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Thermal modulation of epicardial Ca(2+) dynamics uncovers molecular mechanisms of Ca(2+) alternans

Ca(2+) alternans (Ca-Alts) are alternating beat-to-beat changes in the amplitude of Ca(2+) transients that frequently occur during tachycardia, ischemia, or hypothermia that can lead to sudden cardiac death. Ca-Alts appear to result from a variation in the amount of Ca(2+) released from the sarcopla...

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Autores principales: Millet, Jose, Aguilar-Sanchez, Yuriana, Kornyeyev, Dmytro, Bazmi, Maedeh, Fainstein, Diego, Copello, Julio A., Escobar, Ariel L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797898/
https://www.ncbi.nlm.nih.gov/pubmed/33410862
http://dx.doi.org/10.1085/jgp.202012568
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author Millet, Jose
Aguilar-Sanchez, Yuriana
Kornyeyev, Dmytro
Bazmi, Maedeh
Fainstein, Diego
Copello, Julio A.
Escobar, Ariel L.
author_facet Millet, Jose
Aguilar-Sanchez, Yuriana
Kornyeyev, Dmytro
Bazmi, Maedeh
Fainstein, Diego
Copello, Julio A.
Escobar, Ariel L.
author_sort Millet, Jose
collection PubMed
description Ca(2+) alternans (Ca-Alts) are alternating beat-to-beat changes in the amplitude of Ca(2+) transients that frequently occur during tachycardia, ischemia, or hypothermia that can lead to sudden cardiac death. Ca-Alts appear to result from a variation in the amount of Ca(2+) released from the sarcoplasmic reticulum (SR) between two consecutive heartbeats. This variable Ca(2+) release has been attributed to the alternation of the action potential duration, delay in the recovery from inactivation of RYR Ca(2+) release channel (RYR2), or an incomplete Ca(2+) refilling of the SR. In all three cases, the RYR2 mobilizes less Ca(2+) from the SR in an alternating manner, thereby generating an alternating profile of the Ca(2+) transients. We used a new experimental approach, fluorescence local field optical mapping (FLOM), to record at the epicardial layer of an intact heart with subcellular resolution. In conjunction with a local cold finger, a series of images were recorded within an area where the local cooling induced a temperature gradient. Ca-Alts were larger in colder regions and occurred without changes in action potential duration. Analysis of the change in the enthalpy and Q(10) of several kinetic processes defining intracellular Ca(2+) dynamics indicated that the effects of temperature change on the relaxation of intracellular Ca(2+) transients involved both passive and active mechanisms. The steep temperature dependency of Ca-Alts during tachycardia suggests Ca-Alts are generated by insufficient SERCA-mediated Ca(2+) uptake into the SR. We found that Ca-Alts are heavily dependent on intra-SR Ca(2+) and can be promoted through partial pharmacologic inhibition of SERCA2a. Finally, the FLOM experimental approach has the potential to help us understand how arrhythmogenesis correlates with the spatial distribution of metabolically impaired myocytes along the myocardium.
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spelling pubmed-77978982021-08-01 Thermal modulation of epicardial Ca(2+) dynamics uncovers molecular mechanisms of Ca(2+) alternans Millet, Jose Aguilar-Sanchez, Yuriana Kornyeyev, Dmytro Bazmi, Maedeh Fainstein, Diego Copello, Julio A. Escobar, Ariel L. J Gen Physiol Article Ca(2+) alternans (Ca-Alts) are alternating beat-to-beat changes in the amplitude of Ca(2+) transients that frequently occur during tachycardia, ischemia, or hypothermia that can lead to sudden cardiac death. Ca-Alts appear to result from a variation in the amount of Ca(2+) released from the sarcoplasmic reticulum (SR) between two consecutive heartbeats. This variable Ca(2+) release has been attributed to the alternation of the action potential duration, delay in the recovery from inactivation of RYR Ca(2+) release channel (RYR2), or an incomplete Ca(2+) refilling of the SR. In all three cases, the RYR2 mobilizes less Ca(2+) from the SR in an alternating manner, thereby generating an alternating profile of the Ca(2+) transients. We used a new experimental approach, fluorescence local field optical mapping (FLOM), to record at the epicardial layer of an intact heart with subcellular resolution. In conjunction with a local cold finger, a series of images were recorded within an area where the local cooling induced a temperature gradient. Ca-Alts were larger in colder regions and occurred without changes in action potential duration. Analysis of the change in the enthalpy and Q(10) of several kinetic processes defining intracellular Ca(2+) dynamics indicated that the effects of temperature change on the relaxation of intracellular Ca(2+) transients involved both passive and active mechanisms. The steep temperature dependency of Ca-Alts during tachycardia suggests Ca-Alts are generated by insufficient SERCA-mediated Ca(2+) uptake into the SR. We found that Ca-Alts are heavily dependent on intra-SR Ca(2+) and can be promoted through partial pharmacologic inhibition of SERCA2a. Finally, the FLOM experimental approach has the potential to help us understand how arrhythmogenesis correlates with the spatial distribution of metabolically impaired myocytes along the myocardium. Rockefeller University Press 2021-01-07 /pmc/articles/PMC7797898/ /pubmed/33410862 http://dx.doi.org/10.1085/jgp.202012568 Text en © 2021 Millet et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Millet, Jose
Aguilar-Sanchez, Yuriana
Kornyeyev, Dmytro
Bazmi, Maedeh
Fainstein, Diego
Copello, Julio A.
Escobar, Ariel L.
Thermal modulation of epicardial Ca(2+) dynamics uncovers molecular mechanisms of Ca(2+) alternans
title Thermal modulation of epicardial Ca(2+) dynamics uncovers molecular mechanisms of Ca(2+) alternans
title_full Thermal modulation of epicardial Ca(2+) dynamics uncovers molecular mechanisms of Ca(2+) alternans
title_fullStr Thermal modulation of epicardial Ca(2+) dynamics uncovers molecular mechanisms of Ca(2+) alternans
title_full_unstemmed Thermal modulation of epicardial Ca(2+) dynamics uncovers molecular mechanisms of Ca(2+) alternans
title_short Thermal modulation of epicardial Ca(2+) dynamics uncovers molecular mechanisms of Ca(2+) alternans
title_sort thermal modulation of epicardial ca(2+) dynamics uncovers molecular mechanisms of ca(2+) alternans
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797898/
https://www.ncbi.nlm.nih.gov/pubmed/33410862
http://dx.doi.org/10.1085/jgp.202012568
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