Combining patient proteomics and in vitro cardiomyocyte phenotype testing to identify potential mediators of heart failure with preserved ejection fraction

Abstract

BackgroundHeart failure with ejection fraction (HFpEF) is a syndrome resulting from several co-morbidities in which specific mediators are unknown. The platelet proteome responds to disease processes. We hypothesize that the platelet proteome will change composition in patients with HFpEF and may uncover mediators of the syndrome.Methods and resultsProteomic changes were assessed in platelets from hospitalized subjects with symptoms of HFpEF (n = 9), the same subjects several weeks later without symptoms (n = 7) and control subjects (n = 8). Mass spectrometry identified 6102 proteins with five scans with peptide probabilities of ≥0.85. Of the 6102 proteins, 165 were present only in symptomatic subjects, 78 were only found in outpatient subjects and 157 proteins were unique to the control group. The S100A8 protein was identified consistently in HFpEF samples when compared with controls. We validated the fining that plasma S100A8 levels are increased in subjects with HFpEF (654 ± 391) compared to controls (352 ± 204) in an external cohort (p = 0.002). Recombinant S100A8 had direct effects on the electrophysiological and calcium handling profile in human induced pluripotent stem cell-derived cardiomyocytes.ConclusionsPlatelets may harbor proteins associated with HFpEF. S100A8 is present in the platelets of subjects with HFpEF and increased in the plasma of the same subjects. We further established a bedside-to-bench translational system that can be utilized as a secondary screen to ascertain whether the biomarkers may be an associated finding or causal to the disease process. S100A8 has been linked with other cardiovascular disease such as atherosclerosis and risk for myocardial infarction, stroke, or death. This is the first report on association of S100A8 with HFpEF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0774-3) contains supplementary material, which is available to authorized users.

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

“…Examples include long‐QT syndrome (Terrenoire et al , 2013; Malan et al , 2016), catecholaminergic polymorphic ventricular tachycardia (Penttinen et al , 2015) and heart failure with preserved ejection fraction (Raphael et al , 2016). The cardiotoxic effects of anthracyclines in cardio‐oncology (Burridge et al , 2016) have also been recently validated (Avior et al , 2016).…”

Ups and downs in heart failure: the case of proteomics

“…Several studies have hitherto been published concerning, among other issues, protein alterations in conditions such as dilated cardiomyopathy, myocardial hypertrophy, atherosclerosis, atrial fibrillation and myocardial stunning, the identification of biomarkers in ischaemic heart disease and the acquisition of mechanistic insights into myocardial protection during ischaemia and reperfusion . In heart failure (HF), proteome analyses have revealed changes concerning proteins of the extracellular matrix, cardiomyocyte cytoskeleton, contractile apparatus, energy production and cardiomyocyte protection that are up‐ or down‐regulated ( Table ) …”

Molecular Approaches in HFpEF: MicroRNAs and iPSC-Derived Cardiomyocytes

“…A bed-to-bench translational system may be used to identify new potential mediators of HFpEF by combining “-omic” analysis and mechanistic studies in patient-specific iPSC-CMs [60]. The general concept of this strategy is to incorporate bioactivity studies into guiding the selection of biomarkers identified in -omic studies for further investigation and development.…”

“…The overall rationale for this two-step screening process (Fig. 6) is to identify biomarkers that have biological effects in order to increase the likelihood that it is causally involved in the disease process [60]. After miRNA profiling, it can be determined whether a specific miRNA has detrimental or beneficial effects on iPSC-CMs.…”