Disruption of Ca ²⁺ _i Homeostasis and Connexin 43 Hemichannel Function in the Right Ventricle Precedes Overt Arrhythmogenic Cardiomyopathy in Plakophilin-2–Deficient Mice

Loss of PKP2 creates an RV-predominant arrhythmogenic substrate (Ca²⁺ dysregulation) that precedes the cardiomyopathy; this is, at least in part, mediated by a Connexin 43-dependent membrane conduit and repressed by protein kinase C inhibitors. Given that asymmetric Ca²⁺ dysregulation precedes the cardiomyopathic stage, we speculate that abnormal Ca²⁺ handling in RV myocytes can be a trigger for gross structural changes observed at a later stage.