Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings

Alexander P Clark; Michael Clerx; Siyu Wei; Chon Lok Lei; Teun P de Boer; Gary R Mirams; David J Christini; Trine Krogh-Madsen

doi:10.1093/europace/euad243

Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings

Alexander P Clark
, Michael Clerx
, Siyu Wei
, Chon Lok Lei
, Teun P de Boer
, Gary R Mirams
, David J Christini
, Trine Krogh-Madsen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Aims: Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have become an essential tool to study arrhythmia mechanisms. Much of the foundational work on these cells, as well as the computational models built from the resultant data, has overlooked the contribution of seal-leak current on the immature and heterogeneous phenotype that has come to define these cells. The aim of this study is to understand the effect of seal-leak current on recordings of action potential (AP) morphology. Methods and results: Action potentials were recorded in human iPSC-CMs using patch clamp and simulated using previously published mathematical models.

Original language	English
Article number	euad243
Number of pages	12
Journal	Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology
Volume	25
Issue number	9
DOIs	https://doi.org/10.1093/europace/euad243
Publication status	Published - 2 Aug 2023

Keywords

Arrhythmias
Computer simulation
Induced pluripotent stem cells
Ion channels
Patch clamp

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10.1093/europace/euad243Licence: CC BY

euad243Final published version, 1.86 MBLicence: CC BY

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Clark, A. P., Clerx, M., Wei, S., Lei, C. L., de Boer, T. P., Mirams, G. R., Christini, D. J., & Krogh-Madsen, T. (2023). Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 25(9), Article euad243. https://doi.org/10.1093/europace/euad243

Clark, Alexander P ; Clerx, Michael ; Wei, Siyu et al. / Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings. In: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2023 ; Vol. 25, No. 9.

@article{22c2030823e042728728e8a472e386b4,

title = "Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings",

abstract = "Aims: Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have become an essential tool to study arrhythmia mechanisms. Much of the foundational work on these cells, as well as the computational models built from the resultant data, has overlooked the contribution of seal-leak current on the immature and heterogeneous phenotype that has come to define these cells. The aim of this study is to understand the effect of seal-leak current on recordings of action potential (AP) morphology. Methods and results: Action potentials were recorded in human iPSC-CMs using patch clamp and simulated using previously published mathematical models.",

keywords = "Arrhythmias, Computer simulation, Induced pluripotent stem cells, Ion channels, Patch clamp",

author = "Clark, \{Alexander P\} and Michael Clerx and Siyu Wei and Lei, \{Chon Lok\} and \{de Boer\}, \{Teun P\} and Mirams, \{Gary R\} and Christini, \{David J\} and Trine Krogh-Madsen",

note = "Publisher Copyright: {\textcopyright}. We show that compensation of this leak current is difficult due to challenges with obtaining accurate measures of R during an experiment. Using simulation, we show that R measures (i) change during an experiment, invalidating the use of pre-rupture values, and (ii) are polluted by the presence of transmembrane currents at every voltage. Finally, we posit that the background sodium current in baseline iPSC-CM models imitates the effects of seal-leak current and is increased to a level that masks the effects of seal-leak current on iPSC-CMs. Conclusion: Based on these findings, we make recommendations to improve iPSC-CM AP data acquisition, interpretation, and model-building. Taking these recommendations into account will improve our understanding of iPSC-CM physiology and the descriptive ability of models built from such data. ",

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doi = "10.1093/europace/euad243",

language = "English",

volume = "25",

journal = "Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology",

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Clark, AP, Clerx, M, Wei, S, Lei, CL, de Boer, TP, Mirams, GR, Christini, DJ & Krogh-Madsen, T 2023, 'Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings', Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, vol. 25, no. 9, euad243. https://doi.org/10.1093/europace/euad243

Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings. / Clark, Alexander P; Clerx, Michael; Wei, Siyu et al.
In: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, Vol. 25, No. 9, euad243, 02.08.2023.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings

AU - Clark, Alexander P

AU - Clerx, Michael

AU - Wei, Siyu

AU - Lei, Chon Lok

AU - de Boer, Teun P

AU - Mirams, Gary R

AU - Christini, David J

AU - Krogh-Madsen, Trine

N1 - Publisher Copyright: ©. We show that compensation of this leak current is difficult due to challenges with obtaining accurate measures of R during an experiment. Using simulation, we show that R measures (i) change during an experiment, invalidating the use of pre-rupture values, and (ii) are polluted by the presence of transmembrane currents at every voltage. Finally, we posit that the background sodium current in baseline iPSC-CM models imitates the effects of seal-leak current and is increased to a level that masks the effects of seal-leak current on iPSC-CMs. Conclusion: Based on these findings, we make recommendations to improve iPSC-CM AP data acquisition, interpretation, and model-building. Taking these recommendations into account will improve our understanding of iPSC-CM physiology and the descriptive ability of models built from such data.

PY - 2023/8/2

Y1 - 2023/8/2

N2 - Aims: Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have become an essential tool to study arrhythmia mechanisms. Much of the foundational work on these cells, as well as the computational models built from the resultant data, has overlooked the contribution of seal-leak current on the immature and heterogeneous phenotype that has come to define these cells. The aim of this study is to understand the effect of seal-leak current on recordings of action potential (AP) morphology. Methods and results: Action potentials were recorded in human iPSC-CMs using patch clamp and simulated using previously published mathematical models.

AB - Aims: Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have become an essential tool to study arrhythmia mechanisms. Much of the foundational work on these cells, as well as the computational models built from the resultant data, has overlooked the contribution of seal-leak current on the immature and heterogeneous phenotype that has come to define these cells. The aim of this study is to understand the effect of seal-leak current on recordings of action potential (AP) morphology. Methods and results: Action potentials were recorded in human iPSC-CMs using patch clamp and simulated using previously published mathematical models.

KW - Arrhythmias

KW - Computer simulation

KW - Induced pluripotent stem cells

KW - Ion channels

KW - Patch clamp

UR - https://www.scopus.com/pages/publications/85168803290

U2 - 10.1093/europace/euad243

DO - 10.1093/europace/euad243

M3 - Article

C2 - 37552789

SN - 1099-5129

VL - 25

JO - Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology

JF - Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology

IS - 9

M1 - euad243

ER -

Clark AP, Clerx M, Wei S, Lei CL, de Boer TP, Mirams GR et al. Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2023 Aug 2;25(9):euad243. doi: 10.1093/europace/euad243

Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings

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