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

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-beta 1 (TGF-beta 1), 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: BAV(non-dil) or >45 mm: BAV(dil)). Expression changes of the TGF-beta 1 active dimer and ENG were analyzed also by Western blot in ascending aorta samples from other 10 tricuspid aortic valve, 10 BAV(non-dil), and 10 BAV(dil) patients. The serum concentration of study targets was assessed through ELISA and the ratio of serum TGF-beta 1/ENG (T/E) was evaluated. All BAV(non-dil) patients underwent follow-up echocardiography to assess aortic growth rate. In BAV(non-dil) patients, TGF-beta 1 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-beta 1 and ENG. TGF-beta 1 serum concentration significantly decreased in tricuspid aortic valve and BAV(non-dil) patients versus healthy subjects. ENG serum concentration decreased in all patients, more markedly in BAV(dil). A significant increase of the T/E ratio versus healthy subjects was unique of patients with BAV. In BAV(non-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 BAV(non-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.