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Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension
  1. Lars Harbaum1,
  2. Pavandeep Ghataorhe1,
  3. John Wharton1,
  4. Beatriz Jiménez2,
  5. Luke S G Howard3,4,
  6. J Simon R Gibbs3,4,
  7. Jeremy K Nicholson5,
  8. Christopher J Rhodes1,
  9. Martin R Wilkins1
  1. 1 Department of Medicine, Imperial College London, London, UK
  2. 2 Imperial Clinical Phenome Centre, Department of Surgery and Cancer, Imperial College London, London, UK
  3. 3 National Heart and Lung Institute, Imperial College London, London, UK
  4. 4 National Pulmonary Hypertension Service, Imperial College Healthcare Trust NHS, London, UK
  5. 5 Division of Computational Systems Medicine, Department of Surgery and Cancer, and Centre for Digestive and Gut Health, Imperial College London, London, UK
  1. Correspondence to Professor Martin R Wilkins, Department of Medicine, Imperial College London, London W12 0NN, UK; m.wilkins{at}


Background Aberrant lipoprotein metabolism has been implicated in experimental pulmonary hypertension, but the relevance to patients with pulmonary arterial hypertension (PAH) is inconclusive.

Objective To investigate the relationship between circulating lipoprotein subclasses and survival in patients with PAH.

Methods Using nuclear magnetic resonance spectroscopy, 105 discrete lipoproteins were measured in plasma samples from two cohorts of patients with idiopathic or heritable PAH. Data from 1124 plasma proteins were used to identify proteins linked to lipoprotein subclasses. The physical presence of proteins was confirmed in plasma lipoprotein subfractions separated by ultracentrifugation.

Results Plasma levels of three lipoproteins from the small high-density lipoprotein (HDL) subclass, termed HDL-4, were inversely related to survival in both the discovery (n=127) and validation (n=77) cohorts, independent of exercise capacity, comorbidities, treatment, N-terminal probrain natriuretic peptide, C reactive protein and the principal lipoprotein classes. The small HDL subclass rich in apolipoprotein A-2 content (HDL-4-Apo A-2) exhibited the most significant association with survival. None of the other lipoprotein classes, including principal lipoprotein classes HDL and low-density lipoprotein cholesterol, were prognostic. Three out of nine proteins identified to associate with HDL-4-Apo A-2 are involved in the regulation of fibrinolysis, namely, the plasmin regulator, alpha-2-antiplasmin, and two major components of the kallikrein–kinin pathway (coagulation factor XI and prekallikrein), and their physical presence in the HDL-4 subfraction was confirmed.

Conclusion Reduced plasma levels of small HDL particles transporting fibrinolytic proteins are associated with poor outcomes in patients with idiopathic and heritable PAH.

  • primary pulmonary hypertension

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  • CJR and MRW contributed equally.

  • LH and PG contributed equally.

  • Contributors All authors collected data and gave constructive criticism of the manuscript. LH, PG, JW, CJR and MRW performed study design and interpretation, and wrote the manuscript. LH and PG analysed data and performed the experiments.

  • Funding LH was supported by a European Respiratory Society Research Fellowship (LTRF 2016 – 6884). CJR was supported by an Imperial College Junior Research Fellowship and British Heart Foundation Intermediate Basic Science Research Fellowship (FS/15/59/31839). MRW is supported by a British Heart Foundation programme grant (RG/10/16/28575).

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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