During a cardiac ventricular action potential (AP), a small Ca flux across the transverse tubule (TT) membrane activates ryanodine receptor (RyR) channels on the sarcoplasmic reticululum (SR), a process called Ca-induced Ca release (CICR). During diastole, single RyRs can also spontaneously open (albeit infrequently). When one does, the SR Ca released may trigger a localized bout of inter-RyR CICR (a Ca spark). Abnormally frequent or large sparks can evoke propagating Ca waves. By driving surface electrogenic Na-Ca exchange, waves may generate delayed afterdepolarizations (DADs). DADs can be life-threatening arrhythmogenic events and are observed in both catecholaminergic polymorphic ventricular tachycardia (CPVT) and heart failure (HF). A RyR DAD control nexus is diastolic inter-RyR CICR initiation, which is driven by an individual spontaneous RyR opening. The decisive opening produces a local cytosolic Ca signal that either evokes inter-RyR CICR or not. Most diastolic openings do not. But, the likelihood that one will increases during HF and CPVT, elevating DAD propensity Carvedilol is a commonly used FDA-approved ?-blocker. We recently (2011) made a non-?-blocking carvedilol derivative (VK-II-86) that (like carvedilol) reduces RyR open time (OT) and consequently eliminated waves, DADs and CPVT in model mice (50). We removed ?-blocking because it dose-limited the drug?s RyR- targeted action. We have made/screened 100+ carvedilol derivatives and identified some new very promising agents that can dosed to provide an optimal RyR anti-DAD action, independent of ?-block need. Here, we will define the RyR DAD control nexus, determine how CPVT/HF distort operation of this nexus and identify RyR-targeted drugs that normalize the DAD-driving nexus output. We will test the hypothesis that distortion of the spatiotemporal cytosolic Ca signal created by an individual spontaneous diastolic RyR opening is a key pathogenically shared DAD control nexus that can be therapeutically normalized using novel RyR- targeted agents. This multi-PI proposal combines an almost unprecedented combination of single RyR recording, intracellular Ca imaging and muscle cell biology expertise to address our mechanism-to-therapeutic intervention hypothesis. The specific aims are 1) Determine how CPVT and HF distorts the DAD control nexus and whether those distortions are nexus control factor-specific, disease-dependent and/or part of a continuum of RyR dysfunction and 2) Identify RyR-targeted anti-DAD drugs that normalize pathologically distorted single RyR cytosolic Ca signals and thus limit threat of life-threatening arrhythmias in HF and CPVT. This study will provides a strong mechanistic foundation for understanding DAD origination and its involvement in cardiac disease and thus represents a needed step toward rational design of better therapeutic interventions.