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