Lipoprotein(a) integrates monocyte-mediated thrombosis and inflammation in atherosclerotic cardiovascular disease
Although therapies for atherosclerotic cardiovascular disease (ASCVD) have advanced, substantial residual risk of cardiovascular (CV) events remains.  Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL) particle that is causally linked to both ASCVD and CV events.  Lp(a) is thought to drive ASCVD through multiple mechanisms including its effects on cholesterol accumulation, inflammation, and thrombosis.  Although the associations between Lp(a) and ASCVD drivers are clear, the mechanisms that integrate Lp(a)-mediated cholesterol accumulation, inflammation, and thrombosis remain largely unknown.  In this study, we employed systems biology approaches consisting of proteomics, transcriptomics, and mass cytometry to define the immune cellular and molecular phenotypes in ASCVD subjects with high and low Lp(a) levels and the mechanisms through which Lp(a) mediates monocyte activation. In a cohort of stable ASCVD subjects (n=64 [41 with high Lp(a) and 23 with low Lp(a]), we found that circulating markers of inflammation (CCL28, IL-17D) and vascular dysfunction (BNP), tissue factor [TF]) was elevated in subjects with high Lp(a) levels compared with those with low Lp(a) levels.  Additionally, although total monocytes levels and hs-CRP levels were similar between the groups, CD14+ monocytes from ASCVD subjects with an elevated Lp(a) were primed and expressed more TF at baseline and in response to stress.  Mechanistically, we found that Lp(a) itself can activate monocytes through Toll-like receptors (TLR) and nuclear factor kappa B (NF?B) signaling, driving both the induction of TF and TF activity.  Overall, these studies are the first to link Lp(a) to monocyte-mediated inflammation and thrombosis, demonstrating a novel mechanism through TLR2, NF?B, and monocyte TF which Lp(a) amplifies immunothrombotic risk. Overall design: Double-blind, placebo-controlled trial randomized 41 ASCVD subjects with high Lp(a) and 23 with low Lp(a]), we found that circulating markers of inflammation (CCL28, IL-17D) and vascular dysfunction (BNP), tissue factor [TF]) was elevated in subjects with high Lp(a) levels compared with those with low Lp(a) levels. The primary outcomes were the change in lipoproteins, blood viscosity, and circulating immune cell transcriptional response at 2 weeks and 12 weeks with evolocumab compared with matching placebo. Safety was assessed in all subjects who received at least one dose of assigned treatment and analyses were conducted in the intention-to-treat population.