Introduction
Elastic fiber fragmentation (EFF) is a hallmark of aortic valve disease (AVD), and both inflammation and neovascularization have been identified as late findings, presumably due to atherosclerosis through a wound healing like response. However, EFF independently stimulates angiogenesis, suggesting an alternative mechanism for neovascularization in AVD.
Hypothesis
We hypothesized that aberrant angiogenesis would be an early AVD finding, preceding inflammation, due to EFF.
Methods
To examine disease progression, valve tissue was examined using histochemistry and immunohistochemistry from early (<40yo) and late (≥40yo) onset AVD specimens, as well as age-matched autopsy control aortic valves. Angiogenesis (VEGF-A, CD-31, SMA and chondromodulin), EFF (elastin, fibrillin-1, emilin-1, fibulin-5), progenitor valve interstitial cell phenotype (CD-34, CD-45) and inflammation (CD-68, LRP-5) were assessed.
Results
Bicuspid aortic valve was more common in early-onset AVD (n=21), and cardiovascular comorbidities were more common in late-onset AVD (n=11). Early-onset AVD specimens demonstrated angiogenesis without inflammation or atherosclerosis. A distinct pattern of EFF and elastic fiber components surrounded early-onset AVD neovessels, which were not present in control valves, including increased emilin and decreased fibulin-5, and the elastase/anti-elastase ratio and localization were altered in both early and late-onset AVD, suggesting a dynamic disease progression. Interestingly, progenitor VICs were present in control valves at both stages and were unchanged in age-matched AVD specimens.
Conclusions
Aberrant angiogenesis is an early mechanism in AVD pathogenesis preceding inflammation, implicating EFF as an inciting factor. Elucidation of the underlying mechanisms may inform the development of new pharmacologic therapeutics and durable bioprostheses.
Creation of disease-inspired biomaterial environments to mimic pathological events in early calcific aortic valve disease