To investigate the detailed mechanism underlying the putative role of complement system activation in ARVC, we eliminated the key complement component C3 in the desmin knockout mouse model of ARVC by generating Des-/-C3-/- double-knockout mice, providing the first evidence that crosstalk between the complement and coagulation systems can exacerbate the underlying pathology in the context of cardiac injury. This evidence concerns the gene DES and Arrhythmogenic right ventricular dysplasia.