Proteomic diversity of high-density lipoprotein explains its association with clinical outcome in patients with heart failure

J. E. Emmens, Donald J. l. Jones, T. H. Cao, Daniel C. S. Chan, Simon P. R. Romaine, Paulene A. Quinn, Stefan D. Anker, John G. F. Cleland, K. Dickstein, Gerasimos S. Filippatos, Hans L. Hillege, Chim Lang, Piotr Ponikowski, Nilesh J. Samani, Dirk J. van Veldhuisen, Faiez Zannad, Aeilko H. Zwinderman, Marco Metra, Rudolf A. de Boer, Adriaan A. VoorsLeong Loke Ng

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Abstract

Aims: Previously, low high-density lipoprotein (HDL) cholesterol was found to be one of the strongest predictors of mortality and/or heart failure (HF) hospitalisation in patients with HF. We therefore performed in-depth investigation of the multifunctional HDL proteome to reveal underlying pathophysiological mechanisms explaining the association between HDL and clinical outcome. Methods and results: We selected a cohort of 90 HF patients with 1:1 cardiovascular death/survivor ratio from BIOSTAT-CHF. A novel optimised protocol for selective enrichment of lipoproteins was used to prepare plasma. Enriched lipoprotein content of samples was analysed using high resolution nanoscale liquid chromatography-mass spectrometry-based proteomics, utilising a label free approach. Within the HDL proteome, 49 proteins significantly differed between deaths and survivors. An optimised model of 12 proteins predicted death with 76% accuracy (Nagelkerke R 2=0.37, P < 0.001). The strongest contributors to this model were filamin-A (related to crosslinking of actin filaments) [odds ratio (OR) 0.31, 95% confidence interval (CI) 0.15–0.61, P = 0.001] and pulmonary surfactant-associated protein B (related to alveolar capillary membrane function) (OR 2.50, 95% CI 1.57–3.98, P < 0.001). The model predicted mortality with an area under the curve of 0.82 (95% CI 0.77–0.87, P < 0.001). Internal cross validation resulted in 73.3 ± 7.2% accuracy. Conclusion: This study shows marked differences in composition of the HDL proteome between HF survivors and deaths. The strongest differences were seen in proteins reflecting crosslinking of actin filaments and alveolar capillary membrane function, posing potential pathophysiological mechanisms underlying the association between HDL and clinical outcome in HF.

Original languageEnglish
Pages (from-to)260-267
Number of pages8
JournalEuropean Journal of Heart Failure
Volume20
Issue number2
Early online date18 Dec 2017
DOIs
Publication statusPublished - 27 Feb 2018

Keywords

  • Heart failure
  • High-density lipoprotein
  • Proteome
  • Prognosis
  • Lipoproteins, HDL/blood
  • Humans
  • Male
  • United Kingdom/epidemiology
  • Cause of Death/trends
  • Proteome/metabolism
  • Heart Failure/blood
  • Survival Rate/trends
  • Proteomics/methods
  • Biomarkers/blood
  • Female
  • Aged
  • Risk Assessment/methods

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  • Cite this

    Emmens, J. E., Jones, D. J. L., Cao, T. H., Chan, D. C. S., Romaine, S. P. R., Quinn, P. A., Anker, S. D., Cleland, J. G. F., Dickstein, K., Filippatos, G. S., Hillege, H. L., Lang, C., Ponikowski, P., Samani, N. J., van Veldhuisen, D. J., Zannad, F., Zwinderman, A. H., Metra, M., de Boer, R. A., ... Ng, L. L. (2018). Proteomic diversity of high-density lipoprotein explains its association with clinical outcome in patients with heart failure. European Journal of Heart Failure, 20(2), 260-267. https://doi.org/10.1002/ejhf.1101