New disease mechanisms in Arrhythmogenic Cardiomyopathy : Focus on calcium sensitive pathways

Abstract

The heart is the most important muscular organ in the body as it provides oxygen and vital nutrients to all tissues within the body and supports excretion of waste products. Nowadays cardiovascular disease is the number one cause of mortality worldwide. Arrhythmogenic cardiomyopathy (ACM) is a familial myocardial disease and patients with ACM generally manifest with ventricular arrhythmias, palpitations, syncope and have an increased risk for sudden cardiac death (SCD). SCD often is the first, and dramatic, disease manifestation in a high proportion of probands and is often associated with exercise, affecting in particular athletes and young adults. In 60-70% of patients diagnosed with ACM the underlying cause is a mutation in genes encoding desmosomal proteins. In the far majority of inherited ACM cases, in which a desmosomal mutation is found, the affected gene is PKP2 that encodes for the protein plakophilin-2 (PKP2). The identification of ACM-associated mutations in the sarcoplasmic reticulum associated protein phospholamban (PLN) encouraged us to focus in this thesis specifically on calcium (Ca2+) handling related pathways. The general aim of the work described in this thesis was to study new disease mechanisms in ACM and we postulated and confirmed a thus far unrecognized role for Ca2+ handling related disease mechanisms in ACM. Besides that, we explored pharmaceutical interventions to treat the PKP2 and PLN-R14del- related cardiomyopathy. For the future, it is important to re-evaluate the one gene-one disease paradigm, and to focus on studying mutation -and patient specific disease mechanisms.