Impact of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Activation on the Durability of Biological Prostheses in Adipose Rats with Hypercholesterolemia

Objectives: Hypercholesterolemia is a major risk factor for aortic valve disease. PPARγ activation has been shown to reduce the progression of native aortic valve sclerosis, while its effect on bioprosthetic valve degeneration is yet unknown. This project aims to analyze the impact of pioglitazone, a PPARγ agonist, on the degeneration of aortic valve conduits in a standardized model of heterotopic implantation in adipose hypercholesterolemic rats.

Methods: Cryopreserved allogeneic rat aortic conduits (n = 40) were infrarenally implanted into Wistar rats on high-fat diet (34.6% fat). One cohort was treated with pioglitazone (75 mg/kg chow; n = 20, group PIO) and compared to the respective untreated group (n = 20, group C). After 4 or 12 weeks, conduits were explanted and analyzed by histology and immunohistology.

Results: After 4 weeks, a significantly decreased intimamediaratio occurred in group PIO compared to group C (0.25 ± 0.05 vs. 0.67 ± 0.13; p = 0.0064). Also after 12 weeks, a diminished intimamedia ratio was observed, but without statistical significance (0.43 ± 0.11 vs. 0.73 ± 0.10; p = 0.059). Calcification of the intima, as assessed by a von Kossa’s staining score, was reduced by trend after 4 weeks in group PIO versus group C (1.17 ± 0.49 vs. 2.33 ± 0.51; p = 0.1140) and significantly decreased after 12 weeks (0.75 ± 0.46 vs. 5.08 ± 0.87; p = 0.0002). No significant differences were shown for media calcification after 4 and 12 weeks between group PIO and group C. Echocardiographically significant lower regurgitation of the implanted aortic valve conduit was observed in group PIO compared to group C after 4 weeks (velocity time integral ratio: 0.03 ± 0.02 vs. 0.16 ± 0.05; p = 0.02) and 12 weeks (0.14 ± 0.04 vs. 0.51 ± 0.07; p = 0.0004).

Conclusion: Systemic PPARγ activation decreases intima hyperplasia and subsequent calcification of cryopreserved allografts in hypercholesterolemic recipients. Furthermore, it seems to inhibit functional impairment of the implanted aortic valve. Preclinical studies are required to determine the long-term impact of PPARγ agonists on graft durability.