Updated project metadata. Summary: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder. It is classified as the second most common cause of unexpected sudden death by cardiac arrest in the young. ARVC has devastating psychosocial consequences, especially as many patients are young adults, and current therapy is limited to extreme exercise restriction and defibrillator implantation. More than 40% of the reported genetic variants linked to ARVC reside in a gene called PKP2 , which encodes for the plakophilin-2 (PKP2) protein. The pathogenic mechanisms linking this protein to ARVC remain to be elucidated, which is the focus of this project. I aim to identify exactly which proteins in the heart are dysregulated and to identify why exercise is detrimental for carriers of PKP2-deficient hearts. Our approach is based on state-of-the-art mass spectrometry (MS) technologies that allow us to measure all proteins in the heart simultaneously. We used both human heart biopsy material as well as a murine disease model I anticipate to elucidate novel roles of PKP2 that are of utmost importance for understanding ARVC pathogenesis.