State-Dependent DNA Methylation Signatures Distinguish Acute from Stable Coronary Syndromes.

Coronary artery disease presents heterogeneous clinical manifestations ranging from stable coronary syndrome (SCS) to acute coronary syndrome (ACS). Epigenetic mechanisms, particularly DNA methylation, may contribute to both chronic disease progression and acute plaque destabilization. However, genome-wide methylation differences between ACS, SCS, and healthy individuals remain incompletely characterized. Genome-wide DNA methylation analysis was performed in patients with ACS, patients with SCS, and healthy controls using pairwise comparisons (ACS vs. control, SCS vs. control, and ACS vs. SCS). Differentially methylated regions were identified using logistic regression implemented in the methylKit package in R. Regions with a false discovery rate-adjusted q-value < 0.05 and an absolute methylation difference (|Δβ|) > 20% were considered significant. Unsupervised hierarchical clustering revealed clear separation between ACS, SCS, and control samples, indicating distinct epigenetic profiles. ACS showed the most pronounced methylation alterations compared to controls, whereas SCS exhibited more moderate changes consistent with chronic epigenetic remodeling. Direct comparison between ACS and SCS identified dynamic, state-dependent methylation differences. Pathway analysis demonstrated enrichment of stress response, apoptotic signaling, and cell adhesion pathways in ACS, while SCS was primarily associated with pathways related to intercellular communication and vascular signaling. Our findings demonstrate that acute and stable coronary syndromes are characterized by distinct DNA methylation landscapes and pathway signatures. Epigenetic regulation of stress, adhesion, and signaling pathways may contribute to disease acuity and progression, highlighting DNA methylation as a potential molecular marker in coronary artery disease.