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The pharmacological properties of the drug may possibly provide an explanatory approach for these findings.


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Ivabradine is known to bind specifically to the funny -channel at therapeutic concentrations However, it is also possible that Ivabradine operates less specifically at higher concentrations 50 , Thus, it remains unclear whether the effect on BRV parameters caused by high concentrations of Ivabradine is actually due to a specific blockage of the I f currents or whether an unspecific blockade of different ion channels contributes to the effect. Furthermore, it has to be noted that the findings in clinical trials are from patients with a cardiac disease.

It is unknown whether these cardiac diseases are associated with changes in intracellular signaling pathways that might have an additional influence on the drug effect.

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However, it is interesting that the sole application of Metoprolol has no major influence — neither on the beat rate nor on the BRV. These findings are also supported by other in vitro studies 3 , Before drawing any conclusions about the human embryonic phase from these findings, it must be remembered that the physiological processes within an EB have not yet been fully discovered and therefore might differ from those of a human embryo.

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In general, the experiences made with hESC and hiPSC derived EBs were comparable — not only regarding the handling of the cell cultures and the cell differentiation, but also regarding the response to cardioactive drugs. The minor differences between these human cell lines cannot be fully explained due to the present study design.

These differences may not be present when testing a large number of EBs. The diverse effect of high concentrations of Flecainide, which was observed in all three cell lines, appears particularly interesting. Nevertheless, a detailed comparison between murine and human ESC derived tissue is hampered by the fact that murine embryos develop much faster than human embryos.

It is most likely that the development at the cellular level and consequently also the ion channel expression in the cell membrane does not completely match between murine and human ESC derived cardiomyocytes, which influences drug effects. Since the effects were generally comparable, the mESCs might be preferred for in vitro studies because of the easier handling and faster differentiation of the cells. However, if clinical use is desired, human ESC derived tissue, especially hiPSC derived tissue, should be used in addition.

In general, the effect of the tested antiarrhythmic agents was comparable to the experiences made in previous in vivo and in vitro studies. The minor differences between the effect of antiarrhythmic drugs on murine and human ESC derived cardiomyocytes can possibly be explained by diverse ion channel expression on the cell membrane due to different developmental stages. Also, structural differences within the EBs, such as cell-cell interactions or the expression of catecholamine producing cells, may be another explanation for different drug effects. Further studies are needed to address these issues and variables before ESC derived tissue can be used routinely as a preclinical drug testing tool and ultimately as part of a cell replacement therapy.

The datasets analyzed during the current study are available from the corresponding author on request. Mandel, Y. Human embryonic and induced pluripotent stem cell-derived cardiomyocytes exhibit beat rate variability and power-law behavior. Kiskinis, E. Progress toward the clinical application of patient-specific pluripotent stem cells. Niehoff, J. Cellular Physiology and Biochemistry 38 , — Heart rate variability: standards of measurement, physiological interpretation and clinical use.

Stein, P. Heart rate variability: a measure of cardiac autonomic tone. Kleiger, R. Heart rate variability: measurement and clinical utility. Pumprla, J. Functional assessment of heart rate variability: physiological basis and practical applications. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction.

Carpeggiani, C. Early assessment of heart rate variability is predictive of in-hospital death and major complications after acute myocardial infarction. Bilchick, K. Bigger, J. Predicting mortality after myocardial infarction from the response of RR variability to antiarrhythmic drug therapy.

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Fauchier, L. Effect of flecainide on heart rate variability in subjects without coronary artery disease or congestive heart failure. Van Leeuwen, P. Effect of prenatal antiarrhythmic treatment on cardiac function in a twin pregnancy. The effect of flecainide acetate on fetal heart rate variability: a case report. Kurtoglu, E. Ivabradine improves heart rate variability in patients with nonischemic dilated cardiomyopathy. Ben-Ari, M. From beat rate variability in induced pluripotent stem cell-derived pacemaker cells to heart rate variability in human subjects.

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Aronson, D. Effect of beta-blockade on heart rate variability in decompensated heart failure. Lurje, L. Heart rate variability after acute myocardial infarction in patients treated with atenolol and metoprolol. Keeley, E. Influence of metoprolol on heart rate variability in survivors of remote myocardial infarction.

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Cook, J. Effect of atenolol and diltiazem on heart period variability in normal persons. Liang, H. Human and murine embryonic stem cell-derived cardiomyocytes serve together as a valuable model for drug safety screening. Braam, S. Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes. Reppel, M. Effect of cardioactive drugs on action potential generation and propagation in embryonic stem cell-derived cardiomyocytes.

The electrocardiogram of human embryonic stem cell—derived cardiomyocytes.

Reubinoff, B. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro.


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  • Yu, J. Induced pluripotent stem cell lines derived from human somatic cells. Zhang, J. Functional cardiomyocytes derived from human induced pluripotent stem cells. Jovancevic, N. Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor. Fatima, A. In vitro modeling of ryanodine receptor 2 dysfunction using human induced pluripotent stem cells.

    Mummery, C. Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-like cells. Microelectrode arrays: a new tool to measure embryonic heart activity. Ribeiro, M. Functional maturation of human pluripotent stem cell derived cardiomyocytes in vitro — Correlation between contraction force and electrophysiology.

    Tanaka, T. In vitro pharmacologic testing using human induced pluripotent stem cell-derived cardiomyocytes.

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    Brennan, M. Do existing measures of Poincare plot geometry reflect nonlinear features of heart rate variability? Sacha, J. Piskorski, J. Voss, A. Methods derived from nonlinear dynamics for analysing heart rate variability. Tjandra-Maga, T. Learn More. Find out More. News More people to be trained to spot eating disorders thanks to the Welsh Government proposes four week waiting time target for trea When I was around 17 I felt you grew stronger a Search HelpFinder. Wong Chun Wai. On The Beat 29 Sep AM Fix for a better mix THE Tanjung Piai by-election will serve as a good platform for our politicians to stop, or at least, refrain, from using the race and religion cards simply because the Parliamentary constituency has almost equal representation of Malay and Chinese voters.

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