PROJECT SUMMARY Loss-of-function mutations in the genes encoding the cardiac isoform of the voltage-gated sodium channel (Nav1.5) have been associated with the Brugada Syndrome (BrS), and loss-of-function of plakoglobin has been associated with Arrhythmogenic Cardiomyopathy (ACM). Both diseases are associated with inconsistent experimental findings, can be revealed by basic experimental differences, often affect the right ventricle, are associated with intercalated disc proteinopathies, and for both, there are few treatments to prevent arrhythmias. We have previously demonstrated that another loss-of-function in the intercalated disc protein connexin43 can be concealed by choice of experimental perfusate, potentially explaining why disease-related conduction slowing can be measured in some laboratories but can remain concealed in an intact organism with “normal” electrolyte composition. We also previously demonstrated that induced acute interstitial edema (AIE) is greater in the right relative to the left ventricle. Since AIE can unmask gap junction uncoupling, we hypothesize that AIE can unmask two other intercalated disc diseases: BrS and ACM. Finally, if AIE can unmask intercalated disc diseases, our data suggest that these diseases may be treatable by managing intercalated disc microdomain separation. In this project, we propose an innovative hypothesis that the concealed nature of BrS and ACM in intact tissue is mechanistically tied to a newly discovered form of cell-to-cell communication called ephaptic coupling. Upon successful completion of these aims, we will produce new methods to unmask these diseases in their pre- manifest stage, allowing for early detection. Further, the work will suggest important new therapies for two diseases with few effective therapeutic options and poor patient outcomes.