Ryanodine receptors (RyRs) mediate Ca-induced Ca release (CICR) from the sarcoplasmic reticulum (SR). The SR has discrete Ca release sites, each with a cluster of RyRs. During diastole, single -RyRs open infrequently, but when one does, the Ca it releases may ignite localized inter-RyR CICR (a spark). Abnormally frequent or large sparks can evoke propagating Ca waves, ventricular tachycardia and sudden cardiac death. RyRs operate inter-dependently at release sites. Opening of any RyR in a cluster invariably and dynamically (spatially & temporally) alters local [Ca]’s (cytosolic & intra-SR). These [Ca] changes may activate neighboring RyRs. The clustered RyR-geometry at release sites and the inherent positive feedback of CICR pose an ever- present risk of evoking a Ca wave. So, fail-safe release site operation requires keeping local CICR in check. For decades, various single RyR-level mechanisms (inactivation, adaptation, luminal Ca regulation) were proposed to explain the paradoxical CICR stability of release sites. These single-RyR processes were ultimately found to be insufficient. Our pilot studies indicate the reason is the required CICR negative control arises from the collective operation of RyRs, not each RyR acting independently of one another. Collective-RyR operation at release sites is still essentially a black box even though we know a lot about its components, from single-RyR structure-function to sparks. Previous simulations importantly revealed details of “elementary” Ca release. But, these applied some strong simplifications. For example, single-RyR gating is complex and this was just not captured in the past. Common pool compartment models were used (and still are), where all RyRs always “see” the same [Ca], but this literally eliminates the very phenomenon (dynamic nano-scale spatiotemporal [Ca] gradients) that drives collective-RyR operation at release sites. Thus, our foundational principle is, as we have the parts needed, we must meticulously assemble them without the unrealistic assumptions of the past. To this end, we developed an innovative hybrid experimental/computational approach. Our pilot studies have already revealed previously unknown collective-RyR CICR control mechanisms like pernicious attrition (which helps terminates CICR), RyR recruitment bias (that works to shrink inter-RyRCICR events) and long-closed resistance(whichlimits the local spread of CICR within arelease site). The hypothesis tested here is: The normal fail-safe stability and arrhythmogenic instability of diastolic SR Ca release sites are governed by collective-RyR control mechanisms that can be therapeutically manipulated by RyR- targeted drugs. And, the specific aims are 1) Identify collective-RyR control mechanisms that promote the diastolic stability normal human ventricular SR Ca release sites and 2) Define collective-RyR control at human arrhythmogenic diastolic release sites and test RyR-targeted drugs as potential therapeutic collective co...