Ca2+ alternans (Ca-Alts) are alternating beat-to-beat changes in the amplitude of Ca2+ 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 Ca2+ released from the sarcoplasmic reticulum (SR) between two consecutive heartbeats. This variable Ca2+ release has been attributed to the alternation of the action potential duration, delay in the recovery from inactivation of RYR Ca2+ release channel (RYR2), or an incomplete Ca2+ refilling of the SR. In all three cases, the RYR2 mobilizes less Ca2+ from the SR in an alternating manner, thereby generating an alternating profile of the Ca2+ 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 Q10 of several kinetic processes defining intracellular Ca2+ dynamics indicated that the effects of temperature change on the relaxation of intracellular Ca2+ 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 Ca2+ uptake into the SR. We found that Ca-Alts are heavily dependent on intra-SR Ca2+ 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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January 07 2021
Thermal modulation of epicardial Ca2+ dynamics uncovers molecular mechanisms of Ca2+ alternans
Jose Millet,
1
Institute of Information and Communication Technologies, Universitat Politècnica de València and Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Valencia, Spain
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Yuriana Aguilar-Sanchez,
2
Department of Physiology and Biophysics, School of Medicine, Rush University Medical Center, Chicago, IL
3
School of Natural Sciences, University of California, Merced, Merced, CA
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Dmytro Kornyeyev,
Dmytro Kornyeyev
6
Department of Bioengineering, School of Engineering, University of California Merced, Merced, CA
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Maedeh Bazmi,
Maedeh Bazmi
3
School of Natural Sciences, University of California, Merced, Merced, CA
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Diego Fainstein,
Diego Fainstein
4
Facultad de Ingeniería, Universidad Nacional de Entre Ríos, Entre Ríos, Argentina
6
Department of Bioengineering, School of Engineering, University of California Merced, Merced, CA
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Julio A. Copello,
Julio A. Copello
5
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL
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Ariel L. Escobar
6
Department of Bioengineering, School of Engineering, University of California Merced, Merced, CA
Correspondence to Ariel L. Escobar: aescobar4@ucmerced.edu
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Jose Millet
1
Institute of Information and Communication Technologies, Universitat Politècnica de València and Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Valencia, Spain
Yuriana Aguilar-Sanchez
2
Department of Physiology and Biophysics, School of Medicine, Rush University Medical Center, Chicago, IL
3
School of Natural Sciences, University of California, Merced, Merced, CA
Dmytro Kornyeyev
6
Department of Bioengineering, School of Engineering, University of California Merced, Merced, CA
Maedeh Bazmi
3
School of Natural Sciences, University of California, Merced, Merced, CA
Diego Fainstein
4
Facultad de Ingeniería, Universidad Nacional de Entre Ríos, Entre Ríos, Argentina
6
Department of Bioengineering, School of Engineering, University of California Merced, Merced, CA
Julio A. Copello
5
Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL
Ariel L. Escobar
6
Department of Bioengineering, School of Engineering, University of California Merced, Merced, CA
Correspondence to Ariel L. Escobar: aescobar4@ucmerced.edu
*
J. Millet and Y. Aguilar-Sanchez contributed equally to this paper.
Received:
January 14 2020
Revision Received:
November 02 2020
Accepted:
November 30 2020
Online Issn: 1540-7748
Print Issn: 0022-1295
Funding:
National Institutes of Health
(R01 HL-084487)
© 2021 Millet et al.
2021
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/).
J Gen Physiol (2021) 153 (2): e202012568.
Article history
Received:
January 14 2020
Revision Received:
November 02 2020
Accepted:
November 30 2020
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Commentary
Understanding Ca2+ alternans
Citation
Jose Millet, Yuriana Aguilar-Sanchez, Dmytro Kornyeyev, Maedeh Bazmi, Diego Fainstein, Julio A. Copello, Ariel L. Escobar; Thermal modulation of epicardial Ca2+ dynamics uncovers molecular mechanisms of Ca2+ alternans. J Gen Physiol 1 February 2021; 153 (2): e202012568. doi: https://doi.org/10.1085/jgp.202012568
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