Epicardial Adipose Tissue Dysfunction in Pulmonary Arterial Hypertension: Implications for Right Ventricular Dysfunction

Right ventricular (RV) function critically influences outcomes in pulmonary arterial hypertension (PAH), yet the mechanisms behind RV dysfunction are unclear. Epicardial adipose tissue (EAT), uniquely located near the heart, differs significantly in its transcriptome and secretome from other fat depots. EAT can either support the myocardium by providing energy or harm it by releasing pro-inflammatory and profibrotic cytokines. Increased EAT volume is associated with worse PAH outcomes and RV dysfunction, highlighting the need to understand EAT's role better. Our study analyzed EAT from 8 PAH patients and 8 age-matched controls, identifying 1595 upregulated and 2099 downregulated genes (fold change ≥2, adjusted p-value <0.0001) in PAH. Principal component analysis showed unsupervised PAH-control clustering by EAT transcriptome. Gene ontology analysis indicated that downregulated genes were linked to oxidative metabolism and mitochondrial function, while upregulated genes were associated with inflammation. We also found increased levels of IL-1β, IL-6, TNFα, MCP-1, Leptin, and Resistin in PAH EAT. Targeting transcripts for secreted proteins revealed 240 primarily related to fibrosis and inflammation. Validation in 60 PAH patients showed those with decompensated RV had higher blood levels of 23 proteins from these transcripts compared to patients with normal RV function. In conclusion, our study highlights EAT dysfunction in PAH, suggesting its significant impact on RV dysfunction and potential as a therapeutic target.