Interleukin-1β Drives Disease Progression in Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is a genetic form of heart failure that affects 1 in 5,000 people globally and is caused by mutations in cardiac desmosomal genes including PKP2, DSP, and DSG2. Individuals with ACM suffer from ventricular arrhythmias, sudden cardiac death, and heart failure. There are few effective treatments and heart transplantation remains the best option for many affected individuals. Here we performed single nucleus RNA sequencing and spatial transcriptomics on myocardial samples from patients with ACM and control donors. We identified disease-associated spatial niches characterized by coexistence of fibrotic and inflammatory cell types and failing cardiac myocytes. The inflammatory-fibrotic niche colocalized to areas of cardiac myocyte loss and comprised FAP (fibroblast activation protein) and POSTN (periostin) expressing fibroblasts, macrophages that expressed NLRP3, and nuclear factor κB activated genes. Using homozygous Dsg2 mutant (Dsg2^mut/mut) mice, we identified analogous populations of Postn-expressing fibroblasts and inflammatory macrophage populations that co-localized within diseased areas. Detailed single nucleus RNA-sequencing analysis of inflammatory macrophage subsets that were increased in ACM samples revealed high levels of Il1b expression. To delineate the possible benefit of targeting IL1B in ACM, we treated Dsg2^mut/mut mice with an anti-IL1B neutralizing antibody and observed attenuated fibrosis, reduced levels of inflammatory cytokines and chemokines, preserved cardiac function, and diminished conduction slowing and automaticity, key mechanisms of arrhythmogenesis. These results suggest that currently approved therapeutics that target IL1B or IL1 signaling may improve outcomes for patients with ACM.