High plasma levels of heparin-binding epidermal growth factor are associated with a more stable plaque phenotype and reduced incidence of coronary events

Arterioscler Thromb Vasc Biol. 2015 Jan;35(1):222-8. doi: 10.1161/ATVBAHA.114.304369. Epub 2014 Oct 30.


Objective: Rupture of atherosclerotic plaques is the major cause of acute coronary events (CEs). Plaque destabilization is the consequence of an imbalance between inflammatory-driven degradation of fibrous tissue and smooth muscle cell-dependent tissue repair. Proinflammatory factors have been documented extensively as biomarkers of cardiovascular risk but factors that contribute to stabilization of atherosclerotic plaques have received less attention. The present study aimed to investigate whether plasma levels of the smooth muscle cell growth factor epidermal growth factor (EGF), heparin-binding-EGF (HB-EGF), and platelet-derived growth factor correlate with plaque phenotype and incidence of CEs.

Approach and results: HB-EGF, EGF and platelet-derived growth factor were measured in plasma from 202 patients undergoing carotid endarterectomy and in 384 incident CE cases and 409 matched controls recruited from the Malmö Diet and Cancer cohort. Significant positive associations were found between the plasma levels of all 3 growth factors and the collagen and elastin contents of the removed plaques. CE cases in the Malmö Diet and Cancer cohort had lower levels of HB-EGF in plasma, whereas no significant differences were found for EGF and platelet-derived growth factor. After adjusting for cardiovascular risk factors in a Cox proportional hazard model, the hazard ratio for the highest HB-EGF tertile was 0.61 (95% confidence interval, 0.47-0.82; P<0.001).

Conclusions: The associations between high levels of smooth muscle cell growth factors in plasma and a more fibrous plaque phenotype as well as the association between low levels of HB-EGF and incident CEs point to a potential clinically important role for factors that contribute to plaque stabilization by stimulating smooth muscle cells.

Keywords: biomarkers; cardiovascular event; coronary disease; myocytes, smooth muscle.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • Carotid Artery Diseases / blood*
  • Carotid Artery Diseases / epidemiology
  • Carotid Artery Diseases / pathology
  • Carotid Artery Diseases / surgery
  • Case-Control Studies
  • Coronary Disease / blood*
  • Coronary Disease / diagnosis
  • Coronary Disease / epidemiology
  • Endarterectomy, Carotid
  • Epidermal Growth Factor / blood
  • Female
  • Heparin-binding EGF-like Growth Factor / blood*
  • Humans
  • Incidence
  • Kaplan-Meier Estimate
  • Linear Models
  • Male
  • Middle Aged
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Phenotype
  • Plaque, Atherosclerotic
  • Platelet-Derived Growth Factor / analysis
  • Proportional Hazards Models
  • Prospective Studies
  • Protective Factors
  • Risk Assessment
  • Risk Factors
  • Rupture, Spontaneous
  • Sweden / epidemiology
  • Up-Regulation


  • Biomarkers
  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • Platelet-Derived Growth Factor
  • Epidermal Growth Factor