Identification of a Multiplex Biomarker Panel for Hypertrophic Cardiomyopathy Using Quantitative Proteomics and Machine Learning.

Journal: Molecular & cellular proteomics : MCP
Published Date: Jan 1, 2020

Abstract

Hypertrophic cardiomyopathy (HCM) is defined by pathological left ventricular hypertrophy (LVH). It is the commonest inherited cardiac condition and a significant number of high risk cases still go undetected until a sudden cardiac death (SCD) event. Plasma biomarkers do not currently feature in the assessment of HCM disease progression, which is tracked by serial imaging, or in SCD risk stratification, which is based on imaging parameters and patient/family history. There is a need for new HCM plasma biomarkers to refine disease monitoring and improve patient risk stratification. To identify new plasma biomarkers for patients with HCM, we performed exploratory myocardial and plasma proteomics screens and subsequently developed a multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay to validate the 26 peptide biomarkers that were identified. The association of discovered biomarkers with clinical phenotypes was prospectively tested in plasma from 110 HCM patients with LVH (LVH+ HCM), 97 controls, and 16 HCM sarcomere gene mutation carriers before the development of LVH (subclinical HCM). Six peptides (aldolase fructose-bisphosphate A, complement C3, glutathione S-transferase omega 1, Ras suppressor protein 1, talin 1, and thrombospondin 1) were increased significantly in the plasma of LVH+ HCM compared with controls and correlated with imaging markers of phenotype severity: LV wall thickness, mass, and percentage myocardial scar on cardiovascular magnetic resonance imaging. Using supervised machine learning (ML), this six-biomarker panel differentiated between LVH+ HCM and controls, with an area under the curve of ≥ 0.87. Five of these peptides were also significantly increased in subclinical HCM compared with controls. In LVH+ HCM, the six-marker panel correlated with the presence of nonsustained ventricular tachycardia and the estimated five-year risk of sudden cardiac death. Using quantitative proteomic approaches, we have discovered six potentially useful circulating plasma biomarkers related to myocardial substrate changes in HCM, which correlate with the estimated sudden cardiac death risk.

Authors

  • Gabriella Captur
    Institute of Cardiovascular Science, University College London, London, UK.
  • Wendy E Heywood
    Translational Mass Spectrometry Research Group, UCL Institute of Child Health and Great Ormond Street Hospital, 30 Guilford Street, London WC1N 1EH, UK; Institute of Child Health, University College London, London, WC1N 1EH, UK.
  • Caroline Coats
    Translational Mass Spectrometry Research Group, UCL Institute of Child Health and Great Ormond Street Hospital, 30 Guilford Street, London WC1N 1EH, UK; Institute of Cardiovascular Science, University College London, Gower Street, London, WC1E 6BT, UK.
  • Stefania Rosmini
    Barts Heart Center, The Cardiovascular Magnetic Resonance Imaging Unit and The Inherited Cardiovascular Diseases Unit, St. Bartholomew's Hospital, West Smithfield, London, EC1A 7BE, UK.
  • Vimal Patel
    Institute of Cardiovascular Science, University College London, Gower Street, London, WC1E 6BT, UK.
  • Luís R Lopes
    Cardiac Imaging Department, Barts Heart Centre, St Bartholomew's Hospital, London, UK; Institute of Cardiovascular Science, University College London, London, UK.
  • Richard Collis
    Institute of Cardiovascular Science, University College London, Gower Street, London, WC1E 6BT, UK.
  • Nina Patel
    Translational Mass Spectrometry Research Group, UCL Institute of Child Health and Great Ormond Street Hospital, 30 Guilford Street, London WC1N 1EH, UK; Institute of Child Health, University College London, London, WC1N 1EH, UK.
  • Petros Syrris
    Institute of Cardiovascular Science, University College London, Gower Street, London, WC1E 6BT, UK.
  • Paul Bassett
    Biostatistics Joint Research Office, University College London, Gower Street, London, WC1E 6BT, UK.
  • Ben O'Brien
    Department of Perioperative Medicine, St. Bartholomew's Hospital and Barts Heart Center, West Smithfield, London, EC1A 7BE, UK; William Harvey Research Institute, Charterhouse Square, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
  • James C Moon
    Cardiac Imaging Department, Barts Heart Centre, St Bartholomew's Hospital, London, UK; Institute of Cardiovascular Science, University College London, London, UK. Electronic address: j.moon@ucl.ac.uk.
  • Perry M Elliott
    From the Institute of Cardiovascular Science (R.C.L., V.K.K., R.E.F., N.H.C., R.P.H., P.J.T., P.D.L., P.M.E., L.C.) and Metabolism and Experimental Therapeutics, Division of Medicine (R.B.), University College London, United Kingdom; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, United Kingdom (P.R., D.O.-S.); Gene Ontology Consortium (P.R., T.Z.B., D.O.-S., J.A.B., D.P.H.); The Zebrafish Model Organism Database, University of Oregon, Eugene (D.G.H.); Rat Genome Database, Human Molecular Genetics Center, Medical College of Wisconsin, Milwaukee (S.J.F.L.); Arabidopsis Information Resource, Phoenix Bioinformatics, Fremont, CA (T.Z.B.); FlyBase, University of Cambridge, United Kingdom (S.T.); Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME (J.A.B., D.P.H.); Oxbridge BHF Centre of Regenerative Medicine, Department of Physiology, Anatomy and Genetics, University of Oxford, United Kingdom (P.R.R.); and William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (A.T.).
  • Kevin Mills
    Translational Mass Spectrometry Research Group, UCL Institute of Child Health and Great Ormond Street Hospital, 30 Guilford Street, London WC1N 1EH, UK; Institute of Child Health, University College London, London, WC1N 1EH, UK. Electronic address: kevin.mills@ucl.ac.uk.

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