PO50 Transcriptomic Signatures Underlying Phenotypic Heterogeneity in Hypertrophic Cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and a leading cause of sudden cardiac death (SCD) in young individuals. Despite its classical definition as a sarcomeric disorder, HCM shows marked clinical and molecular heterogeneity. Unraveling the transcriptomic features that distinguish HCM from other cardiomyopathies may provide novel biomarkers and therapeutic targets. Purpose To characterize disease-specific transcriptomic signatures in HCM compared to other cardiomyopathies and to investigate molecular programs that may explain phenotypic variability across clinical subgroups of HCM. Methods We performed RNA sequencing on 196 myocardial tissue samples from patients with HCM (n=87), dilated cardiomyopathy (DCM, n=20), arrhythmogenic cardiomyopathy (ACM, n=26), ischemic cardiomyopathy (IC, n=24), SCD cases without structural abnormalities (n=14), and healthy controls (HC, n=25). Differential expression analyses were conducted with DESeq2, followed by pathway enrichment and protein-protein interaction (PPI) network analyses. To explore heterogeneity within HCM, subgroup analyses (myectomy, transplant, and SCD) were based on DEGs identified in the HCM vs HC contrast. Results HCM displayed the largest transcriptional changes (765 upregulated and 593 downregulated genes), with 38 DEGs exclusive to HCM. Enriched pathways included extracellular matrix remodeling, immune signaling dysregulation, and metabolic reprogramming via SREBF-mediated lipid metabolism. PPI analyses highlighted clusters in collagen-containing extracellular matrix, chemokine activity, and MAPK signaling. Only 12 DEGs were shared across all cardiomyopathies, underscoring disease-specific landscapes. Within HCM, heatmap analysis revealed two divergent molecular trajectories:Arrhythmic/remodeling axis (myectomy and SCD): enrichment of cytoskeletal and extracellular matrix remodeling, VEGF signaling, and apoptosis, suggesting structural adaptation with increased arrhythmic vulnerability.Failure/exhaustion axis (transplant): suppression of immune regulation and activation of catabolic metabolism, consistent with advanced heart failure. Importantly, interpretation of the transplant subgroup requires caution, as immunosuppressive therapy may contribute to the observed immune suppression signature. Conclusions This study provides a comprehensive transcriptomic landscape of cardiomyopathies, revealing shared and distinct molecular pathways underlying each condition. In HCM, two molecular trajectories appear to drive patients toward either arrhythmic events or progressive heart failure. The findings highlight candidate biomarkers for risk stratification and potential therapeutic targets. Future research integrating multi-omics approaches and functional studies will be crucial in translating these insights into clinical applications.