Rapamycin-eluting stents in the arterial duct: experimental observations in the pig model.
BACKGROUND
Maintaining arterial duct patency by stent implantation may be advantageous in congenital heart disease management algorithms. Rapamycin, an immunosuppressant drug that demonstrates antiproliferative properties and inhibits smooth muscle cell migration, may deter the intimal hyperplasia that occurs during spontaneous closure and after-stent implantation of the arterial duct.


RESULTS
Twenty-eight Yorkshire piglets (7 to 11 days old; weight, 2.2 to 4.9 kg) underwent stent implantation of the arterial duct (rapamycin-eluting (n=14) or bare metal (n=14) stents, 3.5-mm diameter) and were euthanized at 2, 4, and 6 weeks. Dissected arterial ducts were analyzed for lumen diameter, smooth muscle cell, and extracellular matrix components. Isolated arterial duct-derived smooth muscle cells were cultured in the presence or absence of rapamycin. Cellular proliferation rates were assessed by Ki-67 detection and [(3)H]-thymidine incorporation. No significant neointimal proliferation was present in either stent type at 2 weeks. At 4 weeks, the median luminal diameters of the bare metal stents were 87% (P=0.009), 54% (P=0.004), and 77% (P=0.004) that of the drug-eluting stents at the middle and aortic and pulmonary artery ends, respectively. At 6 weeks, the median luminal diameters of the bare metal stents were 0% (P=0.18), 5% (P=0.25), and 61% (P=0.13) that of the drug-eluting stents at the same respective levels. Complete histological occlusion was found in at least 1 level of the lumen in 9 pigs: 1 (17%) in the BMS group at 4 weeks, 5 (83%) in the BMS group at 6 weeks, and 3 (50%) in the DES group at 6 weeks. In vitro studies demonstrated 50%-lower proliferation rates in rapamycin-treated cultures of duct-derived smooth muscle cell cultures (P<0.001).


CONCLUSIONS
Rapamycin has antiproliferative actions on the arterial duct. Drug-eluting stents may be a more efficient tool than current palliative options for maintaining patency in critically duct-dependent states, but there may be a finite time-related benefit.
Labatt Family Heart Centre, The Hospital for Sick Children, University of Toronto School of Medicine, Toronto, Ontario, Canada. kyong-jin.lee@sickkids.ca
Kyong-Jin
KJ
Lee
Aleksander
A
Hinek
Rajiv R
RR
Chaturvedi
Claudia L
CL
Almeida
Osami
O
Honjo
Gideon
G
Koren
Leland N
LN
Benson
D000818:Animals; D000831:Animals, Newborn; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D054855:Drug-Eluting Stents; D004373:Ductus Arteriosus / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000601:surgery / Q000648:ultrastructure; D004549:Elastin / Q000096:biosynthesis; D006330:Heart Defects, Congenital / Q000601:surgery; D006965:Hyperplasia; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D034421:Sus scrofa; D017539:Tunica Intima / Q000648:ultrastructure; D014463:Ultrasonography
D004549:Elastin; D020123:Sirolimus