CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Jyun-ei Obata, MD, PhD and
Kiyotaka Kugiyama, MD, PhD*
* Department of Internal Medicine II, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo City, Yamanashi Prefecture, 409-3898, Japan (Email: kugiyama{at}yamanashi.ac.jp).
We appreciate the opportunity to reply to questions raised by Dr. Nakazawa and colleagues. Please note that the coronary arteries distal to the stented segment but not the stented lesion were examined for the endothelial vasomotor function in our study (1). As described in our study (1), myocardial ischemia-reperfusion induces endothelial injury in the coronary trees for their entirety distal to the occluded segment in the infarct-related coronary artery. Thus, the healing process of the coronary arteries distal to the stented segment but not the stented lesion affected our data. Our previous reports (2–5) agreed that the atherosclerotic burden strongly affects coronary endothelial vasomotor functions. However, our study (1) showed that the frequencies of the atherosclerotic risk factors were comparable between the drug-eluting stent (DES) and bare-metal stent (BMS) groups. In addition, the 2 groups had no difference in cardiac medications, lesion, and procedural variables of percutaneous coronary intervention except for stent selection, and acute myocardial infarction (AMI)–related variables that potentially influence the coronary endothelial vasomotor function, as described in our study (1). Thus, the implanted stents were only the discriminate factor for the difference in the coronary endothelial vasomotor responses to acetylcholine between the patients treated with BMS and DES.
A number of previous reports (6,7) demonstrated that the vascular endothelial growth factor (VEGF) expression is increased in cardiomyocytes as well as vascular endothelial cells in ischemic or injured hearts and that sirolimus is capable of inhibiting VEGF production and the VEGF-mediated cellular signaling pathway in various types of cells. Our study (1) also showed that VEGF levels in the anterior interventricular vein (AIV), reflecting VEGF levels released from the ischemic myocardium, were increased in AMI patients treated with BMS compared with control subjects. As we described in our study (1), sirolimus levels in AIV in our study were 10- to 500-fold lower than the levels to exert its biological effects in vitro experiments (8,9). Considering the fact that sirolimus is eluted into coronary circulation over a period of 4 weeks, these exposure times were much longer as compared with the in vitro experiments. Moreover, the chronic exposure to the circulating sirolimus might cause a local accumulation of considerable amounts of this drug in the myocardium and the entire vascular bed distal to sirolimus-eluting stent (SES) in the infarct-related coronary artery. Thus, there is a possibility that SES could induce a decrease in VEGF release from myocardium and endothelium of large and resistance vessels, which may play a possible role in the mechanisms for endothelial vasomotor dysfunction in the infarct-related coronary arteries treated with SES.
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1. Obata JE, Kitta Y, Takano H, et al. Sirolimus-eluting stent implantation aggravates endothelial vasomotor dysfunction in the infarct-related coronary artery in patients with acute anterior myocardial infarction J Am Coll Cardiol 2007;50:1305-1309.[Abstract/Free Full Text]2. Kugiyama K, Kerns SA, Morrisett JD, Roberts R, Henry PD. Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins Nature 1990;344:160-162.[CrossRef][Medline] 3. Kugiyama K, Yasue H, Ohgushi M, et al. Deficiency in nitric oxide bioactivity in epicardial coronary arteries of cigarette smokers J Am Coll Cardiol 1996;28:1161-1167.[Abstract] 4. Kugiyama K, Doi H, Motoyama T, Soejima H, et al. Association of remnant lipoprotein levels with impairment of endothelium-dependent vasomotor function in human coronary arteries Circulation 1998;97:2519-2526.[Abstract/Free Full Text] 5. Kawano H, Motoyama T, Kugiyama K, et al. Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery J Am Coll Cardiol 1999;34:146-154.[Abstract/Free Full Text] 6. Hojo Y, Ikeda U, Zhu Y, et al. Expression of vascular endothelial growth factor in patients with acute myocardial infarction J Am Coll Cardiol 2000;35:968-973.[Abstract/Free Full Text] 7. Lee SH, Wolf PL, Escudero R, Deutsch R, Jamieson SW, Thistlethwaite PA. Early expression of angiogenesis factors in acute myocardial ischemia and infarction N Engl J Med 2000;342:626-633.[CrossRef][Web of Science][Medline] 8. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor Nat Med 2002;8:128-135.[CrossRef][Web of Science][Medline] 9. Dichtl W, Stocker EM, Mistlberger K, et al. Countervailing effects of rapamycin (sirolimus) on nuclear factor- B activities in neointimal and medial smooth muscle cells Atherosclerosis 2006;186:321-330.[Medline]
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