PROJECT SUMMARY Sudden cardiac death (SCD) is estimated to cause 4-5 million deaths per year worldwide. In patients with heart failure, SCD is the number one leading cause of death and is linked to the onset of ventricular arrhythmias. Understanding how ventricular arrhythmias arise in patients with heart failure is thus critical to designing effective drugs that prevent SCD and prolong survival in patients with heart failure. In ventricular cardiomyocytes, the foundation of excitation-contraction coupling is intracellular Ca2+ signaling. Specifically, activation of voltage-gated Ca2+ channels cause Ca2+ release from the SR via Ca2+ release channels resulting in local increases in cytoplasmic [Ca2+] known as “sparks.” Sparks then sum to generate global increases in cytoplasmic [Ca2+] across the cell called Ca2+ transients. Under normal circumstances, this is a tightly controlled and coordinated process that leads to synchronous contraction of the ventricles. When disturbed, however, dyssynchronous Ca2+ release across the cell, known as Ca2+ waves, can lead to uncoordinated ventricular contraction i.e. arrhythmia. When studying conditions that are technically challenging—such as visualizing the arrangement of individual Ca2+ release channels on the SR—or investigating conditions that cannot be easily manipulated—such as studying how changing that arrangement affects probability of arrhythmogenic wave formation—computational modeling becomes very useful. Such variables can be easily manipulated to predict experimentally measurable outcomes. While modeling has been used to study Ca2+ sparks and waves previously, current mathematical models make several assumptions about the subcellular properties of Ca2+ release units. More specifically, they assume that only ryanodine receptors are responsible for SR Ca2+ release while ignoring IP3 receptors, which are lowly expressed in healthy ventricular myocytes and show increased expression in failing myocytes. They also assume homogeneous dyadic geometry and spatial arrangement of channels between release sites. While it is known that properties such as the number of release channels in a release unit are variable in healthy myocytes, these effects as well as changes to dyadic geometry become especially prominent in failing ventricular myocytes in which remodeling has occurred, and should thus be included in models. Given the immense clinical need to understand how changes to ventricular myocytes in heart failure predisposes to arrhythmia and SCD yet the difficulty in experimentally manipulating important spatial and geometric changes found in failing myocytes, there is a clear need for accurate mathematical models of intracellular Ca2+ signaling in failing compared to healthy myocytes. I plan to address this need by developing more accurate models of Ca2+ sparks and Ca2+ waves that account for (1) heterogeneity in Ca2+ release units and (2) the expression of IP3 receptors in both healthy and diseased ventric...