Abstract 12000: A Novel Human Arterial Transcriptomic Signature Associated With Major Adverse Cardiovascular Events and Oxidative Stress

Introduction: The biology of human vascular wall is implicated in cardiovascular pathology. We applied discovery transcriptomics to internal mammary arteries (IMAs) obtained from cardiac surgery patients, to identify pathways that can be treated therapeutically. Methods: Weighted correlation network analysis was conducted in sequencing data from IMAs RNA in 205 patients (Arm 1). Association with future incidence of major adverse cardiovascular events [MACE: cardiovascular death (CVD), non-fatal myocardial infarction or stroke, or new-onset heart failure] was assessed with Cox regression models (adjusted for age, sex, hypertension, dyslipidaemia, diabetes mellitus, and plasma TNFa). Arm 2 included 497 patients in whom segments of IMA were used for ex-vivo quantification of NADPH-stimulated superoxide by lucigenin chemiluminescence. Results: We identified 10 coexpressed gene ‘modules’ in the human arterial wall, through unsupervised transcriptomic analysis. The “red” module was found to cluster with arterial NADPH oxidase activity, while its eigengene values had the most significant correlation ( a ). Patients with high eigengene values for the “red” module showed a 3-fold higher risk of MACE ( b ), and enrichment analysis revealed top pathways ( c ). The Study Arm 2 population was followed up for a median of 6.35 years [IQR: 3.97-8.38], with 50 CVD and 101 MACE. High NADPH oxidases activity was independently predictive of cardiovascular mortality ( d ) and MACE (adj. hazard ratio 1.58 [1.07-2.36], p=0.02). Conclusion: We demonstrate that arterial oxidative stress leads to high risk of MACE in patients with atherosclerosis. We also identify a novel, redox-related arterial transcriptomic signature that predicts long-term cardiovascular risk. Pathways related with oxidative stress, or glucose metabolism or Hypoxia-Inducible Factor-1 in the human arterial wall, may be rational therapeutic targets to reduce cardiovascular risk in secondary prevention.