title: The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes.
abstract: Healthy human heart rate fluctuates overtime showing long-range fractal correlations. In contrast, various cardiac diseases and normal aging show the breakdown of fractal complexity. Recently, it was shown that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) intrinsically exhibit fractal behavior as in humans. Here, we investigated the fractal complexity of hiPSC-derived long QT-cardiomyocytes (LQT-CMs). We recorded extracellular field potentials from hiPSC-CMs at baseline and under the effect of various compounds including β-blocker bisoprolol, ML277, a specific and potent IKscurrent activator, as well as JNJ303, a specific IKsblocker. From the peak-to-peak-intervals, we determined the long-range fractal correlations by using detrended fluctuation analysis. Electrophysiologically, the baseline corrected field potential durations (cFPDs) were more prolonged in LQT-CMs than in wildtype (WT)-CMs. Bisoprolol did not have significant effects to the cFPD in any CMs. ML277 shortened cFPD in a dose-dependent fashion by 11 % and 5-11 % in WT- and LQT-CMs, respectively. JNJ303 prolonged cFPD in a dose-dependent fashion by 22 % and 7-13 % in WT- and LQT-CMs, respectively. At baseline, all CMs showed fractal correlations as determined by short-term scaling exponent α. However, in all CMs, the α was increased when pharmacological compounds were applied indicating of breakdown of fractal complexity. These findings suggest that the intrinsic mechanisms contributing to the fractal complexity are not altered in LQT-CMs. The modulation of IKschannel and β1-adrenoreceptors by pharmacological compounds may affect the fractal complexity of the hiPSC-CMs.
authors.affiliation: Institute of Biomedical Technology, University of Tampere, Tampere, Finland.|BioMediTech, Tampere, Finland.
authors.forename: Jukka
authors.identifier: 0000-0002-3327-2403
authors.initials: J
authors.lastname: Kuusela
authors.affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.
authors.forename: Jiyeong
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Physics, Tampere University of Technology, Tampere, Finland.
authors.forename: Esa
authors.initials: E
authors.lastname: Räsänen
authors.affiliation: Institute of Biomedical Technology, University of Tampere, Tampere, Finland. katriina.aalto-setala@uta.fi.|BioMediTech, Tampere, Finland. katriina.aalto-setala@uta.fi.|School of Medicine, University of Tampere and Tampere University Hospital, Finn-Medi 5, Biokatu 12, FI-33014, Tampere, Finland. katriina.aalto-setala@uta.fi.|Heart Hospital, Tampere University Hospital, Tampere, Finland. katriina.aalto-setala@uta.fi.
authors.forename: Katriina
authors.initials: K
authors.lastname: Aalto-Setälä
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D000328:Adult; D017298:Bisoprolol / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D017709:Fractals; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008133:Long QT Syndrome / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: C576869:(R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide; D058671:Adrenergic beta-1 Receptor Antagonists; D010880:Piperidines; D013844:Thiazoles; D014105:Tosyl Compounds; D017298:Bisoprolol
keywords: Cardiomyocytes; Detrended fluctuation analysis; Fractals; Induced pluripotent stem cell; Long QT syndrome; Multielectrode array; Nonlinear dynamics