Research Papers

Computational Investigation of Drug Action on Human-Induced Stem Cell-Derived Cardiomyocytes

[+] Author and Article Information
Ralf Frotscher

Biomechanics Laboratory,
Institute for Bioengineering,
Aachen University of Applied Sciences,
Jülich 52428, Germany
e-mail: frotscher@fh-aachen.de

Jan-Peter Koch

Biomechanics Laboratory,
Institute for Bioengineering,
Aachen University of Applied Sciences,
Jülich 52428, Germany

Manfred Staat

Biomechanics Laboratory,
Institute for Bioengineering,
Aachen University of Applied Sciences,
Jülich 52428, Germany
e-mail: m.staat@fh-aachen.de

1Corresponding author.

Manuscript received November 27, 2014; final manuscript received March 13, 2015; published online June 2, 2015. Assoc. Editor: Pasquale Vena.

J Biomech Eng 137(7), 071002 (Jul 01, 2015) (7 pages) Paper No: BIO-14-1593; doi: 10.1115/1.4030173 History: Received November 27, 2014; Revised March 13, 2015; Online June 02, 2015

We compare experimental and computational results for the actions of the cardioactive drugs Lidocaine, Verapamil, Veratridine, and Bay K 8644 on a tissue monolayer consisting of mainly fibroblasts and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSc-CM). The choice of the computational models is justified and literature data is collected to model drug action as accurately as possible. The focus of this work is to evaluate the validity and capability of existing models for native human cells with respect to the simulation of pharmaceutical treatment of monolayers and hiPSc-CM. From the comparison of experimental and computational results, we derive suggestions for model improvements which are intended to computationally support the interpretation of experimental results obtained for hiPSc-CM.

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Takahashi, K., and Yamanaka, S., 2006, “Induction of Pluripotent Stem Cells From Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors,” Cell, 126(4), pp. 663–676. [CrossRef] [PubMed]
Linder, P., Trzewik, J., Rüffer, M., Artmann, G. M., Digel, I., Kurz, R., Rothermel, A., Robitzki, A., and Temiz Artmann, A., 2010, “Contractile Tension and Beating Rates of Self-Exciting Monolayers and 3D-Tissue Constructs of Neonatal Rat Cardiomyocytes,” Med. Biol. Eng. Comput., 48(1), pp. 59–65. [CrossRef] [PubMed]
Frotscher, R., Goßmann, M., Raatschen, H.-J., Temiz-Artmann, A., and Staat, M., 2015, “Simulation of Cardiac Cell-Seeded Membranes Using the Edge-Based Smoothed FEM,” Shell and Membrane Theories in Mechanics and Biology, H.Altenbach and G. I.Mikhasev, eds., Springer International, Vol. 45, pp. 187–212. [CrossRef]
Frotscher, R., Koch, J.-P., Raatschen, H.-J., and Staat, M., 2014, “Evaluation of a Computational Model for Drug Action on Cardiac Tissue,” 11th World Congress on Computational Mechanics (WCCM XI), 5th European Conference on Computational Mechanics (ECCM V), 6th European Conference on Computational Fluid Dynamics (ECFD VI), Oñate, E., Oliver, J., and Huerta, A., eds., pp. 1425–1436. http://www.wccm-eccm-ecfd2014.org/admin/files/fileabstract/a633.pdf
Aaronson, P., Ward, J., and Connelly, M., 2012, The Cardiovascular System at a Glance, 4 ed., Wiley Blackwell, Oxford, UK.
ten Tusscher, K. H. W. J., and Panfilov, A. V., 2006, “Alternans and Spiral Breakup in a Human Ventricular Tissue Model,” Am. J. Physiol. Heart Circ. Physiol., 291(3), pp. H1088–H1100. [CrossRef] [PubMed]
McAllister, R. E., Noble, D., and Tsien, R. W., 1975, “Reconstruction of the Electrical Activity of Cardiac Purkinje Fibres,” J. Physiol., 251(1), pp. 1–59. [CrossRef] [PubMed]
Seemann, G., Höper, C., Sachse, F. B., Dössel, O., Holden, A. V., and Zhang, H., 2006, “Heterogeneous Three-Dimensional Anatomical and Electrophysiological Model of Human Atria,” Philos. Trans. Ser. A, 364(1843), pp. 1465–1481. [CrossRef]
Chandler, N. J., Greener, I. D., Tellez, J. O., Inada, S., Musa, H., Molenaar, P., Difrancesco, D., Baruscotti, M., Longhi, R., Anderson, R. H., Billeter, R., Sharma, V., Sigg, D. C., Boyett, M. R., and Dobrzynski, H., 2009, “Molecular Architecture of the Human Sinus Node: Insights Into the Function of the Cardiac Pacemaker,” Circulation, 119(12), pp. 1562–1575. [CrossRef] [PubMed]
Rhodes, S. S., Ropella, K. M., Camara, A. K. S., Chen, Q., Riess, M. L., and Stowe, D. F., 2003, “How Inotropic Drugs Alter Dynamic and Static Indices of Cyclic Myoplasmic [Ca2+] to Contractility Relationships in Intact Hearts,” J. Cardiovasc. Pharmacol., 42(4), pp. 539–553. [CrossRef] [PubMed]
Honerjäger, P., Loibl, E., Steidl, I., Schönsteiner, G., and Ulm, K., 1986, “Negative Inotropic Effects of Tetrodotoxin and Seven Class 1 Antiarrhythmic Drugs in Relation to Sodium Channel Blockade,” Naunyn-Schmiedeberg's Arch. Pharmacol., 332(2), pp. 184–195. [CrossRef]
Rocchetti, M., Armato, A., Cavalieri, B., Micheletti, M., and Zaza, A., 1999, “Lidocaine Inhibition of the Hyperpolarization-Activated Current (I(f)) in Sinoatrial Myocytes,” J. Cardiovasc. Pharmacol., 34(3), pp. 434–439. [CrossRef] [PubMed]
Sirenko, O., Crittenden, C., Callamaras, N., Hesley, J., Chen, Y.-W., Funes, C., Rusyn, I., Anson, B., and Cromwell, E. F., 2013, “Multiparameter In Vitro Assessment of Compound Effects on Cardiomyocyte Physiology Using iPSC Cells,” J. Biomol. Screening, 18(1), pp. 39–53. [CrossRef]
Wright, A.-B., 2011, “Stem Cell Derived Human Cardiomyocytes: Utility for Risk Evaluation and Determining Complex Mechanisms of Drug Action,” ChanTest Corporation. Available at: http://www.chantest.com/media/cms/pdf/SC-hCM-Webinar-1101.pdf
Stoelzle, S., Haythornthwaite, A., Kettenhofen, R., Kolossov, E., Bohlen, H., George, M., Brüggemann, A., and Fertig, N., 2011, “Automated Patch Clamp on mESC-Derived Cardiomyocytes for Cardiotoxicity Prediction,” J. Biomol. Screening, 16(8), pp. 910–916. [CrossRef]
Hill, R. J., Duff, H. J., and Sheldon, R. S., 1989, “Class I Antiarrhythmic Drug Receptor: Biochemical Evidence for State-Dependent Interaction With Quinidine and Lidocaine,” Mol. Pharmacol., 36(1), pp. 150–159. [PubMed]
Zhang, S., Zhou, Z., Gong, Q., Makielski, J. C., and January, C. T., 1999, “Mechanism of Block and Identification of the Verapamil Binding Domain to HERG Potassium Channels,” Circ. Res., 84(9), pp. 989–998. [CrossRef] [PubMed]
Kramer, J., Obejero-Paz, C. A., Myatt, G., Kuryshev, Y. A., Bruening-Wright, A., Verducci, J. S., and Brown, A. M., 2013, “MICE Models: Superior to the HERG Model in Predicting Torsade de Pointes,” Sci. Rep., 3, Article No. 2100. [CrossRef] [PubMed]
Liang, P., Lan, F., Lee, A. S., Gong, T., Sanchez-Freire, V., Wang, Y., Diecke, S., Sallam, K., Knowles, J. W., Wang, P. J., Nguyen, P. K., Bers, D. M., Robbins, R. C., and Wu, J. C., 2013, “Drug Screening Using a Library of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveals Disease-Specific Patterns of Cardiotoxicity,” Circulation, 127(16), pp. 1677–1691. [CrossRef] [PubMed]
Zahradníková, A., Minarovic, I., and Zahradník, I., 2007, “Competitive and Cooperative Effects of Bay K8644 on the L-Type Calcium Channel Current Inhibition by Calcium Channel Antagonists,” J. Pharmacol. Exp. Ther., 322(2), pp. 638–645. [CrossRef] [PubMed]
Saleh, S., Yeung, S. Y. M., Prestwich, S., Pucovsky, V., and Greenwood, I., 2005, “Electrophysiological and Molecular Identification of Voltage-Gated Sodium Channels in Murine Vascular Myocytes,” J. Physiol., 568(Pt 1), pp. 155–169. [CrossRef] [PubMed]
Galper, J. B., and Catterall, W. A., 1978, “Developmental Changes in the Sensitivity of Embryonic Heart Cells to Tetrodotoxin and D600,” Dev. Biol., 65(1), pp. 216–227. [CrossRef] [PubMed]
Pang, D. C., and Sperelakis, N., 1982, “Veratridine Stimulation of Calcium Uptake by Chick Embryonic Heart Cells in Culture,” J. Mol. Cell. Cardiol., 14(12), pp. 703–709. [CrossRef] [PubMed]
Chen, X., 2002, “L-Type Ca2+ Channel Density and Regulation are Altered in Failing Human Ventricular Myocytes and Recover After Support With Mechanical Assist Devices,” Circ. Res., 91(6), pp. 517–524. [CrossRef] [PubMed]
Kang, J., Chen, X.-l., Ji, J., Lei, Q., and Rampe, D., 2012, “Ca2+ Channel Activators Reveal Differential L-Type Ca2+ Channel Pharmacology Between Native and Stem Cell-Derived Cardiomyocytes,” J. Pharmacol. Exp. Ther., 341(2), pp. 510–517. [CrossRef] [PubMed]
Ji, J., Kang, J., and Rampe, D., 2014, “L-Type Ca(2+) Channel Responses to Bay K 8644 in Stem Cell-Derived Cardiomyocytes are Unusually Dependent on Holding Potential and Charge Carrier,” Assay Drug Dev. Technol., 12(6), pp. 352–360. [CrossRef] [PubMed]
Obiol-Pardo, C., Gomis-Tena, J., Sanz, F., Saiz, J., and Pastor, M., 2011, “A Multiscale Simulation System for the Prediction of Drug-Induced Cardiotoxicity,” J. Chem. Inf. Model., 51(2), pp. 483–492. [CrossRef] [PubMed]
Niederer, S. A., and Smith, N. P., 2008, “An Improved Numerical Method for Strong Coupling of Excitation and Contraction Models in the Heart,” Prog. Biophys. Mol. Biol., 96(1–3), pp. 90–111. [CrossRef] [PubMed]
Hunter, P. J., McCulloch, A. D., and ter Keurs, H., 1998, “Modelling the Mechanical Properties of Cardiac Muscle,” Prog. Biophys. Mol. Biol., 69(2–3), pp. 289–331. [CrossRef] [PubMed]
Courtemanche, M., Ramirez, R. J., and Nattel, S., 1998, “Ionic Mechanisms Underlying Human Atrial Action Potential Properties: Insights From a Mathematical Model,” Am. J. Physiol., 275(1), pp. H301–H321. [PubMed]
Wiegerinck, R. F., Cojoc, A., Zeidenweber, C. M., Ding, G., Shen, M., Joyner, R. W., Fernandez, J. D., Kanter, K. R., Kirshbom, P. M., Kogon, B. E., and Wagner, M. B., 2009, “Force Frequency Relationship of the Human Ventricle Increases During Early Postnatal Development,” Pediatr. Res., 65(4), pp. 414–419. [CrossRef] [PubMed]
Mehta, A., Chung, Y. Y., Ng, A., Iskandar, F., Atan, S., Wei, H., Dusting, G., Sun, W., Wong, P., and Shim, W., 2011, “Pharmacological Response of Human Cardiomyocytes Derived From Virus-Free Induced Pluripotent Stem Cells,” Cardiovasc. Res., 91(4), pp. 577–586. [CrossRef] [PubMed]
Harris, K., Aylott, M., Cui, Y., Louttit, J. B., McMahon, N. C., and Sridhar, A., 2013, “Comparison of Electrophysiological Data From Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes to Functional Preclinical Safety Assays,” Toxicol. Sci., 134(2), pp. 412–426. [CrossRef] [PubMed]


Grahic Jump Location
Fig. 1

Bulge test in the CellDrumTM: (a) pressure-deflection curves, (b) change in deflection during individual beats, and (c) schematic drawing (figure composed from Ref. [3])

Grahic Jump Location
Fig. 2

Inotropic effect of Lidocaine in experiment (dashed line), simulation paced at 1 Hz (continuous, square markers), and paced at measured frequencies (continuous, triangular markers)

Grahic Jump Location
Fig. 3

Inotropic effect of Verapamil in experiment (dashed line), simulation using the models TT–NHS (continuous, square markers), and MNT–HMT (continuous, circular markers)

Grahic Jump Location
Fig. 4

Inotropic effect of Veratridine in experiment (dashed line), simulation paced at 1 Hz (continuous, square markers), and paced at measured frequencies (continuous, triangular markers)

Grahic Jump Location
Fig. 5

Inotropic effect of Bay K 8644 in experiment (dashed line), simulation paced at 1 Hz (continuous, square markers), and paced at measured frequencies (continuous, triangular markers)

Grahic Jump Location
Fig. 6

Chronotropic effect of Lidocaine in experiment (dashed line), MNT simulation (continuous, circular markers), Chandler simulation (continuous, diamond markers), and Seemann simulation (continuous, rectangular markers)

Grahic Jump Location
Fig. 7

Chronotropic effect of Veratridine in experiment (dashed line), MNT simulation (continuous, circular markers), Chandler simulation (continuous, diamond markers), and Seemann simulation (continuous, rectangular markers)

Grahic Jump Location
Fig. 8

Chronotropic effect of Bay K 8644 in experiment, Chandler simulation (continuous, diamond markers), and Seemann simulation (continuous, rectangular markers)



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