Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure.

The role of I(KCa) in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of I(KCa) blockade in controls, chronic heart failure (HF) and HF with sustai...

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Autores principales:	Ingrid M Bonilla, Victor P Long, Pedro Vargas-Pinto, Patrick Wright, Andriy Belevych, Qing Lou, Kent Mowrey, Jae Yoo, Philip F Binkley, Vadim V Fedorov, Sandor Györke, Paulus M L Janssen, Ahmet Kilic, Peter J Mohler, Cynthia A Carnes
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6a6220e6898943efbd5f6ac67f57f16c
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spelling	oai:doaj.org-article:6a6220e6898943efbd5f6ac67f57f16c2021-11-25T05:58:20ZCalcium-activated potassium current modulates ventricular repolarization in chronic heart failure.1932-620310.1371/journal.pone.0108824https://doaj.org/article/6a6220e6898943efbd5f6ac67f57f16c2014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0108824https://doaj.org/toc/1932-6203The role of I(KCa) in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of I(KCa) blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The I(KCa) blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n = 5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n = 7). A group of age-matched canine controls were used (n = 8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by I(KCa) blockade in all of the groups studied. I(KCa) blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. I(KCa) blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, I(KCa) blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for I(KCa) in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles.Ingrid M BonillaVictor P LongPedro Vargas-PintoPatrick WrightAndriy BelevychQing LouKent MowreyJae YooPhilip F BinkleyVadim V FedorovSandor GyörkePaulus M L JanssenAhmet KilicPeter J MohlerCynthia A CarnesPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 10, p e108824 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ingrid M Bonilla Victor P Long Pedro Vargas-Pinto Patrick Wright Andriy Belevych Qing Lou Kent Mowrey Jae Yoo Philip F Binkley Vadim V Fedorov Sandor Györke Paulus M L Janssen Ahmet Kilic Peter J Mohler Cynthia A Carnes Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure.
description	The role of I(KCa) in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of I(KCa) blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The I(KCa) blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n = 5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n = 7). A group of age-matched canine controls were used (n = 8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by I(KCa) blockade in all of the groups studied. I(KCa) blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. I(KCa) blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, I(KCa) blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for I(KCa) in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles.
format	article
author	Ingrid M Bonilla Victor P Long Pedro Vargas-Pinto Patrick Wright Andriy Belevych Qing Lou Kent Mowrey Jae Yoo Philip F Binkley Vadim V Fedorov Sandor Györke Paulus M L Janssen Ahmet Kilic Peter J Mohler Cynthia A Carnes
author_facet	Ingrid M Bonilla Victor P Long Pedro Vargas-Pinto Patrick Wright Andriy Belevych Qing Lou Kent Mowrey Jae Yoo Philip F Binkley Vadim V Fedorov Sandor Györke Paulus M L Janssen Ahmet Kilic Peter J Mohler Cynthia A Carnes
author_sort	Ingrid M Bonilla
title	Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure.
title_short	Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure.
title_full	Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure.
title_fullStr	Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure.
title_full_unstemmed	Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure.
title_sort	calcium-activated potassium current modulates ventricular repolarization in chronic heart failure.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/6a6220e6898943efbd5f6ac67f57f16c
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Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure.

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