Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure

Abstract

Background Identifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies. Methods and Results To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as the first hospitalization for HF, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20 000 individuals). Controls were matched on cohort, follow-up time, age, and sex. Two independent sample sets (a discovery set with 286 cases and 591 controls and a replication set with 276 cases and 280 controls) were used to discover and replicate the findings. Two hundred fifty-two circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase. These 38 proteins pointed to 4 main network clusters underlying incident HF: (1) inflammation and apoptosis, indicated by the expression of the TNF (tumor necrosis factor)-family members; (2) extracellular matrix remodeling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function, and vascular homeostasis; (3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin-angiotensin-aldosterone system; and (4) metabolism, associated with cholesterol and atherosclerosis. Conclusions Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodeling, blood pressure control, and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02556450.

Keywords: apoptosis; atherosclerosis; blood pressure; heart failure; proteomics.

Figure.

Induced network analysis: protein interactions, biochemical interactions, and gene regulatory interactions. Please see Table IV in the Data Supplement for the full names of the biomarkers and intermediates. ACE indicates angiotensin-converting enzyme; ADM, adrenomedullin; AGRP, agouti-related protein; BNP, B-type natriuretic peptide; AGT, angiotensinogen; CCL16, C-C motif chemokine 16; CEACAM8, carcinoembryonic antigen-related cell adhesion molecule 8; CERCAM, cerebral endothelial cell adhesion molecule; FAP, fibroblast activation protein alpha; FBLN1, fibulin-1; FGF23, fibroblast growth factor 23; GAL9, galectin 9; GALNT18, polypeptide N-acetylgalactosaminyltransferase 18; GDF-15, growth differentiation factor 15; GHRL, ghrelin; HNF1B, hepatocyte nuclear factor-1-β; IGFBP7, insulin-like growth factor-binding protein 7; LAMA1, laminin subunit alpha 1; LARGE, LARGE xylosyl- and glucuronyltransferase 1; LTA, lymphotoxin alpha; MMP-12, matrix metalloproteinase 12; NAGLU, N-acetyl-alpha-glucosaminidase; NF-κB, nuclear factor κB; OPN, osteopontin; PAR1, proteinase-activated receptor 1; PGF, placenta growth factor; PLC, perlecan; PLGF, placenta growth factor; RARRES2, retinoic acid receptor responder protein 2; SLAMF1, signalling lymphocytic activation molecule family member 1; SPON2, spondin-2; TNFRSF, tumor necrosis factor receptor superfamily member; TRAF, TNF receptor associated factor 1; TRAILR2, trail receptor 2; TWEAK, tumor necrosis factor ligand superfamily member 12; UPAR, urokinase plasminogen activator surface receptor; VEGFA, vascular endothelial growth factor A; and VSIG2, v-set and immunoglobulin domain-containing protein 2.