Author + information
- Received August 14, 2008
- Revision received January 12, 2009
- Accepted January 12, 2009
- Published online May 5, 2009.
- Jin Won Kim, MD, PhD,
- Hong Seog Seo, MD, PhD,
- Jae Hyoung Park, MD,
- Jin Oh Na, MD,
- Cheol Ung Choi, MD,
- Hong Euy Lim, MD, PhD,
- Eung Ju Kim, MD, PhD,
- Seung-Woon Rha, MD, PhD,
- Chang Gyu Park, MD, PhD and
- Dong Joo Oh, MD, PhD* ()
- ↵*Reprint requests and correspondence:
Dr. Dong Joo Oh, Guro Hospital Cardiovascular Center, Korea University, 97 Gurodong-Gil Guro-gu, Seoul, Republic of Korea, 152-703
Objectives We prospectively compared coronary endothelial dysfunction in patients with zotarolimus-eluting stent (ZES) versus sirolimus-eluting stent (SES) implantation at 6-month follow-up.
Background A ZES has been associated with uniform and rapid healing of the endothelium.
Methods Fifty patients were randomly treated with intravascular ultrasound-guided stenting with a single stent to the mid-segment of the left anterior descending artery (20 ZES, 20 SES, and 10 bare-metal stents), and endothelial function was estimated before and after intervention at 6-month follow-up by incremental acetylcholine (Ach) (10, 20, 50, and 100 μg/min) and nitrate (200 μg/min) infusions into the left coronary ostium. The vascular response was quantitatively measured in the 5-mm segments proximal and distal to the stent.
Results In the drug-eluting stent groups, more intense vasoconstriction to incremental doses of Ach was observed at 6-month follow-up compared with the responses before stenting. Endothelial function associated with the ZES was more preserved at 6-month follow-up compared with the SES. Vasoconstriction to Ach was more prominent in the distal segments than the proximal segments in both the ZES and SES groups. Endothelium-independent vasodilation to nitrate did not differ significantly among the study groups.
Conclusions Vasoconstriction in response to Ach in the peri-stent region was less pronounced in the ZES group than the SES group at 6-month follow-up, which suggests that endothelial function associated with ZES can be more preserved than the SES.
Coronary stenting leads to disruption of the endothelial layer and leaves a thrombogenic metallic surface exposed to the blood stream. Finn et al. (1) showed that sirolimus or paclitaxel released from a drug-eluting stent (DES) impaired the normal healing processes of the injured arterial wall, even over a period of 40 months after implantation, and the heterogeneity of healing in the stents was associated with late stent thrombi. Our previous report (2) provided in vivo evidence that both sirolimus-eluting stents (SES) (Cypher, Cordis Corporation, Hialeah, Florida) and paclitaxel-eluting stents (Taxus, Boston Scientific Corporation, Natick, Massachusetts) can equally impair endothelial function and that their effects were demonstrable 6 months after implantation, especially in the arterial segments distal to the DES 6 months after stenting.
A zotarolimus-eluting stent (ZES) (Endeavor, Medtronic Vascular, Inc., Santa Rosa, California) has been reported to promote rapid and uniform healing of the endothelium (3), but little is known about the functional impairment of the endothelium after ZES implantation. Therefore, this study was prospectively designed to compare coronary endothelial dysfunction in patients with a ZES versus a SES or a bare-metal stent (BMS) (Driver, the ZES platform BMS, Medtronic Vascular) at pre- and post-intervention 6-month follow-up.
A total of 55 patients who were diagnosed with stable angina and treated with a single stent for a de novo single lesion of the left anterior descending artery were enrolled. The operators were not blinded to group assignment, because preparation requirements were needed for procedures. After the patient took a consent form, randomization was done by the research nurse with a sequentially numbered, opaque, sealed envelope in a 2:2:1 ratio. All patients were prospectively recruited from the Department of Cardiology at Guro Hospital, Korea University, Seoul, Korea. Intravascular ultrasound (IVUS)-guided stenting was performed in all patients. Stenting was performed up to minimum stent lumen cross sectional area ≥80% of the average of proximal and distal reference lumen area and full stent-vessel wall apposition. Additional adjunctive ballooning with noncompliant balloon was applied to a shorter area than the stent length to avoid areas subject to balloon injury until these criteria were reached. The exclusion criteria were the presence of a ≥50% stenotic lesion except for a culprit lesion, ≥50% coronary vasoconstriction in response to acetylcholine (Ach) infusion during the pre-intervention test, a history of acute coronary syndrome or coronary vasospasm, ejection fraction ≤30%, in-stent or in-segment restenosis (50%), reference diameters <2.5 mm, or other serious medical conditions. This study was approved by the Institutional Review Board of Korea University. Written informed consent was obtained from all patients before study entry.
Protocol for evaluation of endothelial function
All anti-anginal agents that influence vasomotor tone, including long-acting nitrate, calcium-channel blockers, and beta-blockers, were withheld for at least 72 h before coronary angiography except for sublingual nitroglycerin as needed. Endothelial function was estimated by measuring the coronary vasoreactivity in response to Ach infusion into the left coronary ostium at the pre-intervention and 6-month follow-up. Before wiring to the target lesion, vasomotor reactivity was estimated by infusing incremental doses of Ach into the left coronary ostium through a Judkins guiding catheter (Ach1, 10 μg; Ach2, 20 μg; Ach3, 50 μg; and Ach4, 100 μg for 1 min, performed at an infusion rate of 5 ml/min); a 5-min interval was allowed between doses. When the maximum dose was reached, an intracoronary bolus injection of nitroglycerin (200 μg) was administered. End-diastolic images for each segment were chosen and analyzed with the automated edge detection program (FD-10, Philips, Best, the Netherlands). Two orthogonal views with less foreshortening or without overlapping of side branches were selected and averaged for biplane assessment by 2 experts blinded to stent type. Two segments in study vessel were chosen for analysis, specifically, 5-mm proximal and distal to the site of stenting. Changes in coronary diameter in response to Ach and nitrate coronary infusion were expressed as percent changes versus baseline angiograms. At the 6-month follow-up, endothelial vasomotor reactivity was estimated with the same method described in the preceding text. Inter- and intra-observer variability for repeated measurements of quantitative coronary angiography in the same recordings of 20 randomly selected patients were 0.056 ± 0.04 mm and 0.018 ± 0.04 mm, respectively.
Commercially available computer software (SPSS, version 16.0, SPSS, Inc., Chicago, Illinois) was used for all analyses. All continuous data are presented as mean ± SD. Group demographic data were compared with a 1-way analysis of variance with a Scheffe test for multiple comparisons for continuous variables, or analysis of variance on ranks for categorical variables. To minimize the potential influence of differences in baseline characteristics, changes in coronary diameters in response to drug infusions among groups were compared with a general linear model with the stent length and late loss as covariates. For within-group comparisons, such as changes in proximal versus distal sites, a paired Student ttest was used. Statistical significance was accepted at a p ≤ 0.05.
At pre-intervention Ach test, 5 patients with more than 50% vasoconstriction in response to any dose of Ach were excluded, and thus the remaining 50 patients were randomly assigned to 3 groups (20 SES, 20 ZES, and 10 BMS). Six-month follow-up angiography was done in all patients except for 1 patient in the SES group who was lost to follow-up. One patient each in the ZES and BMS groups had in-stent restenosis (Fig. 1).
Table 1summarized the baseline characteristics of the patients. At 6-month follow-up, there were no significant differences of medications among 3 groups except for clopidogrel, which was discontinued in the BMS group after 1 month. The IVUS demonstrated that the plaque burden at sites 5-mm proximal and distal to stents were not different among the 3 groups (proximal sites: 24.9 ± 11.6 vs. 25.7 ± 13.0 vs. 24.4 ± 12.8, p = NS; distal sites: 19.9 ± 7.9 vs. 21.1 ± 11.8 vs. 22.4 ± 9.9, p = NS; SES vs. ZES vs. BMS, respectively) and confirmed no dissections at both proximal and distal to stents in all patients. Six-month late loss associated with SES was significantly lower (0.13 mm) compared with those of ZES or BMS (0.61 mm, p = 0.002 and 0.74 mm, p < 0.001, respectively).
Endothelial vasomotor reactivity among the ZES, SES, and BMS groups
Longer stents were used in the DES group compared with the BMS group (Table 2).No differences were observed among the SES, ZES, and BMS groups in terms of reference segment diameter proximal and distal to the stents (Table 2). The segments proximal to the stents were more strongly constricted to the Ach1 to Ach4 doses of the Ach infusion in the SES group compared with the BMS group. In contrast, between the ZES and BMS group, a significant difference in vasomotor reactivity was observed after only the Ach4 dose of the Ach infusion (Table 2). The magnitude of the estimated differences in vascular changes was mildly attenuated after adjustment for stent length and late loss as potential confounding factors. However, the differences among SES, ZES, and BMS remained significant (Table 2, Fig. 2).
The segment distal to the stent was more strongly constricted to the Ach1 to Ach4 doses of the Ach infusion in the SES group and to the Ach2 to Ach4 doses of the Ach infusion in the ZES group as compared with the BMS group (Table 2). The diameter changes between the SES and the ZES had significant differences of vasoreactivity in response to the Ach1 to Ach4 doses in sites distal to the stents but not the sites proximal to the stents (Fig. 2). The diameter changes in response to the Ach infusion were greater at the sites distal to the stent than proximal to the stent in both the SES and ZES (Table 2).
Angiographic analysis: endothelial dysfunction between pre-intervention and 6-month post-intervention
When comparing the diameter changes to the Ach infusion between the pre- and post-intervention, there was a more intense vasoconstriction in the SES group than the ZES group. The degree of vasoconstriction was greater at the 6-month post-stenting in the proximal segments after the Ach2 to Ach4 doses of the Ach infusion and in the distal segments after the Ach1 to Ach4 doses of the Ach infusion in the SES group as compared with pre-intervention. However, in the ZES group, the significant changes between the pre-stenting and 6-month post-stenting were observed only in the distal segments after the Ach3 to Ach4 doses of the Ach infusion (Fig. 3).
Vasoreactivity in response to nitrate infusion
The ZES, SES, and BMS groups showed no differences of vasodilation in response to nitrate infusion between the pre- and post-intervention or between the sites proximal and distal to stents (Table 2).
In the present study, endothelial vasomotor reactivity at the 6-month post-intervention was significantly impaired in both the ZES and SES groups compared with the BMS group. However, the endothelial function associated with the ZES was more preserved at the 6-month follow-up compared with the SES. This is the first published comparison to provide in vivo evidence that endothelial-dependent vasomotor reactivity associated with the ZES could be more preserved compared with the SES.
There is compelling clinical evidence that ZES carries an extremely low risk of late stent thrombosis (4). In humans, the ZES is associated with a greater amount of neointimal hyperplasia by IVUS at 8 months (5) and a homogeneous complete healing by optical coherence tomography (OCT) at 6 months compared with the SES (6). In the current study, despite a greater degree of endothelial dysfunction compared with the BMS, the ZES was associated with lesser vasoconstriction to Ach compared with the SES. The present study was prospectively designed to compare the changes in endothelial dysfunction in response to Ach infusion between pre-stenting and 6-month post-stenting, and hence the influence of existing endothelial dysfunction per se without relation to the stent could be minimized. We speculated that, on the basis of optical conference tomography data (6) and current results, the more preserved endothelial function at 6 months in the ZES could be associated with more complete endothelial coverage compared with the SES and contribute to the safety profiles in terms of late thrombosis, although actual data regarding the direct relationship between endothelial function and healing over struts or clinical outcomes are lacking.
The differential effects of DES on endothelial function could be explained by the characteristics of the loaded drug. Obata et al. (7) showed that sirolimus released from the SES reduced the level of vascular endothelial growth factor in the coronary circulation 2 weeks after SES implantation. An in vitro study by Jabs et al. (8) reported continuous sirolimus exposure causes impaired endothelium-dependent vascular relaxation by stimulation of mitochondrial reactive oxygen species release. However, until now, there has been no comparable evidence regarding the potency of sirolimus and zotarolimus. Another potential explanation for the early restoration of endothelial function after ZES implantation might relate to the rapid elution of the coating drug. Whereas, in the SES, the loaded drug is released from the stent up to 60 days after stent implantation, the ZES maintains effective drug levels through initial loading of arterial tissue with the drug only during the first 2 weeks of elution from the stent (9), and thus local toxicity is minimized. In addition, the unique characteristics of the phosphorylcholine polymer could contribute to the differential effects of DES (3). A recent study by Hamilos et al. (10) showed that the biolimus A9-eluting stent, on the basis of a bioabsorbable polymer, showed a better-preserved endothelium-dependent vasomotion response at adjacent stent segments compared with the SES. The phosphorylcholine-based polymer of ZES has, despite the permanent polymer, hydrophilic properties that are expected to generate less interfacial tension in the aqueous body environment and is thus more highly biocompatible compared with the hydrophobic polymer of the SES, which has been shown to resist fibrinogen adsorption and cause less platelet and monocyte activation (3). Finally, the struts of the ZES were thinner than those of the SES platform. A previous study reported that reduced arterial injury and restenosis are associated with thinner struts (11).
Despite strong evidence of more rapid restoration of endothelial dysfunction associated with ZES compared with SES, it is unknown whether the ZES is associated with any clinical benefits. The late loss associated with ZES has been known to be higher compared with those of SES and could influence the clinical outcomes. Nonetheless, in-stent late loss up to 0.75 mm in low-risk populations is clinically acceptable in terms of major adverse cardiac events (12). Therefore, despite the greater in-stent late loss, taken together with our data, it is conceivable that a second-generation DES, the ZES, could be more beneficial in specific clinical situations in which they are needed—for example, in the patients who inevitably discontinue dual antiplatelet agents within 12 months as guideline-recommended due to scheduled surgery or patients with questionable compliance for dual antiplatelet agents. To answer these questions and clarify the clinical relevance of the ZES as related to preserved endothelial function, well-designed randomized clinical trials on special subpopulations are warranted.
The number of enrolled patients was relatively small. Although angiographic images of both pre-procedure and follow-up studies were analyzed by side to side viewing to compare the matched sites, it was hard to identify and estimate the exact same sites. The IVUS was not performed at 6-month follow-up, and thus the influence of plaque at proximal and distal edges to stent could not be completely excluded. Another limitation was the possibility that tethering effect by the stent itself could influence the results. Additionally, ethnicity might influence our results. Asians show a higher degree of coronary vasoconstriction in response to Ach infusion than Caucasians (13). To solve this issue, further studies on diverse races will be required.
This study provided in vivo evidence that endothelial function associated with the ZES could be more preserved than after SES, despite a greater late loss of the ZES.
The authors thank B. W. Cheon, S. G. Moon, and S. P. Hong for their technical assistance.
This study was supported by the Seoul R & BD Program (10526) to Drs. Chang Gyu Park and Seo.
- Abbreviations and Acronyms
- bare-metal stent(s)
- drug-eluting stent(s)
- intravascular ultrasound
- sirolimus-eluting stent(s)
- zotarolimus-eluting stent(s)
- Received August 14, 2008.
- Revision received January 12, 2009.
- Accepted January 12, 2009.
- American College of Cardiology Foundation
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