Proteomic Pathways across Ejection Fraction Spectrum in Heart Failure: an EXSCEL Substudy

Of N=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 three EF groups. Levels of the majority of proteins (83%) demonstrated concordance between HFmrEF and HFpEF, but higher levels in HFrEF, predominated by the domain of extracellular matrix regulation, e.g. COL28A1 and tenascin C [TNC]; p<0.0001. Concordance between HFmrEF and HFrEF was observed in a minority of proteins (1%) including MMP-9 (p<0.0001). Biologic pathways of epithelial-mesenchymal transition, ECM receptor interaction, complement and coagulation cascades, and cytokine receptor interaction demonstrated enrichment among proteins with the dominant pattern, i.e. HFmrEF-HFpEF concordance. Baseline levels of 208 (94%) of the 221 proteins were associated with time-to-incident HF hospitalization including domains of extracellular matrix (COL28A1, TNC), angiogenesis (ANG2, VEGFa, VEGFd), myocyte stretch (NT-proBNP), and renal function (cystatin-C). Change in levels of 10 of the 221 proteins from baseline to 12 months (including increase in TNC) predicted incident HF hospitalization (p<0.05). Levels of 30 of the 221 significant proteins (including TNC, NT-proBNP, ANG2) were reduced differentially by EQW compared with placebo (interaction p<0.0001). ### Competing Interest Statement A.E.P is supported by the National Heart Lung and Blood Institute (T32HL069749) and has received honoraria from Cytokinetics. J.B.G. receives research support from Merck, Roche and Boehringer Ingelheim/Lilly; honoraria for consulting from Boehringer Ingelheim/Lilly, NovoNordisk, AstraZeneca, Pfizer, Sanofi, Bayer, Anji, Valo, Vertex, Merck. H.S. receives research support (to the Medical University of Graz) from Boehringer Ingelheim, Eli Lilly, NovoNordisk and Sanofi and honoraria from AstraZeneca, Amarin, Bayer, Boehringer Ingelheim, Daiichy Sankyo, Eli Lilly, NovoNordisk and Sanofi. R.R.H. reports research support from AstraZeneca, Bayer and Merck Sharp & Dohme, and personal fees from Anji Pharmaceuticals, AstraZeneca, Novartis and Novo Nordisk. R.J.M. has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. S.H.S. receives research support through sponsored research agreements with Lilly Inc., Verily Inc., AstraZeneca Inc. and nference. ### Funding Statement EXSCEL was sponsored and funded by Amylin Pharmaceuticals, Inc., a wholly owned subsidiary of AstraZeneca. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data and biospecimens for this study originated from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. The EXSCEL trial was conducted jointly by the Duke Clinical Research Institute and the University of Oxford Diabetes Trials Unit in collaboration with the sponsor, Amylin Pharmaceuticals, a wholly owned subsidiary of AstraZeneca. The protocol, which was approved by the ethics committee at each participating site (687 sites in 35 countries); the full list of participating site is available as a supplements to the original primary publication (Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. New England Journal of Medicine 2017;377:1228-39) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Due to its proprietary nature and confidentiality agreements, supporting data cannot be made openly available.