The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes

Stem Cell Rev Rep. 2016 Dec;12(6):698-707. doi: 10.1007/s12015-016-9686-0.

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 IKs current activator, as well as JNJ303, a specific IKs blocker. 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 IKs channel and β1-adrenoreceptors by pharmacological compounds may affect the fractal complexity of the hiPSC-CMs.

Keywords: Cardiomyocytes; Detrended fluctuation analysis; Fractals; Induced pluripotent stem cell; Long QT syndrome; Multielectrode array; Nonlinear dynamics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-1 Receptor Antagonists / pharmacology
  • Adult
  • Bisoprolol / pharmacology
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Female
  • Fractals
  • Heart Conduction System / drug effects
  • Heart Conduction System / physiopathology*
  • Heart Rate / drug effects
  • Heart Rate / physiology*
  • Humans
  • Induced Pluripotent Stem Cells
  • Long QT Syndrome / pathology
  • Long QT Syndrome / physiopathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / physiology*
  • Piperidines / pharmacology
  • Thiazoles / pharmacology
  • Time Factors
  • Tosyl Compounds / pharmacology

Substances

  • (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide
  • Adrenergic beta-1 Receptor Antagonists
  • Piperidines
  • Thiazoles
  • Tosyl Compounds
  • Bisoprolol