European Heart Journal Advance Access published online on June 17, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn258
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Vascular endothelial growth factor protein levels and gene expression in peripheral monocytes after stenting: a randomized comparative study of sirolimus-eluting and bare-metal stents
Department of Cardiology
Cardiovascular Research Institute Maastricht (CARIM)
University of Maastricht
P. Debyelaan 25, PO Box 5800
6202 AZ Maastricht
The Netherlands
Department of Cardiology
Cardiovascular Research Institute Maastricht (CARIM)
University of Maastricht
P. Debyelaan 25, PO Box 5800
6202 AZ Maastricht
The Netherlands
Tel.: +31 43 387 5106
Fax: +31 43 387 5104
Email: j.waltenberger{at}cardio.azm.nl
With great interest, we read the article by Kochiadakis et al.1 dealing with the relationship between monocyte vascular endothelial growth factor (VEGF) gene expression, VEGF serum level, and in-stent late luminal loss following stenting in stable coronary artery disease (CAD) patients. The authors demonstrate that the VEGF serum level 1 month after stenting was significantly lower in patients who received a sirolimus-eluting stent (SES) compared with those who received a bare-metal stent (BMS). Furthermore, monocyte VEGF gene expression 1 month after stenting positively correlated with in-stent late luminal loss after 6 months. This is an important study as it (i) highlights clearly detectable systemic effects of SES and (ii) underscores the usefulness of circulating monocytes as diagnostic tools.2
Kochiadakis et al. suggest that the lower VEGF level in the SES group can be attributed to the decreased VEGF gene expression of their circulating monocytes probably resulting in reduced VEGF protein production. Monocytes are certainly attractive indicators for drug-influenced gene regulation because of their easy accessibility. However, although serving as bioreactors and reservoirs for (paracrine) cytokines and chemokines during tissue repair and remodelling, monocytes/macrophages may not be regarded as important contributors to the VEGF concentration in human blood. Indeed, thrombocytes were shown to be the major source of VEGF in serum samples following its release during the in vitro clotting process.3 Elevated VEGF levels indicate local inflammation and are closely related to the presence of atherosclerotic risk factors.3 In contrast, the reduced VEGF serum level as well as the reduced VEGF monocyte level following SES implantation may rather reflect a systemic effect of rapamycin on cellular VEGF production.
Sirolimus-eluting stent-related reduction in VEGF serum levels may not only be beneficial, as proposed by Kochiadakis et al.1 Previously, it was shown that VEGF inhibition is associated with enhanced endothelial dysfunction and apoptosis.4 Likewise, the use of the VEGF inhibitor bevacizumab (Avastin®) is potentially associated with increased cardiovascular complications.5 Therefore, decreased VEGF levels following SES implantation may reflect a reduced stimulus for endothelial regeneration and may therefore be causally linked with the elevated risk for SES-related late stent thrombosis.6
A recent study highlighted the positive correlation between maximal circulating monocyte count after coronary stenting with in-stent neointimal volume after 6 month follow-up.7 Although this publication is cited by Kochiadakis et al. as an argument that monocytes contribute to neointima formation, the authors did not provide monocyte count data themselves. It would be interesting to see whether the absolute monocyte count did differ in the two study groups following stent implantation. Instead, the authors suggest that the higher monocyte VEGF gene expression in the BMS group reflects monocyte activation after stent implantation, leading to inflammatory reactions which trigger pathophysiological mechanisms and ultimately restenosis. Further investigation of functional aspects of monocytes such as adhesion or chemotaxis may be a clue to get a clearer picture of the link between monocyte activation and potential consequences for neointima formation following coronary stenting.
References
- Kochiadakis GE, Marketou ME, Panutsopulos D, Arfanakis DA, Skalidis EI, Igoumenidis NE, Hamilos MI, Sourvinos G, Chlouverakis G, Spandidos D, Vardas PE. Vascular endothelial growth factor protein levels and gene expression in peripheral monocytes after stenting: a randomized comparative study of sirolimus: eluting and bare metal stents. Eur Heart J (2008) 29:733–740.
[Abstract/Free Full Text] - Waltenberger J, Lange J, Kranz A. Vascular endothelial growth factor-A-induced chemotaxis of monocytes is attenuated in patients with diabetes mellitus: a potential predictor for the individual capacity to develop collaterals. Circulation (2000) 102:185–190.
[Abstract/Free Full Text] - Kimura K, Hashiguchi T, Deguchi T, Horinouchi S, Uto T, Oku H, Setoyama S, Maruyama I, Osame M, Arimura K. Serum VEGF—as a prognostic factor of atherosclerosis. Atherosclerosis (2007) 194:182–188.[CrossRef][Web of Science][Medline]
- Waltenberger J. Growth factor signal transduction defects in the cardiovascular system. Cardiovasc Res (2005) 65:574–580.
[Abstract/Free Full Text] - Ratner M. Genentech discloses safety concerns over Avastin. Nat Biotechnol (2004) 22:1198.[CrossRef][Web of Science][Medline]
- Kastrati A, Dibra A, Eberle S, Mehilli J, Suarez de Lezo J, Goy JJ, Ulm K, Schomig A. Sirolimus-eluting stents vs paclitaxel-eluting stents in patients with coronary artery disease: meta-analysis of randomized trials. J Am Med Assoc (2005) 294:819–825.
[Abstract/Free Full Text] - Fukuda D, Shimada K, Tanaka A, Kawarabayashi T, Yoshiyama M, Yoshikawa J. Circulating monocytes and in-stent neointima after coronary stent implantation. J Am Coll Cardiol (2004) 43:18–23.
[Abstract/Free Full Text]
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