Proteomic Profiling of Early-Stage Heart Failure Identifies Candidate Biomarkers and Molecular Pathways of Cardiac Inflammation in the Project Baseline Health Study

BackgroundAsymptomatic structural heart disease, or stage B heart failure (HF), is clinically relevant for early HF diagnosis and prevention; circulating biomarkers could have prognostic significance for this. Thus, we performed proteomics discovery in a well-phenotyped cohort, the Project Baseline Health Study (PBHS). MethodsPBHS recruited participants with and without cardiovascular risk, collecting enrollment plasma biospecimens and cardiac imaging. Proteomic profiling (N=289) was performed using mass spectrometry on 503 individuals (185 stage B HF cases, 318 stage A HF controls). Logistic regression identified stage B-associated proteins, which were then eligible for inclusion in a joint protein score derived via elastic net. Scores were assessed for incident HF prediction in the UK Biobank (UKB) and the Exenatide Study of Cardiovascular Event Lowering (EXSCEL), examined for exenatide interactions in EXSCEL, and tested for imaging trait associations in PBHS and UKB. Mechanistic analyses of multivariate significant proteins included incident HF prediction in UKB and EXSCEL, Mendelian randomization (MR), and targeted methylation loci associations with stage B HF in PBHS. ResultsSixty-five proteins were associated with cases, of which 32 (49%) were retained via elastic net modeling; the resulting protein score showed good discrimination for cases versus controls (AUC 0.71, 95% CI [0.60, 0.82]). The protein score was significantly associated with incident HF in UKB and EXSCEL and left ventricular mass index (LVMI) in PBHS, as well as beneficially modified by exenatide in EXSCEL. Multivariate analysis prioritized 11 proteins associated with cases for mechanistic study, of which 4 (B2M, EFEMP1, CST3, HBB) showed significant incident HF associations in UKB and EXSCEL; CST3 and HBB were significant in MR. Methylation of cg08099136 in PSMB8 was significantly associated with cases in PBHS. ConclusionsOur findings highlight inflammatory biomarkers and mechanisms underpinning stage B HF. CpG hypomethylation at PSMB8 may be implicated in inflammation, resulting in increased LVMI (a known HF risk factor), with circulating B2M a byproduct of this process. ClinicalTrials.gov IdentifierNCT03154346