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J Am Coll Cardiol, 2007; 50:1305-1309, doi:10.1016/j.jacc.2007.06.031 (Published online 14 September 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY

Sirolimus-Eluting Stent Implantation Aggravates Endothelial Vasomotor Dysfunction in the Infarct-Related Coronary Artery in Patients With Acute Myocardial Infarction

Jyun-ei Obata, MD, PhD, Yoshinobu Kitta, MD, Hajime Takano, MD, PhD, Yasushi Kodama, MD, Takamitsu Nakamura, MD, Akira Mende, MD, Ken-ichi Kawabata, MD, PhD, Yukio Saitoh, MD, Daisuke Fujioka, MD, Tsuyoshi Kobayashi, MD, Toshiaki Yano, MD and Kiyotaka Kugiyama, MD, PhD*

Department of Internal Medicine II, University of Yamanashi, Yamanashi Prefecture, Japan.

Manuscript received April 9, 2007; revised manuscript received June 7, 2007, accepted June 19, 2007.

* Reprint requests and correspondence: Dr. Kiyotaka Kugiyama, Department of Internal Medicine II, University of Yamanashi, Faculty of Medicine, 1110 Shimokato, Chuo City, Yamanashi Prefecture, 409-3898 Japan. (Email: kugiyama{at}yamanashi.ac.jp).


   Abstract
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 Abstract
Methods
 Results
 Discussion
 Conclusions
 References
 
Objectives: This study examined whether sirolimus-eluting stent (SES) implantation may affect endothelial vasomotor dysfunction in resistance and epicardial infarct-related coronary arteries in acute myocardial infarction (AMI).

Background: Myocardial ischemia-reperfusion causes endothelial injury entirely in the vasculature of the infarct-related coronary artery. Sirolimus-eluting stent implantation inhibits re-endothelialization at the site of stenting.

Methods: This study included 29 patients with a first AMI due to occlusion of the left anterior descending coronary artery (LAD) and successful reperfusion therapy using a SES (n = 13) or bare-metal stent (BMS) (n = 16). The diameter of the epicardial segment distal to the site of SES deployment and coronary blood flow in the LAD in response to an intracoronary infusion of acetylcholine were measured at 2 weeks after AMI. Levels of vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunoadsorbent assay in plasma obtained from the aortic root (AO) and the anterior interventricular vein (AIV) in all patients.

Results: The epicardial coronary artery was more severely constricted in response to acetylcholine in the SES than in the BMS group. The increase in coronary blood flow in response to acetylcholine was lower in the SES than in the BMS group. Vascular endothelial growth factor levels in the AIV were significantly lower than in the AO in the SES group but not in the BMS group.

Conclusions: During the course of AMI, SES implantation adversely affects endothelium-dependent vasomotor function in resistance and epicardial coronary arteries after the ischemia-reperfusion in association with a reduction in myocardial VEGF secretion.

Abbreviations and Acronyms
  ACh = acetylcholine
  AIV = anterior interventricular vein
  AMI = acute myocardial infarction
  AO = aortic root
  BMS = bare-metal stent(s)
  DES = drug-eluting stent(s)
  LAD = left anterior descending coronary artery
  LCx = left circumflex artery
  SES = sirolimus-eluting stent(s)
  VEGF = vascular endothelial growth factor

Myocardial ischemia-reperfusion induces endothelial injury in the entire vascular trees of the infarct-related coronary artery (1). Endothelial damage that occurrs during reperfusion injury may limit the restoration of blood flow to potentially viable ischemic myocardium, which importantly contributes to infarct extension and poor prognosis after acute myocardial infarction (AMI) (2). Vascular endothelial growth factor (VEGF) is produced and expressed in the myocardium and the coronary vascular bed, and its expression is elevated in patients with AMI (3). The up-regulation of VEGF may be a compensatory mechanism for the reversal of reperfusion-induced coronary microvascular injury via endothelial repair and microvessel growth in the infarcted myocardium (3–5).

Drug-eluting stents (DES) in percutaneous coronary intervention remarkably reduce restenosis and revascularization rate in comparison with a bare-metal stent (BMS) (6). However, endothelial dysfunction at the peri-DES coronary segments can cause spasm in the stented coronary arteries after implantation of DES (7,8). It has been shown that sirolimus is capable of reducing expression of VEGF in vascular cells and VEGF-induced endothelial proliferation (9). Thus, we examined our hypothesis that diffusion of sirolimus into coronary blood flowing through a stent may directly or indirectly impair the recovery of reperfusion-induced endothelial injury entirely in the infarct-related coronary artery beyond the distal edge of the SES early after AMI.


   Methods
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 Abstract
 Methods
Results
 Discussion
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Study patients and control subjects.   This study included 29 consecutive patients with a first AMI due to occlusion of a proximal segment of the left anterior descending coronary artery (LAD), who were admitted within 12 h after symptom onset to Yamanashi University Hospital between January 2004 and July 2006. Diagnosis of AMI was based on the presence of all of the following criteria: typical chest pain persisting for ≥30 min, ST-segment elevation of >0.2 mV in ≥2 contiguous leads on the standard 12-lead electrocardiogram, and elevation of serum creatine kinase levels to more than twice the upper limit of normal. All of the study patients received emergent coronary angiography and successful reperfusion therapy by primary percutaneous coronary intervention using sirolimus-eluting stents (SES) (n = 13) or BMS (n = 16) after ballooning coronary angioplasty. Because SES did not become available in Japan until August 2004, all patients treated before this date received BMS. Because clopidogrel was not available until May 2006 in Japan, SES was used only in patients who were confirmed to have no side effects from the previous use of ticlopidine, and BMS was used in the remaining patients. The exclusion criteria were as follows: 1) residual organic stenosis ≥30% in the LAD; 2) previous percutaneous coronary intervention in the LAD; 3) percutaneous coronary intervention at multiple segments of the LAD; 4) previous coronary artery bypass surgery; 5) congestive heart failure at 1 week after AMI; 6) persistent atrial fibrillation or a paced rhythm; 7) presence of collaterals to the LAD with Rentrop grade ≥2 at the emergent coronary angiography; 8) coronary artery spasm in the LAD (≥40% decrease in coronary epicardial diameter from baseline) in response to the intracoronary infusion of acetylcholine (ACh) (10); and 9) valvular heart diseases, secondary hypertension, stroke, renal dysfunction (serum creatinine concentration >2.0 mg/dl), or other serious diseases. This study also included 12 control subjects who were selected from 57 consecutive subjects with normal coronary angiograms and left ventriculograms to match the age, gender, and other traditional risk factors of the AMI patients. These control subjects served as a reference group for the coronary vasomotor response and the plasma VEGF concentrations. The clinical characteristics of the patients with AMI and the control subjects are shown in Table 1. Written informed consent was obtained from all patients and control subjects before the study. The study was in agreement with the guidelines approved by the ethics committee at Yamanashi University Hospital.


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  		Table 1 Comparisons of Coronary Risk Factors, Cardiac Medications, Baseline Coronary Diameter, and Blood Flow Among AMI Patients Treated With BMS or SES and Control Subjects
 
Study protocol and assays.   Coronary angiography was performed twice in all AMI patients, immediately after admission during the acute phase of AMI and at 2 weeks after AMI. The measurements of coronary vasomotor response and left ventriculography were performed at the second coronary angiography after an overnight fast in all of the AMI patients. Blood sampling from the anterior interventricular vein (AIV) and the aortic root (AO) was performed before systemic heparinization on the third day after AMI in 8 patients with SES implantation and at the time of the second coronary angiography in all of the AMI patients, as described in our previous report (10). Also, the measurement of coronary vasomotor response and the blood sampling were performed only once in all of the control subjects. Plasma levels of free VEGF were measured by a sandwich enzyme-linked immunoadsorbent assay (R&D Systems, Minneapolis, Minnesota). Sirolimus levels in whole blood were determined by high-performance liquid chromatography/mass spectroscopy (11). The minimum detection limit for sirolimus was 0.1 ng/ml. All lipid-lowering drugs and vasodilators were withdrawn more than 3 days before the coronary angiographic study in patients with AMI and control subjects.

Protocol for measurements of coronary vasomotor responses.   After the blood sampling, a quantitative coronary angiographic study was performed in all of the AMI patients and the control subjects as in our previous report (10). After baseline angiography, incremental doses of ACh (5, 10, and 50 µg/min) were infused directly into the left coronary artery through the Judkins catheter. After an additional 15 min, intracoronary sodium nitroprusside (10 µg/min) was infused in the same manner as ACh. After another 15 min, intracoronary isosorbide dinitrate (1 mg) was administered. Coronary angiography was repeated before and during each infusion.

Quantitative coronary angiography and coronary blood flow measurement.   Luminal diameter at the segment between 15 and 25 mm distal to the stent edge in the LAD and at the proximal segment with no previous percutaneous coronary intervention in left circumflex artery (LCx) as a reference was measured quantitatively (Cardio 500, Kontron Instruments, Munich, Germany) (10). Luminal diameter at the midsegment of the LAD was measured in all of the control subjects in the same manner as in the AMI patients.

Blood flow velocity was measured using a 0.014-inch wire equipped with a Doppler crystal at its tip (FloWire, Cardiometrics, Mountain View, California). The wire was carefully positioned in a segment of the LAD 5 to 15 mm from distal edge of the stent (10). Coronary blood flow (ml/min) was estimated from coronary blood flow velocity (Flow Map, Cardiometrics), as described previously (10).

Responses of the coronary artery diameter and coronary blood flow to infusions of ACh, nitrates, and sodium nitroprusside were expressed as percent changes from baseline values taken just before each infusion.

Statistical analysis.   Data are expressed as the mean ± standard deviation or percentage. The frequencies between 2 groups of patients and the 2 mean values were compared using chi-square test and Student paired or unpaired t test, respectively. When more than 2 groups were compared, a 1-way analysis of variance was performed followed by a Sheffe test for post-hoc comparison of group means. The mean values of coronary vasomotor responses between the 2 patient groups were compared using 2-way analysis of variance for repeated measures followed by post-hoc testing with a Sheffe test. When frequencies among the patients with SES, those with BMS, and control subjects were compared, chi-square test using a 2 x 3 contingency table was initially examined for independence of frequencies among the 3 groups. When significant in independence by chi-square test, wholly significant difference was calculated (Tukey test) between the 2 groups. A confidence level of p < 0.05 was considered statistically significant. Analyses were performed in part with StatView 5.0 (SAS Institute, Cary, North Carolina).


   Results
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 Results
Discussion
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 References
 
Comparisons of coronary risk factors, cardiac medications, lesion and procedural variables of coronary intervention, and AMI-related variables among patients groups and control subjects.   There were no statistically significant differences in the coronary risk factors among the AMI patients treated with SES or BMS, and the control subjects, as shown in Table 1. There was no significant difference in cardiac medications and variables related to AMI and coronary intervention between the SES and the BMS groups (Tables 1 and 2).Go Intravascular ultrasound study at the end of the second coronary angiographic study showed no dissections on the LAD in both the SES and the BMS groups (data not shown).


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  		Table 2 Comparisons of AMI-Related Variables and Lesion and Procedural Variables During PCI
 
Response of epicardial coronary vasomotor and coronary blood flow.   At baseline, the epicardial diameters of the LAD and LCx and coronary blood flow of the LAD were similar among the AMI patients treated with SES, those with BMS, and the control subjects (Table 1). Infusion of ACh into the LAD, the infarct-related coronary artery, resulted in less epicardial dilation and increase in blood flow in patients treated with SES or BMS as compared with control subjects (Figs. 1A and 1C). Moreover, the LAD in patients treated with SES had a greater impairment of epicardial dilation and less of a blood flow increase in response to ACh as compared with that in patients treated with BMS (Figs. 1A and 1C). The epicardial dilation and the increase in blood flow of LAD in response to endothelium-independent vasodilators, isosorbide dinitrate or sodium nitroprusside, were comparable among the SES- and BMS-treated patients, and the control subjects (Fig. 2). Moreover, the epicardial coronary vasomotor responses to ACh and nitrates of the LCx, as a reference artery, were similar between the SES- and BMS-treated patients with AMI (Figs. 1B and 2A).


Figure 1
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  		Figure 1 Comparisons of Coronary Vasomotor Responses to ACh in AMI Patients and Control Subjects

Comparisons of vasomotor responses to acetylcholine (ACh) in acute myocardial infarction (AMI) patients treated with a sirolimus-eluting stent (SES) (n = 13) or bare-metal stent (BMS) (n = 16) and control subjects (n = 12). (A) Percent change in epicardial diameter of the left anterior descending coronary artery (LAD) from baseline in response to ACh. (B) Percent change in epicardial diameter of the left circumflex artery (LCx), a reference artery, from baseline in response to ACh. (C) Percent change in coronary blood flow (CBF) of the LAD from baseline in response to ACh.

 

Figure 2
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  		Figure 2 Comparisons of Coronary Vasomotor Responses to ISDNs or SNP in AMI Patients and Control Subjects

Comparisons of vasomotor responses to isosorbide dinitrates (ISDNs) or sodium nitroprusside (SNP) in AMI patients treated with an SES (n = 13) or BMS (n = 16) and control subjects (n = 12). (A) Percent change in epicardial diameter of the LAD and the LCx from baseline in response to ISDN. (B) Percent change in CBF of the LAD from baseline in response to SNP. Abbreviations as in Figure 1.

 
VEGF levels.   The AO levels of VEGF were significantly higher in the AMI patients treated with either SES or BMS than in control subjects, as shown in Figure 3. The AO levels of VEGF were similar between the AMI patients treated with SES and BMS. However, the AIV levels of VEGF were significantly lower than the AO levels in the SES patients, whereas the AIV levels of VEGF were similar to the AO levels in the BMS patients (Fig. 3).


Figure 3
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  		Figure 3 VEGF Levels in the Plasma From the AIV and the AO in AMI Patients and in Control Subjects

Vascular endothelial growth factor (VEGF) levels (pg/ml) in the plasma from the anterior interventricular vein (AIV) and the aortic root (AO) at 2 weeks after AMI in AMI patients treated with an SES (n = 13) or BMS (n = 16) and in control subjects (n = 12). Abbreviations as in Figure 1.

 
Plasma sirolimus concentrations.   The AIV levels of sirolimus were significantly higher than the AO levels after SES implantation on the third day and at 2 weeks after AMI (the third day after AMI: 0.47 ± 0.03 ng/ml vs. 0.37 ± 0.02 ng/ml, respectively, n = 8, p = 0.03; 2 weeks after AMI: 0.19 ± 0.01 ng/ml vs. 0.17 ± 0.01 ng/ml, respectively, n = 13, p = 0.03).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
Conclusions
 References
 
The present study demonstrated that SES implantation aggravated endothelium-dependent vasomotor dysfunction in both large vessels and the microvasculature of the infarct-related coronary artery after reperfusion therapy during the early course of AMI. The present study revealed that low but significant levels of sirolimus (0.14 {approx} 0.68 ng/ml [0.15 {approx} 0.74 nmol/l]) were detected in both AIV and AO and that sirolimus was released from SES into coronary blood until at least 2 weeks after the SES implantation. These concentrations were 10 {approx} 1,000-fold lower than the levels that inhibited endothelium-dependent relaxation in the animal experiments (12,13). However, it cannot be excluded that chronic exposure to sirolimus in the coronary circulation for 2 weeks might cause a considerable accumulation of this drug in the vascular bed distal to the site of SES implantation, leading to selective aggravation of endothelial vasomotor dysfunction in the infarct-related coronary artery.

Furthermore, the present study demonstrated that there was a step down in VEGF levels from the AO to AIV in patients with SES implantation but not in those with BMS implantation. These findings suggest that SES implantation may decrease the release of VEGF from the myocardial region supplied by the LAD, which may play a possible role in endothelial vasomotor dysfunction in infarct-related coronary arteries treated with SES.

A limitation of the present study was that the stent type was not randomized, and a small number of patients were enrolled. The data are preliminary, and large randomized studies are required to confirm the present data.


   Conclusions
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
References
 
Sirolimus-eluting stent implantation aggravates endothelium-dependent vasomotor dysfunction in resistance and large vessels of the infarct-related coronary arteries in association with a reduction in myocardial VEGF secretion during the early course of AMI.


   Footnotes
 
This study was supported by Grants-in-Aid for (B)(2)-15390244 from the Ministry of Education, Culture, Sports, Science, and Technology, Health and Labor Sciences Research Grants for Comprehensive Research on Aging and Health (H15-Choju-012), Tokyo, Japan.


   References
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 Abstract
 Methods
 Results
 Discussion
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 References
 

  1. Ku DD. Coronary vascular reactivity after myocardial ischemia Science 1982;218:576-578.[Abstract/Free Full Text]
  2. Yamamuro A, Akasaka T, Tamita K, et al. Coronary flow velocity pattern immediately after percutaneous coronary intervention as a predictor of complications and in-hospital survival after acute myocardial infarction Circulation 2002;106:3051-3056.[Abstract/Free Full Text]
  3. Lee SH, Wolf PL, Escudero R, et al. Early expression of angiogenesis factors in acute myocardial ischemia and infarction N Engl J Med 2000;342:626-633.[Abstract/Free Full Text]
  4. Matsunaga T, Warltier DC, Weihrauch DW, et al. Ischemia-induced coronary collateral growth is dependent on vascular endothelial growth factor and nitric oxide Circulation 2000;102:3098-3103.[Abstract/Free Full Text]
  5. Luo Z, Diaco M, Murohara T, et al. Vascular endothelial growth factor attenuates myocardial ischemia-reperfusion injury Ann Thorac Surg 1997;64:993-998.[Abstract/Free Full Text]
  6. Moses JW, Leon MB, Popma JJ, et al. SIRIUS Investigators Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery N Engl J Med 2003;349:1315-1323.[Abstract/Free Full Text]
  7. 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]
  8. Hofma SH, van der Giessen WJ, van Dalen BM, et al. Indication of long-term endothelial dysfunction after sirolimus-eluting stent implantation Eur Heart J 2006;27:166-170.[Abstract/Free Full Text]
  9. 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][ISI][Medline]
  10. Takano H, Kodama Y, Kitta Y, et al. Transcardiac adiponectin gradient is independently related to endothelial vasomotor function in large and resistance coronary arteries in humans Am J Physiol Heart Circ Physiol 2006;291:H2641-H2646.[Abstract/Free Full Text]
  11. Vetrovec GW, Rizik D, Williard C, et al. Sirolimus PK trial: a pharmacokinetic study of the sirolimus-eluting Bx Velocity stent in patients with de novo coronary lesions Catheter Cardiovasc Interv 2006;67:32-37.[CrossRef][ISI][Medline]
  12. Ramzy D, Rao V, Tumiati LC, et al. Role of endothelin-1 and nitric oxide bioavailability in transplant-related vascular injuryComparative effects of rapamycin and cyclosporine. Circulation 2006;114(Suppl I):214-219.
  13. Long C, Cook LG, Hamilton SL, et al. FK506 binding protein 12/12.6 depletion increases endothelial nitric oxide synthase threonine 495 phosphorylation and blood pressure Hypertension 2007;49:569-576.[Abstract/Free Full Text]



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This Article
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