Whole blood epigenomic and transcriptomic characterization identifies vulnerable molecular subtypes of chronic coronary disease

Chronic coronary disease (CCD) remains a leading cause of morbidity and mortality worldwide. However, current clinical assessments, including tests of inducible ischemia or coronary artery disease severity poorly discriminate risk for future cardiovascular (CV) disease events among this population with established CCD. To address this gap, our study leverages high-dimensional molecular data from the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) Trials biorepository to molecularly characterize patients with CCD. By integrating transcriptomic (N = 646) and methylomic (N = 732) data with core-lab confirmed clinical phenotyping, we describe molecular signatures associated with disease severity and identify distinct whole-blood molecular subtypes of CCD. These subtypes demonstrate differential risks of CV events, independent of traditional clinical risk scores, and have distinct molecular and immune profiles. Validation of the transcriptomic and methylomic subtypes in two independent external cohorts confirms the clinical relevance and generalizability of our findings. These findings underscore the potential of blood-based multi-omic approaches to refine risk stratification, improve personalized treatment strategies and advance secondary prevention in CCD. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT01471522; https://clinicaltrials.gov/ct2/show/NCT01471522.