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Different Bicuspid Aortic Valve Morphotypes Show Distinct Mechanisms of Gene Expression Alteration in the Aorta: Relevance to the Identification of Potential Circulating Biomarkers

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BICUSPID AORTIC VALVE MORPHOTYPES SHOW DISTINCT MECHANISMS OF GENE EXPRESSION ALTERATION IN THE AORTA: RELEVANCE TO THE IDENTIFICATION OF POTENTIAL CIRCULATING BIOMARKERS

A. Della Corte, C. Bancone, M. Buonocore, G. Cobellis, M. Cipollaro, U. Galderisi, M. De Feo, G. Limongelli, A. Forte
Second University of Naples, Naples, Italy


OBJECTIVE

The pathogenesis of the aortopathy underlying the increased risk of aortic dilatation and dissection in bicuspid aortic valve (BAV) patients is currently poorly understood. Moreover, no available circulating biomarker, related to the risk or severity of the aortopathy, has been identified so far.

The Transforming Growth Factor-β (TGF-β) network is attracting an increasing attention, by virtue of its role in fibrosis, inflammation, cell proliferation and migration and extracellular matrix (ECM) remodeling and in light of its involvement in aortopathy syndromes, such as Loeys-Dietz and Marfan syndromes (Fig. 1).

In this study we aimed to gain more in-depth insights in the pathogenesis of aortopathy in BAV patients and to the identification of potential early biomarkers of diseas, by coupling a differential gene expression study in aortic samples with serum assay of the respective products.

METHODS

Patients: Aortic wall samples from 120 patients with aortic valve stenosis undergoing surgery, with or without associated aortopathy, and from 22 heart transplant donors with negative personal and familial history of BAV and/or aortopathy were included. Fifty patients had tricuspid aortic valve (TAV) stenosis with normal or mildly dilated ascending aorta (echocardiography-measured maximal aortic diameter ≤45mm), 39 (non-familial, non-syndromic) had a stenotic congenital BAV with normal or mildly dilated aorta (≤45mm, BAVnon-dil group) and 31 had BAV stenosis with “ascending phenotype” aortic dilatation (>45mm, BAVdil group). Clinical characteristics are summarized in Table 1.

Aortic wall and blood sample collection: At surgery, two aortic samples were retrieved from the so-called convexity (CVX: greater curvature) and the concavity (CCV: lesser curvature) regions respectively, 1–2 cm distal to the sino-tubular junction (from the ends of the transverse aortotomy in patients without dilatation). Samples were immediately stored in RNALater (Qiagen) at −80°C for subsequent RNA extraction. Blood samples were obtained preoperatively by venipuncture from all BAV and TAV patients as well as from 11 healthy volunteers in whom the presence of BAV or aortic diseases had been previously excluded.

RT-PCR and ELISA assays: We evaluated by RT-PCR gene expression variations of TGF-β1, connective tissue growth factor (CTGF), matrix-metalloproteinase 2 (MMP-2), MMP-14, endoglin (ENG) and superoxide dismutase 3 (SOD3) in the ascending aorta of TAV and BAV stenosis patients, and assessed by ELISA the serum concentration of the respective products. 

RESULTS

RT-PCR data reveal that even in BAVnon-dilstenosis patients, significant changes of gene expression vs. control aortas occur, including increased expression of TGF-β1, CTGF and MMP-2, decreased expression of MMP-14 and ENG and lack of the increased expression of SOD3 that was observed in TAV stenosis patients (Fig. 2). The expression levels of different genes showed morphotype-specific correlations, including MMP-2/TGF-β1 and SOD3/ENG expression in both RL- and RN-BAV patients (Fig. 3), and ENG/MMP-14 in RL-BAV and TGF-β1/MMP-14 in RN-BAV patients only (r=0.723 and 0.714, respectively, p=0.001).

TGF-β1 serum concentration significantly decreased in TAV and BAVnon-dil patients vs. healthy subjects. ENG serum concentration decreased in all patients, more markedly in BAVdil patients (Fig. 4).

RL-BAV patients and RN-BAV patients showed distinctive correlations between expression levels of some genes and serum concentration of the respective products: these included a significant correlation of both MMP-2 and TGF-β1 gene expression with serum concentration of MMP-2 in RL-BAV group, and with serum SOD3 concentration in RN-BAV (Fig. 5).

Finally, for what concerns the association between RT-PCR and/or ELISA data and medications, we highlighted a significantly lower TGF-β1 concentration in the serum of BAV-RL patients treated with Angiotensin receptor blockers (ARBs) (Fig. 6).

CONCLUSIONS

The results of this study suggest differences between valve morphotypes in the pathogenetic mechanisms underlying aortic wall maladaptive remodeling.

Different molecules could be tested as potential biomarkers in RL and RN types of BAV. Our results also highlight the importance of careful phenotypic stratification of patients in future trials testing the use of ARBs and other medications for prevention of aneurysm development in BAV patients.

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