Comparison of in vitro and computational experiments on the relation of inter-beat interval and duration of repolarization in a specific type of human induced pluripotent stem cell-derived cardiomyocytes


Autoři: Philipp Kügler aff001;  Georg Rast aff002;  Brian D. Guth aff002
Působiště autorů: Institute of Applied Mathematics and Statistics, Computational Science Lab, University of Hohenheim, Stuttgart, Germany aff001;  Department of Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany aff002;  Department of Pharmaceutical Sciences, North-West University, Potchefstroom Campus, Potchefstroom, South Africa aff003
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0221763

Souhrn

We compared a published computational model of the action potential of a specific type of human induced pluripotent stem cell -derived cardiomyocytes (hiPSC-CM) with experimental field potential data with regard to their inter-beat interval and the duration of repolarization. In particular, concomitant changes in inter-beat interval and duration of repolarization were calculated after reduction and/or augmentation of specific ion channel conductances as a surrogate for pharmacological manipulation. The observed mismatches between calculations and experimental data indicate that there is information missing about the cellular test system. Based on our results we hypothesize that, among other currents, the actual If (“funny current”) may deviate from the prediction. We show that replacement of the If formulation by alternative equations causes the model predictions to change qualitatively, however, none of the available formulations is actually achieving a satisfactory match with experimental data. We suggest a strategy to clarify whether the mismatch can be completely resolved at all using single cell models and, if yes, how this goal could be reached.

Klíčová slova:

Research and analysis methods – Simulation and modeling – Mathematical and statistical techniques – Mathematical functions – Curve fitting – Animal studies – Experimental organism systems – Animal models – Rabbits – Biology and life sciences – Physiology – Electrophysiology – Membrane potential – Action potentials – Neurophysiology – Neuroscience – Biochemistry – Proteins – Cell biology – Cellular types – Animal cells – Anatomy – Biological tissue – Organisms – Eukaryota – Animals – Vertebrates – Amniotes – Mammals – Leporids – Medicine and health sciences – Muscle tissue – Muscle cells – Cardiomyocytes – Physical sciences – Physics – Biophysics – Mathematics – Algebra – Polynomials – Computer and information sciences – Data visualization – Infographics – Graphs


Zdroje

1. Rast G, Kraushaar U, Buckenmaier S, Ittrich C, Guth BD. Influence of field potential duration on spontaneous beating rate of human induced pluripotent stem cell-derived cardiomyocytes: Implications for data analysis and test system selection. J Pharmacol Toxicol Methods. 2016; 82: 74–82. doi: 10.1016/j.vascn.2016.08.002 27521052

2. Guo L, Abrams RM, Babiarz JE, Cohen JD, Kameoka S, Sanders MJ, et al. Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2011; 123(1): 281–289. doi: 10.1093/toxsci/kfr158 21693436

3. Nakamura Y, Matsuo J, Miyamoto N, Ojima A, Ando K, Kanda Y, et al. Assessment of testing methods for drug-induced repolarization delay and arrhythmias in an iPS cell-derived cardiomyocyte sheet: multi-site validation study. J Pharmacol Sci. 2014; 124(4): 494–501. 24694996

4. Qu Y, Vargas HM. Proarrhythmia Risk Assessment in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Using the Maestro MEA Platform. Toxicol Sci. 2015; 147(1): 286–295. doi: 10.1093/toxsci/kfv128 26117837

5. Paci M, Hyttinen J, Aalto-Setälä K, Severi S. Computational models of ventricular- and atrial-like human induced pluripotent stem cell derived cardiomyocytes. Ann Biomed Eng. 2013; 41(11): 2334–2348. doi: 10.1007/s10439-013-0833-3 23722932

6. Paci M, Passini E, Severi S, Hyttinen J, Rodriguez B. Phenotypic variability in LQT3 human induced pluripotent stem cell-derived cardiomyocytes and their response to antiarrhythmic pharmacologic therapy: An in silico approach. Heart Rhythm. 2017; 14(11):1704–1712. doi: 10.1016/j.hrthm.2017.07.026 28756098

7. Paci M, Pölönen RP, Cori D, Penttinen K, Aalto-Setälä K, Severi S, et al. Automatic Optimization of an in Silico Model of Human iPSC Derived Cardiomyocytes Recapitulating Calcium Handling Abnormalities. Front Physiol. 2018; 9: 709. doi: 10.3389/fphys.2018.00709 29997516

8. Paci M, Hyttinen J, Rodriguez B, Severi S. Human induced pluripotent stem cell-derived versus adult cardiomyocytes: an in silico electrophysiological study on effects of ionic current block. Br J Pharmacol. 2015; 172(21): 5147–5160. doi: 10.1111/bph.13282 26276951

9. Severi S, Fantini M, Charawi LA, DiFrancesco D. An updated computational model of rabbit sinoatrial action potential to investigate the mechanisms of heart rate modulation. J Physiol. 2012; 590(18): 4483–4499. doi: 10.1113/jphysiol.2012.229435 22711956

10. Koivumäki JT, Naumenko N, Tuomainen T, Takalo J, Oksanen M, Puttonen KA, et al. Structural Immaturity of Human iPSC-Derived Cardiomyocytes: In Silico Investigation of Effects on Function and Disease Modeling. Front Physiol. 2018; 9(80). doi: 10.3389/fphys.2018.00080 29467678

11. Fabbri A, Fantini M, Wilders R, Severi S. Computational analysis of the human sinus node action potential: model development and effects of mutations. J Physiol. 2017;595(7):2365–2396. doi: 10.1113/JP273259 28185290

12. Rast G, Weber J, Disch C, Schuck E, Ittrich C, Guth BD. An integrated platform for simultaneous multi-well field potential recording and Fura-2-based calcium transient ratiometry in human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. J Pharmacol Toxicol Methods. 2015; 75: 91–100. doi: 10.1016/j.vascn.2015.04.005 25921432

13. Passini E, Britton OJ, Lu HR, Rohrbacher J, Hermans AN, Gallacher DJ, et al. Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity. Front Physiol. 2017; 8:668. doi: 10.3389/fphys.2017.00668 28955244

14. Vaden SL, Adams HR. Inotropic, chronotropic and coronary vasodilator potency of forskolin. Eur J Pharmacol. 1985; 118(1–2): 131–137. doi: 10.1016/0014-2999(85)90671-5 3002808

15. Moroni A, Barbuti A, Altomare C, Viscomi C, Morgan J, Baruscotti M, et al. Kinetic and ionic properties of the human HCN2 pacemaker channel. Pflugers Arch. 2000; 439(5): 618–626. doi: 10.1007/s004249900225 10764222

16. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995; 81(2): 299–307. doi: 10.1016/0092-8674(95)90340-2 7736582

17. Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R. Effects of three fluoroquinolones on QT interval in healthy adults after single doses. Clin Pharmacol Ther. 2003; 73(4): 292–303. doi: 10.1016/s0009-9236(03)00009-2 12709719

18. Chaves AA, Keller WJ, O'Sullivan S, Williams MA, Fitzgerald LE, McPherson HE, et al. Cardiovascular monkey telemetry: sensitivity to detect QT interval prolongation. J Pharmacol Toxicol Methods. 2006; 54(2): 150–158. doi: 10.1016/j.vascn.2006.03.004 16679034

19. Chaves AA, Zingaro GJ, Yordy MA, Bustard KA, O'Sullivan S, Galijatovic-Idrizbegovic A, et al. A highly sensitive canine telemetry model for detection of QT interval prolongation: studies with moxifloxacin, haloperidol and MK-499. J Pharmacol Toxicol Methods. 2007; 56(2): 103–114 doi: 10.1016/j.vascn.2007.04.007 17643323

20. Markert M, Stubhan M, Mayer K, Trautmann T, Klumpp A, Schuler-Metz A, et al. Validation of the normal, freely moving Göttingen minipig for pharmacological safety testing. J Pharmacol Toxicol Methods. 2009; 60(1): 79–87. doi: 10.1016/j.vascn.2008.12.004 19427912

21. Harris K, Aylott M, Cui Y, Louttit JB, McMahon NC, Sridhar A. Comparison of electrophysiological data from human-induced pluripotent stem cell-derived cardiomyocytes to functional preclinical safety assays. Toxicol Sci. 2013; 134(2): 412–426. doi: 10.1093/toxsci/kft113 23690542

22. Himmel HM, Bussek A, Hoffmann M, Beckmann R, Lohmann H, Schmidt M, et al. Field and action potential recordings in heart slices: correlation with established in vitro and in vivo models. Br J Pharmacol. 2012; 166(1): 276–296. doi: 10.1111/j.1476-5381.2011.01775.x 22074238

23. Crumb WJ Jr, Vicente J, Johannesen L, Strauss DG. An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel. J Pharmacol Toxicol Methods. 2016; 81:251–62. doi: 10.1016/j.vascn.2016.03.009 27060526

24. Tertoolen LGJ, Braam SR, van Meer BJ, Passier R, Mummery CL. Interpretation of field potentials measured on a multi electrode array in pharmacological toxicity screening on primary and human pluripotent stem cell-derived cardiomyocytes. Biochem Biophys Res Commun. 2018; 497(4): 1135–1141. doi: 10.1016/j.bbrc.2017.01.151 28153730

25. Du DT, Hellen N, Kane C, Terracciano CM. Action potential morphology of human induced pluripotent stem cell-derived cardiomyocytes does not predict cardiac chamber specificity and is dependent on cell density. Biophys J. 2015; 108(1): 1–4. doi: 10.1016/j.bpj.2014.11.008 25564842

26. Harada K, Iijima T. Differential modulation by adenylate cyclase of Ca2+ and delayed K+ current in ventricular myocytes. Am J Physiol. 1994; 266(4 Pt 2): H1551–H1557. doi: 10.1152/ajpheart.1994.266.4.H1551 8184933

27. Lengyel C, Iost N, Virág L, Varró A, Lathrop DA, Papp JG. Pharmacological block of the slow component of the outward delayed rectifier current (I(Ks)) fails to lengthen rabbit ventricular muscle QT(c) and action potential duration. Br J Pharmacol. 2001; 132(1): 101–110. doi: 10.1038/sj.bjp.0703777 11156566

28. Pueyo E, Smetana P, Laguna P, Malik M. Estimation of the QT/RR hysteresis lag. J Electrocardiol. 2003; 36 Suppl: 187–190.

29. Verheijck EE, van Ginneken AC, Bourier J, Bouman LN. Effects of delayed rectifier current blockade by E-4031 on impulse generation in single sinoatrial nodal myocytes of the rabbit. Circ Res. 1995; 76(4): 607–615. doi: 10.1161/01.res.76.4.607 7895335

30. Abbate E, Boulakia M, Coudière Y, Gerbeau JF, Zitoun P, Zemzemi N. In silico assessment of the effects of various compounds in MEA/hiPSC-CM assays: Modeling and numerical simulations. J Pharmacol Toxicol Methods. 2018; 89:59–72. doi: 10.1016/j.vascn.2017.10.005 29066291


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2019 Číslo 9
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