Project Summary Sudden, unexpected death in epilepsy (SUDEP) is a fatal complication, occurring in patients with epilepsy, who were otherwise healthy. Dravet syndrome (DS), which results from a loss of function of the sodium channel (NaV) isoform NaV1.1, is associated with a particularly high risk of SUDEP. Notably, the unexpected mortality of SUDEP mirrors cases of sudden cardiac death (SCD) – unexpected death resulting from cardiac arrhythmias. Emerging evidence points to physiological commonalities between the brain and the heart, suggesting that the very molecular mechanisms that underlie epileptic disorders could also directly impact the heart, leading to life- threatening cardiac arrhythmias and thereby, SCD. However, the precise mechanisms by which DS directly impact the heart to promote cardiac arrhythmias and SCD remain unknown. Thus, we propose to utilize models of DS to address this gap in knowledge and to explore the role of direct cardiac remodeling in SCD. Using these models, we will test the hypothesis that defects in NaVs that underlie inherited epileptic disorders, such as Dravet syndrome, dysregulate cardiac Na+/Ca2+ cycling, thereby promoting life-threatening arrhythmias and contributing to SCD. Thus, we propose to: 1) Define the phenotypic and structural impacts of tissue-specific expression of DS-associated defects. 2) Determine the functional impact of DS-associated Na+/Ca2+ signaling nanodomain remodeling on cardiac Ca2+ handling. 3) Assess efficacy of targeting Na+/Ca2+ signaling nanodomains for SCD prevention. Information gleaned from these studies will be used to develop new therapeutic approaches to treat SCD in DS.