Abstract Body: Aims: Arrhythmogenic cardiomyopathy caused by pathogenic variants in desmoplakin (DSP) is characterized by patchy fibrosis, myocardial inflammation, and progressive functional decline. How disease-associated cell states organize spatially within the myocardium and communicate to drive regional remodeling remains poorly defined. We aimed to define the transcriptional and spatial architecture of remodeling after adult cardiomyocyte-specific Dsp inactivation in mice and to identify niche-specific cell–cell communication programs governing fibrotic and inflammatory remodeling.

Methods and Results: We induced cardiomyocyte-restricted Dsp deletion in adult mice and performed single-nucleus RNA sequencing alongside high-resolution spatial transcriptomics using multiplexed error-robust fluorescence in situ hybridization (MERFISH). Adult Dsp loss caused rapid cardiomyocyte death, robust immune infiltration, and patchy fibrosis with a subepicardial predominance. Single-nucleus profiling identified disease-associated cardiomyocyte, fibroblast, and macrophage states that were selectively expanded in Dsp-deficient hearts. Spatial mapping demonstrated that these states self-organize into discrete ventricular zones, including fibrotic niches enriched for activated fibroblasts and inflammatory macrophages. Cell–cell communication analysis identified transforming growth factor–β (TGFβ) signaling as a dominant pathway within fibrotic niches, with activated fibroblasts acting as key sender/receiver nodes. Pharmacologic neutralization of TGFβ reduced fibrotic remodeling and profibrotic gene expression but did not improve cardiac function or survival and modestly increased immune cell infiltration.

Conclusion(s): Adult cardiomyocyte-specific Dsp loss induces spatially restricted remodeling niches defined by coordinated fibroblast–macrophage signaling and maladaptive cardiomyocyte states. Although TGFβ signaling contributes to fibrotic remodeling, its inhibition is insufficient to rescue ventricular dysfunction, supporting a model in which fibrosis is a downstream consequence of desmosome-mediated myocardial injury rather than its primary driver.