Targeted Anti-IL-1 Immunomodulatory Therapy in Pediatric Onset PPP1R13L-Related Arrhythmogenic Cardiomyopathy

Autosomal recessive loss-of-function variants in PPP1R13L cause an ultra-rare cardiocutaneous syndrome characterized by rapidly progressive arrhythmogenic cardiomyopathy (ACM). PPP1R13L encodes iASPP, which has two potentially overlapping mechanisms driving ACM as both a regulator of NFκB-mediated inflammation and a binding partner within the cardiac desmosome. This study explores immunotherapy and the underlying pathophysiology in two pediatric cases. Two patients (aged 47 and 32 months) with biallelic PPP1R13L variants presented with refractory ventricular arrhythmias and heart failure. Both received IL-1 blockade as adjunct therapy. Explanted heart tissue was analyzed via quantitative immunofluorescent microscopy to assess NFκβ nuclear localization and desmin localization at the intercalated disks (ID). IL-1 blockade was associated with reduced ventricular ectopy and normalized serum cytokine levels (IL-1, IL-10) but without contractile recovery. Histology analysis revealed increased NFκβ signaling only in non-cardiomyocytes but with loss of desmin at the ID in PPP1R13L cardiomyopathy compared to non-PPP1R13L dilated cardiomyopathy controls. PPP1R13L cardiomyopathy involves systemic inflammation, but loss of desmin-desmosome anchoring in cardiomyocytes appears to be the central mechanism of PPP1R13L cardiomyopathy. Targeted IL-1 blockade can be considered as adjunctive therapy for patients with PPP1R13L cardiomyopathy but further studies on treatments directed at the underlying mechanism are needed.