Inflammatory response, drug-eluting stent and restenosis

Cardiovascular diseases are the major cause of mortality in the Western world and it is expected that this will remain so during the foreseeable future.1 Among them, coronary artery disease (CAD) is the most important underlying cause of death due to cardiovascular disease.2 Current treatment of patients with CAD includes mainly risk factor management, drug therapy and revascularization techniques. Percutaneous coronary intervention (PCI) has been considered a great advance in the treatment of CAD. During the last decades, changes in vascularization techniques were developed that favor a number of patients that can be treated by means of PCI instead of the more invasive coronary artery bypass grafting (CABG).3 According to published data, more than 1.5 million patients have been subjected to PCI per year in USA.4 Although the devices and strategies of PCI have been rapidly progressing, the potential efficacy and safety issues are still major concerns as PCI technique continues to develop. The investigations of PCI-related complications and its mechanisms are ongoing, even in the era of drug-eluting stents (DES).5,6 Inflammation is a complication that continues to be investigated and has been linked to PCI since the development in angioplasty.7 In this article, we review the current status of inflammation linked to PCI, especially as it relates to restenosis, drug-eluting stents and its clinical implications. RESTENOSIS: A CHALLENGE FOR CORONARY INTERVENTION The development of coronary stents has revolutionized the field of interventional cardiology by reducing the incidence of restenosis after balloon angioplasty.4 Intracoronary stents not only increase procedural success rates, but also increase the safety of procedures by decreasing the need for emergency CABG surgery. However, the introduction of stents is still associated with a serious complication, namely, in-stent restenosis (ISR).8 Regardless of which percutaneous approach is chosen to treat an in-stent restenotic lesion, including balloon angioplasty, stent, rotational atherectomy or laser angioplasty, 30% to 80% of the patients will develop restenosis within the stent, at the stent edges or both sites. Knowledge of the development of ISR, therefore, is important for effective, safe strategies for prevention and intervention.9 Restenosis following coronary stenting has long been attributed to elastic recoil immediately following balloon deflation, neointimal proliferation triggered by injury to the vessel wall and late negative remodeling.5 Investigators including basic and clinical researches, have been researching this problem for a decade. Despite intensive studies have been performed on restenosis the factors that contribute to the ISR have not been fully elucidated.6 Currently, extensive data available from randomized control studies have suggested that three kinds of major factors might be contributing to ISR, namely, factors related to the lesion or the procedure, factors that are patient-related and genetic-related factors. Lesion- and procedure-related factors have been demonstrated to be closely associated with ISR.10 Among them, the most important lesion characteristics that influence restensosis in clinical practice are the reference vessel diameter, preprocedural minimal lumen diameter, lesion length and postprocedural minimal lumen diameter.11 Patient-related factors that have been most consistently associated with an increased risk of stent restenosis are the presence of diabetes, the clinical setting of acute coronary syndromes and an inherent tendency to develop stent restenosis.6 Consistent with previous studies, our published data in the Chinese Han population indicated that conventional coronary risk factors such as hypertension, hyperlipidemia and history of CAD were not associated with a higher rate of restenosis caused by bare metal stent (BMS) or DES implantation.3 Some genetic variations are proven to be correlated with transcriptional activity and/or protein production.12 Interestingly, the intensity of the inflammatory process and the angiographic or clinical outcome after stenting are also influenced by genetic factors.13 A number of studies carried out in the last decade have consistently indicated that inflammatory mechanisms play a pivotal role in the process of neointimal proliferation and stent restenosis.14-17 CORONARY STENTING: A STIMULUS OF INFLAMMATORY RESPONSE What triggers the inflammatory response following coronary stenting? An experimental study showed that leukocyte recruitment could be detected at the level of the coronary segment injured by the stent within 10-15 minutes of stent deployment.16 Leukocyte invasion is also associated with massive deposition of activated platelets. The invading neutrophils, platelets and coronary endothelium injured by the stent undergo functional changes manifested by a significant increase of the cellular surface expression of a variety of ligands; platelets activate their inducible fibrinogen receptors and neutrophils up-regulate Mac-1 and L-selection receptors.18 Of note, none of these changes occurs across the stenotic non-dilated coronary artery segments. Initially, the recruitment of inflammatory cells at the level of the stent is caused by local endothelial release of powerful chemo-attractant molecules and interleukins (IL).16 In addition, several clinical studies have focused on the early markers or initiators of the inflammatory response following coronary stenting. Aggarwal et al19 demonstrated that among the inflammatory markers, including C-reactive protein (CRP), IL-6, and IL-1 receptor antagonist (IL-1Ra), soluble CD40 ligand (sCD40L) exhibited the greatest relative rise in the first 10 minutes after coronary stenting. This indicates that sCD40 may be an early inflammatory marker in the initiation of inflammation after coronary stenting. In our time course study of inflammatory response after renal artery stenting, we found that renal artery stenting could trigger an inflammatory response as evidenced by increased plasma levels of CRP and IL-6. IL-6, however, was an early initiator of inflammatory cytokines and CRP was a later marker of systemic inflammatory response to renal artery stenting.15 Recently, Gach et al20 measured serum myeloperoxydase, lactoferrin, elastase, CRP and cytokines (IL-6, IL-8 and IL-11) in patients with acute coronary syndrome. They found that in patients with unstable angina, coronary stenting is associated with immediate neutrophil activation followed by release of inflammatory cytokines and CRP elevation. This study pointed out a potential role of myeloperoxydase as a trigger for the inflammatory reaction in patients with unstable coronary syndromes undergoing PCI. These early markers of inflammatory response following coronary stenting may be a trigger for an inflammatory cascade and, therefore, a target for controlling ISR. Paroli et al21 observed the plasma levels of substance P (SP), neurokini A (NKA), tachykini, interferon (INF)-γ and tumor necrosis factor (TNF)-α in patients with both stable angina and acute coronary syndrome following coronary stenting. They found that plasma levels of both INF-γ and TNF-α were significantly higher in patients with chronic or acute coronary artery disease than the levels in control subjects at the time of presentation. Levels of NKA and INF-γ were also significantly increased at 15 minutes during acute coronary syndrome compared with patients with stable coronary disease. The analysis performed during and after PCI revealed that INF-α levels increased 15 minutes after stent implantation in both chronic and acute coronary syndrome patients and TNF-γ levels increased in chronic patients only when compared to basal values. In addition, a significant decrease of both NKA and SPA levels 48 hours after the end of the revascularization procedure were observed in acute coronary syndrome patients. These data suggest that modulation of tachykinin and/or cytokine release with proinflammatory activity in chronic or acute cardiac ischemia, and following coronary stenting, might play an important role in heart tissue damage and in long-term inflammatory complications of PCI. Moreover, the magnitude of the local inflammatory response may affect the process of restenosis. The data have indicated that patients with a higher release of IL-6 immediately after stent deployment have a higher risk of restenosis.22 Furthermore, the antibody binding capacity for 8B2 monoclonal antibody against an activationdependent neoepitope or Mac-1 (8B2) is also important. 23 This molecule is responsible for firm leukocyte adhesion to platelet and fibrinogen and increases within 10 minutes after stent deployment; increase is more prominent in patients who will develop ISR than in patients without restenosis. Finally, it is likely that the magnitude and persistence of the local inflammatory reaction is partly controlled by individual genetically determined factors. Indeed, the exposure of the metal stent may trigger a persistent inflammatory response to a "foreign body" in susceptible patients that, in turn, may affect neointimal proliferation and stent restenosis.24 Sardella and coworkers25 studied elevated inflammatory markers from 59 patients with stable angina following coronary stenting. They demonstrated that a local release of proinflammatory cytokines, including IL-1 beta and IL-6, occurs shortly (20 minutes) after coronary stent placement, including DES, which is possibly related to plaque rupture and/or endothelium trauma following the stenting procedure. This study suggests that precocious anti-inflammatory treatment could benefit the clinical outcome of PCI. Finally, local inflammation caused by stent deployment also elicits a systemic inflammatory response initially mediated by inflammatory leukins such as IL-1, IL-6 and TNF-α.16 These molecules cause a production of acute phase reactants, such as CRP, in the liver that rapidly increase in the blood and may directly amplify the local response to the inflammatory stimulus.26 Our previous study showed that increased levels of IL-6 and CRP could be detected at 30 minutes and 6 hours respectively following renal artery stenting.17 In patients with stable angina, single vessel disease and normal baseline CRP plasma levels, successful stent implantation is followed by a rapid increase of CRP with peak level 48 hours after stenting. Interestingly, patients with a persistence of elevated CRP levels at 72 hours showed an increased risk of cardiac events during the follow-up.27 This finding strongly supports the hypothesis that genetically determined individual factors might affect local and systemic response to the inflammatory stimulus represented by the stent. Therefore, the risk of restenosis seems dependent on the magnitude and persistence of local inflammation. In addition, the risk also depends upon the magnitude and persistence of the systemic inflammatory response, which in turn, may directly amplify local inflammatory process. INFLAMMATION: A CONTRIBUTOR OF IN-STENT RESTENOSIS Percutaneous coronary stenting induces an early inflammatory reaction. The intensity of such a reaction, as measured by high-sensitivity CRP, has not only proved to be correlated with recurrent ischemic events but also associated with restenosis.27 It is believed that the magnitude of the systemic inflammatory response induced by PCI has an impact on the long-term outcome in patients with both stable angina and unstable angina. Kozinski and coworkers28 investigated whether an inflammatory response appears in ISR patients undergoing balloon angioplasty and to assess its pattern and magnitude in relation to stable angina and unstable angina. A comparison was done of patients with stable angina and unstable angina undergoing single vessel coronary balloon angioplasty followed by stenting versus ISR subjects in who only balloon angioplasty was done. Serum CRP, serum amyloid A (SAA), TNF-α and IL-10 was measured in blood samples collected before and 6 hours, 24 hours and 1 month after procedures. The results showed that a comparable pattern of inflammatory response in terms of CRP and SAA concentrations in subjects undergoing PCI due to ISR and stable angina was present, while in unstable patients the magnitude of the response was substantially higher. CRP and SAA levels increased significantly in each group with the peak value at 24 hours and the baseline levels remarkably correlated with the highest concentration. In contrast, preprocedural TNF-α concentrations were higher in the ISR group when compared with stable and unstable patients. Additionally, in the ISR group a two-fold increase in their values, of borderline significance was noted at 6 hours. Stable and unstable patients were found to have significantly lower TNF-α levels at 6 and 24 hours after the intervention, although the concentrations markedly increased with peak values at 1 month. This study suggests that PCI triggers a systemic inflammatory response in patients with ISR and considerable differences in its pattern are seen when comparing stable and unstable patients. Moreover, a high preprocedural TNF-α level and its increase provoked by PCI in the ISR group warrant the need for further investigation of its possible involvement in the restenosis process. Levels of CRP, SAA and IL-6 can predict coronary restenosis following angioplasty and stent deployment in patients with unstable angina. However, some studies did not support this hypothesis. Gomma et al29 investigated whether measurement of periprocedural inflammatory markers predict the angiographic outcome at 6 months in stable angina patients undergoing coronary stenting. The serum CRP, SAA and IL-6 were determined by high-sensitivity immunoassays before the stent was implanted, and quantitative computer-assistant angiographic analysis was performed at 6 months following coronary stenting. The results showed that preprocedural inflammatory markers in stable angina subjects undergoing coronary artery stent deployment did not correlate with the development of ISR. Differences in pathobiology between stable and unstable angina coronary syndrome, the widespread use of statins with anti-inflammatory activity in their cohort of patients, along with different mechanisms underlying the early angiographic appearances of restenosis as compared to clinical end points most likely explain those findings. Moreover, Blum et al30 studied 30 consecutive patients who underwent coronary stenting with respect to post-procedure endothelial dysfunction and levels of preand post-procedure cytokines. They found that patients with severe impairment of flow-mediated dependent dilation, but not flow-mediated independent dilation, had higher concentrations of CRP before PCI and 24 hours after stenting than patients without severe abnormities of systemic endothelial function. Thus, endothelium dependent dilation abnormalities were related to the systemic inflammatory status, whereas endotheliumindependent dilation abnormalities were not related to the inflammatory response of the patients. Yazdani et al31 also investigated the effect of PCI on the levels of inflammatory markers. They found that following coronary stenting IL-6 was significantly elevated in patients with unstable angina compared with patients with stable angina. However, at 1-month follow-up after stenting, there were no longer any differences between the levels of IL-6 in patients with unstable angina versus patients with stable angina. This suggests that IL-6 levels may correlate with the instability of atheromatous plaque and that the decrease of IL-6 levels after stenting may represent plaque reendothelization and stabilization. Additionally, Saleh et al32 demonstrated that coronary stent implantation and not the pathogen burden, including cytomegalovirus, Chlamydia pneumoniae, Epstein-Barr virus, Helicobacter pylori and herpes simplex virus, was associated with plasma CRP and IL-6 response to percutaneous coronary intervention. DRUG-ELUTING STENT: A DEVICE OF ANTI-INFLAMMATORY ACTION Although coronary artery stenting represents a major improvement in the treatment of patients with CAD, stent restenosis remains a principle drawback with substantial clinical implications.6 Neointimal proliferation is the main mechanism involved in the process of stent restenosis. A number of previous investigations have consistently suggested that inflammation plays a major role in determining ISR via neointimal proliferation.5 The development of DESs have further revolutionized the field of interventional cardiology, based upon the results of recent clinical trials of paclitaxel or sirolimius-eluting stents that have demonstrated significantly reducing ISR in the treatment of coronary artery lesions.33-35 In addition to their anti-proliferative activity, DESs have been demonstrated to possess an anti-inflammatory property, especially for sirolimus-eluting stents that were compared with BMS.36,37 Because neointimal proliferation is ultimately related to the magnitude and persistence of local and systemic inflammation, this reasonable therapeutic approach has been demonstrated to be aimed primarily at the inflammatory pathogenetic mechanisms of ISR.38 It is well-known that neointimal proliferation with plaque formation is the principle cause of CAD. In the neointima, inflammatory cytokines, like TNF-α, are expressed by smooth muscle cells (SMC). These cytokines stimulate proliferation and migration of SMC, events that are crucial to neointima formation. It has been shown that stents liberating rapamycin reduced neointima formation in human coronary arteries. To assess the mechanism for this effect, a study was preformed by Adkins et al37 to determine if rapamycin could inhibit the production of TNF-α by SMC. In their study, SMC were cultured from the saphenous vein segment obtained from patients. Cells were exposed to bacterial lipopolysaccharide (LPS), LPS plus rapamycin or LPS plus isoproterenol for 24 hours. Cells without treatment served as controls. The culture medium was then removed and analyzed for TNF-α. Additionally, the effect of treatment on cell viability was also determined by assay of the mitochondrial activity. TNF-α release into the culture medium is expressed as pg TNF-α/mg cell protein. The data showed that with control cells, TNF-α was undetectable in the culture medium. The addition of LPS (10 mg/ml) increased TNF-α release to (4321±705) at 24 hours. The addition of 1 rapamycin with LPS TNF-α production LPS A of TNF-α release was seen with 1 and rapamycin isoproterenol cell These data that rapamycin the release of TNF-α from SMC with inflammatory like is an that Therefore, a potential mechanism for the of stents is of inflammatory cytokine expression by SMC. In rapamycin has significant anti-proliferative and anti-inflammatory and neointimal formation after angioplasty in patients with CAD. effect on transcriptional neointima formation has also been investigated et analyzed the effect of rapamycin on expression during neointimal formation in a human culture angioplasty, renal artery were cultured for or in the or presence of expression analysis of revealed with a peak after of those were associated with recruitment of blood cells and inflammatory of the vessel and cytokines, such as factor IL-8 and were found in response to vessel of a recruitment and of cells were also In this rapamycin the and expression pattern along with of related to proliferation and study indicated that injury to of a expression pattern in the vessel wall even in the of These events could a for the recruitment of and the expression of such rapamycin may to a reduced recruitment of and after an effect that may play a role for its in reducing ISR. In addition, clinical studies in have also suggested that DES an anti-inflammatory effect which is associated with reducing ISR. It is that DES early and of anti-inflammatory et that DES be associated with early in inflammatory release after PCI. In their study, a of patients with acute coronary syndrome underwent percutaneous coronary intervention in a randomized to the relative against PCI dysfunction and PCI among and in 30 study of and compared with CRP, IL-6, and on normal expression and were 24 hours after PCI. DES use was at the treated with DES versus were more likely to have before PCI and the artery as the artery The increase in CRP and was lower among patients undergoing DES implantation for CRP, for even after for randomized before status, artery and and IL-6 was lower with DESs on analysis but not and did not with DES They that among patients with acute coronary syndrome undergoing DES, implantation more in markers of inflammation and necrosis than patients Furthermore, et compared plasma CRP levels after DES implantation with levels after implantation in patients DES, CRP levels were determined before intervention and at 48 hours, 72 hours and after coronary stenting. They found that plasma CRP levels at 48 hours and 72 hours were significantly higher in the group than those in the DES They indicated that DES showed significantly lower plasma CRP levels after coronary stenting compared with This may the of DES on acute inflammatory induced by coronary intervention. inflammation plays a major role in determining stent restenosis via neointimal DES has been shown to decrease ISR in clinical trials and in the world practice of interventional Although stent restenotic with DES may be mainly due to its anti-proliferative activity, an anti-inflammatory may also be an important for controlling the process. A FOR It has been demonstrated that coronary stent implantation could trigger an early inflammatory response in the local vessel and systemic In addition, previous studies indicated that the magnitude of the systemic inflammation is associated with early and late clinical such as restenosis, and death following Therefore, to systemic inflammatory response after stenting may be of potential to interventional The procedures of current coronary intervention mainly of three stenting and in an to stent and are aimed at reducing restenosis and cardiovascular events after PCI. coronary stent deployment without balloon is coronary It has been since the development of and was with during the current PCI era it can decrease procedure time and exposure and as as the procedure there are several potential to use a stenting it injury and and reduced restenosis from Although a randomized trials comparing the coronary stenting approach with conventional techniques to a significant in restenosis in the stenting has still widespread due to reduced procedure-related and a of coronary stenting randomized trials indicated a of clinical including restenosis, when compared with a the sirolimus-eluting This suggests that coronary stenting may to the benefit of stenting during the DES are studies that inflammation plays an important role in the initiation and as as of that is an inflammatory disease. The the role of inflammatory in different clinical of coronary artery disease has also been the mechanisms restenosis is not fully studies have shown that inflammation may be a for restenosis, and reduced restenosis rate by DES may be associated with the anti-inflammatory of In addition to their anti-proliferative activity, DESs have been demonstrated to possess an anti-inflammatory compared with However, the of interventional technique when devices with the introduction of DES, concerns have been that coronary DES implantation may further the inflammatory response, and the benefit of This may to interventional techniques to world clinical practice in the DES