Plasma proteomic approach in patients with heart failure: insights into pathogenesis of disease progression and potential novel treatment targets

Abstract

Aims: To provide insights into pathogenesis of disease progression and potential novel treatment targets for patients with heart failure by investigation of the plasma proteome using network analysis.

Methods and results: The plasma proteome of 50 patients with heart failure who died or were rehospitalised were compared with 50 patients with heart failure, matched for age and sex, who did not have an event. Peptides were analysed on two-dimensional liquid chromatography coupled to tandem mass spectrometry (2D LC ESI-MS/MS) in high definition mode (HDMSE). We identified and quantified 3001 proteins, of which 51 were significantly up-regulated and 46 down-regulated with more than two-fold expression changes in those who experienced death or rehospitalisation. Gene ontology enrichment analysis and protein-protein interaction networks of significant differentially expressed proteins discovered the central role of metabolic processes in clinical outcomes of patients with heart failure. The findings revealed that a cluster of proteins related to glutathione metabolism, arginine and proline metabolism, and pyruvate metabolism in the pathogenesis of poor outcome in patients with heart failure who died or were rehospitalised.

Conclusions: Our findings show that in patients with heart failure who died or were rehospitalised, the glutathione, arginine and proline, and pyruvate pathways were activated. These pathways might be potential targets for therapies to improve poor outcomes in patients with heart failure.

Keywords: Heart failure; Mass spectrometry; Metabolism; Pathogenesis; Proteomics; Treatment target.

Figure 1

Volcano plot for proteins identified in both heart failure groups. The volcano plot displays proteins identified with differential expressions between both heart failure groups (death/rehospitalisation vs. no events). The horizontal axis (x‐axis) corresponds to the log 2 fold change value and the vertical axis (y‐axis) describes the negative value of log 10 (P‐value). The red dashed line represents P = 0.05 and the blue dashed lines represents the fold change = 2.

Figure 2

Gene ontology (GO) enrichment analysis of significant differentially expressed proteins in patients with heart failure with poor outcomes. (A) Proportions of significant differentially expressed proteins that were found in involving with biological processes. (B) Numbers of significant differentially expressed proteins that correspond to biological processes.

Figure 3

Protein–protein interaction networks of significant differentially expressed proteins revealed the central role of metabolism in poor clinical outcomes of patients with heart failure. A cluster of significant differentially expressed proteins is displayed that relates to glutathione metabolism, arginine and proline metabolism, and pyruvate metabolism in the pathogenesis of disease progression in heart failure and their involvement with poor clinical outcomes in patients with heart failure. The expression of these significant differentially expressed proteins is presented in more details in the online supplementary Table S1. ALDH9A1, 4‐trimethylaminobutyraldehyde dehydrogenase; DLD, dihydrolipoyl dehydrogenase mitochondrial; GGCT, gamma‐glutamylcyclotransferase; GLO1, lactoylglutathione lyase; GSTM5, glutathione S‐transferase Mu 5; MGST3, microsomal glutathione S‐transferase 3; P4HA1, prolyl 4‐hydroxylase subunit alpha‐1; SRM, spermidine synthase.

Figure 4

Schematic plasma proteomic approach to understand the pathogenesis and its link with clinical outcomes in patients with heart failure.