Extracellular Vesicle Proteins Associated with Systemic Vascular Events Correlate with Heart Failure: An Observational Study in a Dyspnoea Cohort

PLoS One. 2016 Jan 28;11(1):e0148073. doi: 10.1371/journal.pone.0148073. eCollection 2016.


Background: SerpinF2, SerpinG1, CystatinC and CD14 are involved in inflammatory processes and plasma extracellular vesicle (EV) -levels of these proteins have been reported to be associated with systemic vascular events. Evidence is accumulating that inflammatory processes may play a pivotal role both in systemic vascular events and in heart failure. Therefore, we studied the association between plasma extracellular vesicle SerpinF2-, SerpinG1-, CystatinC and CD14-levels and the occurrence of acute heart failure in patients.

Methods and result: Extracellular vesicle protein levels of SerpinG1, SerpinF2, CystatinC and CD14 were measured in an observational study of 404 subjects presenting with dysponea at the emergency department (4B-cohort). Plasma extracellular vesicles were precipitated in a total extracellular vesicles (TEX)-fraction and in separate LDL- and HDL-subfractions. Extracellular vesicle protein levels were measured with a quantitative immune assay in all 3 precipitates. Out of 404 subjects, 141 (35%) were diagnosed with acutely decompensated heart failure. After correction for confounders (including comorbidities and medications), levels of CD14 in the HDL-fraction (OR 1.53, p = 0.01), SerpinF2 in the TEX-and LDL-fraction (ORs respectively 0.71 and 0.65, p<0.05) and SerpinG1 in the TEX-fraction (OR 1.55, p = 0.004) were statistically significantly related to heart failure. Furthermore, extracellular vesicle CD14- and SerpinF2-levels were significantly higher in heart failure patients with preserved ejection fraction than in those with reduced ejection fraction.

Conclusion: Extracellular vesicle levels of CD14, SerpinG1 and SerpinF2 are associated with the occurrence of heart failure in subjects suspected for acute heart failure, suggesting common underlying pathophysiological mechanisms for heart failure and vascular events.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adult
  • Aged
  • Complement C1 Inactivator Proteins / analysis*
  • Complement C1 Inhibitor Protein
  • Cross-Sectional Studies
  • Cystatin C / analysis
  • Cystatin C / blood*
  • Extracellular Vesicles / pathology*
  • Female
  • Heart Failure / blood*
  • Heart Failure / pathology
  • Humans
  • Lipopolysaccharide Receptors / analysis
  • Lipopolysaccharide Receptors / blood*
  • Male
  • Middle Aged
  • alpha-2-Antiplasmin / analysis*


  • Complement C1 Inactivator Proteins
  • Complement C1 Inhibitor Protein
  • Cystatin C
  • Lipopolysaccharide Receptors
  • SERPINF2 protein, human
  • SERPING1 protein, human
  • alpha-2-Antiplasmin

Grants and funding

This study is partly supported by a start up grant National University of Singapore to Dominique PV de Kleijn; National Medical Research Council Centre Grant (http://www.nmrc.gov.sg/content/nmrc_internet/home.html) to Dominique PV de Kleijn, Arthur Mark Richards, Carolyn SP Lam; Queen of Hearts program Dutch Heart Foundation (https://www.hartstichting.nl/) 2013T084 to Hester M den Ruijter and Dominique PV de Kleijn; National Medical Research Council CS-IRG (http://www.nmrc.gov.sg/content/nmrc_internet/home/grant/compgrants/irg11.html) to Carolyn SP Lam and Dominique PV de Kleijn; ATTRaCT SPF grant (http://www.a-star.edu.sg/Awards-Scholarship/Overview.aspx) to Arthur Mark Richards, Dominique PV de Kleijn, Carolyn SP Lam; KNAW strategic grant (https://www.knaw.nl/en) to Dominique PV de Kleijn.