Oral everolimus inhibits neointimal proliferation in prosthetic pulmonary valved stents in pigs

J Heart Valve Dis. 2008 Jul;17(4):465-72.


Background and aim of the study: Growth factor-dependent cell proliferation can cause in-stent neointimal hyperplasia. The study aim was to evaluate whether oral everolimus inhibits the intimal proliferation associated with the implantation of prosthetic pulmonary valved stents.

Methods: Prosthetic pulmonary valves were implanted in 12 pigs (mean bodyweight 25 kg) using a transcatheter technique. Tricuspid valves were prepared from a titanium-coated polymer and sewn into a self-expanding nitinol stent (diameter 20 mm). Valved stents were implanted in the pulmonary position, where they remained for three months. In six animals, treatment with 2 mg/kg everolimus (Certican; Novartis) per day was started three days before implantation and continued throughout the course of the experiment. The other six pigs acted as controls. Adjuvant anticoagulation treatment consisted of acetylsalicylic acid and oral clopidogrel. After three months, hemodynamic valve function was investigated at catheterization and with MRI. At postmortem investigation the valved stents were explanted and subjected to macroscopic, histological and electron microscopic examination.

Results: There were no adverse side effects due to everolimus treatment. The overall mean everolimus plasma level during the study was 4.2 +/- 2.4 ng/ml. MRI revealed intact valve function with a regurgitation fraction of 7.3 +/- 4.2% in controls and 4.3 +/- 3.1% in the everolimus group (p <0.01). On macroscopic inspection and histological examination, the everolimus group showed only a thin tissue coverage of the stent struts. The valve cusps were free from intimal thickening, and electron microscopy showed a thin continuous cellular coating. In contrast, substantial neointimal formation was noted in controls. Tissue neogenesis was pronounced at the base of the valve, extended to the valve cusps, and caused valve thickening and foreshortening.

Conclusion: The oral administration of everolimus effectively inhibits tissue neogenesis in pulmonary valved stents in pigs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects*
  • Everolimus
  • Heart Valve Prosthesis
  • Heart Valve Prosthesis Implantation
  • Hemodynamics
  • Hyperplasia / etiology
  • Hyperplasia / pathology
  • Hyperplasia / prevention & control*
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use*
  • Microscopy, Electron, Scanning
  • Pulmonary Valve
  • Sirolimus / analogs & derivatives*
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use
  • Stents / adverse effects*
  • Swine
  • Tunica Intima / cytology
  • Tunica Intima / drug effects


  • Immunosuppressive Agents
  • Everolimus
  • Sirolimus