The key conclusions of this study are: (1) EPAC1, the primary EPAC isoform in vessels, is detectable in the blood of patients with suspected CAD; (2) EPAC1 demonstrates superior diagnostic performance compared to current biomarkers for identifying severe CAD in this population; and (3) hypoxia-driven mechanisms that suppress EPAC1 production in human coronary foam-SMCs—a major pathological SMC phenotype in atherosclerotic plaques—likely contribute to the reduced circulating EPAC1 levels observed in patients with advanced CAD. The gene discussed is RAPGEF4; the disease is coronary artery disorder.