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

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Abstract

Sudden death in heart failure patients is a major clinical problem worldwide, but it is unclear how arrhythmogenic early after depolarizations (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) spatio-temporal 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 non-failing 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 a new approach for treating heart failure and reduce the risk for sudden cardiac death.
Original languageEnglish
Pages (from-to)2687-2692
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number5
Early online date22 Jan 2020
DOIs
Publication statusPublished - 4 Feb 2020

Keywords

  • Heart
  • Arrhythmia
  • Cardiac myocytes
  • Action potential
  • Ca2+ sparks

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