European Atherosclerosis Society (EAS) 2019 Congress is coming up next week, May 26-29. The keynote speakers is Paul Ridker, a leader in the field of inflammation as a cardiovascular risk factor. He was the prinicipal investigator for the CANTOS and CIRT trials. 

Speaking of inflammation and the EAS Congress.......Norman Wong of Resverlogix will be presenting a poster at the same EAS Congress highlighting the potent anti-inflammatory effects of apabetalone. A busy few weeks ahead for Resverlogix, with EAS, Gordon Conference, BIO Internation, ADA and ERA-EDTA coming up. The abstract they will be presenting at EAS next week is below. A similar title is listed for the upcoming ADA meeting too. Apabetalone SMASH inflammation!

APABETALONE (RVX-208) ATTENUATES INFLAMMATORY MILIEU UNDERLYING ADHESION OF MONOCYTES TO ENDOTHELIAL CELLS IN TYPE 2 DIABETES MELLITUS WITH CARDIOVASCULAR DISEASE PATIENTS

Background and Aims: To explore mechanisms behind the 57% relative risk reduction of major adverse cardiovascular events (MACE) in patients (pts) with type 2 diabetes mellitus (T2DM) and CVD given 200 mg apabetalone (APL, RVX-208, inhibitor of bromodomain and extra-terminal [BET] proteins that are epigenetic readers of histone acetylated lysine).

Methods: SOMAscan proteomics of patient plasma given APL (n=25) or placebo (n=30) and cultured monocyte (THP-1) or endothelial (HUVEC) cells.

Results: Plasma proteomics from CVD+/-T2DM pts given APL or placebo showed changes in 4 well-known pathologic pathways and inflammation triggered by TNFa underpinning CVD. Proteins induced by TNFa (p<0.001; z-score = 2.270) were attenuated by APL (p<0.001; z-score = -2.308). To replicate this inflammatory milieu, TNFa (10 ng/ml) or high glucose (HG, 25.6 mM) was added to co-cultures of THP-1 and HUVEC leading to enhanced adhesion 12- and 2.4-fold, respectively but inhibited by APL (44-32%). Very Late Antigen-4 (VLA-4) a THP-1 adhesion mRNA rose 1.3-fold in HG and APL suppressed it >50%. Similarly, E-selectin, MCP-1, and MYD88 mRNAs that mediated adhesion rose by 2-, 2- and 1.3-fold, respectively in HUVECs exposed to HG while APL attenuated (30-90%). Furthermore, Nanostring data from HUVECs showed HG induced many inflammatory genes underlying CVD but APL blocked ~90% of these. Gene Set Enrichment and functional Gene Ontology Analysis showed many inflammatory and immunoregulatory genes were positively impacted by HG but negatively affected by APL.

Conclusions: APL lowers MACE in T2DM and CVD pts by attenuating monocyte adhesion to endothelial cells and thereby possibly reducing atheroma formation.