A Possible Early Biomarker for Bicuspid Aortopathy: Circulating Transforming Growth Factor β-1 to Soluble Endoglin Ratio

Circ Res. 2017 May 26;120(11):1800-1811. doi: 10.1161/CIRCRESAHA.117.310833. Epub 2017 Apr 18.

Abstract

Rationale: The pathogenesis of bicuspid aortic valve (BAV)-associated aortopathy is poorly understood, and no prognostic biomarker is currently available.

Objective: We aimed to identify putative circulating biomarkers pathogenetically and prognostically linked to bicuspid aortopathy.

Methods and results: By reverse transcription polymerase chain reaction, we evaluated gene expression variations (versus normal aorta) of transforming growth factor-β1 (TGF-β1), connective tissue growth factor, matrix metalloproteinase-2 (MMP-2), MMP-14, endoglin (ENG), and superoxide dismutase 3 in ascending aorta samples from 50 tricuspid and 70 patients with BAV undergoing surgery for aortic stenosis (aorta diameter ≤45 mm: BAVnon-dil or >45 mm: BAVdil). Expression changes of the TGF-β1 active dimer and ENG were analyzed also by Western blot in ascending aorta samples from other 10 tricuspid aortic valve, 10 BAVnon-dil, and 10 BAVdil patients. The serum concentration of study targets was assessed through ELISA and the ratio of serum TGF-β1/ENG (T/E) was evaluated. All BAVnon-dil patients underwent follow-up echocardiography to assess aortic growth rate. In BAVnon-dil patients, TGF-β1 and MMP-2 gene expression increased significantly, whereas MMP-14 and ENG expression decreased versus controls. Expression changes were confirmed at protein level for TGF-β1 and ENG. TGF-β1 serum concentration significantly decreased in tricuspid aortic valve and BAVnon-dil patients versus healthy subjects. ENG serum concentration decreased in all patients, more markedly in BAVdil. A significant increase of the T/E ratio versus healthy subjects was unique of patients with BAV. In BAVnon-dil patients, a T/E ≥9 was independently associated in multivariable analysis with higher MMP-2 and lower superoxide dismutase 3 gene expression, independent of age and aortic diameter. A significant correlation was observed between baseline T/E ratio and aortic diameter growth rate in BAVnon-dil patients (r=0.66, P<0.001).

Conclusions: The novel evidence of a possible value of the T/E ratio as a biomarker of BAV aortopathy was presented: further validation studies are warranted.

Keywords: aortic disease; aortic valve stenosis; bicuspid; biomarkers; endoglin; transforming growth factor-β1.

MeSH terms

  • Adult
  • Aged
  • Aortic Valve / abnormalities*
  • Aortic Valve / diagnostic imaging
  • Aortic Valve / surgery
  • Aortic Valve Stenosis / blood*
  • Aortic Valve Stenosis / diagnostic imaging*
  • Aortic Valve Stenosis / surgery
  • Bicuspid Aortic Valve Disease
  • Biomarkers / blood
  • Echocardiography
  • Endoglin / blood*
  • Female
  • Follow-Up Studies
  • Heart Valve Diseases / blood*
  • Heart Valve Diseases / diagnostic imaging*
  • Heart Valve Diseases / surgery
  • Humans
  • Male
  • Middle Aged
  • Transforming Growth Factor beta1 / blood*

Substances

  • Biomarkers
  • ENG protein, human
  • Endoglin
  • Transforming Growth Factor beta1