title: Combining patient proteomics and in vitro cardiomyocyte phenotype testing to identify potential mediators of heart failure with preserved ejection fraction.
abstract: BACKGROUND
  Heart 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.
  
  
  RESULTS
  Proteomic 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.
  
  
  CONCLUSIONS
  Platelets 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.
authors.affiliation: Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA. rraphael@mcw.edu.
authors.forename: Roseanne
authors.initials: R
authors.lastname: Raphael
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA. Purushotham.diana@mayo.edu.
authors.forename: Diana
authors.initials: D
authors.lastname: Purushotham
authors.affiliation: Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA. vandusen.courtney@gmail.com.|Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA. vandusen.courtney@gmail.com.|Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI, USA. vandusen.courtney@gmail.com.
authors.forename: Courtney
authors.initials: C
authors.lastname: Gastonguay
authors.affiliation: Biotechnology and Bioengineering, Medical College of Wisconsin, Milwaukee, WI, USA. mchesnik@mcw.edu.
authors.forename: Marla A
authors.initials: MA
authors.lastname: Chesnik
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA. wmkwok@mcw.edu.
authors.forename: Wai-Meng
authors.initials: WM
authors.lastname: Kwok
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA. hsiang4070@gmail.com.
authors.forename: Hsiang-En
authors.initials: HE
authors.lastname: Wu
authors.affiliation: Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. sanjiv.shah@northwestern.edu.
authors.forename: Sanjiv J
authors.initials: SJ
authors.lastname: Shah
authors.affiliation: Biotechnology and Bioengineering, Medical College of Wisconsin, Milwaukee, WI, USA. smirza@mcw.edu.
authors.forename: Shama P
authors.initials: SP
authors.lastname: Mirza
authors.affiliation: Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI, USA. jstrande@mcw.edu.|Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA. jstrande@mcw.edu.|Division of Cardiovascular Medicine, Medical College of Wisconsin, Milwaukee, WI, USA. jstrande@mcw.edu.|, MEB/CVC 4579, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA. jstrande@mcw.edu.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Strande
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D040501:Calgranulin A / Q000097:blood; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D020543:Proteome / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D011994:Recombinant Proteins / Q000494:pharmacology; D015203:Reproducibility of Results; D013318:Stroke Volume / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D014463:Ultrasonography
chemical_list: D040501:Calgranulin A; D010455:Peptides; D020543:Proteome; D011994:Recombinant Proteins