The First-Generation Drug-Eluting Stents and Coronary Endothelial Dysfunction
Lakshmana K. Pendyala, MD*,
Xinhua Yin, MD, PhD ,
Jinsheng Li, MD, PhD,
Jack P. Chen, MD,
Nicolas Chronos, MD,
Dongming Hou, MD, PhD,*
* Department of Cardiology, University of Louisville, Louisville, Kentucky
Saint Joseph's Research Institute, Saint Joseph's Hospital of Atlanta, Atlanta, Georgia
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Abstract
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Recently, a growing body of clinical data has shown that the first generation of drug-eluting stents (1st-gen DES) implantation could elicit coronary conduit artery vasomotor dysfunction at nonstented reference segments as late as 12 months after implantation compared with that seen with bare-metal stents. The mechanism of this phenomenon is still not fully understood. Pathological studies have implicated delayed arterial healing and poor re-endothelialization after the 1st-gen DES implantation. Given the vast use of DES globally, a thorough understanding of the early and long-term safety of these devices is paramount. Therefore, this article systematically reviews the current clinical, pathophysiological, and histopathological available data regarding 1st-gen DES-associated vascular endothelial dysfunction. Meanwhile, we will also review the newer generation of DES and emerging endothelial-friendly technology.
Key Words: drug-eluting stents • endothelial • vasomotor dysfunction
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Abbreviations and Acronyms
| | Ach = acetylcholine | | BES = biolimus-eluting stent(s) | | BMS = bare-metal stent(s) | | CAD = coronary artery disease | | DES = drug-eluting stent(s) | | EC = endothelial cell | | ED = endothelial dysfunction | | EES = everolimus-eluting stent(s) | | eNOS = endothelial nitric oxide synthase | | EPC = endothelial progenitor cell | | ET = endothelin | | IC = intracoronary | | LST = late stent thrombosis | | NO = nitric oxide | | NSRS = nonstented reference segment(s) | | PES = paclitaxel-eluting stent(s) | | SES = sirolimus-eluting stent(s) | | SMC = smooth muscle cell | | ZES = zotarolimus-eluting stent(s) | | 1st-gen DES = first-generation drug-eluting stent |
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Development and widespread utilization of drug-eluting stents (DES) has provided a novel and efficacious treatment for coronary artery disease (CAD), allowing for localized elution of neointimal inhibiting drugs, thereby reducing in-stent restenosis and target lesion revascularization rates compared with bare-metal stents (BMS) (1,2). However, numerous reports have suggested increased incidences of late stent thrombosis (LST) and very LST with the first-generation drug-eluting stent (1st-gen DES), especially after discontinuation of dual antiplatelet therapy (3–5).
Although many factors such as patient, lesion, as well as procedural characteristics are likely contributory, clinical, histopathological, and pathophysiological studies have implicated that delayed arterial healing and poor re-endothelialization may play a major role in the pathogenesis of LST (6,7). More recently, a variety of studies have also reported that 1st-gen DES sirolimus-eluting (Cypher, Cordis Corporation, Miami Lakes, Florida) and paclitaxel-eluting (TAXUS, Boston Scientific Corporation, Natick, Massachusetts) stents elicited focal endothelium-dependent vasomotor dysfunction in both proximal and distal nonstented reference segments (NSRS) of coronary arteries for 6 to 12 months post-stent implantation (8–12).
The endothelium is a monolayer organ with autocrine, paracrine, and endocrine functions. Under healthy conditions, endothelial cells (ECs) produce many vasoactive substances, which maintain vascular homeostasis and normal vasomotor tone (13,14). Nitric oxide (NO), a key factor generated by ECs, is associated with inhibition of platelet and leukocyte activation, and maintenance of vascular smooth muscle in a nonproliferative state. In addition to being the main determinant of basal vascular smooth muscle tone, NO opposes the actions of potent endothelium-derived contracting factors such as angiotensin-II and endothelin (ET)-1 (15–18). Impairment of NO bioactivity or bioavailability and/or imbalance between endothelium-derived relaxing and contracting factors is crucial in the mechanisms of endothelial dysfunction (ED). The pathophysiological hallmarks of dysfunctional endothelium include vascular inflammation, thrombogenesis, as well as abnormal vasomotor function. Indeed, many studies have demonstrated that ED is an independent predictor for cardiovascular disease (19–22). In the coronary bed, ED could cause vessel spasm, which leads to reduced myocardial perfusion and myocardial ischemia. However, ED also has been shown to enhance the vulnerability of plaque lesion and subsequent likelihood of plaque rupture (23). Higo et al. (24) reported sirolimus-eluting stents (SES) promoting the formation of atherosclerotic yellow neointima in the stent-implanted lesion at 10 months follow-up. This intense yellow appearance has been commonly observed in patients with an advanced atherosclerotic plaque (25).
There are many tools to determine the integrity of vasomotor function in response to physiological and pharmacological stimuli. Acetylcholine (Ach) evokes a NO-mediated vasodilatory response in healthy arteries via muscarinic endothelial membrane receptors, but this effect is blunted, and paradoxical vasoconstriction may be observed with ED (26,27). Quantitative coronary angiography after intracoronary (IC) Ach infusion is currently one of the most utilized invasive methods for the evaluation of vasomotor dysfunction after DES implantation (9,11). Therefore, in the current article, we will systematically review the available clinical as well as pathophysiological and histopathological data on DES-associated ED. Meanwhile, the newer generation DES (namely, 2nd-gen) and novel future emerging endothelial-friendly technology are also discussed.
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SES and Coronary ED
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Sirolimus is a macrolide antibiotic that binds to the cytosolic receptor FKBP12 and inhibits down-regulation of the cyclin-dependent kinase inhibitor p27kip1, thereby inhibiting vascular smooth muscle cell (SMC) proliferation and migration (28).
Experimental studies.
The effects of sirolimus on endothelial function in vitro are summarized in Tables 1 and 2. This compound has been reported to inhibit not only SMC proliferation but also endothelial regeneration in vitro. Mohacsi et al. (29) reported sirolimus inhibition of growth factor-induced proliferation of both cultured EC and SMC. In their in vitro porcine coronary artery model, Jeanmart et al. (30) observed severe impairment of relaxant responses to serotonin and bradykinin in epicardial arteries exposed to sirolimus, suggesting a direct adverse effect of sirolimus on endothelial function. Through deactivation of the p70 S6 kinase pathway, an essential step in cell cycle progression in response to growth factors, sirolimus exerts inhibition on EC proliferation (31). More recent data indicate that sirolimus may also affect the growth and differentiation of endothelial progenitor cells (EPCs) (32).
Using a large clinically relevant animal model, we investigated endothelial function in vitro using an organ chamber tensiometry in coronary artery segments distal to polymer-coated BMS, and SES at 1 month after implantation (33). Distal conduit arteries devoid of direct mechanical injury demonstrated vasomotor dysfunction in SES, but not BMS or polymer stents. Increased contractile and endothelium-independent relaxation responses, as well as reduced endothelium-dependent relaxation, were also noted even beyond duration of nearly complete drug release. We, therefore, hypothesized that even though SES showed effective neointimal inhibition, the eluted drug and durable polymer can also adversely affect vasomotor function of downstream coronary segments.
Clinical studies.
Table 3
summarizes clinical studies evaluating SES and endothelial function. The normal response to increased flow in coronary conductance vessels is vasodilation, due to stimulation of endothelial NO synthesis and release in response to shear stress. If paradoxical vasoconstriction occurs, there is likely underlying damaged endothelium or abnormal endothelial function. In their first published clinical study, Togni et al. (10) studied exercise-induced coronary vasodilatory function in patients with known CAD after DES implantation. Using biplane quantitative coronary angiography at rest and during supine bicycle exercise, 25 patients were assessed at 6 ± 1 month after percutaneous coronary intervention. Eleven patients received BMS (control group) and 14 received SES (DES group). Coronary segments proximal and distal to the stent showed anticipated exercise-induced vasodilation in the control BMS arm. The percentage diameter changes were +15 ± 3% and +17 ± 4% for proximal and distal segments, respectively. In contrast, exercise-induced vasoconstriction of the proximal and distal vessel segments adjacent to SES was clearly noticed (–2 ± 4% and –15 ± 6%, respectively; p < 0.001 vs. corresponding segments of control subjects). Sublingual nitroglycerin was associated with maximal vasodilation in both groups. The authors concluded that BMS does not affect physiological response to exercise proximal and distal to the stent. This indicates that in atherosclerotic arteries stented with BMS the vasomotor recovers quickly, while SES is clearly associated with exercise-induced paradoxical vasoconstriction at the same follow-up time point. Similarly, Hofma et al. (9) reported abnormal coronary vasoconstrictive responses to IC infusion of Ach after SES implantation. The investigators prospectively studied 15 patients undergoing stenting for a single de novo lesion. Endothelial function was assessed at baseline and 6 months post-intervention. Significantly more vasoconstriction was observed distal to stented segment for SES in comparison with BMS. More recently, Fuke et al. (11) also reported similar coronary vasomotor dysfunction with IC infusion of Ach 6 months after SES implantation in 35 patients with stable angina. The coronary vasomotor function was evaluated by Obata et al. (12) at 2 weeks post-stent implantation (SES vs. BMS), following successful reperfusion therapy after acute myocardial infarction. In the SES group, more severe constriction of distal epicardial coronary arteries in response to Ach was evidenced compared with that seen in the BMS patients. The authors further found coronary blood flow and vascular endothelial growth factor levels were also significantly diminished for SES than BMS. The authors concluded that, in the initial phase of acute myocardial infarction, SES implantation adversely affects endothelium-dependent vasomotor function in both resistance and epicardial coronary arteries, with associated reduction in myocardial vascular endothelial growth factor secretion.
All of the studies noted in the preceding text have concluded that SES implantation produced a vasoconstrictive response in coronary segments proximal and/or distal to the stent during coronary provocative test, whereas BMS did not. These clinical results indeed were confirmed and underscored by pre-clinical in vitro physiology organ chamber findings that the SES impairs endothelial function at NSRS in coronary conduit arteries.
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Paclitaxel-Eluting Stents (PES) and Coronary ED
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Paclitaxel binds specifically to the beta-tubulin subunit of microtubules and appears to antagonize the disassembly of this key cytoskeletal protein; this action results in accumulation of microtubule bundles and aberrant microtubular-derived structures in the mitotic phase of the cell cycle (34).
Experimental studies.
Tables 1 and 2 summarize the pre-clinical studies evaluating endothelial function after PES. By in vitro cell assay, Axel et al. (35) demonstrated that high-dose paclitaxel is a potent inhibitor of not only SMC, but also EC proliferation and migration. Similarly, Farb et al. (36) have revealed a dose-dependent decrease in neointimal formation and subsequent increase in vessel wall toxicity from paclitaxel.
Using both in vivo and in vitro methods in our laboratory, Pendyala et al. (37) performed the first systematic evaluation of vasomotor function of coronary epicardial arteries both at proximal and distal NSRS, as well as in perfusion bed intramyocardial resistance arteries, after overlapping PES implantation in laboratory swine. We also analyzed the inflammatory response at overlapped regions and superoxide anion (O2
·–) production at both proximal and distal NSRS. The results demonstrated that while PES is effective in inhibiting neointimal growth, a profound adverse effect on vasomotor function was observed in both conduit and resistance arteries distant from the site of direct mechanical injury. Such widespread influence on vasomotor function from the stented locale appears to be associated with extensive localized inflammation at the stent site, as well as increased O2
·– production in the proximal and distal NSRS. Beyond vasomotor dysfunction, this study also illustrated significantly increased contractile response to PGF2 and ET-1 in both the proximal and distal NSRS for PES.
Clinical studies.
Table 3 is a summary of clinical studies evaluating endothelial function after PES implantation. Two recent clinical investigations demonstrated that PES implantation was associated with long-term coronary ED when compared with the BMS counterpart. Togni et al. (38), using exercise-induced flow-mediated vasodilation, studied 27 patients with CAD. They observed that PES implantation is associated with exercise-induced vasoconstriction in the 10-mm peri-stent regions, suggesting ED as the underlying mechanism. Improvement of vascular function occurred over time, indicating delayed vascular healing. Persistent de-endothelialization by balloon angioplasty barotrauma would not be expected in these regions; therefore, incomplete or even absent re-endothelialization is likely not responsible for this phenomenon.
Similarly, Shin et al. (39) studied endothelial function in patients without 6-month angiographic evidence of restenosis after single BMS or DES (SES and PES) implantation. The authors reported that both SES (n = 9) and PES (n = 8) groups demonstrated a similar pattern of abnormal coronary vasoconstriction in response to Ach at the long distal portion (distal and far distal segments) of the treated vessel (Fig. 1). However, endothelium-independent vasodilation was preserved in all groups. These results suggested that SES or PES implantation may be associated with coronary ED in remote portions of the treated vessel. Similarly, in another recent study (40), both PES and SES deployment resulted in greater endothelium-dependent vasoconstriction than the BMS group at corresponding segments, while nitrate-induced endothelium-independent vasodilation did not differ significantly.
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Figure 1 Examples of Coronary Angiogram With Endothelial Function Test at 6 to 9 Months After Stent Implantation
Coronary angiogram showed a marked vasoconstriction to incremental acetylcholine infusion, in particular in the segment distal to the sirolimus-eluting stent (SES) (A) and paclitaxel-eluting stent (PES) (B) compared with those of the bare-metal stent (BMS) (C) or mid-segments of the left circumflex artery as a reference nonstented artery.
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Possible Mechanisms for the 1st Gen DES-Induced ED
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Molecular mechanisms of vascular endothelial functional impairment after DES implantation remain incompletely defined, but recent work has provided profound insight into the potential etiologies of this complex phenomenon. Multiple factors may be involved, including direct toxic effect from the entrapped drug and/or an acute or delayed hypersensitivity reaction from the polymer and/or drug. As shown, the vasa vasorum interna in porcine coronary arteries originating directly from the arterial lumen can extend over several centimeters along the coronary artery wall (41). Therefore, the antiproliferative drugs and vasoactive chemicals may locally diffuse through these tiny channels to the NSRS.
In a recent study (42) comparing the histology of the abdominal aortas that were perfused with barium sulfate in rabbits 9 weeks after implantation of BMS or sirolimus DES, there appears to be a correlation between the number of vasa vasorum induced and the type of stent used and the actual healing process. After 9 weeks, the qualitative intrastent luminal diameter was fairly uniform in both the DES and the BMS. The thickness of neointima was similar in both groups. The number of vasa vasorum in the sirolimus DES increased compared with that in the BMS (p < 0.05). An increased number of vasa vasorum produced by the DES when compared with the BMS shows a difference in response to local vessel injury in rabbits. This result suggests that vasa vasorum may play a role in the persistent inflammation generated by DES (42).
SES and ED.
Long et al. (43), in a mice model, reported that acute in vitro sirolimus treatment, as well as genetic deletion of the sirolimus-receptor isoform FKBP12.6, increased protein kinase C-mediated endothelial nitric oxide synthase (eNOS) threonine 495 phosphorylation, thereby leading to decreased vascular NO production and subsequent ED. They demonstrated that displacement of FKBP12/12.6 from endothelial ryanodine receptors resulted in intracellular Ca2+ leakage, which in turn decreases NO production and endothelium-dependent vasodilation. This observation supports the findings of Takeda et al. (44) who reported decreased eNOS activity in aortic EC from rats treated with FK506 for 4 weeks. Similarly, Jabs et al. (45) showed that a 7-day continuous infusion of sirolimus into Wistar rats produced a marked degree of ED. The investigators postulated sirolimus-associated increases in vascular O2
·– concentrations, with resultant loss of vascular NO bioavailability by up-regulation of both mitochondrial O2
·– release and nicotinamide adenine dinucleotide phosphate oxidase-driven O2
·– production. Although the rat model was one of prolonged systemic exposure to sirolimus, the authors proposed that the same processes could contribute to the observed ED noted after deployment of sirolimus-coated stents. There are several important limitations to this study. First, generalizability of sirolimus dosing in the rat study to that of DES implantation in the human coronary artery is not established. Secondly, the attribution of sirolimus to long-term ED must be tempered with the observation that vascular dysfunction after SES deployment persists long after the drug is gone. If the compound is, in fact, the cause, this implies that its effect must persist beyond drug exposure. In the current experiment, however, the exposure of sirolimus continued to the end of the study. Therefore, although both these studies indicated that the drug may be contributory, the potential role of the polymer cannot be ruled out.
The Cypher stents contain a 5-µm coating of the drug sirolimus combined with nonerodable polymers, covered with a layer of drug-free polymer to allow the drug gradual release. As most of the drug is eluted from the polymer coating by 28 days (46) and fully eluted by 60 days (47), the abnormal vasomotion observed at 6 months in the clinical trials is likely not a direct effect of sirolimus itself. However, the lingering effects of a persistent abnormality in endothelial regeneration cannot be excluded. Alternatively, the polymer from which the drug elutes, which may have contributed to a case of a marked hypersensitivity reaction (47), may have impaired vasomotion; however, this effect also remains speculative.
PES and ED.
Aside from the metallic struts, PES contain 2 important components: nonbiodegradable synthetic polymer and paclitaxel. The polymer used in PES is highly lipophilic such that only 10% of the initial drug dose is eluted from the current slow-release formulation of PES, leaving the residual 90% in a tissue bound form (48,49). We recently reported (37) a significantly higher level of O2
·– in conduit arteries proximal and distal to PES, as compared with that seen for BMS and naive vessels. Due to chronically increased production of reactive oxygen species, NO bioavailability may be decreased, resulting in impairment of endothelium-mediated vascular relaxation response. Thus, underlying direct drug toxicity and/or polymer incompatibility and potentiation of superoxide activity may be culprit mechanisms in ED. Beyond vasorelaxation impairment, our data also illustrated significantly increased contractile response to PGF2 and ET-1 in both the proximal and distal NSRS for PES.
In general, the 1st-gen DES have shown to enhance vasoconstriction when compared with BMS. This lower set point for contraction might be anticipated to cause adverse effects on distal myocardial perfusion and regional myocardial function. Indeed, severe diffuse coronary artery spasm after both PES and SES was well-documented in clinical case reports (50–54). So far, the potential contribution of such flow pattern impairment to DES thrombosis is still unknown. We postulate that this phenomenon would result in blood flow reduction and exacerbation of nonlaminar flow within the stented vessel, which likely link to increases in inflammatory and thrombotic risks (Fig. 2).
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The Newer Generation of DES
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Although 1st-gen DES have resulted in unquestioned reductions in in-stent restenosis, long-term safety issues have arisen, demanding further reconciliation of the key properties of deliverability, efficacy, and safety. To avoid these undesirable and potentially devastating side-effects, biocompatible and bioabsorbable polymers, as well as polymer-free DES have been developed. Bioabsorbable stents, both polymeric and metallic, have also been designed to decrease potential late complications.
Zotarolimus is a tetrazole-containing macrocyclic immunosuppressant that has extremely low water solubility. The Endeavor stent (zotarolimus-eluting stent [ZES], Medtronic Corporation, Minneapolis, Minnesota) is composed of a cobalt alloy and contains 10-µg zotarolimus/mm stent length with a novel biocompatible phosphorylcholine polymer. Hamilos et al. (55) examined the influence of BMS and DES on endothelium-dependent vasomotion. SES and PES caused blunted or absent vasodilation, respectively. In contrast, ZES and biolimus-eluting stents (BES) (Terumo Corporation, Tokyo, Japan) exhibited vasodilatory responses similar to those of BMS. Endothelium-dependent coronary vasoconstriction was not associated with abnormal systemic markers of endothelial inflammation and showed no relation to in-stent late lumen loss. The authors concluded that 1st-gen DES seem to cause ED of the implanted coronary vessel, whereas newer generation DES, such as ZES and BES, demonstrated preserved endothelial-dependent vasomotion at comparable time points, similar to BMS. Similarly, other recently published studies (56–58) comparing coronary endothelial function between ZES and SES reported that the latter group demonstrated abnormal coronary vasoconstriction at the long distal portion of the treated vessel, as late as at 6 to 9 months of follow-up. Conversely, no significant impairment of vasomotor function was observed with ZES. Haraguchi et al. (59) evaluated eNOS mRNA expression and vascular function of ZES and both the 1st-gen DES at 1 and 3 months in a porcine model. Both proximal and distal stented segments of ZES expressed significantly more eNOS mRNA than either DES. Both SES- and PES-implanted vessels exhibited vasoconstriction in response to ACh as compared with ZES at 1 month in this experimental setting. Although ZES restores ED, the late luminal loss compared with that seen in SES is slightly higher in low-risk patient populations. Therefore, endothelial impairment may represent a local effect related to the implantation of specific DES brand types (55–59).
The everolimus-eluting stent (EES) (Xience, Abbott Corporation, Abbott Park, Illinois) is loaded with another analogue of rapamycin and was designed for enhanced flexibility. This 2nd-gen DES features thin cobalt-chromium struts and a potentially more biocompatible fluoropolymer. Joner et al. (60) analyzed the endothelial surface coverage in various polymeric DES using a well-characterized rabbit iliofemoral artery model. Endothelial coverage between struts occurred more rapidly than above struts, where differences in the various stent platforms were most notable at 14 days. EES and BMS control stents showed a greater extent of endothelial coverage above struts relative to ZES, PES, and SES at 14 days. BES is a 2nd-gen DES using a bioresorbable polymer (polylactic acid) from which biolimus A9, an analogue of sirolimus, is eluted.
All studies to date point toward less ED and faster endothelial structural recovery with the newer DES compared with the 1st-gen DES. Although the reasons for this observation have not been fully elucidated, several previous studies suggest possible clues. While all newer DES contain agents belonging to the limus family (biolimus, everolimus, and zotarolimus), similar to sirolimus, they all differ from SES in release kinetics and stent platforms. Zotarolimus and biolimus A9 are more lipophilic drugs than sirolimus and quickly bind to the target, lipid-rich tissue on release. This action may result in a more localized effect and reduced systemic drug exposure. Moreover, biolimus is present only on the vessel side (abluminally) and thus has minimal penetration into the peripheral circulation. Additionally, the controlled drug release is characterized by a small initial burst followed by sustained simultaneous drug release and polymer degradation over 6 months, resulting in lower drug concentration in the surrounding tissue. Although the polymer in the SES platform has been associated with fibrin deposition and late hypersensitivity reactions, the biocompatible phosphorylcholine and fluoropolymer coatings incorporated into ZES and EES, respectively, have demonstrated in vitro resistance to fibrinogen adsorption. Additionally, the newer polymers are associated with decreased platelet and monocyte activation. Improved stent designs with thinner struts, more biocompatible polymers, or complete elimination of polymers will likely have a profound impact on drug elution profiles, endothelial coverage, and functional recovery. Further studies are needed to clarify the mechanisms and relative benefits of these differences according to DES type.
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Future Bio-Active, Pro-Healing, and Pro-Endothelialization Stents
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The ability of the endothelium to self-repair is dependent upon both the migration of surrounding mature EC and the attraction and adhesion of circulating EPC to the injured region. The EPC, in turn, differentiate into endothelial-like cells. Endovascular therapy with DES interrupts this natural response. Accelerating the re-endothelialization of the damaged arterial segment after stent implantation is an attractive means to hasten the natural process of healing. DES with such beneficial properties may result in reduction of neointimal hyperplasia and LST. Studies are on-going to identify agents that augment the mobilization and recruitment of EPC to the injured area (statins, exercise, estrogen, and cytokines). Other investigations have evaluated seeding stents with EC and/or EPC. The Genous Bio-engineered R stent (Orbus Neich, Fort Lauderdale, Florida) is a stainless steel bio-engineered stent, coated with antibodies specific to CD34+ to capture circulating EPC derived from bone marrow.
In their study evaluating an eNOS gene-eluting stent, Sharif et al. (61) used a phosphorylcholine-coated stent for adenovirus-mediated gene delivery to the vessel wall. The data demonstrated a significant acceleration of re-endothelialization in the eNOS-stented vessels as early as 14 days and persisted for more than 28 days. Another report (62) evaluated the effects of heptapeptide angiotensin-(1-7) infusion on vasodilation in rat thoracic aorta and found improvement of endothelial function after chronic angiotensin-(1-7) infusion.
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Conclusions
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Regardless of the mechanisms of vasomotor dysfunction after DES deployment, the following questions remain: what are the clinical implications and potential remedies? One consistent finding in most long-term follow-up analyses of DES versus BMS is the lack of improvement in the hard outcomes of death and myocardial infarction (63). Indeed, in some studies, the mortality risk of DES appears greater than would be expected from stent thrombosis (64). It is unknown whether the now well-documented phenomenon vasomotor dysfunction imparts any clinical risk. Present data suggest less ED and faster endothelial structural recovery with the newer DES compared with SES and PES. Therefore, further insight into the mechanisms and duration of SES- and PES-associated paradoxical constriction are needed. Whether ED in this setting will adversely affect prognosis, as has been shown in other clinical contexts (65), as well as the effects of approaches manipulating endothelial response, are to be determined.
In summary, the optimal DES should have minimal impact on EC structural and functional recovery along with maximal inhibitory effect on SMC proliferation and migration. Utilization of novel imaging modalities such as optical coherence tomography might help identify the time course of neointimal formation and any correlation with ED. Improved clinical efficacy and safety of the second generation stents awaits longer-term follow-up.
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Footnotes
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Dr. Yin is currently affiliated with the 1st Affiliated Hospital of Harbin Medical University (HMU), China.
* Reprint requests and correspondence: Dr. Dongming Hou, Saint Joseph's Translational Research Institute, Saint Joseph's Hospital of Atlanta, 5673 Peachtree Dunwoody Road N.E., Suite 675, Atlanta, Georgia 30342 (Email: dhou{at}sjha.org).
Manuscript received September 1, 2009;
revised manuscript received September 30, 2009,
accepted October 7, 2009.
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REFERENCES
|
|---|
- Ellis SG, Colombo A, Grube E, et al. Incidence, timing and correlates of stent thrombosis with the polymeric paclitaxel drug-eluting stent: a TAXUS II, IV, V, and VI meta-analysis of 3,445 patients followed for up to 3 years J Am Coll Cardiol 2007;49:1043-1051.[Abstract/Free Full Text]
- Mauri L, Hsieh WH, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents N Engl J Med 2007;356:1020-1029.[CrossRef][Medline]
- Jensen LO, Maeng M, Kaltoft A, et al. Stent thrombosis, myocardial infarction, and death after drug-eluting and bare-metal stent coronary interventions J Am Coll Cardiol 2007;50:463-470.[Abstract/Free Full Text]
- Bavry AA, Kumbhani DJ, Helton T, et al. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials Am J Med 2006;119:1056-1061.[CrossRef][Web of Science][Medline]
- Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study Lancet 2007;369:667-678.[CrossRef][Medline]
- Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk J Am Coll Cardiol 2006;48:193-202.[Abstract/Free Full Text]
- Finn AV, Nakazawa G, Joner M, et al. Vascular responses to drug eluting stents: importance of delayed healing Arterioscler Thromb Vasc Biol 2007;27:1500-1510.[Abstract/Free Full Text]
- Togni M, Raber L, Cocchia R, et al. Local vascular dysfunction after coronary paclitaxel-eluting stent implantation Int J Cardiol 2007;120:212-220.[CrossRef][Web of Science][Medline]
- Hofma S, Van der Giessen W, Van Dalen B, et al. Indication of long-term endothelial dysfunction after sirolimus-eluting stent implantation Eur Heart J 2006;27:166-170.[Abstract/Free Full Text]
- 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]
- Fuke S, Maekawa K, Kawamoto K, et al. Impaired endothelial vasomotor function after sirolimus-eluting stent implantation Circ J 2007;71:220-225.[CrossRef][Web of Science][Medline]
- 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 myocardial infarction J Am Coll Cardiol 2007;50:1305-1309.[Abstract/Free Full Text]
- Vane JR, Anggard EE, Botting RM. Regulatory function of the vascular endothelium N Engl J Med 1990;323:27-36.[Web of Science][Medline]
- Moncada S, Higgs A. The L-arginine-nitric oxide pathway N Engl J Med 1993;329:2002-2012.[CrossRef][Web of Science][Medline]
- Furchgott RF, Zawadzki JV. The obligatory role of the endothelial cells in relaxation of arterial smooth muscle by acetylcholine Nature 1980;288:373-376.[CrossRef][Medline]
- Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells Nature 1988;332:411-415.[CrossRef][Medline]
- Fuchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors FASEB J 1989;3:2007-2018.[Abstract]
- Vanhoutte PM. The other endothelium-derived vasoactive factors Circulation 1993;87:V9-V17.
- Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease Circulation 2000;101:1899-1906.[Abstract/Free Full Text]
- Vanhoutte PM. Endothelial control of vasomotor function Circ J 2003;67:572-575.[CrossRef][Web of Science][Medline]
- Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk Aterioscler Thromb Vasc Biol 2003;23:168-175.[Abstract/Free Full Text]
- Lavi S, Yang EH, Prasad A, et al. The interaction between coronary endothelial dysfunction, local oxidative stress, and endogenous nitric oxide in humans Hypertension 2008;51:127-133.[Abstract/Free Full Text]
- Libby P. Current concepts of the pathogenesis of the acute coronary syndromes Circulation 2001;104:365-372.[Free Full Text]
- Higo T, Ueda Y, Oyabu J, et al. Atherosclerotic and thrombogenic neointima formed over sirolimus drug-eluting stent: an angioscopic study J Am Coll Cardiol Img 2009;2:616-624.[Abstract/Free Full Text]
- Nakazawa G, Vorpahl M, Finn AV, et al. One step forward and two steps back with drug-eluting-stents from preventing restenosis to causing late thrombosis and nouveau atherosclerosis J Am Coll Cardiol Img 2009;2:625-628.[Free Full Text]
- Farouque HMO, Meredith IT. The assessment of endothelial function in humans Coron Artery Dis 2001;12:445-454.[CrossRef][Web of Science][Medline]
- Kasprzak JD, Klosinska M, Drozdz J. Clinical aspects of assessment of endothelial function Pharmacol Rep 2006;58:33-40.[Medline]
- Marx SO, Marks AR. Bench to bedside: the development of rapamycin and its application to stent restenosis Circulation 2001;104:852-855.[Free Full Text]
- Mohacsi PJ, Tuller D, Hulliger B, Winjgaard PLJ. Different inhibitory effects of the immunosuppressive drugs on the human and rat aortic smooth muscle and endothelial cell proliferation stimulated by platelet derived growth factor J Heart Lung Transplant 1997;16:484-492.[Web of Science][Medline]
- Jeanmart H, Malo O, Carrier M, Nickner C, Desjardines N. Comparative study of cyclosporine vs newer immunosuppresants mycophenalate mofetil and rapamycin on the coronary endothelial function J Heart Lung Transplant 2002;21:990-998.[CrossRef][Web of Science][Medline]
- Vinals F, Chambard JC, Pouyssegur J. p70 S6 kinase-mediated protein synthesis is a critical step for vascular endothelial cell proliferation J Biol Chem 1999;274:26776-26782.[Abstract/Free Full Text]
- Fukuda D, Sata M, Tanaka K. Potent inhibitory effect of sirolimus on circulating vascular progenitor cells Circulation 2005;111:926-931.[Abstract/Free Full Text]
- Li J, Jabara R, Pendyala L, et al. Abnormal vasomotor function of porcine coronary arteries distal to sirolimus-eluting stents J Am Coll Cardiol Intv 2008;1:279-285.[Abstract/Free Full Text]
- Abal M, Andreu JM, Barasoain I. Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action Curr Cancer Drug Targets 2003;3:193-203.[CrossRef][Medline]
- Axel DI, Kunert W, Goggelmann C, et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery Circulation 1997;96:636-645.[Abstract/Free Full Text]
- Farb A, Heller PF, Shroff S, et al. Pathological analysis of local delivery of paclitaxel via a polymer-coated stent Circulation 2001;104:473-479.[Abstract/Free Full Text]
- Pendyala LK, Li J, Shinke T, Geva S. Endothelium-dependent vasomotor dysfunction in pig coronary arteries with paclitaxel-eluting stents is associated with inflammation and oxidative stress J Am Coll Cardiol Intv 2009;2:253-262.[Abstract/Free Full Text]
- Togni M, Raber L, Cocchia R, et al. Local vascular dysfunction after coronary paclitaxel-eluting stent implantation Int J Cardiol 2007;120:212-220.[CrossRef][Web of Science][Medline]
- Shin DI, Kim PJ, Seung KB, et al. Drug-eluting stent implantation could be associated with long-term coronary endothelial dysfunction Int Heart J 2007;48:553-567.[CrossRef][Web of Science][Medline]
- Kim JW, Suh SY, Choi CU. Six-month comparison of coronary endothelial dysfunction associated with sirolimus-eluting stent versus paclitaxel-eluting stent J Am Coll Cardiol Intv 2008;1:65-71.[Abstract/Free Full Text]
- Gössl M, Rosol M, Malyar NM. Functional anatomy and hemodynamic characteristics of vasa vasorum in the walls of porcine coronary arteries Anat Rec A Discov Mol Cell Evol Biol 2003;272:526-537.[CrossRef][Medline]
- Sahler LG, Davis D, Saad WE. Comparison of vasa vasorum after intravascular stent placement with sirolimus drug-eluting and bare metal stents J Med Imaging Radiat Oncol 2008;52:570-575.[CrossRef][Web of Science][Medline]
- Long C, Cook LG, Wu GY, Mitchell BM. Removal of FKBP12/12.6 from endothelial ryanodine receptors leads to an intracellular calcium leak and endothelial dysfunction Arterioscler Thromb Vasc Biol 2007;27:1580-1586.[Abstract/Free Full Text]
- Takeda Y, Miyamori I, Furukawa K, Inaba S, Mabuchi H. Mechanisms of FK 506-induced hypertension in the rat Hypertension 1999;33:130-136.[Abstract/Free Full Text]
- Jabs A, Göbel S, Wenzel P, et al. Sirolimus-induced vascular dysfunction: increased mitochondrial and nicotinamide adenosine dinucleotide phosphate oxidase-dependent superoxide production and decreased vascular nitric oxide formation J Am Coll Cardiol 2008;51:2130-2138.[Abstract/Free Full Text]
- Klugherz BD, Llanos G, Lieuallen W. Twenty-eight-day efficacy and pharmacokinetics of the sirolimus-eluting stent Coron Artery Dis 2002;13:183-188.[CrossRef][Web of Science][Medline]
- Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent. Should we be cautious?. Circulation 2004;109:701-705.[Abstract/Free Full Text]
- Shinke T, Geva S, Pendyala L. Low-dose paclitaxel elution by novel bioerodible sol-gel coating on stents inhibits neointima with low toxicity in porcine coronary arteries Int J Cardiol 2009;12:93-101.
- Pendyala L, Jabara R, Shinke T. Drug-eluting stents: present and future Cardiovasc Hematol Agents Med Chem 2008;6:105-115.[CrossRef][Medline]
- Virmani R, Liistro F, Stankovic G, et al. Mechanism of late in-stent restenosis after implantation of a paclitaxel derivate-eluting polymer stent system in humans Circulation 2002;106:2649-2651.[Abstract/Free Full Text]
- Kim JW, Park CG, Seo HS, et al. Delayed severe multivessel spasm and aborted sudden death after Taxus stent implantation Heart 2005;91:e15.[Abstract/Free Full Text]
- Wheatcroft S, Byrne J, Thomas M, et al. Life-threatening coronary artery spasm following sirolimus-eluting stent deployment J Am Coll Cardiol 2006;47:1911-1912.[Free Full Text]
- Brott BC, Anayiotos AS, Chapman GD, et al. Severe diffuse coronary artery spasm after drug-eluting stent placement J Invasive Cardiol 2006;18:284-292.
- Maekawa K, Kawamoto K, Fuke S, et al. Severe endothelial dysfunction after sirolimus-eluting stent implantation Circulation 2006;113:e850-e851.[Free Full Text]
- Hamilos M, Sarma J, Ostojic M. Interference of drug-eluting stents with endothelium-dependent coronary vasomotion: evidence for device-specific responses Circ Cardiovasc Intervent 2008;1:193-200.[CrossRef]
- Shin DI, Seung KB, Kim PJ, et al. Long-term coronary endothelial function after zotarolimus-eluting stent implantation Int Heart J 2008;49:639-652.[CrossRef][Web of Science][Medline]
- Kim JW, Seo HS, Park JH, et al. A prospective, randomized, 6-month comparison of the coronary vasomotor response associated with a zotarolimus- versus a sirolimus-eluting stent J Am Coll Cardiol 2009;53:1653-1659.[Abstract/Free Full Text]
- Hamilos MI, Ostojic M, Beleslin B. Differential effects of drug-eluting stents on local endothelium-dependent coronary vasomotion J Am Coll Cardiol 2008;51:2123-2129.[Abstract/Free Full Text]
- Haraguchi G, Pruitt S, Brodeur A, et al. Increased expression of eNOS by Endeavor zotarolimus-eluting stents compared to other DES in porcine coronary artery implants Am J Cardiol 2006;98:32-33.[CrossRef]
- Joner M, Nakazawa G, Finn AV. Endothelial cell recovery between comparator polymer-based drug-eluting stents J Am Coll Cardiol 2008;52:333-342.[Abstract/Free Full Text]
- Sharif F, Hynes SO, Cooney R. Gene-eluting stents: adenovirus-mediated delivery of eNOS to the blood vessel wall accelerates re-endothelialization and inhibits restenosis Mol Ther 2008;16:1674-1680.[CrossRef][Web of Science][Medline]
- Langeveld BE, Henning RH, de Smet BJA. Rescue of arterial function by angiotensin-(1-7): towards improvement of endothelial function by drug-eluting stents Neth Heart J 2008;16:291-292.[Web of Science][Medline]
- Stettler C, Wandel S, Allemann S. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis Lancet 2007;370:937-948.[CrossRef][Web of Science][Medline]
- Lagerqvist B, James SK, Stenestrand U. Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden N Engl J Med 2007;356:1009-1019.[CrossRef][Medline]
- Suwaidi JA, Hamasaki S, Higano ST. A long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction Circulation 2000;101:948-954.[Abstract/Free Full Text]
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Abstract
SES and Coronary ED