Arrhythmogenic late Ca2+ sparks in failing heart cells and their control by action potential configuration

Fowler, Ewan D., Wang, Nan, Hezzell, Melanie, Chanoit, Guillaume, Hancox, Jules C. and Cannell, Mark B. 2020. Arrhythmogenic late Ca2+ sparks in failing heart cells and their control by action potential configuration. Proceedings of the National Academy of Sciences 117 (5) , pp. 2687-2692. 10.1073/pnas.1918649117

PDF - Published Version Available under License Creative Commons Attribution. Download (1MB)

Abstract

Sudden death in heart failure patients is a major clinical problem worldwide, but it is unclear how arrhythmogenic early afterdepolarizations (EADs) are triggered in failing heart cells. To examine EAD initiation, high-sensitivity intracellular Ca2+ measurements were combined with action potential voltage clamp techniques in a physiologically relevant heart failure model. In failing cells, the loss of Ca2+ release synchrony at the start of the action potential leads to an increase in number of microscopic intracellular Ca2+ release events (“late” Ca2+ sparks) during phase 2–3 of the action potential. These late Ca2+ sparks prolong the Ca2+ transient that activates contraction and can trigger propagating microscopic Ca2+ ripples, larger macroscopic Ca2+ waves, and EADs. Modification of the action potential to include steps to different potentials revealed the amount of current generated by these late Ca2+ sparks and their (subsequent) spatiotemporal summation into Ca2+ ripples/waves. Comparison of this current to the net current that causes action potential repolarization shows that late Ca2+ sparks provide a mechanism for EAD initiation. Computer simulations confirmed that this forms the basis of a strong oscillatory positive feedback system that can act in parallel with other purely voltage-dependent ionic mechanisms for EAD initiation. In failing heart cells, restoration of the action potential to a nonfailing phase 1 configuration improved the synchrony of excitation–contraction coupling, increased Ca2+ transient amplitude, and suppressed late Ca2+ sparks. Therapeutic control of late Ca2+ spark activity may provide an additional approach for treating heart failure and reduce the risk for sudden cardiac death.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Additional Information:	This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date of First Compliant Deposit:	5 October 2021
Date of Acceptance:	4 February 2020
Last Modified:	12 May 2023 20:19
URI:	https://orca.cardiff.ac.uk/id/eprint/144667

Citation Data

Cited 12 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item