Ann Thorac Surg 2005;79:2201-2202
© 2005 The Society of Thoracic Surgeons
Correspondence
Adverse Effects of Local or Systemic Application of Rapamycin for the Prevention of Neointimal Hyperplasia
Beat H. Walpoth, MD, FAHA
Department of Surgery, University Hospital of Geneva, Geneva, CH 1211 Switzerland
(E-mail: beat.walpoth{at}hcuge.ch).
To the Editor:
Schachner and colleagues [1] have shown in an elegant experimental study that rapamycin could inhibit the development of neointimal hyperplasia in vein grafts. This was done in a mouse autologous graft transplantation model (vein to artery), with and without a peri-paravascular application of rapamycin. Significant reduction of neointimal hyperplasia was observed in the rapamycin-treated groups. Furthermore, immunohistochemical staining demonstrated a reduced proliferative activity on a cellular level in the rapamycin-treated vein graft segments.
In a recently published study we were able to show a reduction of neointimal hyperplasia with a high dose of systemic rapamycin treatment (3 mg/Kg BW) either after 30 or 60 days in a rat infrarenal graft model. This dosage is similar to the one used in the transplantation model. However, we observed drug-related side effects as well as a catabolic metabolism with lack of weight increase [2].
Furthermore, animals treated with the high dose rapamycin (topical or systemic) showed a significant increase in vascular thrombosis (Fig 1). Thus, we concluded that high dose rapamycin required to induce a reduction of intimal proliferation has several side effects that may limit its clinical application.
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Fig 1. Thrombus formation shows scores of 0 to 3, with 0 = none and 3 = severe. Animals of group 2 show a markedly higher thrombus formation score than the control and mycophenolate mofetil (MMF) treated animals.
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Several recent studies including a notification to physicians from the United States Food and Drug Administration relating to the sirolimus-eluting stents have reported an increasing number of subacute stent thrombosis, despite the dramatic reduction of stent re-stenosis [3, 4]. Thus, a word of caution should be used when sirolimus- coated stents are used in conjunction with vascular applications.
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References
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- Schachner T, Zou Y, Oberhuber Y, et al. Local application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts Ann Thorac Surg 2004;77:1580-1585.[Abstract/Free Full Text]
- Walpoth BH, Pavlicek M, Celik B, et al. Prevention of neointimal proliferation by immunosuppression in synthetic vascular grafts Eur J Cardiothorac Surg 2001;19(4):487-492.[Abstract/Free Full Text]
- Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent Circulation 2004;109:38-42.
- FDA advises physicians of adverse events associated with Cordis Cypher coronary stents. US Food and Drug Administration Public Health Web Notification, October 29, 2003:T03-T71 (http://www.fda.gov/cdrh/safety/cypher3.html)..
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