The Ca²⁺ release units of ventricular myocytes are clusters of Ca²⁺ release channels (ryanodine receptors; RyRs) in the sarcoplasmic reticulum (SR) membrane, which arrange discretely and periodically inside the cell. Intra-cluster RyRs open and close together during a local Ca²⁺ release event, termed a Ca²⁺ spark, by a Ca²⁺-induced Ca²⁺ release (CICR) mechanism. A sparkles release has also been reported, presumably from single RyRs that release too little Ca²⁺ to open their neighbors.

Diastolic arrhythmias during heart failure are a leading cause of death in developed countries. A fraction of those arrhythmias originate at the SR, and are observed as spatially propagating, temporally regenerative, waves of Ca²⁺ release. It is noteworthy that, for regenerative CICR to occur, the Ca²⁺ leaked through one RyR cluster must reach the neighboring cluster in sufficient amounts, and this process repeat iteratively despite the intra-cluster distance and intra-cluster buffering. This indicates that, during heart failure, RyRs are dramatically sensitive to their environment. And indeed, fundamental publications have revealed that RyR are hyperphosphorylated during heart failure and that hyperphosphorylation leads to increased channel activity.

However, additional considerations greatly cloud the above picture. Diseased myocytes progressively decrease the SR Ca²⁺ load, leading to a mechanistic paradox. The behavior of diseased cells is counterintuitive because, as their total cellular Ca²⁺ decreases, the probability of spontaneous RyR openings and CICR should also decrease. Therefore, cells should be able to easily prevent the "extra" diastolic release. This stability is, in fact, observed in healthy cells regardless of the initial RyR tendency to open.

The current dissertation demonstrates, both for mouse and rabbit myocytes, that a substantial portion of the global RyR-mediated SR Ca²⁺ leak (J_leak) occurs in the form of non-sparks. Moreover: by using maximal β-adrenergic stimulation in rabbit healthy cells, it is demonstrated that the fraction of spark-mediated J_leak is increased relative to the basal levels of RyR phosphorylation, and that sparks are wider. Therefore, since more sparks occur for a given J_leak and sparks are wider, the chances of CICR and diastolic Ca²⁺ waves are maximized even in healthy cells. These results partially explain the success of β-blocker therapy in heart failure patients.