{
  "abstract": "Introduction Pulmonary arterial hypertension (PAH) covers a range of diseases characterised by increased pulmonary vessel pressures, which result in right heart failure and death if left untreated. Mutations in genes such as eukaryotic translation initiation factor 2 α kinase 4 (which encodes general control nonderepressible 2, GCN2) and bone morphogenetic protein receptor type 2 (BMPR2) cause heritable pulmonary veno-occlusive disease (PVOD) and heritable PAH respectively, which have particularly poor outcomes. The majority of PVOD patients die within 1–2 years unless transplanted. We sought to find novel plasma biomarkers that would enable us to accurately and swiftly identify whether patients have genetic mutations.Methods Plasma samples from patients with GCN2-associated PVOD (n=8), BMPR2-associated PAH (n=14), and age- and sex-matched healthy volunteers (n=12, who were confirmed to have no history of PAH, thromboembolic disease and not on anticoagulants) were submitted for plasma proteomic analysis. Demographic data and details of the diagnostic right heart catheterisation (for patients) were also collected.Results and discussion We identified two plasma proteins, Caveolae Associated Protein 2 (Cavin-2) and caldesmon which were elevated in the GCN2-associated PVOD cohort alone. Both cavin-2 and caldesmon levels were capable of distinguishing between GCN2-associated PVOD and healthy volunteers (AUC of 0.90, P=0.0045 for cavin-2 and AUC of 0.85, P=0.013 for caldesmon). Intriguingly, they were also both capable of distinguishing between GCN2-associated PVOD and BMPR2-associated PAH (AUC of 0.82, P=0.014 for cavin-2 and AUC of 0.79, P=0.03 for caldesmon). Both proteins are biologically plausible as biomarkers. Cavin-2-deficient mice are more susceptible to hypoxia-induced pulmonary vasoconstriction. Cavin-2 forms complexes with caveolin-1 and mutations in caveolin-1 can cause heritable PAH. Blockade of caldesmon reduces endothelin-1-induced contraction in pulmonary artery smooth muscle cells. Interestingly there is also an inflammatory signal common to both GCN2-associated PVOD and BMPR2-associated PAH, with elevated levels of serum amyloid A, heparanase and myeloblastin.Conclusions It may be possible to identify a metabolic signature unique to different types of genetically-driven pulmonary vascular disease. This will be validated in an independent Spanish cohort. This approach may be advantageous as it is potentially faster and cheaper than conventional genetic testing.",
  "authors": [
    {
      "affiliations": [
        "University of Cambridge, Cambridge, UK"
      ],
      "name": "E Swietlik"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, UK"
      ],
      "name": "M Schwiening"
    },
    {
      "affiliations": [
        "Centro de Investigaciones Biológicas Margarita Salas, Madrid, Spain"
      ],
      "name": "L de Batisda-Casero"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, UK"
      ],
      "name": "NW Morrell"
    },
    {
      "affiliations": [
        "Unidad Multidisciplinar de Hipertensión Pulmonar, Madrid, Spain"
      ],
      "name": "A Cruz-Utrilla"
    },
    {
      "affiliations": [
        "Centro de Investigaciones Biológicas Margarita Salas, Madrid, Spain"
      ],
      "name": "E Oliver"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, UK"
      ],
      "name": "SJ Marciniak"
    },
    {
      "affiliations": [
        "University of Cambridge, Cambridge, UK"
      ],
      "name": "E Soon"
    }
  ],
  "title": "S142 Proteomic signatures for GCN2 and BMPR2-mutation driven pulmonary vascular disease",
  "uid": "a2257b8e-26c2-5753-945d-f9c989245ff9"
}