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Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue
AIMS: Chronic tachypacing is commonly used in animals to induce cardiac dysfunction and to study mechanisms of heart failure and arrhythmogenesis. Human induced pluripotent stem cells (hiPSC) may replace animal models to overcome species differences and ethical problems. Here, 3D engineered heart ti...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314638/ https://www.ncbi.nlm.nih.gov/pubmed/31598634 http://dx.doi.org/10.1093/cvr/cvz245 |
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author | Lemme, Marta Braren, Ingke Prondzynski, Maksymilian Aksehirlioglu, Bülent Ulmer, Bärbel M Schulze, Mirja L Ismaili, Djemail Meyer, Christian Hansen, Arne Christ, Torsten Lemoine, Marc D Eschenhagen, Thomas |
author_facet | Lemme, Marta Braren, Ingke Prondzynski, Maksymilian Aksehirlioglu, Bülent Ulmer, Bärbel M Schulze, Mirja L Ismaili, Djemail Meyer, Christian Hansen, Arne Christ, Torsten Lemoine, Marc D Eschenhagen, Thomas |
author_sort | Lemme, Marta |
collection | PubMed |
description | AIMS: Chronic tachypacing is commonly used in animals to induce cardiac dysfunction and to study mechanisms of heart failure and arrhythmogenesis. Human induced pluripotent stem cells (hiPSC) may replace animal models to overcome species differences and ethical problems. Here, 3D engineered heart tissue (EHT) was used to investigate the effect of chronic tachypacing on hiPSC-cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS: To avoid cell toxicity by electrical pacing, we developed an optogenetic approach. EHTs were transduced with lentivirus expressing channelrhodopsin-2 (H134R) and stimulated by 15 s bursts of blue light pulses (0.3 mW/mm(2), 30 ms, 3 Hz) separated by 15 s without pacing for 3 weeks. Chronic optical tachypacing did not affect contractile peak force, but induced faster contraction kinetics, shorter action potentials, and shorter effective refractory periods. This electrical remodelling increased vulnerability to tachycardia episodes upon electrical burst pacing. Lower calsequestrin 2 protein levels, faster diastolic depolarization (DD) and efficacy of JTV-519 (46% at 1 µmol/L) to terminate tachycardia indicate alterations of Ca(2+) handling being part of the underlying mechanism. However, other antiarrhythmic compounds like flecainide (69% at 1 µmol/L) and E-4031 (100% at 1 µmol/L) were also effective, but not ivabradine (1 µmol/L) or SEA0400 (10 µmol/L). CONCLUSION: We demonstrated a high vulnerability to tachycardia of optically tachypaced hiPSC-CMs in EHT and the effective termination by ryanodine receptor stabilization, sodium or hERG potassium channel inhibition. This new model might serve as a preclinical tool to test antiarrhythmic drugs increasing the insight in treating ventricular tachycardia. |
format | Online Article Text |
id | pubmed-7314638 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-73146382020-07-13 Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue Lemme, Marta Braren, Ingke Prondzynski, Maksymilian Aksehirlioglu, Bülent Ulmer, Bärbel M Schulze, Mirja L Ismaili, Djemail Meyer, Christian Hansen, Arne Christ, Torsten Lemoine, Marc D Eschenhagen, Thomas Cardiovasc Res Original Articles AIMS: Chronic tachypacing is commonly used in animals to induce cardiac dysfunction and to study mechanisms of heart failure and arrhythmogenesis. Human induced pluripotent stem cells (hiPSC) may replace animal models to overcome species differences and ethical problems. Here, 3D engineered heart tissue (EHT) was used to investigate the effect of chronic tachypacing on hiPSC-cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS: To avoid cell toxicity by electrical pacing, we developed an optogenetic approach. EHTs were transduced with lentivirus expressing channelrhodopsin-2 (H134R) and stimulated by 15 s bursts of blue light pulses (0.3 mW/mm(2), 30 ms, 3 Hz) separated by 15 s without pacing for 3 weeks. Chronic optical tachypacing did not affect contractile peak force, but induced faster contraction kinetics, shorter action potentials, and shorter effective refractory periods. This electrical remodelling increased vulnerability to tachycardia episodes upon electrical burst pacing. Lower calsequestrin 2 protein levels, faster diastolic depolarization (DD) and efficacy of JTV-519 (46% at 1 µmol/L) to terminate tachycardia indicate alterations of Ca(2+) handling being part of the underlying mechanism. However, other antiarrhythmic compounds like flecainide (69% at 1 µmol/L) and E-4031 (100% at 1 µmol/L) were also effective, but not ivabradine (1 µmol/L) or SEA0400 (10 µmol/L). CONCLUSION: We demonstrated a high vulnerability to tachycardia of optically tachypaced hiPSC-CMs in EHT and the effective termination by ryanodine receptor stabilization, sodium or hERG potassium channel inhibition. This new model might serve as a preclinical tool to test antiarrhythmic drugs increasing the insight in treating ventricular tachycardia. Oxford University Press 2020-07-01 2019-10-09 /pmc/articles/PMC7314638/ /pubmed/31598634 http://dx.doi.org/10.1093/cvr/cvz245 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Articles Lemme, Marta Braren, Ingke Prondzynski, Maksymilian Aksehirlioglu, Bülent Ulmer, Bärbel M Schulze, Mirja L Ismaili, Djemail Meyer, Christian Hansen, Arne Christ, Torsten Lemoine, Marc D Eschenhagen, Thomas Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue |
title | Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue |
title_full | Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue |
title_fullStr | Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue |
title_full_unstemmed | Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue |
title_short | Chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue |
title_sort | chronic intermittent tachypacing by an optogenetic approach induces arrhythmia vulnerability in human engineered heart tissue |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314638/ https://www.ncbi.nlm.nih.gov/pubmed/31598634 http://dx.doi.org/10.1093/cvr/cvz245 |
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