Possiamo fare luce sui meccanismi alla base delle aritmie nella cardiomiopatia aritmogena?

Arrhythmogenic Cardiomyopathy (ACM) is a genetic cardiac disorder that predisposes young individuals and athletes to malignant arrhythmias and sudden cardiac death. While traditionally regarded as a cardiomyocyte-centered disease, emerging evidence suggests that additional cardiac and extracardiac cell types contribute to disease onset and progression. Mutations in Desmoplakin (DSP) are among the most arrhythmogenic, causing either dominant DSP-cardiomyopathy (DSP-CM) or the recessive Carvajal syndrome. However, the mechanisms linking genetic defects in DSP and other ACM-causing genes to arrhythmia vulnerability remain incompletely understood. The overarching aim of this doctoral project was to explore ACM within a multicellular framework, by investigating both sympathetic neuron (SN) dysfunction and fibroblast-driven remodeling as key determinants of the arrhythmogenic substrate. To this end, I established a novel CRISPR/Cas9 knock-in mouse line carrying the DspS311A mutation, orthologous to the human hotspot DSPS299R. This model revealed a dose-dependent phenotype: heterozygotes reproduced key features of dominant DSP-CM, while homozygotes developed recessive Carvajal syndrome with severe dysfunction and spontaneous arrhythmias. Importantly, this represents one of the few murine ACM models exhibiting intrinsic arrhythmic vulnerability, thereby providing a robust platform for mechanistic and translational studies. I further demonstrated that SNs are directly affected by ACM mutations. Analyses in both Dsg2mut/mut and DspS311A mouse models uncovered morphological abnormalities, impaired sprouting, and early remodeling of cardiac innervation, with mutation-specific patterns emerging in the DspS311A model. Finally, by combining cell-targeted stimulation with 3D structure–function, I investigated how structural remodeling, gap junction alterations, and fibroblast–cardiomyocyte interactions converge to promote arrhythmia initiation, with optogenetic studies ongoing. Together, these findings reposition ACM as a multicellular, genotype-dependent disease involving multiple cardiac cell types (i.e. cardiomyocytes, fibroblasts, and SNs). Beyond advancing mechanistic understanding, this doctoral work highlights the value of integrative and multidisciplinary approaches, while providing both a conceptual framework and experimental resources that may inform improved risk stratification and therapeutic strategies in DSP- and DSG2-related cardiomyopathy.