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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 5; pp. 2687 - 2692
• Main Authors: Fowler, Ewan D., Wang, Nan, Hezzell, Melanie, Chanoit, Guillaume, Hancox, Jules C., Cannell, Mark B.
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 04.02.2020
• Subjects: Action potential; Biological Sciences; Calcium (intracellular); Calcium ions; Calcium signalling; Computer simulation; Configurations; Congestive heart failure; Contraction; Electric potential; Heart failure; Intracellular; Mathematical models; Positive feedback; Restoration; Ripples; Risk reduction; Voltage; Wave propagation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1918649117

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.