Degeneration of biological heart valve grafts in a rat model of superoxide dismutase-3 deficiency.

Abstract

While oxidative stress is known as key element in the pathogenesis of atherosclerosis and calcific aortic valve disease, its role in the degeneration of biological cardiovascular grafts has not been clarified yet. Therefore, the present study aimed to examine the impact of oxidative stress on the degeneration of biological cardiovascular allografts in a standardized chronic implantation model realized in rats exhibiting superoxide dismutase 3 deficiency (SOD3(-) ). Rats with SOD3 loss-of-function mutation (n=24) underwent infrarenal implantation of cryopreserved valved aortic conduits, while SOD3-competent recipients served as controls (n=28). After a follow-up period of 4 or 12 weeks, comparative analyses addressed degenerative processes, hemodynamics, and evaluation of the oxidative stress model. SOD3(-) rats presented decreased circulating SOD activity (p=.0079). After 12 weeks, 58% of the implant valves in SOD3(-) rats showed regurgitation (vs. 31% in controls, p=.2377). Intima hyperplasia and chondro-osteogenic transformation contributed to progressive graft calcification (p=.0024). At 12 weeks, hydroxyapatite deposition (p=.0198) and the gene expression of runt-related transcription factor-2 (Runx2) (p=.0093) were significantly enhanced in group SOD3(-) . This study provides the first in vivo evidence that impaired systemic antioxidant activity contributes to biological cardiovascular graft degeneration.