Rapamycin-Eluting Stents in the Arterial Duct

Abstract

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. Methods and 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 (nϭ14) or bare metal (nϭ14) 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% (Pϭ0.009), 54% (Pϭ0.004), and 77% (Pϭ0.004) 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% (Pϭ0.18), 5% (Pϭ0.25), and 61% (Pϭ0.13) 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 (PϽ0.001). 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.

Fracture of Cardiovascular Stents in Patients With Congenital Heart Disease

“…As stent technology evolves and with increasing interest in bioabsorbable stents and stents as drug delivery mechanisms even in CHD, 98,99 there will be changes inevitably in the frequency, patterns, and even implications of stent fracture in congenital applications. Although stents are well established in the armamentarium of pediatric and congenital interventional cardiologists, their history in this field is still young relative to the life expectancy of most of these patients.…”

Pharmacokinetics of Sirolimus-Eluting Stents Implanted in the Neonatal Arterial Duct

“…Pediatric systemic sirolimus levels after SES had not been reported at the start of this clinical series and were expected to be low based on the adult literature and estimates by a Pediatric Clinical Pharmacologist (12). We thought it prudent to measure sirolimus levels prospectively for the purposes of clinical monitoring/quality assurance because symptoms consistent with infection or necrotizing enterocolitis occur frequently in these neonates.…”

“…12 Our objective was to establish the pharmacokinetics of SES in human neonates because sirolimus is also an immunosuppressive agent, before more extensive neonatal use. In this pilot study, we only used a single SES even if multiple stents were required to cover the whole arterial duct.…”

“…12 Pharmacokinetic studies of SES in adult pigs 10 and humans 13 have shown low peak serum drug levels occurring at 1 and between 3 and 4 hours, respectively, with minimal detectable levels by 3 and 7 days, respectively. SES implantation has been reported in children, but little is known regarding subsequent pharmacokinetics in the pediatric population.…”

“…11 SES implanted in the porcine neonatal arterial duct have higher patency rates compared with bare-metal stents and also exhibit an antiproliferative action on arterial duct smooth muscle. 12 Pharmacokinetic studies of SES in adult pigs 10 and humans 13 have shown low peak serum drug levels occurring at 1 and between 3 and 4 hours, respectively, with minimal detectable levels by 3 and 7 days, respectively. SES implantation has been reported in children, but little is known regarding subsequent pharmacokinetics in the pediatric population.…”