Proteomic Signatures During Treatment in Different Stages of Heart Failure

Abstract

Background: Proteomics have already provided novel insights into the pathophysiology of heart failure (HF) with reduced ejection fraction. Previous studies have evaluated cross-sectional protein signatures of HF, but few have characterized proteomic changes following HF with reduced ejection fraction treatment with ARNI (angiotensin receptor/neprilysin inhibitor) therapy or left ventricular assist devices. Methods: In this retrospective omics study, we performed targeted proteomics (N=625) of whole blood sera from patients with American College of Cardiology/American Heart Association stage D (N=29) and stage C (N=12) HF using proximity extension assays. Samples were obtained before and after (median=82 days) left ventricular assist device implantation (stage D; primary analysis) and ARNI therapy initiation (stage C; matched reference). Oblique principal component analysis and point biserial correlations were used for feature extraction and selection; standardized mean differences were used to assess within and between-group differences; and enrichment analysis was used to generate and cluster Gene Ontology terms. Results: Core sets of proteins were identified for stage C (N=9 proteins) and stage D (N=18) HF; additionally, a core set of 5 shared HF proteins (NT-proBNP [N-terminal pro-B type natriuretic peptide], ESM [endothelial cell-specific molecule]-1, cathepsin L1, osteopontin, and MCSF-1) was also identified. For patients with stage D HF, moderate (δ, 0.40–0.60) and moderate-to-large (δ, 0.60–0.80) sized differences were observed in 8 of their 18 core proteins after left ventricular assist devices implantation. Additionally, specific protein groups reached concentration levels equivalent ( g <0.10) to stage C HF after initiation on ARNI therapy. Conclusions: HF with reduced ejection fraction severity associates with distinct proteomic signatures that reflect underlying disease attributes; these core signatures may be useful for monitoring changes in cardiac function following initiation on ARNI or left ventricular assist device implantation.

Biomarkers in heart failure clinical trials. A review from the Biomarkers Working Group of the Heart Failure Association of the European Society of Cardiology

“…A panel of biomarkers reflecting different cardiac alterations, such as collagen peptides or sST2 associated with fibrosis, C‐reactive protein and interleukins with inflammation, endothelin or adrenomedullin with endothelial dysfunction, antigen carbohydrate 125 or bio‐adrenomedullin with fluid overload, urinary sodium for monitoring decongestion, or direct renin for renin–angiotensin–aldosterone system activation could provide additional useful information regarding the pathophysiological impact on cardiac remodelling features 73 . In addition, an unbiased ‐omic approach could be more accurate than the simple evaluation of biomarkers more closely associated with specific disease mechanisms 74–76 ( Figure ). The heterogeneous setting of HFpEF seems particularly well‐suited for this kind of approach 77 …”

Circulating heart failure biomarkers beyond natriuretic peptides: review from the Biomarker Study Group of the Heart Failure Association (HFA), European Society of Cardiology (ESC)

“…207 As well, proteomics approaches may provide unique insights for understanding different severities of HF and how HF therapies such as left ventricular assist device placement or sacubitril/valsartan therapy affect the proteome after treatment. 208 This may therefore allow for understanding of new therapeutic targets for care of HF. Proteomics could shed light on the pathophysiological mechanism behind the transition from shock to HF.…”

“…LRG1 seemed to be involved with fibrogenesis and angiogenesis by modulating TGF‐β signalling 207 . As well, proteomics approaches may provide unique insights for understanding different severities of HF and how HF therapies such as left ventricular assist device placement or sacubitril/valsartan therapy affect the proteome after treatment 208 . This may therefore allow for understanding of new therapeutic targets for care of HF.…”

Loop diuretic management after sacubitril/valsartan initiation in heart failure with preserved ejection fraction: deceptively simple or more than meets the eye?

“…13 Conversely, proteomic analyses of Stage C HFrEF suggest that sacubitril/valsartan affects circulating proteins reflective of vascular development/remodelling, cell migration/adhesion, and immune regulation. 14 These data suggest the possibility of unique effects of sacubitril/valsartan upon HFpEF as compared with HFrEF, and the current investigation by Chatur et al serves as an additional indicator of complex interplay between drug and disease state (Figure 1). Despite several differences, sacubitril/valsartan importantly reduces risk of clinically relevant kidney outcomes across both HFrEF and HFpEF.…”

“…In HFpEF, sacubitril/valsartan significantly altered 14 of 369 circulating proteins over 5 weeks, and 9 of these 14 proteins were reflecting of the TGF‐β signalling pathway 13 . Conversely, proteomic analyses of Stage C HFrEF suggest that sacubitril/valsartan affects circulating proteins reflective of vascular development/remodelling, cell migration/adhesion, and immune regulation 14 . These data suggest the possibility of unique effects of sacubitril/valsartan upon HFpEF as compared with HFrEF, and the current investigation by Chatur et al .…”