Introduction Lp(a) levels has been associated with increased cardiovascular risk and is a therapeutic target in cardiovascular prevention. However, the mechanisms behind this association are unclear. A new radiotranscriptomic library (the oxHVF platform) uses RNA sequencing data from human arteries and perivascular adipose tissue (PVAT) as ground truth for the development of machine-learning powered imaging biomarkers of vascular biology. We aimed to use this radiotranscriptomic platform to understand the mechanisms by which Lp(a) affects vascular function in patients with advanced atherosclerosis. Methods A cohort of 1472 patients undergoing CABG surgery were recruited. Plasma Lp(a) levels were measured before surgery. We performed genotyping to identify a combination of the top 7 SNPs that are associated with high Lp(a) levels. Internal mammary arteries (IMA) segments were obtained to quantify ex vivo superoxide generation and phenotype vascular inflammation. 369 of these patients underwent CCTA, and PVAT inflammation in the IMA and the aorta was measured using a recently developed radiotranscriptomic signature of vascular cytokine-driven inflammation (C19-RS) (A). A subgroup of 50 patients had CCTAs at 6 months and 5 years after surgery, to access progression of SVG disease. Results Patients with high plasma Lp(a) levels (>95th centile, >106mg/dL) had higher vascular inflammation measured by C19RS (B and C). Similarly, patients carrying a genetic signature associated with high Lp(a) levels also experienced high C19RS (D), suggesting a causal association. Patients with high Lp(a) (E) or genetically determined Lp(a) elevation (F) also had higher O2- generation in their IMAs (E, F). In the subgroup with paired CCTA scans, high Lp(a) levels at baseline had significantly greater changes in SVG intimal hyperplasia compared with those with low Lp(a) levels (G). Conclusions High Lp(a) levels and a genetic signature driving plasma Lp(a), are related with vascular redox dysregulation, resulting into increased vascular inflammation measured by using CCTA radiotranscriptomic phenotyping (C19RS), in patients with advanced atherosclerosis. Moreover, Lp(a) levels predict the development of intima hyperplasia in the SVGs of the same patients, implying involvement in atherosclerotic disease progression. Conflict of Interest Nil