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Beat-to-Beat Variability in Field Potential Duration in Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters for Assessment of Arrhythmogenic Risk, and a Case Study of Its Application

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DOI: 10.4236/pp.2014.51017    3,968 Downloads   6,485 Views   Citations

ABSTRACT

We established a QT interval assessment system that uses human embryonic stem cell-derived cardiomyocyte clusters (hES-CMCs) in which the field potential duration (FPD) or corrected FPD (FPDc) was measured as an indicator of drug-induced QT interval prolongation. To investigate the applicability of the hES-CMC system to drug safety assessment, we investigated short-term variability in FPDc (STVFPDc) (beat rate rhythmicity) as a marker of torsadogenic risk. We investigated the FPDc and STVFPDc of hES-CMCs treated with hERG channel blockers (E-4031 or cisapride) or with our proprietary compounds X, Y, and Z. We also evaluated the electrocardiograms and hemodynamics of dogs treated with compound X, Y, or Z. The torsadogenic hERG channel blockers increased STVFPDc and prolonged FPDc. Compounds X, Y, and Z had hERG inhibitory activity. Compound X prolonged FPDc with increased STVFPDc, whereas compounds Y and Z tended to shorten FPDc in the hES-CMC system. In the in vivo canine study, compound X prolonged corrected QT (QTc), and compounds Y and Z tended to shorten QTc, showing a good correlation with the results in hES-CMCs. These findings suggest that combined assessment of FPDc and STVFPDc in the hES-CMC system increases the predictability of torsadogenic risk.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

K. Yamazaki, T. Hihara, H. Kato, T. Fukushima, K. Fukushima, T. Taniguchi, T. Yoshinaga, N. Miyamoto, M. Ito and K. Sawada, "Beat-to-Beat Variability in Field Potential Duration in Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters for Assessment of Arrhythmogenic Risk, and a Case Study of Its Application," Pharmacology & Pharmacy, Vol. 5 No. 1, 2014, pp. 117-128. doi: 10.4236/pp.2014.51017.

References

[1] H. R. Lu, E. Vlaminckx, A. N. Hermans, J. Rohrbacher, K. Van Ammel, R. Towart, M. Pugsley and D. J. Gallacher, “Predicting Drug-Induced Changes in QT Interval and Arrhythmias: QT-Shortening Drugs Point to Gaps in the ICHS7B Guidelines,” British Journal of Pharmacology, Vol. 154, No. 7, 2008, pp. 1427-1438.
http://dx.doi.org/10.1038/bjp.2008.191
[2] P. L. Hedley, P. Jørgensen, S. Schlamowitz, R. Wangari, J. Moolman-Smook, P. A. Brink, J. K. Kanters, V. A. Corfield and M. Christiansen, “The Genetic Basis of Long QT and Short QT Syndromes: A Mutation Update,” Human Mutation, Vol. 30, No. 11, 2009, pp. 1486-1511.
http://dx.doi.org/10.1002/humu.21106
[3] R. L. Martin, J. S. McDermott, H. J. Salmen, J. Palmatier, B. F. Cox and G. A. Gintant, “The Utility of hERG and Repolarization Assays in Evaluating Delayed Cardiac Repolarization: Influence of Multi-Channel Block,” Journal of Cardiovascular Pharmacology, Vol. 43, No. 3, 2004, pp. 369-379.
[4] Y. Asai, M. Tada, T. G. Otsuji and N. Nakatsuji, “Combination of Functional Cardiomyocytes Derived from Human Stem Cells and a Highly-Efficient Microelectrode Array System: An Ideal Hybrid Model Assay for Drug Development,” Current Stem Cell Research and Therapy, Vol. 5, No. 3, 2010, pp. 227-232.
http://dx.doi.org/10.2174/157488810791824502
[5] M. K. B. Jonsson, G. Duker, C. Tropp, B. Andersson, P. Sartipy, M. A. Vos and T. A. B. van Veen, “Quantified Proarrhythmic Potential of Selected Human Embryonic Stem Cell-Derived Cardiomyocytes,” Stem Cell Research, Vol. 4, No. 3, 2010, pp. 189-200.
http://dx.doi.org/10.1016/j.scr.2010.02.001
[6] M. Pekkanen-Mattila, H. Chapman, E. Kerkelä, R. Suuronen, H. Skottman, A. P. Koivisto and K. Aalto-Setälä, “Human Embryonic Stem Cell-Derived Cardiomyocytes: Demonstration of a Portion of Cardiac Cells with Fairly Mature Electrical Phenotype,” Experimental Biology and Medicine (Maywood), Vol. 235, No. 4, 2010, pp. 522-530. http://dx.doi.org/10.1258/ebm.2010.009345
[7] S. Peng, A. E. Lacerda, G. E. Kirsch, A. M. Brown and A. Bruening-Wright, “The Action Potential and Comparative Pharmacology of Stem Cell-Derived Human Cardiomyocytes,” Journal of Pharmacological and Toxicological Methods, Vol. 61, No. 3, 2010, pp. 277-286.
http://dx.doi.org/10.1016/j.vascn.2010.01.014
[8] K. Yamazaki, T. Hihara, T. Taniguchi, N. Kohmura, T. Yoshinaga, M. Ito and K. Sawada, “A Novel Method of Selecting Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters for Assessment of Potential to Influence QT Intervals,” Toxicology in Vitro, Vol. 26, No. 2, 2012, pp. 335-342.
http://dx.doi.org/10.1016/j.tiv.2011.12.005
[9] P. T. Nguyen, M. M. Scheinman and J. Seger, “Polymorphous Ventricular Tachycardia: Clinical Characterization, Therapy, and the QT Interval,” Circulation, Vol. 74, No. 2, 1986, pp. 340-349.
http://dx.doi.org/10.1161/01.CIR.74.2.340
[10] S. H. Hohnloser, T. Klingenheben and B. N. Singh, “Amiodarone-Associated Proarrhythmic Effects. A Review with Special Reference to Torsade de Pointes Tachycardia,” Annals of Internal Medicine, Vol. 121, No. 7, 1994, pp. 529-535.
http://dx.doi.org/10.7326/0003-4819-121-7-199410010-00009
[11] L. M. Hondeghem, L. Carlsson and G. Duker, “Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolon gation Is Antiarrhythmic,” Circulation, Vol. 103, No. 15, 2001, pp. 2004-2013.
http://dx.doi.org/10.1161/01.CIR.103.15.2004
[12] T. D. Gbadebo, R. W. Trimble, M. S. Khoo, J. Temple, D. M. Roden and M. E. Anderson, “Calmodulin Inhibitor W7 Unmasks a Novel Electrocardiographic Parameter That Predicts Initiation of Torsade de Pointes,” Circulation, Vol. 105, No. 6, 2002, pp. 770-774.
http://dx.doi.org/10.1161/hc0602.103724
[13] S. Kääb, M. Hinterseer, M. Näbauer and G. Steinbeck, “Sotalol Testing Unmasks Altered Repolarization in Patients with Suspected Acquired Long-QT-Syndrome— A Case-Control Pilot Study Using i.v. Sotalol,” European Heart Journal, Vol. 24, No. 7, 2003, pp. 649-657.
http://dx.doi.org/10.1016/S0195-668X(02)00806-0
[14] M. B. Thomsen, S. C. Verduyn, M. Stengl, J. D. Beekman, G. de Pater, J. van Opstal, P. G. Volders and M. A. Vos, “Increased Short-Term Variability of Repolarization Predicts d-Sotalol-Induced Torsades de Pointes in Dogs,” Circulation, Vol. 110, No. 16, 2004, pp. 2453-2459.
http://dx.doi.org/10.1161/01.CIR.0000145162.64183.C8
[15] M. B. Thomsen, J. Matz, P. G. Volders and M. A. Vos, “Assessing the Proarrhythmic Potential of Drugs: Current Status of Models and Surrogate Parameters of Torsades de Pointes Arrhythmias,” Pharmacology and Therapeutics, Vol. 112, No. 1, 2006, pp. 150-170.
http://dx.doi.org/10.1016/j.pharmthera.2005.04.009
[16] C. Antzelevitch, “Heterogeneity and Cardiac Arrhythmias: An Overview,” Heart Rhythm, Vol. 4, No. 7, 2007, pp. 964-972. http://dx.doi.org/10.1016/j.hrthm.2007.03.036
[17] M. Hinterseer, M. B. Thomsen, B.-M. Beckmann, A. Pfeufer, R. Schimpf, H.-E. Wichmann, G. Steinbeck, M. A. Vos and S. Kaab, “Beat-to-Beat Variability of QT Intervals Is Increased in Patients with Drug-Induced Long-QT Syndrome: A Case Control Pilot Study,” European Heart Journal, Vol. 29, No. 2, 2008, pp. 185-190.
http://dx.doi.org/10.1093/eurheartj/ehm586
[18] N. Abi-Gerges, J. P. Valentin and C. E. Pollard, “Dog Left Ventricular Midmyocardial Myocytes for Assessment of Drug-Induced Delayed Repolarization: Short-Term Variability and Proarrhythmic Potential,” British Journal of Pharmacology, Vol. 159, No. 1, 2010, pp. 77-92. http://dx.doi.org/10.1111/j.1476-5381.2009.00338.x
[19] T. Taniguchi, M. Uesugi, T. Arai, T. Yoshinaga, N. Miyamoto and K. Sawada, “Chronic Probucol Treatment Decreases the Slow Component of the Delayed-Rectifier Potassium Current in CHO Cells Transfected with KCNQ1 and KCNE1: A Novel Mechanism of QT Prolongation,” Journal of Cardiovascular Pharmacology, Vol. 59, No. 4, 2012, pp. 377-386.
http://dx.doi.org/10.1097/FJC.0b013e318245e0c5
[20] R. L. Martin, J. T. Limberis, X. Liu, K. Houseman, Z. Su, W. Niforatos, B. F. Cox and G. A. Gintant, “Optimization of a Cav1.2 Cell Line for Use on QPatch and PatchXpress,” Biophysical Journal, Vol. 98, No. 3, 2010, p. 339a. http://dx.doi.org/10.1016/j.bpj.2009.12.1836
[21] J. Kutchinsky, S. Friis, M. Asmild, R. Taboryski, S. Pedersen, R. K. Vestergaard, R. B. Jacobsen, K. Krzywkowski, R. L. Schrøder, T. Ljungstrøm, N. Hélix, C. B. Sørensen, M. Bech and N. J. Willumsen, “Characteri zation of Potassium Channel Modulators with QPatch Automated Patch-Clamp Technology: System Characteristics and Performance,” Assay and Drug Development Technologies, Vol. 1, No. 5, 2003, pp. 685-693.
http://dx.doi.org/10.1089/154065803770381048
[22] R. Webster, G. Allan, K. Anto-Awuakye, A. Harrison, T. Kidd, D. Leishman, J. Phipps and D. Walker, “Pharmacokinetic/Pharmacodynamic Assessment of the Effects of E4031, Cisapride, Terfenadine and Terodiline on Monophasic Action Potential Duration in Dog,” Xenobiotica, Vol. 31, No. 8-9, 2001, pp. 633-650.
http://dx.doi.org/10.1080/00498250110054632
[23] L. Nalos, R. Varkevisser, M. K. B. Jonsson, M. J. C. Houtman, J. D. Beekman, R. van der Nagel, M. B. Thomsen, G. Duker, P. Sartipy, T. P. de Boer, M. Peschar, M. B. Rook, T. A. B. van Veen, M. A. G. van der Heyden and M. A. Vos, “Comparison of the IKr Blockers Moxifloxacin, Dofetilide and E-4031 in Five Screening Models of Pro-Arrhythmia Reveals Lack of Specificity of Isolated Cardiomyocytes,” British Journal of Pharmacology, Vol. 165, No. 2, 2012, pp. 467-478.
http://dx.doi.org/10.1111/j.1476-5381.2011.01558.x
[24] T. J. Campbell, “Kinetics of Onset of Rate-Dependent Effects of Class I Antiarrhythmic Drugs Are Important in Determining Their Effects on Refractoriness in Guinea-Pig Ventricle, and Provide a Theoretical Basis for Their Subclassification,” Cardiovascular Research, Vol. 17, No. 6, 1983, pp. 344-352.
http://dx.doi.org/10.1093/cvr/17.6.344
[25] K. R. Wyse, V. Ye and T. J. Campbell, “Action Potential Prolongation Exhibits Simple Dose-Dependence for Sotalol, but Reverse Dose-Dependence for Quinidine and Disopyramide: Implication for Proarrhythmia Due to Triggered Activity,” Journal of Cardiovascular Pharmacology, Vol. 21, No. 2, 1993, pp. 316-322.
http://dx.doi.org/10.1097/00005344-199302000-00019
[26] L. Wu, D. Guo, H. Li, J. Hackett, G. X. Yan, Z. Jiao, C. Antzelevitch, J. C. Shryock and L. Belardinelli, “Role of Late Sodium Current in Modulating the Proarrhythmic and Antiarrhythmic Effects of Quinidine,” Heart Rhythm, Vol. 5, No. 12, 2008, pp. 1726-1734.
http://dx.doi.org/10.1016/j.hrthm.2008.09.008
[27] V. Elharra, “Recovery from Use-Dependent Block of Vmax and Restitution of Action Potential Duration in Canine Cardiac Purkinje Fibers,” The Journal of Pharmacology and Experimental Therapeutics, Vol. 246, No. 1, 1988, pp. 235-242.
[28] U. Borchard and M. Boisten, “Effects of Flecainide on Action Potentials and Alternating Current-Induced Arrhythmia in Mammalian Myocardium,” Journal of Cardiovascular Pharmacology, Vol. 4, No. 2, 1982, pp. 205-212.
http://dx.doi.org/10.1097/00005344-198203000-00007
[29] A. Zaza, L. Belardinelli and J. C. Shryock, “Pathophysiology and Pharmacology of the Cardiac ‘Late Sodium Current’,” Pharmacology and Therapeutics, Vol. 119, No. 3, 2008, pp. 326-339.
http://dx.doi.org/10.1016/j.pharmthera.2008.06.001
[30] R. G. McAllister Jr., D. W. Bourne and L. W. Dittert, “The Pharmacology of Verapamil. I. Elimination Kinetics in Dogs and Correlation of Plasma Levels with Effect on the Eletrocardiogram,” The Journal of Pharmacology and Experimental Therapeutics, Vol. 202, No. 1, 1977, pp. 38-44.
[31] S. Wakabayashi, S. Mochizuki, A. Tomiyama and S. Shibata, “Effects of KT-362, a New Calcium Release Blocker, on Vascular Selectivity and Hemodynamic Actions in Anesthetized Dogs,” The Japanese Journal of Pharmacology, Vol. 54, No. 1, 1990, pp. 23-32.
http://dx.doi.org/10.1254/jjp.54.23
[32] M. Manabe, S. Motomura and K. Hashimoto, “Interaction between Diltiazem and Halothane or Enflurane in the Canine Blood-Perfused Papillary Muscle and Sinoatrial Node Preparations Cross-Circulated by Chronically Instrumented Conscious Donor Dog,” Journal of Anesthesia, Vol. 2, No. 1, 1988, pp. 50-62.
http://dx.doi.org/10.1007/s0054080020050

  
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