Signaling Pathways in the Development of Bicuspid Aortopathy: from the Expression Patterns of Circulating microRNAs to the Formation of Aortic Aneurysm

Objectives: Little is known about the signaling pathways of aortopathies and the pathogenetic interaction between circulating microRNAs and the development of aortopathy is unknown. We aimed to elucidate the signaling pathways between expression patterns of circulating microRNAs and the formation of aortopathy in bicuspid aortic valve (BAV) disease.

Methods: We reviewed our institutional prospective BAV registry to identify all patients who underwent aortic valve repair/replacement ± proximal aortic replacement due to BAV disease with or without concomitant aortic aneurysm. All patients underwent peripheral blood sampling before the surgery for subsequent analysis of circulating biomarkers and intraoperative aortic tissue collection from the ascending aorta. Circulating microRNAs analysis included 11 microRNAs (miR-1, miR-17, miR-18a, miR-19a, miR-20a, miR-21, miR-29b, miR-106a, miR-133a, miR-143, and miR-145). The expression of those 11 microRNAs was analyzed in the aortic tissue, as well as the expression of MMP2 and TIMP1-2. Primary endpoint was the association between circulating and aortic tissue microRNAs. Furthermore, the correlation between the aortic tissue microRNAs and MMP2/TIMP1-2 expression was analyzed.

Results: Simultaneous analyzes of the circulating and aortic tissue microRNAs were prospectively performed in 65 consecutive BAV patients (mean age, 53 ± 12 years, 75% male). We found a significant correlation between circulating and aortic tissue microRNAs, which confirms the hypothesis that circulating microRNAs may be reflective of the ongoing aortic wall remodeling. The strongest correlation between circulating and aortic tissue microRNAs was found for miR-133a (r = 0.51, p = 0.01) and miR-143 (r = 0.47, p = 0.01). Furthermore, we found a significant association between miR-133a and TIMP1 expression in the aortic tissue (r = 0.48, p = 0.01), which is showing that microRNAs may influence MMP/TIMP homeostasis. Moreover, there was a significant correlation between miR-143 and MMP2 expression in the aortic tissue (r = 0.37, p = 0.045).

Conclusion: Our findings indicate that circulating microRNAs may sufficiently reflect remodeling processes in the proximal aorta in BAV aortopathy patients. Circulating microRNAs seem to exert their regulatory effects on the aortic remodeling through their direct impact on the MMPs/TIMPs homeostasis. Larger prospective cohorts are needed to validate our findings and to establish microRNAs as prognostically relevant biomarkers in the aortopathy prediction.

No conflict of interest has been declared by the author(s).