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Pilot study identifying myosin heavy chain 7, desmin, insulin-like growth factor 7, and annexin A2 as circulating biomarkers of human heart failure

Authors

  • Shaan Chugh,

    1. Department of Physiology, University of Toronto, Toronto, ON, Canada
    2. Heart and Stroke/Richard Lewar Centre of Cardiovascular Excellence, Toronto, ON, Canada
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  • Maral Ouzounian,

    1. Heart and Stroke/Richard Lewar Centre of Cardiovascular Excellence, Toronto, ON, Canada
    2. Division of Medicine, University Health Network, Toronto, ON, Canada
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  • Zhen Lu,

    1. Department of Physiology, University of Toronto, Toronto, ON, Canada
    2. Heart and Stroke/Richard Lewar Centre of Cardiovascular Excellence, Toronto, ON, Canada
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  • Shanas Mohamed,

    1. Heart and Stroke/Richard Lewar Centre of Cardiovascular Excellence, Toronto, ON, Canada
    2. Division of Medicine, University Health Network, Toronto, ON, Canada
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  • Wenping Li,

    1. Department of Physiology, University of Toronto, Toronto, ON, Canada
    2. Heart and Stroke/Richard Lewar Centre of Cardiovascular Excellence, Toronto, ON, Canada
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  • Nicolas Bousette,

    1. Department of Physiology, University of Toronto, Toronto, ON, Canada
    2. Heart and Stroke/Richard Lewar Centre of Cardiovascular Excellence, Toronto, ON, Canada
    Current affiliation:
    1. Montreal Heart Institute, Montreal, QC H1T 1C8, Canada
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  • Peter P. Liu,

    1. Heart and Stroke/Richard Lewar Centre of Cardiovascular Excellence, Toronto, ON, Canada
    2. Division of Medicine, University Health Network, Toronto, ON, Canada
    3. University of Ottawa Heart Institute, Ottawa, ON, Canada
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  • Anthony O. Gramolini

    Corresponding author
    1. Heart and Stroke/Richard Lewar Centre of Cardiovascular Excellence, Toronto, ON, Canada
    2. Division of Medicine, University Health Network, Toronto, ON, Canada
    • Department of Physiology, University of Toronto, Toronto, ON, Canada
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Correspondence: Dr. Anthony Gramolini, Department of Physiology, University of Toronto, 112 College St. Rm. 307, Toronto, Ontario M5G 1L6, Canada

E-mail: anthony.gramolini@utoronto.ca

Fax: +416-978-8528

Abstract

In-depth proteomic analyses offer a systematic way to investigate protein alterations in disease and, as such, can be a powerful tool for the identification of novel biomarkers. Here, we analyzed proteomic data from a transgenic mouse model with cardiac-specific overexpression of activated calcineurin (CnA), which results in severe cardiac hypertrophy. We applied statistically filtering and false discovery rate correction methods to identify 52 proteins that were significantly different in the CnA hearts compared to controls. Subsequent informatic analysis consisted of comparison of these 52 CnA proteins to another proteomic dataset of heart failure, three available independent microarray datasets, and correlation of their expression with the human plasma and urine proteome. Following this filtering strategy, four proteins passed these selection criteria, including myosin heavy chain 7, insulin-like growth factor-binding protein 7, annexin A2, and desmin. We assessed expression levels of these proteins in mouse plasma by immunoblotting, and observed significantly different levels of expression between healthy and failing mice for all four proteins. We verified antibody cross-reactivity by examining human cardiac explant tissue by immunoblotting. Finally, we assessed protein levels in plasma samples obtained from four unaffected and four heart failure patients and demonstrated that all four proteins increased between twofold and 150-fold in heart failure. We conclude that MYH7, IGFBP7, ANXA2, and DESM are all excellent candidate plasma biomarkers of heart failure in mouse and human.

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