016/j.scr.2009.11.004] [PMID: 20034863]
[12]
Asakura, K.; Hayashi, S.; Ojima, A.; Taniguchi, T.; Miyamoto, N.; Nakamori, C.; Nagasawa, C.; Kitamura, T.; Osada, T.; Honda, Y.; Kasai, C.; Ando, H.; Kanda, Y.; Sekino, Y.; Sawada, K. Improvement of acquisition and analysis methods in multi-electrode array experiments with iPS cell-derived cardiomyocytes. J. Pharmacol. Toxicol. Methods, 2015, 75, 17-26.
[http://dx.doi.org/10.1016/j.vascn.2015.04.002] [PMID: 25910965]
[13]
Kitaguchi, T.; Moriyama, Y.; Taniguchi, T.; Ojima, A.; Ando, H.; Uda, T.; Otabe, K.; Oguchi, M.; Shimizu, S.; Saito, H.; Morita, M.; Toratani, A.; Asayama, M.; Yamamoto, W.; Matsumoto, E.; Saji, D.; Ohnaka, H.; Tanaka, K.; Washio, I.; Miyamoto, N. CSAHi study: Evaluation of multi-electrode array in combination with human iPS cell-derived cardiomyocytes to predict drug-induced QT prolongation and arrhythmia--effects of 7 reference compounds at 10 facilities. J. Pharmacol. Toxicol. Methods, 2016, 78, 93-102.
[http://dx.doi.org/10.1016/j.vascn.2015.12.002] [PMID: 26657830]
[14]
Nozaki, Y.; Honda, Y.; Watanabe, H.; Saiki, S.; Koyabu, K.; Itoh, T.; Nagasawa, C.; Nakamori, C.; Nakayama, C.; Iwasaki, H.; Suzuki, S.; Washio, I.; Takahashi, E.; Miyamoto, K.; Yamanishi, A.; Endo, H.; Shinozaki, J.; Nogawa, H.; Kunimatsu, T. CSAHi study: Validation of multi-electrode array systems (MEA60/2100) for prediction of drug-induced proarrhythmia using human iPS cell derived cardiomyocytes -assessment of inter-facility and cells lot-to-lot-variability. Regul. Toxicol. Pharmacol., 2016, 77, 75-86.
[http://dx.doi.org/10.1016/j.yrtph.2016.02.007] [PMID: 26884090]
[15]
Kitaguchi, T.; Moriyama, Y.; Taniguchi, T.; Maeda, S.; Ando, H.; Uda, T.; Otabe, K.; Oguchi, M.; Shimizu, S.; Saito, H.; Toratani, A.; Asayama, M.; Yamamoto, W.; Matsumoto, E.; Saji, D.; Ohnaka, H.; Miyamoto, N. CSAHi study: Detection of drug-induced ion channel/receptor responses, QT prolongation, and arrhythmia using multi-electrode arrays in combination with human induced pluripotent stem cell-derived cardiomyocytes. J. Pharmacol. Toxicol. Methods, 2017, 85, 73-81.
[http://dx.doi.org/10.1016/j.vascn.2017.02.001] [PMID: 28163191]
[16]
Nozaki, Y.; Honda, Y.; Watanabe, H.; Saiki, S.; Koyabu, K.; Itoh, T.; Nagasawa, C.; Nakamori, C.; Nakayama, C.; Iwasaki, H.; Suzuki, S.; Tanaka, K.; Takahashi, E.; Miyamoto, K.; Morimura, K.; Yamanishi, A.; Endo, H.; Shinozaki, J.; Nogawa, H.; Shinozawa, T.; Saito, F.; Kunimatsu, T. CSAHi study-2: Validation of multi electrode array systems (MEA60/2100) for prediction of drug induced proarrhythmia using human iPS cell-derived cardiomyocytes: Assessment of reference compounds and comparison with non-clinical studies and clinical information. Regul. Toxicol. Pharmacol., 2017, 88, 238-251.
[http://dx.doi.org/10.1016/j.yrtph.2017.06.006] [PMID: 28634147]
[17]
Ando, H.; Yoshinaga, T.; Yamamoto, W.; Asakura, K.; Uda, T.; Taniguchi, T.; Ojima, A.; Shinkyo, R.; Kikuchi, K.; Osada, T.; Hayashi, S.; Kasai, C.; Miyamoto, N.; Tashibu, H.; Yamazaki, D.; Sugiyama, A.; Kanda, Y.; Sawada, K.; Sekino, Y. A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes. J. Pharmacol. Toxicol. Methods, 2017, 84, 111-127.
[http://dx.doi.org/10.1016/j.vascn.2016.12.003] [PMID: 27956204]
[18]
Yamazaki, D.; Kitaguchi, T.; Ishimura, M.; Taniguchi, T.; Yamanishi, A.; Saji, D.; Takahashi, E.; Oguchi, M.; Moriyama, Y.; Maeda, S.; Miyamoto, K.; Morimura, K.; Ohnaka, H.; Tashibu, H.; Sekino, Y.; Miyamoto, N.; Kanda, Y. Proarrhythmia risk prediction using human induced pluripotent stem cell derived cardiomyocytes. J. Pharmacol. Sci., 2018, 136(4), 249-256.
[http://dx.doi.org/10.1016/j.jphs.2018.02.005] [PMID: 29555184]
[19]
Asphahani, F.; Zhang, M. Cellular impedance biosensors for drug screening and toxin detection. Analyst (Lond.), 2007, 132(9), 835-841.
[http://dx.doi.org/10.1039/b704513a] [PMID: 17710258]
[20]
Peters, M.F.; Lamore, S.D.; Guo, L.; Scott, C.W.; Kolaja, K.L. Human stem cell-derived cardiomyocytes in cellular impedance assays: bringing cardiotoxicity screening to the front line. Cardiovasc. Toxicol., 2015, 15(2), 127-139.
[http://dx.doi.org/10.1007/s12012-014-9268-9] [PMID: 25134468]
[21]
Polgár, L.; Lajkó, E.; Soós, P.; Láng, O.; Manea, M.; Merkely, B.; Mező, G.; Kőhidai, L. Drug targeting to decrease cardiotoxicity - determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells. Beilstein J. Org. Chem., 2018, 14, 1583-1594.
[http://dx.doi.org/10.3762/bjoc.14.136] [PMID: 30013686]
[22]
Guo, L.; Abrams, R.M.; Babiarz, J.E.; Cohen, J.D.; Kameoka, S.; Sanders, M.J.; Chiao, E.; Kolaja, K.L. Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol. Sci., 2011, 123(1), 281-289.
[http://dx.doi.org/10.1093/toxsci/kfr158] [PMID: 21693436]
[23]
Guo, L.; Coyle, L.; Abrams, R.M.; Kemper, R.; Chiao, E.T.; Kolaja, K.L. Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol. Sci., 2013, 136(2), 581-594.
[http://dx.doi.org/10.1093/toxsci/kft205] [PMID: 24052561]
[24]
Scott, C.W.; Zhang, X.; Abi-Gerges, N.; Lamore, S.D.; Abassi, Y.A.; Peters, M.F. An impedance-based cellular assay using human iPSC-derived cardiomyocytes to quantify modulators of cardiac contractility. Toxicol. Sci., 2014, 142(2), 331-338.
[http://dx.doi.org/10.1093/toxsci/kfu186] [PMID: 25237062]
[25]
Dolnikov, K.; Shilkrut, M.; Zeevi-Levin, N.; Danon, A.; Gerecht-Nir, S.; Itskovitz-Eldor, J.; Binah, O. Functional properties of human embryonic stem cell-derived cardiomyocytes. Ann. N. Y. Acad. Sci., 2005, 1047, 66-75.
[http://dx.doi.org/10.1196/annals.1341.006] [PMID: 16093485]
[26]
Parikh, S.S.; Blackwell, D.J.; Gomez-Hurtado, N.; Frisk, M.; Wang, L.; Kim, K.; Dahl, C.P.; Fiane, A.; Tønnessen, T.; Kryshtal, D.O.; Louch, W.E.; Knollmann, B.C. Thyroid and glucocorticoid hormones promote functional t-tubule development in human-induced pluripotent stem cell-derived cardiomyocytes. Circ. Res., 2017, 121(12), 1323-1330.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.311920 PMID: 28974554]
[27]
Zhang, X.; Guo, L.; Zeng, H.; White, S.L.; Furniss, M.; Balasubramanian, B.; Lis, E.; Lagrutta, A.; Sannajust, F.; Zhao, L.L.; Xi, B.; Wang, X.; Davis, M.; Abassi, Y.A. Multi-parametric assessment of cardiomyocyte excitation-contraction coupling using impedance and field potential recording: A tool for cardiac safety assessment. J. Pharmacol. Toxicol. Methods, 2016, 81, 201-216.
[http://dx.doi.org/10.1016/j.vascn.2016.06.004] [PMID: 27282640]
[28]
Doerr, L.; Thomas, U.; Guinot, D.R.; Bot, C.T.; Stoelzle-Feix, S.; Beckler, M.; George, M.; Fertig, N. New easy-to-use hybrid system for extracellular potential and impedance recordings. J. Lab. Autom., 2015, 20(2), 175-188.
[http://dx.doi.org/10.1177/2211068214562832] [PMID: 25532527]
[29]
Maddah, M.; Heidmann, J.D.; Mandegar, M.A.; Walker, C.D.; Bolouki, S.; Conklin, B.R.; Loewke, K.E. A non-invasive platform for functional characterization of stem-cell-derived cardiomyocytes with applications in cardiotoxicity testing. Stem Cell Reports, 2015, 4(4), 621-631.
[http://dx.doi.org/10.1016/j.stemcr.2015.02.007 PMID: 25801505]
[30]
Lee, E.K.; Kurokawa, Y.K.; Tu, R.; George, S.C.; Khine, M. Machine learning plus optical flow: A simple and sensitive method to detect cardioactive drugs. Sci. Rep., 2015, 5, 11817.
[http://dx.doi.org/10.1038/srep11817] [PMID: 26139150]
[31]
Mannhardt, I.; Breckwoldt, K.; Letuffe-Brenière, D.; Schaaf, S.; Schulz, H.; Neuber, C.; Benzin, A.; Werner, T.; Eder, A.; Schulze, T.; Klampe, B.; Christ, T.; Hirt, M.N.; Huebner, N.; Moretti, A.; Eschenhagen, T.; Hansen, A. Human engineered heart tissue: Analysis of contractile force. Stem Cell Reports, 2016, 7(1), 29-42.
[http://dx.doi.org/10.1016/j.stemcr.2016.04.011] [PMID: 27211213]
[32]
Takeda, M.; Miyagawa, S.; Fukushima, S.; Saito, A.; Ito, E.; Harada, A.; Matsuura, R.; Iseoka, H.; Sougawa, N.; Mochizuki-Oda, N.; Matsusaki, M.; Akashi, M.; Sawa, Y. Development of in vitro drug-induced cardiotoxicity assay by using three-dimensional cardiac tissues derived from human induced pluripotent stem cells. Tissue Eng. Part C Methods, 2018, 24(1), 56-67.
[http://dx.doi.org/10.1089/ten.tec.2017.0247] [PMID: 28967302]
[33]
van der Linde, H.J.; Van Deuren, B.; Somers, Y.; Loenders, B.; Towart, R.; Gallacher, D.J. The electro-mechanical window: a risk marker for Torsade de Pointes in a canine model of drug induced arrhythmias. Br. J. Pharmacol., 2010, 161(7), 1444-1454.
[http://dx.doi.org/10.1111/j.1476-5381.2010.00934.x PMID: 21054337]
[34]
Isobe, T.; Honda, M.; Komatsu, R.; Tabo, M. Conduction and contraction properties of human iPS cell-derived cardiomyocytes: analysis by motion field imaging compared with the guinea-pig isolated heart model. J. Toxicol. Sci., 2018, 43(8), 493-506.
[http://dx.doi.org/10.2131/jts.43.493] [PMID: 30078835]
[35]
Kawatou, M.; Masumoto, H.; Fukushima, H.; Morinaga, G.; Sakata, R.; Ashihara, T.; Yamashita, J.K. Modelling Torsade de Pointes arrhythmias in vitro in 3D human iPS cell-engineered heart tissue. Nat. Commun., 2017, 8(1), 1078.
[http://dx.doi.org/10.1038/s41467-017-01125-y PMID: 29057872]
[36]
Harmer, A.R.; Abi-Gerges, N.; Morton, M.J.; Pullen, G.F.; Valentin, J.P.; Pollard, C.E. Validation of an in vitro contractility assay using canine ventricular myocytes. Toxicol. Appl. Pharmacol., 2012, 260(2), 162-172.
[http://dx.doi.org/10.1016/j.taap.2012.02.007] [PMID: 22373797]
[37]
Mukherjee, R.; Crawford, F.A.; Hewett, K.W.; Spinale, F.G. Cell and sarcomere contractile performance from the same cardiocyte using video microscopy. J. Appl. Physiol., 1993, 74(4), 2023-2033.
[http://dx.doi.org/10.1152/jappl.1993.74.4.2023] [PMID: 8514725]
[38]
Feaster, T.K.; Cadar, A.G.; Wang, L.; Williams, C.H.; Chun, Y.W.; Hempel, J.E.; Bloodworth, N.; Merryman, W.D.; Lim, C.C.; Wu, J.C.; Knollmann, B.C.; Hong, C.C. Matrigel Mattress: A method for the generation of single contracting human-induced pluripotent stem cell-derived cardiomyocytes. Circ. Res., 2015, 117(12), 995-1000.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.307580 PMID: 26429802]
[39]
Ahola, A.; Kiviaho, A.L.; Larsson, K.; Honkanen, M.; Aalto-Setälä, K.; Hyttinen, J. Video image-based analysis of single human induced pluripotent stem cell derived cardiomyocyte beating dynamics using digital image correlation. Biomed. Eng. Online, 2014, 13, 39.
[http://dx.doi.org/10.1186/1475-925X-13-39] [PMID: 24708714]
[40]
Czirok, A.; Isai, D.G.; Kosa, E.; Rajasingh, S.; Kinsey, W.; Neufeld, Z.; Rajasingh, J. Optical-flow based non-invasive analysis of cardiomyocyte contractility. Sci. Rep., 2017, 7(1), 10404.
[http://dx.doi.org/10.1038/s41598-017-10094-7 PMID: 28871207]
[41]
Hayakawa, T.; Kunihiro, T.; Ando, T.; Kobayashi, S.; Matsui, E.; Yada, H.; Kanda, Y.; Kurokawa, J.; Furukawa, T. Image-based evaluation of contraction-relaxation kinetics of human-induced pluripotent stem cell-derived cardiomyocytes: Correlation and complementarity with extracellular electrophysiology. J. Mol. Cell. Cardiol., 2014, 77, 178-191.
[http://dx.doi.org/10.1016/j.yjmcc.2014.09.010] [PMID: 25257913]
[42]
Hayakawa, T.; Kunihiro, T.; Dowaki, S.; Uno, H.; Matsui, E.; Uchida, M.; Kobayashi, S.; Yasuda, A.; Shimizu, T.; Okano, T. Noninvasive evaluation of contractile behavior of cardiomyocyte monolayers based on motion vector analysis. Tissue Eng. Part C Methods, 2012, 18(1), 21-32.
[http://dx.doi.org/10.1089/ten.tec.2011.0273] [PMID: 21851323]
[43]
Sala, L.; van Meer, B.J.; Tertoolen, L.G.J.; Bakkers, J.; Bellin, M.; Davis, R.P.; Denning, C.; Dieben, M.A.E.; Eschenhagen, T.; Giacomelli, E.; Grandela, C.; Hansen, A.; Holman, E.R.; Jongbloed, M.R.M.; Kamel, S.M.; Koopman, C.D.; Lachaud, Q.; Mannhardt, I.; Mol, M.P.H.; Mosqueira, D.; Orlova, V.V.; Passier, R.; Ribeiro, M.C.; Saleem, U.; Smith, G.L.; Burton, F.L.; Mummery, C.L. Muscle motion: A versatile open software tool to quantify cardiomyocyte and cardiac muscle contraction in vitro and in vivo. Circ. Res., 2018, 122(3), e5-e16.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.312067 PMID: 29282212]
[44]
Kitani, T.; Ong, S.G.; Lam, C.K.; Rhee, J.W.; Zhang, J.Z.; Oikonomopoulos, A.; Ma, N.; Tian, L.; Lee, J.; Telli, M.L.; Witteles, R.M.; Sharma, A.; Sayed, N.; Wu, J.C. Human induced pluripotent stem cell model of trastuzumab-induced cardiac dysfunction in breast cancer patients. Circulation, 2019, 139(21), 2451-2465.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.037357] [PMID: 30866650]
[45]
Ribeiro, A.J.; Ang, Y.S.; Fu, J.D.; Rivas, R.N.; Mohamed, T.M.; Higgs, G.C.; Srivastava, D.; Pruitt, B.L. Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness. Proc. Natl. Acad. Sci. USA, 2015, 112(41), 12705-12710.
[http://dx.doi.org/10.1073/pnas.1508073112] [PMID: 26417073]
[46]
Ribeiro, A.J.S.; Schwab, O.; Mandegar, M.A.; Ang, Y.S.; Conklin, B.R.; Srivastava, D.; Pruitt, B.L. Multi-imaging method to assay the contractile mechanical output of micropatterned human iPSC-derived cardiac myocytes. Circ. Res., 2017, 120(10), 1572-1583.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.310363 PMID: 28400398]
[47]
Hazeltine, L.B.; Simmons, C.S.; Salick, M.R.; Lian, X.; Badur, M.G.; Han, W.; Delgado, S.M.; Wakatsuki, T.; Crone, W.C.; Pruitt, B.L.; Palecek, S.P. Effects of substrate mechanics on contractility of cardiomyocytes generated from human pluripotent stem cells. Int. J. Cell Biol., 2012, 2012, 508294
[http://dx.doi.org/10.1155/2012/508294] [PMID: 22649451]
[48]
Ronaldson-Bouchard, K.; Ma, S.P.; Yeager, K.; Chen, T.; Song, L.; Sirabella, D.; Morikawa, K.; Teles, D.; Yazawa, M.; Vunjak-Novakovic, G. Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature, 2018, 556(7700), 239-243.
[http://dx.doi.org/10.1038/s41586-018-0016-3] [PMID: 29618819]
[49]
Rodriguez, M.L.; Graham, B.T.; Pabon, L.M.; Han, S.J.; Murry, C.E.; Sniadecki, N.J. Measuring the contractile forces of human induced pluripotent stem cell-derived cardiomyocytes with arrays of microposts. J. Biomech. Eng., 2014, 136(5) 051005
[http://dx.doi.org/10.1115/1.4027145] [PMID: 24615475]
[50]
Pointon, A.; Pilling, J.; Dorval, T.; Wang, Y.; Archer, C.; Pollard, C. From the cover: High-throughput imaging of cardiac microtissues for the assessment of cardiac contraction during drug discovery. Toxicol. Sci., 2017, 155(2), 444-457.
[http://dx.doi.org/10.1093/toxsci/kfw227] [PMID: 28069985]
[51]
Kopljar, I.; De Bondt, A.; Vinken, P.; Teisman, A.; Damiano, B.; Goeminne, N.; Van den Wyngaert, I.; Gallacher, D.J.; Lu, H.R. Chronic drug-induced effects on contractile motion properties and cardiac biomarkers in human induced pluripotent stem cell-derived cardiomyocytes. Br. J. Pharmacol., 2017, 174(21), 3766-3779.
[http://dx.doi.org/10.1111/bph.13713] [PMID: 28094846]
[52]
Ma, X.; Dewan, S.; Liu, J.; Tang, M.; Miller, K.L.; Yu, C.; Lawrence, N.; McCulloch, A.D.; Chen, S. 3D printed micro-scale force gauge arrays to improve human cardiac tissue maturation and enable high throughput drug testing. Acta Biomater., 2019, 95, 319-327.
[PMID: 30576862]
[53]
Schroer, A.; Pardon, G.; Castillo, E.; Blair, C.; Pruitt, B. Engineering hiPSC cardiomyocyte in vitro model systems for functional and structural assessment. Prog. Biophys. Mol. Biol., 2019, 144, 3-15.
[http://dx.doi.org/10.1016/j.pbiomolbio.2018.12.001] [PMID: 30579630]
[54]
Huebsch, N.; Loskill, P.; Deveshwar, N.; Spencer, C.I.; Judge, L.M.; Mandegar, M.A.; Fox, C.B.; Mohamed, T.M.; Ma, Z.; Mathur, A.; Sheehan, A.M.; Truong, A.; Saxton, M.; Yoo, J.; Srivastava, D.; Desai, T.A.; So, P.L.; Healy, K.E.; Conklin, B.R. Miniaturized iPS-cell-derived cardiac muscles for physiologically relevant drug response analyses. Sci. Rep., 2016, 6, 24726.
[http://dx.doi.org/10.1038/srep24726] [PMID: 27095412]
[55]
Polacheck, W.J.; Chen, C.S. Measuring cell-generated forces: A guide to the available tools. Nat. Methods, 2016, 13(5), 415-423.
[http://dx.doi.org/10.1038/nmeth.3834] [PMID: 27123817]
[56]
Denning, C.; Borgdorff, V.; Crutchley, J.; Firth, K.S.; George, V.; Kalra, S.; Kondrashov, A.; Hoang, M.D.; Mosqueira, D.; Patel, A.; Prodanov, L.; Rajamohan, D.; Skarnes, W.C.; Smith, J.G.; Young, L.E. Cardiomyocytes from human pluripotent stem cells: From laboratory curiosity to industrial biomedical platform. Biochim. Biophys. Acta, 2016, 1863(7 Pt B), 1728-1748.
[http://dx.doi.org/10.1016/j.bbamcr.2015.10.014] [PMID: 26524115]
[57]
Gintant, G.; Sager, P.T.; Stockbridge, N. Evolution of strategies to improve preclinical cardiac safety testing. Nat. Rev. Drug Discov., 2016, 15(7), 457-471.
[http://dx.doi.org/10.1038/nrd.2015.34] [PMID: 26893184]
[58]
Robertson, C.; Tran, D.D.; George, S.C. Concise review: Maturation phases of human pluripotent stem cell-derived cardiomyocytes. Stem Cells, 2013, 31(5), 829-837.
[http://dx.doi.org/10.1002/stem.1331] [PMID: 23355363]
[59]
Lu, H.R.; Whittaker, R.; Price, J.H.; Vega, R.; Pfeiffer, E.R.; Cerignoli, F.; Towart, R.; Gallacher, D.J. High throughput measurement of Ca++ dynamics in human stem cell-derived cardiomyocytes by kinetic image cytometery: A cardiac risk assessment characterization using a large panel of cardioactive and inactive compounds. Toxicol. Sci., 2015, 148(2), 503-516.
[http://dx.doi.org/10.1093/toxsci/kfv201] [PMID: 26358003]
[60]
Zeng, H.; Roman, M.I.; Lis, E.; Lagrutta, A.; Sannajust, F. Use of FDSS/μCell imaging platform for preclinical cardiac electrophysiology safety screening of compounds in human induced pluripotent stem cell-derived cardiomyocytes. J. Pharmacol. Toxicol. Methods, 2016, 81, 217-222.
[http://dx.doi.org/10.1016/j.vascn.2016.05.009] [PMID: 27222351]
[61]
Kopljar, I.; Hermans, A.N.; Teisman, A.; Gallacher, D.J.; Lu, H.R. Impact of calcium-sensitive dyes on the beating properties and pharmacological responses of human iPS-derived cardiomyocytes using the calcium transient assay. J. Pharmacol. Toxicol. Methods, 2018, 91, 80-86.
[http://dx.doi.org/10.1016/j.vascn.2018.02.004] [PMID: 29421525]
[62]
Sirenko, O.; Cromwell, E.F.; Crittenden, C.; Wignall, J.A.; Wright, F.A.; Rusyn, I. Assessment of beating parameters in human induced pluripotent stem cells enables quantitative in vitro screening for cardiotoxicity. Toxicol. Appl. Pharmacol., 2013, 273(3), 500-507.
[http://dx.doi.org/10.1016/j.taap.2013.09.017] [PMID: 24095675]
[63]
Sirenko, O.; Crittenden, C.; Callamaras, N.; Hesley, J.; Chen, Y.W.; Funes, C.; Rusyn, I.; Anson, B.; Cromwell, E.F. Multiparameter in vitro assessment of compound effects on cardiomyocyte physiology using iPSC cells. J. Biomol. Screen., 2013, 18(1), 39-53.
[http://dx.doi.org/10.1177/1087057112457590] [PMID: 22972846]
[64]
Abi-Gerges, N.; Pointon, A.; Oldman, K.L.; Brown, M.R.; Pilling, M.A.; Sefton, C.E.; Garside, H.; Pollard, C.E. Assessment of extracellular field potential and Ca2+ transient signals for early QT/pro arrhythmia detection using human induced pluripotent stem cell derived cardiomyocytes. J. Pharmacol. Toxicol. Methods, 2017, 83, 1-15.
[http://dx.doi.org/10.1016/j.vascn.2016.09.001] [PMID: 27622857]
[65]
Laurila, E.; Ahola, A.; Hyttinen, J.; Aalto-Setälä, K. Methods for in vitro functional analysis of iPSC derived cardiomyocytes - Special focus on analyzing the mechanical beating behavior. Biochimica et Biophysica Acta, 2015, S0167-4889(15), 00434-00436.
[66]
Spencer, C.I.; Baba, S.; Nakamura, K.; Hua, E.A.; Sears, M.A.; Fu, C.C.; Zhang, J.; Balijepalli, S.; Tomoda, K.; Hayashi, Y.; Lizarraga, P.; Wojciak, J.; Scheinman, M.M.; Aalto-Setälä, K.; Makielski, J.C.; January, C.T.; Healy, K.E.; Kamp, T.J.; Yamanaka, S.; Conklin, B.R. Calcium transients closely reflect prolonged action potentials in iPSC models of inherited cardiac arrhythmia. Stem Cell Reports, 2014, 3(2), 269-281.
[http://dx.doi.org/10.1016/j.stemcr.2014.06.003] [PMID: 25254341]
[67]
Bedut, S.; Seminatore-Nole, C.; Lamamy, V.; Caignard, S.; Boutin, J.A.; Nosjean, O.; Stephan, J-P.; Coge, F. High-throughput drug profiling with voltage- and calcium-sensitive fluorescent probes in human iPSC-derived cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol., 2016, 311(1), H44-H53.
[http://dx.doi.org/10.1152/ajpheart.00793.2015] [PMID: 27199128]
[68]
Prajapati, C.; Pölönen, R-P.; Aalto-Setälä, K. Simultaneous recordings of action potentials and calcium transients from human induced pluripotent stem cell derived cardiomyocytes. Biol. Open, 2018, 7(7), 1-14.
[http://dx.doi.org/10.1242/bio.035030] [PMID: 29970475]
[69]
January, C.T.; Moscucci, A. Cellular mechanisms of early afterdepolarizations. Ann. N. Y. Acad. Sci., 1992, 644, 23-32.
[http://dx.doi.org/10.1111/j.1749-6632.1992.tb30999.x] [PMID: 1562117]
[70]
Qu, Y.; Gao, B.; Fang, M.; Vargas, H.M. Human embryonic stem cell derived cardiac myocytes detect hERG-mediated repolarization effects, but not Nav1.5 induced depolarization delay. J. Pharmacol. Toxicol. Methods, 2013, 68(1), 74-81.
[http://dx.doi.org/10.1016/j.vascn.2013.03.001] [PMID: 23518063]
[71]
Hondeghem, L.M. Use and abuse of QT and TRIaD in cardiac safety research: Importance of study design and conduct. Eur. J. Pharmacol., 2008, 584(1), 1-9.
[http://dx.doi.org/10.1016/j.ejphar.2008.01.016] [PMID: 18304526]
[72]
Lu, H.R.; Yan, G.X.; Gallacher, D.J. A new biomarker--index of cardiac electrophysiological balance (iCEB)--plays an important role in drug-induced cardiac arrhythmias: Beyond QT-prolongation and Torsades de Pointes (TdPs). J. Pharmacol. Toxicol. Methods, 2013, 68(2), 250-259.
[http://dx.doi.org/10.1016/j.vascn.2013.01.003] [PMID: 23337247]
[73]
Robyns, T.; Lu, H.R.; Gallacher, D.J.; Garweg, C.; Ector, J.; Willems, R.; Nuyens, D. Evaluation of Index of Cardio-Electrophysiological Balance (iCEB) as a new biomarker for the identification of patients at increased arrhythmic risk. Ann. Noninvasive Electrocardiol., 2016, 21(3), 294-304.
[http://dx.doi.org/10.1111/anec.12309] [PMID: 26305685]
[74]
Guns, P.J.; Johnson, D.M.; Van Op den Bosch, J.; Weltens, E.; Lissens, J. The electro-mechanical window in anaesthetized guinea pigs: a new marker in screening for Torsade de Pointes risk. Br. J. Pharmacol., 2012, 166(2), 689-701.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01795.x ] [PMID: 22122450]
[75]
Limprasutr, V.; Pirintr, P.; Kijtawornrat, A.; Hamlin, R.L. An increasing electromechanical window is a predictive marker of ventricular fibrillation in anesthetized rabbit with ischemic heart. Exp. Anim., 2018, 67(2), 175-183.
[http://dx.doi.org/10.1538/expanim.17-0100] [PMID: 29162767]
[76]
Kramer, J.; Obejero-Paz, C.A.; Myatt, G.; Kuryshev, Y.A.; Bruening-Wright, A.; Verducci, J.S.; Brown, A.M. MICE models: Superior to the HERG model in predicting Torsade de Pointes. Sci. Rep., 2013, 3, 2100.
[http://dx.doi.org/10.1038/srep02100] [PMID: 23812503]
[77]
Johannesen, L.; Vicente, J.; Mason, J.W.; Erato, C.; Sanabria, C.; Waite-Labott, K.; Hong, M.; Lin, J.; Guo, P.; Mutlib, A.; Wang, J.; Crumb, W.J.; Blinova, K.; Chan, D.; Stohlman, J.; Florian, J.; Ugander, M.; Stockbridge, N.; Strauss, D.G. Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial. Clin. Pharmacol. Ther., 2016, 99(2), 214-223.
[http://dx.doi.org/10.1002/cpt.205] [PMID: 26259627]
[78]
Blinova, K.; Dang, Q.; Millard, D.; Smith, G.; Pierson, J.; Guo, L.; Brock, M.; Lu, H.R.; Kraushaar, U.; Zeng, H.; Shi, H.; Zhang, X.; Sawada, K.; Osada, T.; Kanda, Y.; Sekino, Y.; Pang, L.; Feaster, T.K.; Kettenhofen, R.; Stockbridge, N.; Strauss, D.G.; Gintant, G. International multisite study of human-induced pluripotent stem cell-derived cardiomyocytes for drug proarrhythmic potential assessment. Cell Rep., 2018, 24(13), 3582-3592.
[http://dx.doi.org/10.1016/j.celrep.2018.08.079] [PMID: 30257217]
[79]
Blinova, K.; Stohlman, J.; Vicente, J.; Chan, D.; Johannesen, L.; Hortigon-Vinagre, M.P.; Zamora, V.; Smith, G.; Crumb, W.J.; Pang, L.; Lyn-Cook, B.; Ross, J.; Brock, M.; Chvatal, S.; Millard, D.; Galeotti, L.; Stockbridge, N.; Strauss, D.G. Comprehensive translational assessment of human-induced pluripotent stem cell derived cardiomyocytes for evaluating drug-induced arrhythmias. Toxicol. Sci., 2017, 155(1), 234-247.
[http://dx.doi.org/10.1093/toxsci/kfw200] [PMID: 27701120]
[80]
Lemoine, M.D.; Mannhardt, I.; Breckwoldt, K.; Prondzynski, M.; Flenner, F.; Ulmer, B.; Hirt, M.N.; Neuber, C.; Horváth, A.; Kloth, B.; Reichenspurner, H.; Willems, S.; Hansen, A.; Eschenhagen, T.; Christ, T. Human iPSC-derived cardiomyocytes cultured in 3D engineered heart tissue show physiological upstroke velocity and sodium current density. Sci. Rep., 2017, 7(1), 5464.
[http://dx.doi.org/10.1038/s41598-017-05600-w] [PMID: 28710467]
[81]
Nguyen, N.; Nguyen, W.; Nguyenton, B.; Ratchada, P.; Page, G.; Miller, P.E.; Ghetti, A.; Abi-Gerges, N. Adult human primary cardiomyocyte-based model for the simultaneous prediction of drug induced inotropic and pro-arrhythmia risk. Front. Physiol., 2017, 8, 1073.
[http://dx.doi.org/10.3389/fphys.2017.01073] [PMID: 29311989]
[82]
Pointon, A.; Harmer, A.R.; Dale, I.L.; Abi-Gerges, N.; Bowes, J.; Pollard, C.; Garside, H. Assessment of cardiomyocyte contraction in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol. Sci., 2015, 144(2), 227-237.
[http://dx.doi.org/10.1093/toxsci/kfu312] [PMID: 25538221]
[83]
Mummery, C.; Ward-van Oostwaard, D.; Doevendans, P.; Spijker, R.; van den Brink, S.; Hassink, R.; van der Heyden, M.; Opthof, T.; Pera, M.; de la Riviere, A.B.; Passier, R.; Tertoolen, L. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Circulation, 2003, 107(21), 2733-2740.
[http://dx.doi.org/10.1161/01.CIR.0000068356.38592.68] [PMID: 12742992]
[84]
Li, S.; Chen, G.; Li, R.A. Calcium signalling of human pluripotent stem cell-derived cardiomyocytes. J. Physiol., 2013, 591(21), 5279-5290.
[http://dx.doi.org/10.1113/jphysiol.2013.256495] [PMID: 24018947]
[85]
Kolanowski, T.J.; Antos, C.L.; Guan, K. Making human cardiomyocytes up to date: Derivation, maturation state and perspectives. Int. J. Cardiol., 2017, 241, 379-386.
[http://dx.doi.org/10.1016/j.ijcard.2017.03.099] [PMID: 28377185]
[86]
Millard, D.; Dang, Q.; Shi, H.; Zhang, X.; Strock, C.; Kraushaar, U.; Zeng, H.; Levesque, P.; Lu, H.R.; Guillon, J.M.; Wu, J.C.; Li, Y.; Luerman, G.; Anson, B.; Guo, L.; Clements, M.; Abassi, Y.A.; Ross, J.; Pierson, J.; Gintant, G. Cross-Site Reliability of Human Induced Pluripotent stem cell-derived cardiomyocyte based safety assays using microelectrode arrays: Results from a blinded CiPA pilot study. Toxicol. Sci., 2018, 164(2), 550-562.
[http://dx.doi.org/10.1093/toxsci/kfy110] [PMID: 29718449]
[87]
Pfeiffer-Kaushik, E.R.; Smith, G.L.; Cai, B.; Dempsey, G.T.; Hortigon-Vinagre, M.P.; Zamora, V.; Feng, S.; Ingermanson, R.; Zhu, R.; Hariharan, V.; Nguyen, C.; Pierson, J.; Gintant, G.A.; Tung, L. Electrophysiological characterization of drug response in hSC-derived cardiomyocytes using voltage-sensitive optical platforms. J. Pharmacol. Toxicol. Methods, 2019,. 106612
[http://dx.doi.org/10.1016/j.vascn.2019.106612] [PMID: 31319140]


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VOLUME: 21
ISSUE: 9
Year: 2020
Published on: 09 June, 2020
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DOI: 10.2174/1389201020666191024172425
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