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
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Early online date22 Jan 2020
DOIs
Publication statusE-pub ahead of print - 22 Jan 2020

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Keywords

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

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