Ca²⁺ dependent cardiac arrhythmias are associated with cellular Ca²⁺ instability which has been attributed to excess Ca²⁺ within the sarcoplasmic reticulum (SR) or "[Ca²⁺]_SR overload". Independent experiments attribute this arrhythmic tendency to SR Ca²⁺ "leak." Ironically, Ca²⁺ -dependent arrhythmias are observed in conditions where the steady-state [Ca²⁺]_SR is low. This paradoxical result is observed in heart failure and in specific genetic arrhythmic conditions. In this presentation, experimental findings are combined with mathematical modeling results to suggest a resolution to the paradox.

The sarcoplasmic reticulum (SR) in heart muscle cells is the intracellular Ca²⁺ store that contributes most of the Ca²⁺ to the transient elevation of [Ca²⁺]_i within the cytosol that occurs with each heartbeat and underlies contraction. The SR Ca²⁺ concentration ([Ca²⁺]_SR) is a major factor that determines the level of the elevated [Ca²⁺]_i during the transient. [Ca²⁺]_SR is established primarily by two opposing processes -- the SR/ER Ca²⁺ ATPase (SERCA2a) that pumps Ca²⁺ into the SR and the SR Ca²⁺ loss ("leak") primarily through the SR Ca²⁺ release channels (ryanodine receptors, RyR2s). The RyR2s Ca²⁺ release channels are normally activated to release Ca²⁺ by cytosolic Ca²⁺ concentration ([Ca²⁺]_i) but this process is highly regulated. While the low but measureable opening rate for RyR2s in heart cells under diastolic conditions leads to a low rate of diastolic Ca²⁺ sparks, the stereotyped SR Ca²⁺ release event in heart cell, this opening rate is subject to regulation. For example, the RyR2 sensitivity to [Ca²⁺]_i is increased by elevated [Ca²⁺]_SR and when this occurs the diastolic Ca²⁺ spark rate increases. When [Ca²⁺]_SR is very high ("Ca²⁺ overload"), Ca²⁺ release instability is observed to occur and underlies the generation of propagated Ca²⁺ waves within myocytes that contribute to single cell "arrhythmogenesis". The RyR2s are broadly regulated by diverse processes including phosphorylation of RyR2 and association of diverse co-factors, cellular and SR lumenal proteins and the RyR2 redox state.

While increased RyR2 sensitivity to [Ca²⁺]_i tends to increase SR Ca²⁺ instability at constant [Ca²⁺]_SR, this increased RyR2 sensitivity of [Ca²⁺]_i also tends to reduce SR Ca²⁺ by increasing the open probability of RyR2 and thereby increasing leak. Thus pump and leak of SR Ca²⁺ determine dynamically [Ca²⁺]_SR. How these processes interact to enable Ca²⁺ instability arrhythmogenesis to develop in single cells under diverse yet relevant conditions is discussed.

Supported by the National Heart Lung and Blood Institute, the Leducq Fondation, the American Heart Association and the Maryland State Stem Cell Initiative.