Using a cardiac KO mouse model of ARVC, we identified fundamental mechanisms behind disruption of PKP2-associated desmosome function and revealed its broad impact at the transcriptional level on GJs, sarcomere, ion channels and Ca2+ handling systems, and multiple pathways that critically regulate metabolism, inflammation, apoptosis, and fibrosis. Here, PKP2 is linked to arrhythmogenic right ventricular cardiomyopathy.