A Role for Peroxisome Proliferator-Activated Receptor Gamma (PPARy) Agonists in Counteracting the Degeneration of Cardiovascular Grafts

Objectives: Aortic valve replacement in case of high-grade stenosis is a standard procedure in modern cardiovascular medicine. Unfortunately, biological prostheses have several limitations due to progressive degenerative calcification and subsequent final implant failure. Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARy) agonist was shown to decrease the degeneration of native aortic valves. In the current study, we examined the impact of pioglitazone on the degeneration of aortic valve conduits in a standardized rat model of heterotopic implantation.

Methods: Cryopreserved allogenic rat aortic conduits (n = 40) were infrarenally implanted into Wistar rats treated with pioglitazone (75 mg/kg chow; n = 20, group PIO) or untreated (n = 20, group C). After 4 or 12 weeks, conduits were explanted and analyzed by histology, immunohistology, and PCR.

Results: Significantly reduced macrophage-mediated inflammation (CD 68) occurred in group PIO compared to group C after 4 weeks (10.14 ± 1.346 vs. 14.74 ± 1.4; p = 0.0287) and after 12 weeks (10.86 ± 0.82 vs. 16.31 ± 1.87; p = 0.0169). The amount of chondrogenic transformation, assessed by a Syndecan-3 staining, was significantly decreased in group PIO compared to group C after 12 weeks (1.31 ± 0.15 vs. 2.31 ± 0.2; p = 0.0011). Calcification of the intima as well as of the media, as assessed by a von Kossa staining score, was significantly reduced after 12 weeks in group PIO versus group C (intima: 2.06 ± 0.28 vs. 4.38 ± 0.52; p = 0.0286; media: 3.00 ± 0.46 vs. 7.75 ± 1.52; p = 0.0286). Accordingly, echocardiography revealed significantly lower regurgitation of the implanted aortic valve conduit in group PIO compared to group C after 12 weeks (velocity time integral ratio: 0.007 ± 0.01 vs. 0.21 ± 0.06; p = 0.001). Interestingly, significantly increased intima hyperplasia could be observed in group PIO compared to group C after 12 weeks (1.09 ± 0.13 vs. 0.34 ± 0.09; p = 0.0001).

Conclusion: Systemic PPARγ activation significantly prevents inflammation as well as intima and media calcification in aortic valve conduits, and seems to inhibit functional impairment of the implanted aortic valve. To further elucidate the therapeutic role of PPARγ regulation for biological graft durability, particularly analyzing effects on intima hyperplasia, translational studies and long-term follow-up data should be striven for.

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