Acute effects of cardiac contractility modulation on human induced pluripotent stem cell–derived cardiomyocytes

Abstract Cardiac contractility modulation (CCM) is an intracardiac therapy whereby nonexcitatory electrical simulations are delivered during the absolute refractory period of the cardiac cycle. We previously evaluated the effects of CCM in isolated adult rabbit ventricular cardiomyocytes and found a...

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Autores principales:	Tromondae K. Feaster, Maura Casciola, Akshay Narkar, Ksenia Blinova
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	calcium handling cardiac contractility modulation cardiomyocytes hiPSC‐CM Physiology QP1-981
Acceso en línea:	https://doaj.org/article/6a69747c11ce4564bb31ab1efdd522c0
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spelling	oai:doaj.org-article:6a69747c11ce4564bb31ab1efdd522c02021-11-15T09:54:40ZAcute effects of cardiac contractility modulation on human induced pluripotent stem cell–derived cardiomyocytes2051-817X10.14814/phy2.15085https://doaj.org/article/6a69747c11ce4564bb31ab1efdd522c02021-11-01T00:00:00Zhttps://doi.org/10.14814/phy2.15085https://doaj.org/toc/2051-817XAbstract Cardiac contractility modulation (CCM) is an intracardiac therapy whereby nonexcitatory electrical simulations are delivered during the absolute refractory period of the cardiac cycle. We previously evaluated the effects of CCM in isolated adult rabbit ventricular cardiomyocytes and found a transient increase in calcium and contractility. In the present study, we sought to extend these results to human cardiomyocytes using human induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) to develop a robust model to evaluate CCM in vitro. HiPSC‐CMs (iCell Cardiomyocytes2, Fujifilm Cellular Dynamic, Inc.) were studied in monolayer format plated on flexible substrate. Contractility, calcium handling, and electrophysiology were evaluated by fluorescence‐ and video‐based analysis (CellOPTIQ, Clyde Biosciences). CCM pulses were applied using an A‐M Systems 4100 pulse generator. Robust hiPSC‐CMs response was observed at 14 V/cm (64 mA) for pacing and 28 V/cm (128 mA, phase amplitude) for CCM. Under these conditions, hiPSC‐CMs displayed enhanced contractile properties including increased contraction amplitude and faster contraction kinetics. Likewise, calcium transient amplitude increased, and calcium kinetics were faster. Furthermore, electrophysiological properties were altered resulting in shortened action potential duration (APD). The observed effects subsided when the CCM stimulation was stopped. CCM‐induced increase in hiPSC‐CMs contractility was significantly more pronounced when extracellular calcium concentration was lowered from 2 mM to 0.5 mM. This study provides a comprehensive characterization of CCM effects on hiPSC‐CMs. These data represent the first study of CCM in hiPSC‐CMs and provide an in vitro model to assess physiologically relevant mechanisms and evaluate safety and effectiveness of future cardiac electrophysiology medical devices.Tromondae K. FeasterMaura CasciolaAkshay NarkarKsenia BlinovaWileyarticlecalcium handlingcardiac contractility modulationcardiomyocyteshiPSC‐CMPhysiologyQP1-981ENPhysiological Reports, Vol 9, Iss 21, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	calcium handling cardiac contractility modulation cardiomyocytes hiPSC‐CM Physiology QP1-981
spellingShingle	calcium handling cardiac contractility modulation cardiomyocytes hiPSC‐CM Physiology QP1-981 Tromondae K. Feaster Maura Casciola Akshay Narkar Ksenia Blinova Acute effects of cardiac contractility modulation on human induced pluripotent stem cell–derived cardiomyocytes
description	Abstract Cardiac contractility modulation (CCM) is an intracardiac therapy whereby nonexcitatory electrical simulations are delivered during the absolute refractory period of the cardiac cycle. We previously evaluated the effects of CCM in isolated adult rabbit ventricular cardiomyocytes and found a transient increase in calcium and contractility. In the present study, we sought to extend these results to human cardiomyocytes using human induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) to develop a robust model to evaluate CCM in vitro. HiPSC‐CMs (iCell Cardiomyocytes2, Fujifilm Cellular Dynamic, Inc.) were studied in monolayer format plated on flexible substrate. Contractility, calcium handling, and electrophysiology were evaluated by fluorescence‐ and video‐based analysis (CellOPTIQ, Clyde Biosciences). CCM pulses were applied using an A‐M Systems 4100 pulse generator. Robust hiPSC‐CMs response was observed at 14 V/cm (64 mA) for pacing and 28 V/cm (128 mA, phase amplitude) for CCM. Under these conditions, hiPSC‐CMs displayed enhanced contractile properties including increased contraction amplitude and faster contraction kinetics. Likewise, calcium transient amplitude increased, and calcium kinetics were faster. Furthermore, electrophysiological properties were altered resulting in shortened action potential duration (APD). The observed effects subsided when the CCM stimulation was stopped. CCM‐induced increase in hiPSC‐CMs contractility was significantly more pronounced when extracellular calcium concentration was lowered from 2 mM to 0.5 mM. This study provides a comprehensive characterization of CCM effects on hiPSC‐CMs. These data represent the first study of CCM in hiPSC‐CMs and provide an in vitro model to assess physiologically relevant mechanisms and evaluate safety and effectiveness of future cardiac electrophysiology medical devices.
format	article
author	Tromondae K. Feaster Maura Casciola Akshay Narkar Ksenia Blinova
author_facet	Tromondae K. Feaster Maura Casciola Akshay Narkar Ksenia Blinova
author_sort	Tromondae K. Feaster
title	Acute effects of cardiac contractility modulation on human induced pluripotent stem cell–derived cardiomyocytes
title_short	Acute effects of cardiac contractility modulation on human induced pluripotent stem cell–derived cardiomyocytes
title_full	Acute effects of cardiac contractility modulation on human induced pluripotent stem cell–derived cardiomyocytes
title_fullStr	Acute effects of cardiac contractility modulation on human induced pluripotent stem cell–derived cardiomyocytes
title_full_unstemmed	Acute effects of cardiac contractility modulation on human induced pluripotent stem cell–derived cardiomyocytes
title_sort	acute effects of cardiac contractility modulation on human induced pluripotent stem cell–derived cardiomyocytes
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/6a69747c11ce4564bb31ab1efdd522c0
work_keys_str_mv	AT tromondaekfeaster acuteeffectsofcardiaccontractilitymodulationonhumaninducedpluripotentstemcellderivedcardiomyocytes AT mauracasciola acuteeffectsofcardiaccontractilitymodulationonhumaninducedpluripotentstemcellderivedcardiomyocytes AT akshaynarkar acuteeffectsofcardiaccontractilitymodulationonhumaninducedpluripotentstemcellderivedcardiomyocytes AT kseniablinova acuteeffectsofcardiaccontractilitymodulationonhumaninducedpluripotentstemcellderivedcardiomyocytes
_version_	1718428439076143104

Acute effects of cardiac contractility modulation on human induced pluripotent stem cell–derived cardiomyocytes

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