Key result
Inhibition of L-type Ca2+ channels by nifedipine caused a 61% reduction in calcium spark frequency in hiPSC-derived cardiomyocytes, indicating sparks are predominantly triggered by Ca2+ influx.
Effect estimate: 61% reduction
Spontaneous Ca2+ sparks in hiPSC-CMs are predominantly triggered by L-type Ca2+ channel-mediated Ca2+ influx, similar to adult ventricular myocytes, though focal repetitive sparks suggest an immature status.
Should not guide clinical Ca2+ handling therapies; leaves open translation of hiPSC-CM spark mechanisms to mature human myocardium.
INTRODUCTION: Ca2+ spark constitutes the elementary units of cardiac excitation-contraction (E-C) coupling in mature cardiomyocytes. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes are known to have electrophysiological properties similar to mature adult cardiomyocytes. However, it is unclear if they share similar calcium handling property. We hypothesized that Ca2+ sparks in human induced pluripotent stem cell (hiPSCs)-derived cardiomyocytes (hiPSC-CMs) may display unique structural and functional properties than mature adult cardiomyocytes. METHODS AND RESULTS: Ca2+ sparks in hiPSC-CMs were recorded with Ca2+ imaging assay with confocal laser scanning microscopy. Those sparks were stochastic with a tendency of repetitive occurrence at the same site. Nevertheless, the spatial-temporal properties of Ca2+ spark were analogous to that of adult CMs. Inhibition of L-type Ca2+ channels by nifedipine caused a 61% reduction in calcium spark frequency without affecting amplitude of those sparks and magnitude of caffeine releasable sarcoplasmic reticulum (SR) Ca2+ content. In contrast, high extracellular Ca2+ and ryanodine increased the frequency, full width at half maximum (FWHM) and full duration at half maximum (FDHM) of spontaneous Ca2+ sparks. CONCLUSIONS: For the first time, spontaneous Ca2+ sparks were detected in hiPSC-CMs. The Ca2+ sparks are predominately triggered by L-type Ca2+ channels mediated Ca2+ influx, which is comparable to sparks detected in adult ventricular myocytes in which cardiac E-C coupling was governed by a Ca2+-induced Ca2+ release (CICR) mechanism. However, focal repetitive sparks originated from the same intracellular organelle could reflect an immature status of the hiPSC-CMs.
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Zhang et al. (2013) studied hiPSC-derived cardiomyocytes. Nifedipine vs. Baseline (control) was evaluated on Calcium spark frequency (61% reduction). Inhibition of L-type Ca2+ channels by nifedipine caused a 61% reduction in calcium spark frequency in hiPSC-derived cardiomyocytes, indicating sparks are predominantly triggered by Ca2+ influx.
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