Abstract 13166: Proteomic Pathways Across Ejection Fraction Categories in Heart Failure: An Exscel Substudy

Abstract

Background: Ejection fraction (EF) is a key component of heart failure (HF) categorization, including the newly-proposed HF with mildly reduced EF (HFmrEF) category. The biologic basis of HFmrEF, as an entity distinct from HF with preserved EF (HFpEF) and reduced EF (HFrEF), has not been substantiated. Methods: The EXSCEL trial randomized participants with type 2 diabetes to once-weekly exenatide (EQW) vs. placebo. In participants with prevalent HF, we profiled ~5000 serum proteins. Principal component analysis (PCA) and ANOVA (FDR p<0.1) were used to determine differences in factors and individual proteins between three EF groups, as documented in EXSCEL (EF>55% [HFpEF], EF 40-55% [HFmrEF], EF<40% [HFrEF]). Cox proportional hazards was used to assess relationships between baseline proteins and changes in protein level with incident HF hospitalization. Results: Of 1199 EXSCEL participants with prevalent HF, 284 (24%), 704 (59%) and 211 (18%) had HFpEF, HFmrEF and HFrEF, respectively. Eight PCA protein factors and 221 individual proteins within these factors differed significantly across the 3 groups. Levels of the majority of proteins (83.3%) demonstrated concordance between HFmrEF and HFpEF, but higher levels in HFrEF, including the domain of extracellular matrix, e.g. COL28A1, tenascin C [TNC]; p<0.0001. A minority of proteins (1%) were concordant between HFmrEF and HFrEF including matrix metalloproteinase-9 (p<0.0001). Baseline levels of 94% of the 221 significant proteins were associated with incident HF including domains of extracellular matrix (COL28A1, TNC), angiogenesis (ANG2, VEGFa, VEGFd), myocyte stretch (NTpro-BNP), and renal function (cystatin-C). Change in levels of 18 of these proteins from baseline to 12 months (including increase in TNC) predicted subsequent HF (p<0.05). TNC levels were reduced by EQW compared with placebo (p<0.0001). Conclusions: In this large clinical trial, we found that most proteins were similar between HFmrEF and HFpEF. A key ECM protein, tenascin C, showed this relationship, and baseline level and change in tenascin C predicted HF and changed beneficially with EQW. These results suggest that HFmrEF is more biologically similar to HFpEF and highlight prognostic and modifiable biomarkers that vary by EF.