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

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The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes. / Kuusela, Jukka; Kim, Jiyeong; Räsänen, Esa; Aalto-Setälä, Katriina.

In: Stem Cell Reviews and Reports, Vol. 12, No. 6, 2016, p. 698–707.

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Kuusela, Jukka ; Kim, Jiyeong ; Räsänen, Esa ; Aalto-Setälä, Katriina. / The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes. In: Stem Cell Reviews and Reports. 2016 ; Vol. 12, No. 6. pp. 698–707.

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@article{36d71f9dfbac47cbb5d33518af3e7433,
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 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",
author = "Jukka Kuusela and Jiyeong Kim and Esa R{\"a}s{\"a}nen and Katriina Aalto-Set{\"a}l{\"a}",
year = "2016",
doi = "10.1007/s12015-016-9686-0",
language = "English",
volume = "12",
pages = "698–707",
journal = "Stem Cell Reviews and Reports",
issn = "1550-8943",
publisher = "Springer Verlag",
number = "6",

}

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TY - JOUR

T1 - The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes

AU - Kuusela, Jukka

AU - Kim, Jiyeong

AU - Räsänen, Esa

AU - Aalto-Setälä, Katriina

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Cardiomyocytes

KW - Detrended fluctuation analysis

KW - Fractals

KW - Induced pluripotent stem cell

KW - Long QT syndrome

KW - Multielectrode array

KW - Nonlinear dynamics

U2 - 10.1007/s12015-016-9686-0

DO - 10.1007/s12015-016-9686-0

M3 - Article

VL - 12

SP - 698

EP - 707

JO - Stem Cell Reviews and Reports

JF - Stem Cell Reviews and Reports

SN - 1550-8943

IS - 6

ER -