Finding a Needle in a Haystack: Proteomics in Heart Failure

Abstract

Circulating protein biomarkers provide information regarding pathways in heart failure (HF) and can add important value to clinicians. Advancements in proteomics allow researchers to measure a multitude of proteins simultaneously with excellent sensitivity and selectivity to detect low abundance proteins. This helps identify previously unrecognized pathways in HF and discover biomarkers and potential targets for HF therapies. Although several proteomic methods exist, including mass spectrometry, protein microarray, aptamer, and proximity extension assay-based techniques, each have their unique advantages. This paper provides an overview of the various proteomic methods, with examples of how each has contributed to understanding the pathways in HF.

Keywords: 2-DE, 2-dimensional gel electrophoresis; HF, heart failure; ICM, ischemic cardiomyopathy; MS, mass spectrometry; PEA, proximity extension assay; biomarkers; heart failure; proteomics.

Graphical abstract

Central Illustration

Overview of Omics Fields and Uses Omics give insight into the state of a system, as affected by a stimulus. In the case of proteomics in heart failure (HF), researchers hope to observe the effect of HF on the types and quantities of proteins produced from the RNA transcripts.

Figure 1

Summary of Proteomic Methods Although there are several methods to profile the proteome, the most common means are (A) mass spectrometry, (B) protein microarray chips, (C) Aptamers, and (D) proximity extension assays. Mass spectrometry fragments proteins and measures the mass-to-charge ratios to identify and quantify proteins. The other methods involve highly specific binding of detectors (either antibodies [B and D] or oligonucleotides [C]), to proteins which are measured through fluorescent markers (B and C), or quantitative polymerase chain reaction.

Figure 2

Findings of Yi Et Al. (21) of Processes Regulated in Patients With ICM Of the 1,723 proteins identified through liquid chromatography, a total of 168 proteins were differentially regulated in patients with ischemic cardiomyopathy (ICM). A total of 104 proteins were upregulated, and 63 were downregulated. Although these proteins were involved in different functions, net changes were observed in the extracellular matrix, immune response, metabolism, muscle contraction, and signal transduction.

Figure 3

Proteins Differential With Incident or Manifest Hf and Their Relationship to Hf Reversal (48) (A) In patients with incident heart failure (HF), 16 proteins were differential; when analyzing these same proteins in the HF reversal group after transplantation, only 12 of the 16 were regulated to reflect levels of patients without HF. For both analyses, there was limited network associations with other proteins. (B) In patients with manifest HF, 421 proteins were significantly regulated relative to control subjects; after transplantation, 138 proteins were regulated towards normal levels. After transplantation, many proteins were no longer associated with manifest HF and no longer maintained associations with other proteins. All data provided by Egerstedt et al. (48), and Figures produced with STRING Protein-Protein Interaction Networks v11.0 (53).

Figure 4

Overview of PEA Proteomics in BIOSTAT-CHF Study Proximity extension assay (PEA) proteomics can be applied and used in different substudies. Through changing the analysis cohorts, investigators were able to compare the proteome of ischemic HF versus nonischemic HF (50), sinus fibrillation versus atrial fibrillation in HF with reduced and preserved ejection fraction (51), and HF with preserved ejection fraction versus reduced ejection fraction (52). BIOSTAT-CHF = a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure; ECG = electrocardiography; other abbreviation as in Figure 3.