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Computational Models of Ventricular- and Atrial-Like Human Induced Pluripotent Stem Cell Derived Cardiomyocytes

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Abstract

The clear importance of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) as an in-vitro model highlights the relevance of studying these cells and their function also in-silico. Moreover, the phenotypical differences between the hiPSC-CM and adult myocyte action potentials (APs) call for understanding of how hiPSC-CMs are maturing towards adult myocytes. Using recently published experimental data, we developed two computational models of the hiPSC-CM AP, distinguishing between the ventricular-like and atrial-like phenotypes, emerging during the differentiation process of hiPSC-CMs. Also, we used the computational approach to quantitatively assess the role of ionic mechanisms which are likely responsible for the not completely mature phenotype of hiPSC-CMs. Our models reproduce the typical hiPSC-CM ventricular-like and atrial-like spontaneous APs and the response to prototypical current blockers, namely tetrodotoxine, nifedipine, E4041 and 3R4S-Chromanol 293B. Moreover, simulations using our ventricular-like model suggest that the interplay of immature I Na, I f and I K1 currents has a fundamental role in the hiPSC-CM spontaneous beating whereas a negative shift in I CaL activation causes the observed long lasting AP. In conclusion, this work provides two novel tools useful in investigating the electrophysiological features of hiPSC-CMs, whose importance is growing fast as in-vitro models for pharmacological studies.

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Abbreviations

AP:

Action potential

APA:

AP amplitude

APD:

AP duration

CaMK:

Ca2+/calmodulin-dependent protein kinase II

Chr:

3R4S-Chromanol 293B

CM:

Cardiomyocyte

EAD:

Early After Depolarization

hESC-CM:

Human embryonic stem cell-derived cardiomyocyte

hiPSC:

Human induced pluripotent stem cell

hiPSC-CM:

Human induced pluripotent stem cell-derived cardiomyocyte

iPSC:

Induced pluripotent stem cell

I/V :

Current/voltage

MDP:

Maximum diastolic potential

Nifed:

Nifedipine

V max :

Maximum upstroke velocity

ORd:

O’Hara-Rudy

Peak:

Peak voltage

rappAPD:

Action potential shape factor

SR:

Sarcoplasmic reticulum

TTX:

Tetrodotoxine

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The authors confirm that this article content has no conflicts of interest.

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Authors and Affiliations

  1. Biomedical Engineering Laboratory—DEI, University of Bologna, Via Venezia 52, 47521, Cesena, FC, Italy

    Michelangelo Paci & Stefano Severi

  2. ELT, Tampere University of Technology, Korkeakoulunkatu 3, 33720, Tampere, Finland

    Michelangelo Paci & Jari Hyttinen

  3. IBT, University of Tampere, Biokatu 8, 33520, Tampere, Finland

    Katriina Aalto-Setälä

  4. Tampere University Hospital, Heart Center, Teiskontie 35, 33521, Tampere, Finland

    Katriina Aalto-Setälä

  5. BioMediTech, Biokatu 10, 33520, Tampere, Finland

    Michelangelo Paci, Jari Hyttinen & Katriina Aalto-Setälä

Authors
  1. Michelangelo Paci
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  2. Jari Hyttinen
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  3. Katriina Aalto-Setälä
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  4. Stefano Severi
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Correspondence to Stefano Severi.

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Associate Editor Scott I Simon oversaw the review of this article.

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Paci, M., Hyttinen, J., Aalto-Setälä, K. et al. Computational Models of Ventricular- and Atrial-Like Human Induced Pluripotent Stem Cell Derived Cardiomyocytes. Ann Biomed Eng 41, 2334–2348 (2013). https://doi.org/10.1007/s10439-013-0833-3

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