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

Kuusela, Jukka; Kim, Jiyeong; Räsänen, E.; Aalto‐Setälä, Katriina

doi:10.1007/s12015-016-9686-0

Cited by 13 publications

(12 citation statements)

References 56 publications

(63 reference statements)

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“…Interestingly, the IKr block prolonged the cFPD in hiPSC-CMs from the LQT2 symptomatic but not in asymptomatic ( Figure 5). A past study of LQT1 symptomatic and asymptomatic hiPSC-CMs on MEA did not report any major differences in the effects of the application of IKs blockers [55]. In the current study, IKs block prolonged the cFPD more than the control but similarly for the symptomatic and the asymptomatic LQT2 hiPSC-CM aggregates ( Figure 5).…”

Section: What Is Causing Arrhythmogenic Events In Lqt2?supporting

confidence: 58%

hiPSC-Derived Cardiomyocyte Model of LQT2 Syndrome Derived from Asymptomatic and Symptomatic Mutation Carriers Reproduces Clinical Differences in Aggregates but Not in Single Cells

Shah

Prajapati

Penttinen

et al. 2020

Cells

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Mutations in the HERG gene encoding the potassium ion channel HERG, represent one of the most frequent causes of long QT syndrome type-2 (LQT2). The same genetic mutation frequently presents different clinical phenotypes in the family. Our study aimed to model LQT2 and study functional differences between the mutation carriers of variable clinical phenotypes. We derived human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) from asymptomatic and symptomatic HERG mutation carriers from the same family. When comparing asymptomatic and symptomatic single LQT2 hiPSC-CMs, results from allelic imbalance, potassium current density, and arrhythmicity on adrenaline exposure were similar, but a difference in Ca2+ transients was observed. The major differences were, however, observed at aggregate level with increased susceptibility to arrhythmias on exposure to adrenaline or potassium channel blockers on CM aggregates derived from the symptomatic individual. The effect of this mutation was modeled in-silico which indicated the reactivation of an inward calcium current as one of the main causes of arrhythmia. Our in-vitro hiPSC-CM model recapitulated major phenotype characteristics observed in LQT2 mutation carriers and strong phenotype differences between LQT2 asymptomatic vs. symptomatic were revealed at CM-aggregate level.

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Section: What Is Causing Arrhythmogenic Events In Lqt2?supporting

confidence: 58%

hiPSC-Derived Cardiomyocyte Model of LQT2 Syndrome Derived from Asymptomatic and Symptomatic Mutation Carriers Reproduces Clinical Differences in Aggregates but Not in Single Cells

Shah

Prajapati

Penttinen

et al. 2020

Cells

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“…In our previous work [5], we measured and analyzed the beat-to-beat interval series of hiPSC-derived CMs (hiPSCCMs) and R-R interval of electrocardiogram (ECG), obtained from a healthy individual and symptomatic and asymptomatic long QT syndrome (LQTS, type 1) patients. LQTS is a cardiac disease, characterized by prolonged QT intervals in ECG.…”

Section: Introductionmentioning

confidence: 99%

“…LQTS is a cardiac disease, characterized by prolonged QT intervals in ECG. The inherited forms of LQTS are a result of mutations in the cardiac ion channel coding genes [5]. We also tested the effect of pharmacological compounds, applied directly to the cultured hiPSC-CMs.…”

Section: Introductionmentioning

confidence: 99%

Short- and Long-Range Correlations in Beat Rate Variability of Human Pluripotent-Stem-Cell-Derived Cardiomyocytes

Kim

Kuusela

Aalto‐Setälä

et al. 2017

Computing in Cardiology Conference (CinC)

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A healthy heart exhibits fractal, i.e., long-range correlated fluctuations in heart rate variability (HRV). It is recently shown that fractal dynamics is also an intrinsic feature of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). In this study, we investigate short-and long-range correlations in beat rate variability (BRV) of hiPSC-CMs, obtained from a healthy subject and symptomatic and asymptomatic long QT syndrome patients. It is shown that it is important to distinguish correlation properties in short and long time scales, as the scaling exponents are significantly different and also behave differently in the acute exposure to pharmacological compounds that modulate β1-adrenoreceptors and cardiac ion channel generating delayed, outwardly rectifying K + current (I Ks ). While long-range scaling is sensitive to the drug exposure, short-range scaling is barely affected.

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“…In a rabbit hypertrophic cardiomyopathy model, DFA of maximum QT intervals showed higher scaling exponent in diseased compared to control groups (Sanbe et al, 2005 ). In human induced pluripotent stem cell-derived cardiomyocytes, fractal correlations as determined by α1 was observed (Kuusela et al, 2016 ). In humans, a significant decrease in α1 was observed during sympathetic activation suggesting a breakdown of the short-term fractal organization of heart rate (Tulppo et al, 2005 ).…”

Section: Discussionmentioning

confidence: 99%

Quantification of Beat-To-Beat Variability of Action Potential Durations in Langendorff-Perfused Mouse Hearts

Tse

Hao

et al. 2018

Front. Physiol.

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Background: Beat-to-beat variability in action potential duration (APD) is an intrinsic property of cardiac tissue and is altered in pro-arrhythmic states. However, it has never been examined in mice.Methods: Left atrial or ventricular monophasic action potentials (MAPs) were recorded from Langendorff-perfused mouse hearts during regular 8 Hz pacing. Time-domain, frequency-domain and non-linear analyses were used to quantify APD variability.Results: Mean atrial APD (90% repolarization) was 23.5 ± 6.3 ms and standard deviation (SD) was 0.9 ± 0.5 ms (n = 6 hearts). Coefficient of variation (CoV) was 4.0 ± 1.9% and root mean square (RMS) of successive differences in APDs was 0.3 ± 0.2 ms. The peaks for low- and high-frequency were 0.7 ± 0.5 and 2.7 ± 0.9 Hz, respectively, with percentage powers of 39.0 ± 20.5 and 59.3 ± 22.9%. Poincaré plots of APDn+1 against APDn revealed ellipsoid shapes. The ratio of the SD along the line-of-identity (SD2) to the SD perpendicular to the line-of-identity (SD1) was 8.28 ± 4.78. Approximate and sample entropy were 0.57 ± 0.12 and 0.57 ± 0.15, respectively. Detrended fluctuation analysis revealed short- and long-term fluctuation slopes of 1.80 ± 0.15 and 0.85 ± 0.29, respectively. When compared to atrial APDs, ventricular APDs were longer (ANOVA, P < 0.05), showed lower mean SD and CoV but similar RMS of successive differences in APDs and showed lower SD2 (P < 0.05). No difference in the remaining parameters was observed.Conclusion: Beat-to-beat variability in APD is observed in mouse hearts during regular pacing. Atrial MAPs showed greater degree of variability than ventricular MAPs. Non-linear techniques offer further insights on short-term and long-term variability and signal complexity.

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

Cited by 13 publications

References 56 publications

hiPSC-Derived Cardiomyocyte Model of LQT2 Syndrome Derived from Asymptomatic and Symptomatic Mutation Carriers Reproduces Clinical Differences in Aggregates but Not in Single Cells

hiPSC-Derived Cardiomyocyte Model of LQT2 Syndrome Derived from Asymptomatic and Symptomatic Mutation Carriers Reproduces Clinical Differences in Aggregates but Not in Single Cells

Short- and Long-Range Correlations in Beat Rate Variability of Human Pluripotent-Stem-Cell-Derived Cardiomyocytes

Quantification of Beat-To-Beat Variability of Action Potential Durations in Langendorff-Perfused Mouse Hearts

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