Cilostazol, Not Aspirin, Prevents Stenosis of Bioresorbable Vascular Grafts in a Venous Model

Abstract

Objective Despite successful translation of bioresorbable vascular grafts for the repair of congenital heart disease, stenosis remains the primary cause of graft failure. In this study, we investigated the efficacy of long-term treatment with the anti-platelet drugs aspirin and cilostazol in preventing stenosis and evaluated the effect of these drugs on the acute phase of inflammation and tissue remodeling. Approach and Results C57BL/6 mice were fed a drug-mixed diet of aspirin, cilostazol, or normal chow during the course of follow-up. Bioresorbable vascular grafts, composed of poly(glycolic acid) mesh sealed with poly(l-lactide-co-ε-caprolactone), were implanted as inferior vena cava (IVC) interposition conduits, and followed for 2 weeks (n=10 /group) or 24 weeks (n=15 /group). Both aspirin and cilostazol suppressed platelet activation and attachment onto the grafts. Upon explant at 24 weeks, well-organized neotissue had developed, and cilostazol treatment resulted in 100% graft patency followed by the aspirin (67%) and no treatment (60%) groups (P<0.05). Wall thickness and smooth muscle cell proliferation in the neotissue of the cilostazol group was decreased compared to the no treatment group at 24 weeks. Additionally, cilostazol was shown to have an anti-inflammatory effect on neotissue at 2 weeks by regulating the recruitment and activation of monocytes. Conclusions Cilostazol prevents stenosis of bioresorbable vascular graft in a mouse IVC implantation model up to 24 weeks and is accompanied by reduction of smooth muscle cell proliferation and acute inflammation.

Deconstructing the Tissue Engineered Vascular Graft: Evaluating Scaffold Pre-Wetting, Conditioned Media Incubation, and Determining the Optimal Mononuclear Cell Source

“…17,34 The inflammatory response to intravascular thrombus has been well characterized in models of deep vein thrombosis. 40,41 After a thrombus forms within a vein, the number of infiltrating neutrophils and monocytes increases, and the vein wall thickens, often accompanied by hyperproliferation of smooth muscle cells and myofibroblasts resulting in progressive vessel occlusion.…”

“…17 Scaffolds were manufactured by Gunze, Ltd., sterilized with ethylene oxide gas, and stored at −20 °C until implantation.…”

“…17 Throughout the platelet isolation process, pipetting was performed gently to minimize platelet activation. Blood was centrifuged (120 g for 8 min) to separate red cells and leukocytes (pellet) from platelet rich plasma (PRP, supernatant).…”

Helminth-induced Ly6Chi monocyte-derived alternatively activated macrophages suppress experimental autoimmune encephalomyelitis

“…Monocytes were isolated as previously described65. Briefly, bone marrow cell suspensions were isolated by flushing femurs and tibias from 6- to 8-wk WT C57BL/6 mice with complete RPMI 1640 medium supplemented with 10% fetal calf serum (FCS), 100 units of penicillin/streptomycin, 2 mM glutamine, 25 mM HEPES buffer, and 1% non-essential amino acids (all from Gibco/Brl Division, Grand Island, NY, USA).…”

Quickening: Translational design of resorbable synthetic vascular grafts

“…However, administration of the platelet inhibitor cilostazol did reduce stenosis in wild-type mice. (159) Similarly, inhibiting TGFβ1R1 simultaneously reduced stenosis and macrophage iNOS expression. (160) TGF-β1 inhibition reduced stenosis rates comparably to seeding with BM-MNCs.…”