Introduction: Ventricular arrhythmia is the cardinal manifestation of arrhythmogenic cardiomyopathy (AC), a cause of sudden cardiac death in the young. It is commonly the first manifestation of AC, preceding cardiac dysfunction and fibroadiposis. Mutations in genes encoding desmosome proteins, including desmoplakin (DSP) are the main causes of AC. Deletion of Dsp specifically in cardiac myocytes in mice leads to cardiac dysfunction. Arrhythmias occur concomitant with but not independent of cardiac dysfunction. We posit that non-myocyte cells in the heart are responsible for early arrhythmias in AC.
Objective: To delineate cellular basis of cardiac arrhythmias in AC.
Methods and Results: Cells expressing chondroitin sulfate proteoglycan 4 (CSPG4), a transmembrane protein in neuroglial cells, constituted ~ 5.59±3.27% of the non-myocyte cells in the mouse heart. Immunofluorescence and genetic tagging detected expression of CSPG4 in the cardiac conduction system (CCS). Inducible deletion of Dsp using Cspg4-Cre/Esr1* mice led to ventricular arrhythmias, atrial fibrillation, AV block, and total mortality by 8 weeks of age. In contrast, cardiac function and myocardial histology were normal. Cspg4-Cre/Esr1* mice: DspF/F exhibited palmar-plantar keratosis and alopecia totalis, similar to human cardiocutaneous syndromes. Keratinocytes showed accelerated proliferation and terminal differentiation, consistent with DSP functions in keratinization and cornification.
Conclusions: CSPG4 tags CCS and keratinocytes. Deletion of Dsp in CSPG4pos cells leads to lethal cardiac arrhythmias without cardiac dysfunction, the cardinal feature of AC, and the skin phenotype of keratosis and alopecia, as in cardiocutaneous syndromes. The findings provide a cellular basis for early cardiac arrhythmias in AC and cardiocutaneous syndrome in humans.