Two molecular signatures, one disease: uncovering valve-specific drivers of thoracic aortic aneurysm pathogenesis

Thoracic aortic aneurysm (TAA) is a progressive and silent dilation of the thoracic aorta, with fatal consequences if it ruptures or dissects. Although most TAAs are idiopathic, their incidence is significantly higher in patients with bicuspid aortic valve. Detection is usually incidental, and there are currently no diagnostic or prognostic markers, being surgery the main therapeutic option. Limited understanding of TAA hampers the development of diagnostic tools and treatments.

We aim to investigate the mechanisms involved in the development of TAA in patients with tricuspid and bicuspid aortic valve, thereby identifying the similarities and differences between the two forms.

A total of 124 patients with aortic dilation (n=63) and without (C, n= 61) were classified according to valve type. The biological processes occurring during TAA were analysed in primary vascular smooth muscle cells (VSMCs), mitochondria, aorta and plasma. Data normality was assessed using Shapiro-Wilk test; comparisons were analysed using t-test or Mann-Whitney test. Outliers and possible confounding variables were evaluated. Results were adjusted if needed by multivariate regression models. Values of p ≤ 0.05 were considered significant.

We found that TAA associated to tricuspid valve is characterised by an inflammatory-degenerative profile. There is a diversion of glucose metabolism towards the hexosamine biosynthetic pathway, promoting the accumulation of glycosaminoglycans in the aortic media that ultimately increases intramural stress. In parallel, there is a glycolytic activation (increased lactate levels) that maintains ATP production and mitochondrial respiratory capacity. Although we found that the mitochondria of these patients are dysfunctional, this is compensated by increasing the number and by reprogramming their metabolism towards β-oxidation. This metabolic flexibility preserves short-term cell viability, but promotes stiffness, inflammation and degeneration of the aortic wall over time. We show that TAA associated to bicuspid valve is defined by exacerbated oxidative stress that induces DNA damage and cell-cycle arrest in the S-phase, promoting VSMC apoptosis. Mitochondria of these patients undergo morphological and functional changes that allow ATP production under stress but eventually lead to mitochondrial dysfunction. There is a shift in glucose use towards the pentose phosphate and hexosamine biosynthetic pathways aimed at maintaining lipid and nucleotide biosynthesis and partially counteracting oxidative stress. However, these initially protective responses ultimately result in a weaker and aged aortic wall with poor remodelling capacity.

Both TAA forms share a common pathogenic core, but they show different operating mechanisms. Based on our data, TAA associated to bicuspid or tricuspid aortic valve should be considered distinct clinical entities, pointing to tailored diagnosis and therapeutic approaches.