Ann Thorac Surg 2005;80:1903-1904
© 2005 The Society of Thoracic Surgeons
Case report
Inflammatory Reaction After Sirolimus-Eluting Stent Implant
Walter J. Gomes, MD, PhD
**
,
Oswaldo Giannotti-Filho, MD, PhD
*
,
Nelson A. Hossne, Jr, MD,
Roberto Catani, MD,
Enio Buffolo, MD, PhD
Cardiovascular Surgery Discipline, Escola Paulista de Medicina and São Paulo Hospital, Federal University of São Paulo, São Paulo, Brazil
Accepted for publication May 20, 2004.
** Address correspondence to Dr Gomes, Cardiovascular Surgery Discipline, Escola Paulista de Medicina and São Paulo Hospital, Federal University of São Paulo, Rua Botucatu 740, São Paulo, SP 04023–900, Brazil (Email: wjgomes.dcir{at}epm.br).
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Abstract
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Sirolimus-eluting stents (SES) are supposed to attenuate cell proliferation and reduce restenosis rate. Histologic finding from coronary artery after SES implant showed fibrosis and inflammatory infiltrate, revealing a chronic inflammatory reaction. Extension of coronary inflammatory reaction after stenting needs clarification. The long-term consequences are unknown.
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Introduction
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Conventional stents have been demonstrated to induce an ongoing coronary artery inflammatory reaction whose most apparent consequence is restenosis [1]. The new generation of coronary stents, the drug-eluting stents (DES), are supposed to attenuate the in-stent cell proliferation and therefore prevent the restenosis. The sirolimus (Rapamycin)-eluting stent (SES [Cypher; Cordis, J&J, New Brunswick, NJ]) has been the first of such device to receive Food and Drug Administration approval for routine implant.
We report herein the histologic finding of coronary artery and vein graft samples retrieved from 2 patients who previously underwent SES implant and who subsequently needed coronary artery bypass graft surgery (CABG). These 2 patients were studied, and informed consent for this study was signed by both patients.
The first patient, aged 51 years, had a SES implanted in the left anterior descending coronary artery (LAD) and 12 months later, with return of ischemic symptoms, had an angiogram that disclosed a severe in-segment restenosis. He was referred for CABG, and at the time of operation, a biopsy was taken from the LAD downstream of the stented site, following the protocol previously described [1].
The second patient, also aged 51 years, had a left ventricular aneurysmectomy plus saphenous vein graft to the LAD in 1997. In March 2002, she underwent vein graft stenting with a SES. Sixteen months later, with recurrence of angina, a coronary angiogram disclosed a severe vein graft stenosis along with disease progression in other coronary arteries. The patient was referred for CABG and at the time of operation, the stented vein graft was removed en bloc.
Both patients had been on aspirin antiplatelet therapy. The specimens were fixed in 10% buffered formalin, embedded in paraffin, and 5µ sections were cut. These sections were stained with hematoxylin-eosin, alcian-blue, and Masson's trichrome. The coronary artery histologic study revealed an intense fibrosis and inflammatory infiltrate involving the full-thickness wall, along with collagen and cellular degeneration. At the endothelial layer, leukocyte proliferation can be seen, revealing a chronic inflammatory reaction (Figs 1 and 2).
The vein graft mesoscopic examination showed an unhealed intimal layer, with incomplete endothelialization, leaving exposed part of the stent metal struts (Fig 3). The histologic study displayed fibrotic proliferation replacing the wall structure.
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Fig 1. (A) Photomicrograph of the coronary artery wall. Moderate-to-intense inflammatory reaction with leukocyte infiltration in the endothelial layer (arrows). Also arterial wall thickening and edema of the tunica media. (Hematoxylin & eosin stain; magnification, x40.) (B) The same specimen magnified x400, detailing the leukocyte infiltration in the endothelium.
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Fig 2. Photomicrograph of the coronary artery wall showing intense collagen proliferation in the tunica media. (Masson's trichrome stain; magnification, x100.)
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Fig 3. View of the longitudinally opened vein graft, showing the incomplete endothelialization and exposure of the stent metal frame.
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Comment
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Stent restenosis is largely caused by vascular smooth muscle cell (VSMC) proliferation with neointima formation and is regarded as a vascular reaction of the organic response to injury. Sirolimus, the generic name of Rapamycin, is a macrocyclic lactone immunosuppressive drug, which is highly effective in inhibiting VSMC migration in vitro and in vivo by blocking the cell cycle at the G1/S transition. Restenosis after SES implant remains, however, and the mechanisms implicated are still a matter of controversy. One of these mechanisms, the edge effect, is an induction of lumen narrowing beyond the stent margins (restenosis at the stent ends). It is thought to be caused by declining local drug availability at the stent extremities and vascular barotrauma outside the stent.
Our finding of an intense inflammatory reaction seen at the coronary artery sample, nearly entirely replacing the coronary wall normal structure, seems to confirm that an edge effect is present associated with SES. Also early and late thromboses have been associated with SES implants. Thrombosis has been related to a delayed endothelialization or to a late stent malapposition, but other factors may be involved. Likely related to the drug action, delayed endothelialization allows exposure of the stent metal frame to the blood contact, acting as a matrix for platelet aggregation.
Sirolimus has been implicated in acting as a platelet agonist promoting thrombus formation [2]. A previous study demonstrated that sirolimus significantly potentiates agonist-induced platelet aggregation. Concentrations of rapamycin in the nanogram range, as well as short preincubation times, were sufficient to cause significant enhancement of agonist-induced platelet aggregation [3]. Sirolimus has also been demonstrated to decrease nitric oxide production [4]. Nitric oxide plays a significant role in preventing platelet aggregation and clot formation, promoting vasodilation and inhibiting SMC proliferation.
Recent report showed aneurysmal dilation of coronary artery treated with a Cypher stent and a severe localized hypersensitivity reaction consisting predominantly of T lymphocytes and eosinophils. The stent was surrounded by giant cells and eosinophils, suggesting that a reaction to the polymer may have caused late stent thrombosis [5].
Several implications may emerge from these findings, as well as from our earlier work [1], once the patient needs further CABG surgery: (1) extension of coronary inflammatory reaction (an arteritis) and consequent endothelial dysfunction caused by the stent and its coating needs clarification; the long-term consequences are unknown; (2) as many different types of DES are expected to reach the market in the near future, cardiologists and cardiac surgeons must be aware of side effects of every drug used as a stent coating and carry out specific interventions for such drug; and (3) surgical coronary revascularization may not achieve the same results, as thoroughly demonstrated in medical literature, in patients with previous stenting.
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Footnotes
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* Dr Giannotti-Filho died on April 20, 2004. 
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References
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- Gomes WJ, Giannotti-Filho O, Paez RP, Hossne Jr NA, Catani R, Buffolo E. Coronary artery and myocardial inflammatory reaction induced by intracoronary stent Ann Thorac Surg 2003;76:1528-1532.[Abstract/Free Full Text]
- Choi SB. Cypher coronary stents and risk of thrombosis Can Med Assoc J 2003;169:218.[Free Full Text]
- Babinska A, Markell MS, Salifu MO, Akoad M, Ehrlich YH, Kornecki E. Enhancement of human platelet aggregation and secretion induced by rapamycin Nephrol Dial Transplant 1998;13:3153-3159.[Abstract/Free Full Text]
- Tunon MJ, Sanchez-Campos S, Gutierrez B, Culebras JM, Gonzalez-Gallego J. Effects of FK506 and rapamycin on generation of reactive oxygen species, nitric oxide production and nuclear factor kappa B activation in rat hepatocytes Biochem Pharmacol 2003;66:439-445.[Medline]
- Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent. Should we be cautious? Circulation 2004;109:701-705.[Abstract/Free Full Text]
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Abstract
Introduction
