CORRESPONDENCE: LETTER TO THE EDITOR
Endothelial Dysfunction After Drug-Eluting Stent Was Never Predicted in Preclinical Studies
Nicholas Kipshidze, MD, PhD* and
Martin B. Leon, MD
* Lenox Hill Heart and Vascular Institute and Cardiovascular Research Foundation, 130 East 77th Street, 9th Floor, New York, New York 10021 (Email: NKipshidze{at}lenoxhill.net).
The recent report by Togni et al. (1) presents the results of a study that evaluated the coronary vasomotor response after sirolimus-eluting stent (SES) implantation. The investigators concluded that implantation of SES is associated with endothelial dysfunction in proximal and distal regions of treated coronary segment, whereas in the control group, bare-metal stents did not affect physiologic response to exercise.
Although clinical relevance of this finding is unknown, the underlying mechanism may be delayed vascular healing due to toxic effects of the sirolimus and paclitaxel to endothelial cells (EC). Indeed, studies in our laboratory (2) demonstrated that both drugs are toxic for EC in vitro and slowed their growth kinetics. Moreover, these drugs also negatively affected attachment characteristics of EC; because EC are anchored-dependent cell types without proper attachment, they regenerate very slowly (3).
However, preclinical studies with SES, poclitaxel-eluting stent (PES), and other drug-eluting stent (DES) demonstrated normal vascular healing at 1 month, and endothelial dysfunction was completely missed. This is mostly due to 1) difference in growth characteristics of human and animal EC, and 2) lack of study of endothelial dysfunction in animal models.
We agree with the researchers that endothelial dysfunction and incomplete vascular healing may influence persistent restenosis and late thrombosis and contribute to overall results of DES implantation.
Therefore, we suggest functional studies should be mandatory for contemporary DES preclinical programs.
We also completely agree with the editorial comments of Serry and Penny (4), who postulated that future studies needed to clarify the clinical relevance of these observations.
In conclusion, we want to congratulate Togni et al. (1) on a very interesting study, and we believe that further preclinical and clinical data will finally shed light on the role of endothelium after percutaneous coronary intervention.
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References
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1. Togni M, Windecker S, Cocchia R, et al. Sirolimus-eluting stents associated with paradoxic coronary vasoconstriction J Am Coll Cardiol 2005;46:231-236.[Abstract/Free Full Text]2. Kipshidze N, Moses J, Iversen P, Leon MB. An advanced antisense (AVI-4126) for local and stent-based delivery for prevention of restenosis after PCI (current status and future developments)In: Serruys PW, Gershlick AH, editors. Handbook of Drug-Eluting Stents. London: Taylor & Francis; 2005.[Free Full Text] 3. Kipshidze N, Dangas G, Tsapenko M, et al. Role of the endothelium in modulating neointimal formationvasculoprotective approaches to attenuate restenosis after percutaneous coronary interventions. J Am Coll Cardiol 2004;44:733-739.[Abstract/Free Full Text] 4. Serry R, Penny WF. Endothelial dysfunction after sirolimus-eluting stent placement J Am Coll Cardiol 2005;46:237-238.[Free Full Text]
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