sirolimus and Pulmonary-Veno-Occlusive-Disease

Pulmonary vein obstruction (PVO) frequently occurs after repair of total anomalous pulmonary vein connection with progression of intimal hyperplasia from the anastomotic site toward upstream pulmonary veins (PVs). However, the understanding of mechanism in PVO progression is constrained by lack of data derived from a physiological model of the disease, and no prophylaxis has been established. We developed a new PVO animal model, investigated the mechanisms of PVO progression, and examined a new prophylactic strategy.. We developed a chronic PVO model using infant domestic pigs by cutting and resuturing the left lower PV followed by weekly hemodynamic parameter measurement and angiographic assessment of the anastomosed PV. Subsequently, we tested a novel therapeutic strategy with external application of rapamycin-eluting film to the anastomotic site.. We found the pig PVO model mimicked human PVO hemodynamically and histopathologically. This model exhibited increased expression levels of Ki-67 and phospho-mammalian target of rapamycin in smooth muscle-like cells at the anastomotic neointima. In addition, contractile to synthetic phenotypic transition; that is, dedifferentiation of smooth muscle cells and mammalian target of rapamycin pathway activation in the neointima of upstream PVs were observed. Rapamycin-eluting films externally applied around the anastomotic site inhibited the activation of mammalian target of rapamycin in the smooth muscle-like cells of neointima, and delayed PV anastomotic stenosis.. We demonstrate the evidence on dedifferentiation of smooth muscle-like cells and mammalian target of rapamycin pathway activation in the pathogenesis of PVO progression. Delivery of rapamycin to the anastomotic site from the external side delayed PV anastomotic stenosis, implicating a new therapeutic strategy to prevent PVO progression.

Topics: Angiography; Animals; Biomarkers; Disease Models, Animal; Disease Progression; Muscle, Smooth; Neointima; Pulmonary Veins; Pulmonary Veno-Occlusive Disease; Sirolimus; Swine; TOR Serine-Threonine Kinases; Vascular Remodeling

Everolimus-eluting stents and paclitaxel-coated balloons are used in the interventional treatment of coronary artery disease in adults to reduce the restenosis rate and in small-vessel disease. Both substances are released into the circulation. We report systemic drug exposure after implantation of one everolimus-eluting stent and dilation with one paclitaxel-coated balloon in an 8-month-old infant, which was used as an innovative therapy for recurrent pulmonary vein stenosis.

Topics: Angiography; Angioplasty, Balloon, Coronary; Drug-Eluting Stents; Everolimus; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant, Newborn; Male; Paclitaxel; Pulmonary Veins; Pulmonary Veno-Occlusive Disease; Recurrence; Sirolimus

The outcome of stent implantation for pulmonary vein stenosis (PVS) in children remains poor. Several reports describe placing drug-eluting stents to treat PVS, but their effectiveness remains unknown. In this study, three bare-metal stents (BMSs) and three sirolimus-eluting stents (SESs) were implanted in 1-month-old pigs. The pigs were killed 8 weeks later to compare in-stent stenosis rates. The extent of neointimal thickness, as measured by injury score, was significantly less in the SES group than in the BMS group (injury score 1: BMS 0.351 + or - 0.033 vs SES 0.226 + or - 0.031 mm; P < 0.01; injury score 2: BMS 1.232 + or - 0.244 vs SES 0.609 + or - 0.208 mm; P < 0.01). The pathologic findings showed confluence of inflammatory cells around the stent wires in BMS-treated areas and granuloma formation. Granuloma formation was not seen with SES. The degree of in-stent stenosis was significantly reduced in the SES group, suggesting that the use of drug-eluting stents is an effective treatment for PVS. Because of the small sample size and the considerable variation in injury scores and balloon-to-vein ratios, future studies with larger samples are necessary.

Topics: Animals; Disease Models, Animal; Drug-Eluting Stents; Female; Immunosuppressive Agents; Pulmonary Veno-Occlusive Disease; Secondary Prevention; Sirolimus; Treatment Outcome; Tunica Intima

The increasing use of radiofrequency catheter ablation for the cure of atrial fibrillation has led to iatrogenic pulmonary vein stenosis as a new clinical entity. The optimal diagnostic modality and treatment for pulmonary vein stenosis and restenosis remain unclear. We report the successful treatment of pulmonary vein restenosis following percutaneous balloon angioplasty, and for the first time, following surgical bovine pericardial patch angioplasty, with endovascular stenting and adjuvant oral sirolimus. Both patients remain asymptomatic at 1 year follow-up without evidence of restenosis.

Topics: Administration, Oral; Angioplasty, Balloon; Atrial Fibrillation; Blood Vessel Prosthesis Implantation; Catheter Ablation; Echocardiography, Transesophageal; Humans; Immunosuppressive Agents; Male; Middle Aged; Pulmonary Veno-Occlusive Disease; Recurrence; Sirolimus; Stents; Ultrasonography, Doppler, Color