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Ann Thorac Surg 2006;81:1918-1925
© 2006 The Society of Thoracic Surgeons

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Review

Coronary Stenting and Inflammation: Implications for Further Surgical and Medical Treatment

Cardiovascular Surgery Discipline, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil

Accepted for publication October 17, 2005.

^_* Address correspondence to Dr Gomes, Cardiovascular Surgery Discipline, Escola Paulista de Medicina, Federal University of São Paulo, Rua Botucatu 740, São Paulo, SP 04023-900, Brazil (Email: wjgomes.dcir{at}epm.br).

	Abstract

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
The introduction of percutaneous coronary interventions (PCI) with stent implant has substantially shifted the treatment of coronary artery disease. The current approach to coronary artery disease treatment includes first-choice PCI in selected subgroups; and once this therapy fails, frequently the patient is referred for coronary artery bypass graft surgery. However, evidence of chronic inflammatory reaction and endothelial dysfunction after PCI has been emerging and that might be interfering with patient outcome when surgical or medical treatments are subsequently required. The clinical significance of these complications after PCI, herein examined, has been less studied and needs better assessment. Also, the premise that coronary artery bypass graft surgery can safely be performed in patients with coronary stenting failure may not hold true, as graft patency might be adversely affected. Furthermore, the superimposed inflammatory reaction may blunt the efficacy of medical treatment.

	Introduction

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
The introduction of percutaneous coronary interventions (PCI) with stent implant has substantially shifted the treatment of coronary artery disease. The current approach to coronary artery disease treatment includes first-choice PCI in selected subgroups; and if this therapy fails, the patient is often referred for coronary artery bypass graft (CABG) surgery. However, novel complications associated with inflammatory reaction after PCI have been emerging and might be interfering with patient outcome when surgical or medical treatments are subsequently required.

Stents have evolved from the early concept of providing support to prevent vessel recoil and negative remodeling, becoming elaborate devices, and have culminated with the highly sophisticated technology of drug-eluting stents.

However, unlike balloon angioplasty, in which elastic recoil and vessel remodeling play an important role for vessel luminal loss in the long term, restenosis after coronary stenting takes place because of neointimal proliferation. It also bears a relationship to the extent of the vessel injury and inflammatory response [1].

Recent evidence has demonstrated that implant of coronary stents evokes the advent of a local and systemic inflammatory response syndrome [2–8], and restenosis comprises only part of the manifestation of the inflammatory reaction. The consequent endothelial dysfunction and ischemia are connected events that have not been well studied.

	Pathophysiology of Vascular Injury and Restenosis

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
Experimental animal and human autopsy studies have demonstrated that local arterial reaction to balloon dilatation and stenting follow a response-to-injury sequence of events. In human studies, coronary stents are shown to elicit an initial acute inflammatory cell response within 0 to 3 days, centered at the stent struts, the severity of which is related to the trauma to the vessel wall. Stimulus for the inflammatory and restenosis process is disruption of the coronary endothelial layer. That promptly activates inflammatory cells, with early neutrophil recruitment to the injury site, followed by prolonged macrophage accumulation [9].

By 2 to 4 weeks, acute inflammation subsides and is replaced by chronic inflammatory cells, along with proliferating smooth muscle cells associated with organizing thrombus and a thin provisional extracellular matrix. Beyond 30 days, fibrin and chronic inflammation persist, and smooth muscle cells and extracellular matrix (proteoglycans and collagen) further enrich the expanding neointima [10].

Coronary stenting appears to cause a deeper arterial injury and a more intense inflammatory response into the vessel wall than does balloon angioplasty [11]. Balloon angioplasty is followed only by an early neutrophil infiltration and, in contrast, in stented arteries early neutrophil recruitment is followed by prolonged and abundant recruitment of macrophages within the neointima [11, 12].

The inflammatory reaction triggered by the stent insertion is maintained by several concomitant factors. Besides the mechanism of stent expansion with vessel wall rupture, there are the superimposed permanent radial mechanical strain applied to arterial wall, the presence of an intravascular residual metallic foreign material, and ischemic phenomena induced by endothelial dysfunction. The stent struts cause focal deep vascular trauma, and it has been demonstrated that the initial inflammatory reaction is more accentuated at the points of greatest strain of the stent struts on the arterial wall [12].

Additionally, the main inflammatory and proliferative reactions are not limited to the vessel wall but rather extend from the injured vessel throughout the surrounding tissues, including adjacent myocardium [5, 13].

	Inflammatory Markers After Stenting

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
To date, several studies have demonstrated that PCI induces the release of multiple inflammatory markers [8, 14, 15] that are associated with a later poor prognosis [16].

Clinical investigations have shown that PCI with stent implant results in leukocyte and platelet activation, both locally in the coronary sinus and systemically in the peripheral circulation. It also increases the expression of adhesion molecules, and formation of platelet–leucocyte complexes [17]. Patients expressing high levels of cellular activation are at higher risk for restenosis and cardiac events after successful PCI with stent implant [18].

Rajagopal and associates [16] found that after PCI, white blood cell counts were an independent predictor of long-term mortality and a significant predictor of mortality in the subgroup of patients with an increase in postprocedural creatine kinase–myocardial band (CK-MB) values. Fukuda and associates [19] found that circulating monocytes raise after coronary stent implantation, and the peak monocyte count was related to in-stent neointimal volume. In coronary sinus, blood samples taken 15 minutes after angioplasty showed an augmented expression of adhesion molecules on the surface of neutrophils and monocytes [20], whereas interleukin-6 (IL-6) levels increased as early as after 1 hour [21].

Adverse late clinical outcomes are linked to the magnitude of the systemic inflammation and patients undergoing PCI may be risk stratified according to an increase in concentrations of inflammatory markers before percutaneous intervention as well as an increase in their concentrations afterward [22].

Navarro-Lopez and colleagues [23] demonstrated that at 6 months of follow-up, patients with stent restenosis presented amplified inflammatory activity expressed by a rise of the cytotoxic T lymphocytes CD3+/CD56+ and activated monocytes CD11b. Plasma concentrations of IL-6 and tumor necrosis factor alpha (TNF-) increased significantly after the intervention, but only TNF- concentrations remained high at 6 months [23].

Current studies demonstrated that stent deployment is associated with an increase in C-reactive protein (CRP), and this rise on CRP level was significantly higher in stable plaques rather than unstable plaques. Elevated circulating values of CRP, a sensitive systemic marker of inflammation, shows a significantly increased risk of plaque rupture and coronary events [2, 4, 6–8, 24]. In fact, the most notable association of outcomes and CRP has been with mortality and, to a lesser extent, with myocardial infarction [24].

Almagor and colleagues [2] showed that CRP levels in patients after coronary stent implantation were persistently high and a correlation between increases in the CRP concentration after PCI with stenting and adverse events was also reinforced. Elevation of CRP has been shown to predict death during follow-up after PCI [7, 9]. Additionally, after PCI with stenting, it has been suggested that an increased serum level of CRP is associated with progression of disease at areas remote from the initial stented lesion, and not necessarily to in-stent restenosis per se [25].

An increase in lipid peroxidation accompanied by a reduction in the stable end products of nitric oxide in plasma was observed in patients with stent restenosis several months after PCI. Oxidative stress appears to be involved in several processes that contribute to atherogenesis [26]. Additionally, data from experimental and human studies have suggested that oxidized low-density lipoproteins contain vasoactive moieties, and it is possible that release of such vasoactive substances during PCI may lead to vasoconstriction of the microvasculature and no-reflow phenomenon [27]. Cutlip and associates [28] found that the clinical outcome beyond 1 year after stenting is determined by a high rate of events related to disease progression in coronary segments other than the stented lesion, which itself remains relatively stable [28].

Significant clinical and angiographic stent restenosis occurs in roughly one third of patients with bare stents, but varied grades of restenosis take place in all stented arteries [29].

Several diseases are presently known to evolve with a pattern of persistently high inflammatory markers; the pathogenesis of these diseases, such as cardiovascular and degenerative diseases, infections, and cancer, have been linked to chronic inflammatory processes [30]. Recent studies have identified the role of proinflammatory mediators and endothelial dysfunction in the development and progression of heart failure [31].

	Post-Stenting Endothelial Function

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
Chronic inflammation induces cytokine hypersecretion and eventually leads to changes in endothelial mediators releasing. An enhanced circulating level of proinflammatory cytokines resulting in persistent low-grade inflammation are associated with endothelial dysfunction and is deleterious for vascular functions.

Endothelial damage is a major cause of postangioplasty restenosis [9]. The harm to endothelial function during angioplasty decreases the availability of vasculoprotective molecules such as nitric oxide (NO) and prostacyclin as well as antioxidant systems, with a concomitant increment in the production of growth-promoting substances [32].

Patients who underwent PCI exhibited more severe endothelial dysfunction in the long term after stenting when compared with balloon angioplasty or direct rotational atherectomy, as assessed by the study of the endothelial-dependent vasomotor function at more than 6 months after stent implantation [33]. Prospective works have demonstrated post-PCI inhibition of vasodilatory mediators synthesis (particularly NO) [34] and increased release of endothelin-1, a potent vasoconstrictor [35, 36].

The evaluation of plasma concentrations of NO end product in patients who underwent coronary PCI showed significant decreases in stable NO end products observed 3 and 6 months after the procedure [37]. Impaired NO bioavailability plays a central role in the initiation and progression of atherosclerosis, and also is involved in the complex process of restenosis after arterial injury [9].

Additionally, incomplete stent endothelialization is commonly found late after stenting [38, 39]. Evidence has demonstrated that at least until 18 months after stenting, the neointima remains incompletely healed and retains the potential for shrinkage and further morphologic changes [40].

Recurrence of angina within 6 to 9 months after a PCI is often due to restenosis of the dilated lesion or in-stent stenosis. However, many patients continue to experience angina despite the presence of patent stents, and in these patients, angina may be due to dynamic vasoconstriction resulting from abnormal vasomotor balance due to endothelial dysfunction [41]. Other patients experience recurrence of symptoms over time owing to the progression of the disease in nondilated segments of the coronary arteries [41].

It has been speculated that endothelial dysfunction may lead to repeated episodes of myocardial ischemia and small infarcts that ultimately contribute to the development of heart failure. This hypothesis is supported by the observations that endothelial dysfunction is present in patients with early asymptomatic as well as symptomatic heart failure [42].

Also, the endothelial dysfunction and its consequences may adversely affect graft patency in patients requiring coronary artery bypass graft surgery after PCI. Kamiya and associates [43] compared early and late graft patency in patients with and without previous successful percutaneous transluminal coronary angiography (PTCA). Although not reaching statistical significance owing to the small sample analyzed, the late patency rate of the left internal thoracic artery graft bypassed to the left anterior descending artery in patients with previous PTCA tended to be lower than in patients without previous PTCA [43]. Surely this outcome should be confirmed by further prospective studies.

	Periprocedural Myocardial Injury

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
Periprocedural PCI myocardial injury may play an important role in the cascade of inflammatory events. Acute ischemic process is triggered by three factors related to stent implant procedure. The first is due to atheroembolism elicited by expansion of the stent with rupture of the atherosclerotic plaque and release of its contents, with the formation of emboli clogging the distal coronary microcirculation. The other mechanism involved is the occlusion of the side branches of the coronary artery coming off the stented segment, causing focal infarctions in the territory supplied by these branches. Next, the subsequent microvascular endothelial dysfunction evoked by release of endothelial factors plays a pivotal role in the ensuing cascade of events.

Creatine kinase–myocardial band elevation after PCI occurs in approximately 25% of the patients and has been related to subsequent risk of cardiac death, occurring primarily in the first 3 to 4 months. A recent meta-analysis, pooling data from seven studies and 23,230 patients, revealed that any increase of CK-MB above normal limits is associated with increased mortality [44].

Definitely, mild increase of CK-MB after PCI is the result of discrete microinfarction. This was assessed by contrast-enhanced magnetic resonance imaging demonstrating the correlation between new areas of hyperenhancement within the target vessel perfusion territory and procedure-related CK-MB elevation [45].

Troponin is now deemed a more reliable biochemical marker of myocardial infarction. The incidence of troponin I release has been higher in patients undergoing stent implantation than in patients treated with angioplasty alone [46]. Release of cardiac troponin I after PCI has been reported for roughly 50% of the stented patients [46, 47].

Cantor and colleagues [46], studying the incidence and clinical significance of elevated cardiac troponin I after PCI in a large series of patients, demonstrated that 48% of these patients had elevation of cardiac troponin I levels after PCI. This raise of cardiac troponin I was associated with a significant increase in the risk of death or infarction and worse clinical outcomes in the first 90 days after the procedure. Similar findings were reported by Nageh and colleagues [47].

Selvanayagam and associates [48] showed that all post-PCI patients demonstrating postprocedural elevation in troponin I have evidence of new irreversible myocardial injury on delayed-enhancement cardiovascular MRI. In these patients, the magnitude of irreversible myocardial injury represented, on average, 5% of total left ventricle mass [48]. As an estimate for comparison, cardiac magnetic resonance imaging performed on patients with anteroapical acute infarction and new Q waves in leads V1 to V4 demonstrates irreversible myocardial damage in 10% of absolute left ventricle mass [49].

A recent study found that troponin I elevation was an independent predictor of major cardiac events at 1-year follow-up, particularly the need for repeat revascularization [50].

Distal embolic protection with a balloon-occlusion device failed to improve microvascular flow and reperfusion success. It also failed to reduce infarct size, or enhance event-free survival in acute myocardial infarction patients undergoing primary PCI (the EMERALD trial). Although the device effectively captured atherothrombotic debris in 73% of patients, removal of debris did not have any significant effect on the primary endpoints. The left ventricular infarct size was similar in both groups, and there was no improvement in event-free survival. It seems that the device is not able to impede soluble mediators release and the mechanisms interfering with microcirculatory endothelial function [51].

Depending on the magnitude of the left ventricular damage imposed by this phenomenon, the left ventricular function may be found poorer in case of a subsequent need of CABG surgery.

	Inflammation and Coronary Artery Disease

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
Atherosclerosis is a chronic inflammatory disease characterized by migration of monocytes and T lymphocytes to the area of arterial wall injury. In addition to promoting plaque development, inflammation increases plaque instability, leading to plaque rupture and thrombosis. Several studies have demonstrated an association between inflammatory status and prognosis in coronary artery disease [52].

Stents are usually deployed to the area of the so-called culprit lesion, which is commonly the spot of most intense coronary artery inflammatory process [53]. It has been suggested that the stent deployment acts in synergy with the atherosclerotic plaque, potentiating the inflammatory response that had already taken place in the coronary arterial wall. Eventually this leads to accelerated progression of the inflammatory process and hence atherosclerotic disease. In a study analyzing long-term clinical follow-up after the implantation of second-generation coronary stents, the stented target lesion was clinically stable after the first 12 months. Thereafter, new events resulted almost exclusively from the progression of disease within other segments of the target vessel or in nontarget vessels and continued to grow steadily [28].

	Coronary Aneurysms

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
Mechanical injury and subsequent inflammatory reaction of the coronary artery wall elicit the appearance of weak areas, causing the formation of aneurysms. The incidence of coronary aneurysms after PCI has been reported range from 1.5% to 4% [54]. Outcome and prognosis of patients with coronary artery aneurysms are also poorly understood.

	Late Post-Stenting Structural Changes

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
Few studies have addressed the late morphologic cardiac changes induced by post-stenting inflammatory reaction. Farb and associates [40] studied the chronic phase of neointimal evolution, unveiling that the neointima in stents remains hypercellular up to 18 months after stenting, resembling wounds that are not fully healed.

Kimura and associates [55] evaluated long-term (7 to 11 years) clinical and angiographic outcome in 405 patients after stenting, demonstrating that the luminal response is triphasic, namely, the early restenosis phase (until 6 months) and the intermediate-term regression phase (from 6 months to 3 years) were followed by a late renarrowing phase beyond 4 years.

Inoue and coworkers [38], examining stented coronary arteries obtained from patients autopsied after noncardiac death 2 to 7 years after stenting, found that after 2 years there was chronic inflammatory response surrounding the stent with abundant proliferation of collagen fibers, with presence of helper/inducer T lymphocytes and mild macrophage infiltration around the stent struts. After 4 years, the analysis revealed prominent infiltration by lipid-laden macrophages and covered by nonocclusive mural thrombi. In their words, stainless steel stents evoked a remarkable foreign-body inflammatory reaction to the metal, where these persistent chronic inflammatory cells may accelerate new atherosclerotic changes and consequent plaque vulnerability [38].

	Drug-Eluting Stents

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
The emergence of drug-eluting stents (DES) has introduced another variable interacting with the arterial wall. These drugs possess effects that can lead to the appearance of other specific complications (idiosyncrasy). Instances are the recent launching of stents coated with sirolimus, the generic name of rapamycin (Cypher, Cordis, J&J) and paclitaxel (Taxus, Boston Scientific). Despite the manifest antiproliferative effect of sirolimus (rapamycin) resulting in reduction of the endothelial growth and intrastent restenosis, the inflammatory response seems to be aggravated at the stent extremities (edge effect), producing an exacerbation of the inflammatory response [56]. Also the endothelialization is delayed, leaving an unhealed intima with exposure of metal frame [56].

Sirolimus has been demonstrated to potentiate the effect of some platelet agonists and thus may promote thrombus formation [57]. Concentrations of sirolimus in the nanogram range were sufficient to cause significant enhancement of agonist-induced platelet aggregation [58]. In addition, the sirolimus has been demonstrated to decrease NO production [59]. Nitric oxide plays a significant role in preventing platelet aggregation and clot formation, in addition to promoting vasodilation.

The comparative induction of inflammatory response after bare-metal stents and DES has been currently evaluated. Dibra and colleagues [60] performed serial measurements of CRP in patients who received a sirolimus-eluting stent or a bare-metal stent in the setting of a randomized trial. Median values of CRP before and after stenting were similar between groups, with no statistical difference [60].

The release of interleukin 1ß (IL-1ß) and IL-6 proinflammatory cytokines after elective placement of either bare-metal stents or DES was randomly evaluated. Patients were assigned to receive bare-metal, paclitaxel-eluting, or sirolimus-eluting stents during elective PCI. Levels of IL-1ß and IL-6 were significantly increased in patients receiving either bare, paclitaxel- or sirolimus-eluting stents 20 minutes after stent implantation as compared with basal concentrations. The variation in the level of both cytokines was comparable among the three study groups [61]. Therefore, a local release of proinflammatory cytokines occurs shortly after coronary stent placement, including DES, which is possibly related to plaque rupture or endothelium traumatism after the stenting procedure. These data indicate the lack of an inhibitory effect of these drugs on the local release of proinflammatory mediators in the very first moments of stent implantation. The effect of these drugs (paclitaxel and sirolimus), although released shortly after stent placement, is likely to be unable to counteract the endothelial response after the traumatism induced by the stent placement [61].

Togni and associates [62] studied endothelial function, assessing coronary vasomotor response to exercise after sirolimus-eluting and bare-metal stent implantation. In bare-metal stent patients, the adjacent segments proximal and distal to the stent showed exercise-induced vasodilation. In contrast, there was exercise-induced vasoconstriction of the proximal and distal vessel segments adjacent to the sirolimus-eluting stent. The implantation of a bare-metal stent does not affect physiologic response to exercise. However, the sirolimus-eluting stent was associated with exercise-induced paradoxic coronary vasoconstriction of the adjacent vessel segments, although vasodilatory response to nitroglycerin was maintained. These observations suggest drug-induced endothelial dysfunction as the underlying mechanism [62].

Comparative release of cardiac biomarkers was investigated in patients receiving an sirolimus-eluting stent or conventional bare-metal stent. Postprocedure enzymatic release (as assessed by elevation of CK and CK-MB levels) was similar in both groups [63].

Angiographic follow-up in patients who were randomly assigned to treatment with sirolimus-eluting stent or bare-metal stent in the SIRIUS trial demonstrated that the frequency of late coronary aneurysms was equal in the two groups [64].

Subacute and late stent thrombosis rates in bare-metal stents and DES have previously been reported similar. In clinical trials, the cumulative incidence of DES thrombosis at 9 to 12 months has ranged from 0.4% to 0.6%, depending on the type of DES. By contrast, new findings suggest that this rate in the real world is at least twice as high, about 1.3%. On multivariate analysis, premature discontinuation of antiplatelet therapy, renal failure, bifurcation lesions, diabetes, and lower ejection fraction were identified as predictors of stent thrombosis. The observed mortality among these patients was 45% [65].

Furthermore, satisfactory results after implant of a DES relies heavily on long-term antiplatelet drugs and other medications. Deprived patients, who can not afford the multimedication cost, are at increased risk of worse outcomes.

As many different types of DES are expected to reach the market in the near future, cardiologists and cardiac surgeons must be aware of side effects of the every drug used as a stent coating and carry out specific interventions for each type of device [56]. The consequences of chronic inflammation of the coronary artery (arteritis) and myocardium (myocarditis) are still unknown; we still have to find out how these factors can affect the patient prognosis.

Finally, some drawbacks stem from the current technology applied to PCI. The first is derived from the injury superimposed to the myocardium at the time of the procedure. Proper management of the endothelial dysfunction is the key to the solution. The second is related to the sustained inflammatory reaction, which is much related to the interaction of the permanent metallic foreign body to the vascular wall. Eluting platforms should attenuate the complication.

The true impact of drug-eluting stents and other strategies designed to attenuate or prevent restenosis, however, can only be assessed in the face of effectiveness of reducing the inherent inflammatory and endothelial dysfunction events; and it should be translated into a significant clinical effect.

	Clinical Implications

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
The aftermath of events evoked by PCI with stenting may be better studied when associated with the patient clinical results. As a corollary of the information provided, the clinical implications can be found in a series of systematic reviews of trials.

A meta-analysis of 11 randomized trials comparing PCI and conservative treatment of patients with stable coronary artery disease revealed no significant difference between the two treatment strategies. Therefore, in patients with chronic stable coronary artery disease, in the absence of a recent myocardial infarction, PCI does not offer any benefit in terms of death, myocardial infarction, or the need for subsequent revascularization compared with conservative medical treatment [66].

The RITA-2 trial revealed that initially post-PCI patients experienced a significant improvement of anginal symptoms and exercise tolerance when compared with medical treatment; however, at long-term follow-up the prevalence of angina remained elevated in both groups. An initial policy of PTCA was associated with improved anginal symptoms and exercise times; however, these treatment differences narrowed over time [67].

Al Suwaidi and coworkers [68], in a meta-analysis of 10,347 patients who underwent either stenting or plain balloon angioplasty, found no difference in mortality rates between the two groups, concluding that bare metal stents have similar mortality and nonfatal myocardial infarction rates when compared with plain balloon angioplasty [68].

A meta-analysis of randomized trials comparing bare-metal stents and DES showed that eluting stents are effective at decreasing rates of angiographic restenosis, but there is no evidence that they affect mortality or myocardial infarction rates [69].

Katritsis and coworkers [70], in a meta-analysis comparing DES with bare-metal stents, found that there was a modest increase in the risk of Q-wave myocardial infarction with DES but no difference in non–Q-wave myocardial infarction. Drug-eluting stents also had a nonsignificant trend for higher risk of thrombosis. Drug-eluting stents were equivalent to bare-metal stents in terms of mortality and overall myocardial infarction risk for the first year of follow-up; the meta-analysis excludes with considerable confidence the presence of large, clinically relevant differences for these outcomes [70].

It is worth reemphasizing that all these studies have been conducted in a cohort of selected low-risk patients. Coronary stenting has not consistently been tested in patients with left ventricular dysfunction. The findings of periprocedural myocardial damage and superimposed chronic inflammatory reaction may prove difficult the rationale for such indications, given the currently available devices and techniques. Low-risk patients have better tolerance to periprocedural myocardial damage than high-risk patients.

	Multiple Vulnerable Plaques

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
The recently introduced concept of multiple vulnerable plaques, which are responsible for the development of coronary instability, may help understand the outcomes delineated above. It has become clear that most plaques eliciting a fatal or nonfatal myocardial infarction are less than 70% stenosed. Contemporary studies have emphasized the multifocal nature of vulnerable plaques, many unstable patients have a second or even a third vulnerable plaque [71]. An intravascular ultrasound study by Riofoul and coworkers [72] found that 79% of the patients presenting with an acute coronary syndrome had multiple ruptured plaques at sites other than the culprit lesion that caused the clinical symptoms. Only 37.5% of plaque ruptures were on the culprit lesion [72]. Ruptured plaques appear to develop within the nonstenotic reference segments [73], away from the culprit lesion and therefore remote to the site of stent deployment. That can help explain why left anterior descending artery grafting using a left internal mammary artery conduit, anastomosed downstream far the coronary stenotic site, provides better outcome when compared with PCI.

	Summary

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 
In sum, postprocedural inflammatory response in patients undergoing PCI reveal a wide range of mechanisms, including mechanical disruption of atherosclerotic plaque, arterial wall injury, myocardial necrosis due to distal embolization and endothelial dysfunction, and release of inflammatory factors followed by leukocytes and platelet activation along with the ischemia-reperfusion injury. The clinical significance of these complications has been less studied, and for better assessment, future researches should focus on this subject.

Also, the premise that CABG surgery can safely be performed in patients with coronary stenting failure may not hold true, as graft patency might be adversely affected. Further studies are urgently needed to elucidate this question.

The most obvious implication from all these findings is that CABG surgery may not provide equivalent outcomes in patients with previous stenting. Furthermore, the superimposed inflammatory reaction may blunt efficacy of medical treatment.

	References

Top Abstract Introduction Pathophysiology of Vascular... Inflammatory Markers After... Post-Stenting Endothelial... Periprocedural Myocardial Injury Inflammation and Coronary Artery... Coronary Aneurysms Late Post-Stenting Structural... Drug-Eluting Stents Clinical Implications Multiple Vulnerable Plaques Summary References

 

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