Valve-Dependent Regional Heterogeneity of Wall Mechanics and Collagen Remodeling in Ascending Thoracic Aortic Aneurysms

Ascending thoracic aortic aneurysm (ATAA) pathogenesis varies with aortic valve morphology, yet regional heterogeneity between inner curvature (IC) and outer curvature (OC) remains incompletely characterized. We hypothesized that regional differences between the outer and inner curvature of the ascending aorta are valve-morphology dependent and reflect distinct remodeling mechanisms in bicuspid versus tricuspid aortic valve-associated aortopathy. Ascending aortic tissue from 155 patients (69 tricuspid aortic valve [TAV], 68 bicuspid aortic valve [BAV], 18 non-aneurysmal heart transplantation [HTx] controls) underwent uniaxial tensile testing (<i>n</i> = 66), histological analysis, hydroxyproline assay, and reverse transcription quantitative PCR (RT-qPCR) for collagen (COL1A1, COL3A1, COL4A1, COL5A1, COL11A1) and elastin (ELN) genes. The OC was thinner than the IC in both TAV and BAV (<i>p</i> < 0.001), with no regional differences in HTx. TAV demonstrated increased OC stiffness (E-modulus 0.60 ± 0.31 vs. 0.43 ± 0.24 MPa, <i>p</i> = 0.004) with reduced failure strain (<i>p</i> = 0.013). BAV showed preserved stiffness but reduced OC extensibility (ε_max 56.5 ± 15.1% vs. 72.4 ± 21.7%, <i>p</i> < 0.001). BAV exhibited elevated OC collagen content (hydroxyproline OC/IC ratio 1.42, <i>p</i> = 0.048), whereas TAV showed reduced OC elastin area (<i>p</i> < 0.01). All collagen genes were upregulated at the OC in both TAV (all <i>p</i> < 0.001) and BAV (all <i>p</i> < 0.05), with COL11A1 showing the highest fold change (3.4-fold in TAV). ELN was reduced at the OC in TAV (<i>p</i> < 0.001) but unchanged in BAV. ATAAs exhibit distinct valve-dependent regional heterogeneities. The discordance between collagen gene expression and protein content suggests valve-specific differences in collagen regulation. These findings support distinct pathomechanisms and highlight the limitations of diameter-based risk stratification, motivating further investigation of regional wall assessment as a complement to current size criteria for surgical decision-making.