Arrhythmogenic late Ca 2+ 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: United States 04.02.2020
• Subjects: Action Potentials; Animals; Arrhythmias, Cardiac - metabolism; Arrhythmias, Cardiac - physiopathology; Calcium - metabolism; Excitation Contraction Coupling; Heart Failure - metabolism; Heart Failure - physiopathology; Humans; Myocytes, Cardiac - metabolism; cardiac myocytes; Ca2+ sparks; action potential; arrhythmia; heart
• DOI: 10.1073/pnas.1918649117
• ISSN: 0027-8424

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 Ca measurements were combined with action potential voltage clamp techniques in a physiologically relevant heart failure model. In failing cells, the loss of Ca release synchrony at the start of the action potential leads to an increase in number of microscopic intracellular Ca release events ("late" Ca sparks) during phase 2-3 of the action potential. These late Ca sparks prolong the Ca transient that activates contraction and can trigger propagating microscopic Ca ripples, larger macroscopic Ca waves, and EADs. Modification of the action potential to include steps to different potentials revealed the amount of current generated by these late Ca sparks and their (subsequent) spatiotemporal summation into Ca ripples/waves. Comparison of this current to the net current that causes action potential repolarization shows that late Ca 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 Ca transient amplitude, and suppressed late Ca sparks. Therapeutic control of late Ca spark activity may provide an additional approach for treating heart failure and reduce the risk for sudden cardiac death.