Spatially resolved metabolomics revealed specific nucleotide alterations within the media and adventitia layers in idiopathic thoracic aortic aneurysms associated with tricuspid and bicuspid valves

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Instituto de Salud Carlos III co-supported by FEDER grants and co-funded by the European Union Background Thoracic aortic aneurysms (TAAs) curse silently and asymptomatic. The vast majority are idiopathic, representing 80-95% of the cases. Nevertheless, there is an association between TAA and the presence of bicuspid aortic valve (BAV) constituting BAV an independent risk factor of TAA. The presence of BAV accelerates the growth of the aneurysm affecting younger patients than those with tricuspid aortic valve (TAV). Evidence points to a profound remodeling of the media and adventitia layers, but the underlying mechanisms are unknown, especially the metabolic changes taking place and their in situ localization. Purpose Our aim was to identify, in a spatially resolved manner, the in situ metabolic alterations occurring in TAA human aortas while differentiating between BAV and TAV patients. In a further step, we sought to identify the changes happening particularly within the media and adventitia layers. Methods Mass spectrometry imaging (MSI) was applied to identify metabolic differences between human aortas with (TAA) and without (C) dilatation classified according to their aortic valve and obtained from cardiac surgeries. Clinical groups consisted on TAV-C (n=11), BAV-C (n=12), TAV-TAA (n=12) and BAV-TAA (n=12). Subsequent virtual microdissection histologically guided was applied to identify the specific metabolic changes located within media and/or adventitia. Changes were considered significant if FDR>2 and p-value <0.05. Results Purine metabolism resulted altered in BAV-TAA patients while no differences were found in TAV-TAA ones. Particularly, we detected a significant increase of aortic ATP (FC= 2.92; p-value= 0.030), ADP (FC= 2.04; p-value= 0.020), AMP (FC= 2.42; p-value= 0.011) and GDP (FC= 2.29; p-value= 0.046) in BAV-TAA vs. BAV-C subjects. In contrast, we found an in situ increment in pyrimidine metabolism resulting UDP and UMP increased in both, TAV and BAV associated TAAs. When comparing the arterial layers, media layer was found to be the major driver of BAV-TAA with no nucleotides changes in adventitia. However, TAV-TAA media and adventitia layer behave similarly with the exception of a massive increase of ATP (FC=50.23, p=0.046) in adventitia with no alteration in media of TAV-TAA vs. TAV-C patients. Conclusions Idiopathic TAAs course differently in subjects with bicuspid and tricuspid valves both in terms of mechanisms of action and arterial remodeling within the aortic layers. These findings suggest that TAA patients with bicuspid or tricuspid aortic valve should be treated as independent groups for optimal disease management.