EPAS1 induction drives myocardial degeneration in Desmoplakin-cardiomyopathy [TOMO-seq]

Arrhythmogenic cardiomyopathy (ACM) is frequently attributed to desmosomal mutations, such as those in the desmoplakin (DSP) gene. Patients with DSP- cardiomyopathy are predisposed to myocardial degeneration and arrhythmias. Despite advancements, the underlying molecular mechanisms remain incompletely understood, thus limiting therapeutic options. Here, we employed spatial transcriptomics on an explanted heart from a patient with a pathogenic DSP variant. Our transcriptional analysis revealed endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. Elevated EPAS1 levels were associated with mitochondrial dysfunction and hypoxic stress in both human-relevant in vitro ACM models and additional explanted hearts with genetic cardiomyopathy. Collectively, cardiomyocytes bearing pathogenic DSP variants exhibit mitochondrial dysfunction, increased apoptosis, and impaired contractility, which are linked to the increased EPAS1 levels. These findings implicate EPAS1 as a key regulator of myocardial degeneration in DSP-cardiomyopathy, which expand to other forms of ACM. Spatial transcriptomics by RNA-tomography (TomoSeq) on 20um sections on diseased heart. After isolation, we cryosectioned samples, extracted RNA from the individual sections, and amplified and barcoded mRNA using the CEL-seq protocol as in (Junker 2014, PMID: 25417113). Libraries were sequenced on Illumina NextSeq 500 using 75p paired end sequencing. *************************************************************** Raw files for human/patient samples were not submitted to GEO due to concerns about submitting personally identifiable sequence data for open access. ***************************************************************