The complex molecular and cellular biology of the inflammatory process that promotes atherosclerosis has been elucidated through years of extensive experimental and clinical research. Vascular injury from inflammation initiates plaque formation and dictates the downstream clinical sequelae of atherosclerotic disease. It is essential that interventional cardiologists understand the natural history and pathologic processes of atherosclerosis, as well as the vascular biologic consequences of therapies employed during coronary intervention. This chapter describes (1) the pathophysiology of atherosclerosis; (2) the mechanisms responsible for an unstable plaque in acute coronary syndrome (ACS); and (3) the biology of vascular remodeling leading to restenosis, differences between balloon and stent injury, and therapies for restenosis.
Atherosclerosis is a result of risk factors and chronic arterial inflammation that promote sustained vascular injury.1 Several risk factors (Table 9-1) for atherosclerosis have been identified, including metabolic conditions such as sustained exposure to low-density lipoprotein (LDL) or hyperglycemia and insulin resistance associated with diabetes mellitus or metabolic syndrome. However, additional factors, including age, family history, physical factors (eg, uncontrolled hypertension resulting in changes in shear stress), environmental factors (eg, tobacco smoke), and infectious disease, also contribute to the development of atherosclerotic plaque. Vascular injury results from an inflammatory response that involves a complex sequence of interactions between endothelial and smooth muscle cells, leukocytes, inflammatory cells (eg, macrophages) and their secreted growth factors, and cytokines, which combine with lipoproteins and components of the vascular wall to form a mature atherosclerotic plaque. Inflammation plays a central role in pathogenesis of atherosclerosis; numerous studies have demonstrated a correlation between circulating inflammatory biomarkers (eg, C-reactive protein [CRP]) and an increased risk for atherosclerosis and adverse coronary events.2,3,4
Table 9-1Risk factors for Vascular Injury and Atherosclerosis ||Download (.pdf) Table 9-1 Risk factors for Vascular Injury and Atherosclerosis
Shear forces (eg, hypertension)
Laminar versus nonlaminar blood flow (ie, bifurcation disease)
The biologic mechanisms in atherosclerotic plaque formation include intimal lipid accumulation, leukocyte recruitment, foam cell formation, neointimal growth, and vessel remodeling (Fig. 9-1).
Stages of atherosclerotic plaque growth. A. Initial stage of atherosclerosis involves injury to the vessel wall with subsequent expression of inflammatory adhesion molecules, which leads to leukocyte recruitment. B. Intermediate lesions involve macrophages imbibing oxidized low-density lipoprotein, leading to foam cell formation. There is continued leukocyte recruitment, formation of an early lipid core, and smooth muscle cell proliferation and migration. C. The advanced or mature atherosclerotic plaque consists of a necrotic lipid core with foam cells, necrotic debris, and free cholesterol esters. In addition, there is a fibrous cap consisting of smooth muscle cells and extracellular matrix. (From Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 340:115-126. Copyright © 1999. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)
Intimal Lipid Accumulation
A key event in the early formation of atherosclerotic lesions is the accumulation of LDL within the arterial intima, which subsequently undergoes oxidation and glycation to initiate a cascade of molecular and cellular events including growth factor and cytokine release from inflammatory, endothelial, and smooth muscle cells. It is important to recognize that dyslipidemia results in an inflammatory state and is evident in the presence of inflammatory cells within the initial lesion of atherosclerosis, the fatty streak. Foam cells are the hallmark cell of the atherosclerotic lesion and consist of macrophages that are recruited to the subintima of the vessel wall and subsequently bind and internalize oxidized lipoprotein particles via a number of scavenger receptors on the cell surface. Importantly, lipoproteins can be cytotoxic to macrophages, leading to foam cell necrosis, which, in turn, causes necrotic debris and free cholesterol esters to accumulate within the lesion to form a necrotic core. Inflammatory cells, cytokines, and proteases weaken the fibrous cap surrounding the necrotic core, which can lead to atherothrombosis in the setting of a loss of integrity of the fibrous cap barrier, allowing contact of circulating blood with the thrombotic necrotic core.
Leukocytes, predominantly macrophages, play a pivotal role in atherosclerosis. By releasing cytokines and growth factors, macrophages regulate atherogenesis, but also influence plaque destabilization leading to rupture and thrombosis. The process of leukocyte recruitment, attachment to the extracellular matrix, and migration into the plaque (ie, diapedesis) is a response to vascular injury. Chemokine-stimulated endothelial cells express leukocyte-specific cell adhesion molecules (CAMs), which loosely bind circulating mononuclear cells and allow rolling of the monocytes along the endothelial surface.5 Tight binding of monocytes to the endothelium is mediated by the integrin class of CAMs, which is the final step prior to diapedesis. Although their pathologic role is uncertain, plasma levels of CAMs (eg, E-selectin or intercellular adhesion molecule-1 [ICAM-1]) are associated with the development of coronary atherosclerosis.6
Chemokines are an important group of cytokines produced by a number of cells (eg, smooth muscle cells, endothelial cells, and leukocytes) that act as a chemoattractant for leukocytes to areas of vascular injury. Two important chemokines are monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-8, which participate in the recruitment of monocytes and diapedesis of adherent cells.7,8,9,10
Innate immunity and adaptive immunity have important roles in the development of atherosclerosis.11 Innate immunity is an immediate response to foreign material and relies on phagocytosis through neutrophils and monocytes. Monocytes are felt to be the first leukocytes recruited to the early atheromatous plaque and are differentiated into activated macrophages: type 1 induced by inflammatory cytokines (eg, interferon [IFN]-γ) or type 2 induced by IL-4, IL-13, and other anti-inflammatory cytokines. Type 1 macrophages produce large amounts of reactive oxygen species and inflammatory cytokines, which amplify the immune response to an atheroma. Type 2 macrophages express scavenger receptors and produce extracellular matrix proteins and remodeling stimuli.12,13,14 Other cells of the innate immune response have also been implicated in atherosclerosis, including neutrophils, mast cells, and natural killer cells.15 Adaptive immunity is an antigen-dependent response, and the CD4+ T lymphocyte is the primary cell present at atherosclerotic lesions. T cells actively secrete cytokines, which influence plaque progression and vulnerability.15 T lymphocytes secrete inflammatory cytokines such as IFN-γ, which can impair the extracellular matrix architecture and growth of smooth muscle cells, promote apoptosis, and cause plaque instability.16 CD4+ T cells also express the CD40 ligand to promote proteolysis through matrix metalloproteinases (MMPs) and stimulate cells to produce tissue factor to influence plaque rupture and thrombogenicity.17
As lesions mature, leukocytes accumulate in the “shoulder” regions of plaques (ie, the border between the eccentric plaque and normal vessel architecture), which are more vulnerable to plaque rupture.18 In addition, atherosclerotic lesions develop preferentially at coronary bifurcations. Due to the disturbances in flow patterns at coronary bifurcations, altered shear stress may upregulate CAMs and increase leukocyte recruitment and plaque growth. Monocytes contribute to vascular calcification in response to cytokines such as monocyte colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κ-B (RANKL).19 Importantly, microcalcification is associated with plaque vulnerability.20
Smooth muscle cells and their secreted products are responsible for neointimal growth and for giving structure to the mature atherosclerotic plaque, which initially is a collection of lipids and foam cells. Growth factors and chemokines (eg, platelet-derived growth factor and thrombin) initiate smooth muscle cell migration from the media into the neointima and stimulate cell proliferation. In the neointima, smooth muscle cells expand the extracellular matrix by producing its constituent proteins including collagen, proteoglycans, elastin, fibrin(ogen), fibronectin, and vitronectin. The extracellular matrix accounts for a substantial portion of plaque volume and is vital to the structural integrity of the fibrous cap. Smooth muscle cells also express bone matrix proteins, which highlight their role in vascular calcification.21,22,23 Mineralization of the plaque occurs through deposition of calcium and osteopontin, but calcification does not always equate to plaque stability and is associated with higher risk in some patients (eg, elderly).24
Plaque angiogenesis is important to plaque growth and the pathogenesis of atherosclerotic complications.25 Angiogenic growth factors (eg, hypoxia-inducible factor [HIF] and vascular endothelial growth factor [VEGF]) stimulate the growth of vasa vasorum from the adventitia into the plaque.26 Notably, these vessels can hemorrhage, independent of plaque rupture, and extravasation of erythrocytes provides a source of cholesterol-rich red cell membrane constituents, heme, and iron, which act as stimulants for oxidative stress and vessel growth. Neovessel density is significantly higher in nonstenotic and stenotic noncalcified plaques compared with calcified lesions or vessels without plaque.27 Neoangiogenesis is driven by hypoxia, but the latter also contributes to proteolysis through MMPs. MMPs comprise a family of interstitial collagenases that weaken the fibrous cap and gellatinases that breakdown nonfibrillar collagen and the adhesions between endothelial cells, leading to plaque vulnerability.28,29,30 Hypoxia also promotes proinflammatory cytokine and leukotriene release, which activates macrophages and contributes to plaque growth.29,31
The Mature Atherosclerotic Plaque
The mature atherosclerotic plaque is composed of a fibrous cap consisting of smooth muscle cells and extracellular matrix overlying a necrotic lipid core consisting of free cholesterol esters, foam cells, other leukocytes (eg, T cells), and necrotic debris from dead foam cells (see Fig. 9-1). Mature plaques are typically eccentric and heterogeneous, especially in terms of the thickness of the cap and distribution of leukocytes (highest at the shoulder regions of the plaque). These features are vitally important to plaque stability and the development of ACS.
A major limitation to coronary angiography is that it only provides information on the luminal encroachment of lesions. Intravascular imaging has provided a better understanding of atherosclerotic plaque architecture not only at sites of flow-obstructing lesions but throughout the vessel. Although the interventional cardiologist may be focused on focal obstructive lesions, it is important to realize that atherosclerosis is typically present throughout the entire coronary artery. The severity of lumen narrowing is subject to the amount of plaque growth and vascular remodeling, whereby the latter involves restructuring the cellular and noncellular components of the vessel wall under a variety of stressors (eg, smooth muscle mass increasing to normalize wall stress in hypertensive patients).32 Positive remodeling is a compensatory enlargement of the vessel to preserve the luminal area and maintain coronary blood flow (Fig. 9-2). MMPs are upregulated in areas of vessel wall remodeling and play a central role in plaque rupture.33
Schematic of vascular remodeling. As the atherosclerotic lesion progresses, initial enlargement of the entire vessel allows preservation of luminal area. As atherosclerosis becomes severe, enlargement is overcome by progression of the atherosclerotic plaque, and luminal area is compromised. (Adapted from Glagov S, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Eng J Med. 316: 1371-1375. Copyright © 1980. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)
Clinical Sequelae of Atherosclerosis
The clinical manifestations of coronary artery disease are often described as a spectrum, from stable angina associated with exertional angina and benign outcomes, to ST-segment elevation myocardial infarction (STEMI) associated with sudden thrombotic vessel occlusion and higher rates of morbidity and mortality. Two main mechanisms are primarily responsible for the clinical manifestations of atherosclerosis: (1) luminal narrowing that leads to a mismatch between oxygen supply and demand typically resulting in symptoms of stable angina; or (2) atheromatous plaque rupture resulting in thrombus formation and coronary occlusion.34 Importantly, atherosclerosis can also alter the normal endothelial vasomotor function and autoregulation of blood flow (ie, endothelial dysfunction), which can cause anginal symptoms in patient with and without epicardial coronary stenoses. Nevertheless, it is critical to recognize that thrombotic complications of atherosclerosis depend on plaque morphology and vascular biologic factors, not the severity of coronary stenosis.
Progressive Lumen Encroachment and Stable Angina
Lumen encroachment occurs from the growth and expansion of atherosclerotic lesions (see Fig. 9-2). The extent of luminal narrowing depends on the size of the atherosclerotic lesion and the amount of compensatory vascular remodeling. A coronary stenosis reduces coronary blood flow to a given vascular territory. The decrease in blood flow causes the distal microcirculation to vasodilate and increase coronary blood flow, which, in turn, reduces the ability of the coronary circulation to increase blood supply in response to demand (ie, coronary flow reserve). This process typically leads to exertional angina and is relieved by rest. Importantly, luminal encroachment does not always cause symptoms and depends on many factors including the severity of the stenosis, the oxygen carrying capacity of blood, and the supply demands of the distal myocardial bed.
A general rule is that lesions typically produce symptoms when they reach a 60% to 70% diameter stenosis. However, interrogating the intracoronary hemodynamics with flow and pressure wires has revealed that lesions with the same degree of angiographic stenosis may have very different hemodynamic and ischemic consequences.35 Fractional flow reserve (FFR) has become the predominant method used to assess coronary hemodynamics and is defined as the ratio of the distal pressure in the coronary artery beyond the lesion divided by the aortic pressure. Based on an association with inducible ischemia on stress testing, the initial cut-off point for not performing percutaneous coronary intervention (PCI) after FFR assessment was <0.75, as established in the FFR to Determine Appropriateness of Angioplasty in Moderate Coronary Stenoses (DEFER) study.36 To enhance the sensitivity and exclude ischemia using FFR, the cut-off was increased to >0.80 in the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) trial.37,38 In FAME, routine measurement of the FFR was compared with angiography alone for guiding PCI in patients with multivessel coronary artery disease (CAD). The use of FFR significantly reduced the rate of major adverse cardiac events compared with angiography alone.37,39 Importantly, a subgroup analysis of the lesions that were assessed by FFR in FAME revealed that coronary angiography could not accurately predict the hemodynamic significance of a coronary lesion.40 In FAME, 35% of lesions with an angiographic stenosis of 50% to 70% (ie, intermediate) were hemodynamically significant (FFR ≤0.80), whereas 20% of lesions with an angiographic stenosis of 71% to 90% were not functionally significant by FFR.40 Only when lesions had an angiographic stenosis >90% was coronary angiography able to predict hemodynamic significance, where 96% of lesions with a coronary stenosis of 91% to 99% had an FFR ≤0.80.40 Furthermore, 54% of patients who were classified as having multivessel CAD did not have ≥2 lesions with an FFR ≤0.80. The discordance between hemodynamic significance and angiographic stenosis highlights the need to use adjunctive techniques to assess the ischemic potential of coronary stenoses.
Plaque Rupture and Thrombosis in Acute Coronary Syndromes
The historical view held that stable angina could convert to ACS when an atherosclerotic lesion narrowed the vessel lumen to a critical point where vasospasm or thrombosis in situ could develop and cause a myocardial infarction (MI). For years, considerable debate ensued as to whether thrombus found at autopsy was a pre- or postmortem phenomenon. This widely held view continued despite James Herrick’s landmark publication of thrombus as the predominant cause of sudden coronary obstruction in 1912.41 The pivotal work by DeWood et al42 in 1980 demonstrated angiographically that ST-segment elevation and transmural MI were associated with occlusion of an epicardial coronary vessel predominantly secondary to thrombus (Fig. 9-3). Since this discovery, autopsy studies and angioscopy have confirmed the presence of visible thrombus associated with plaque rupture (Fig. 9-4) in both unstable angina and acute MI (AMI).42
Percentage of vessels totally occluded in patients presenting after acute myocardial infarction as a function of time after onset of symptoms. (Adapted from DeWood MA, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med. 303:897-902. Copyright © 1980. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)
Histologic example of a ruptured plaque with subsequent thrombosis leading to a fatal myocardial infarction. (From Constantinides P. Plaque hemorrhages, their genesis and their role in supra-plaque thrombosis and atherogenesis. In: Glagov S, Newman WP III, Schaffer SA, eds. Pathology of the Human Atherosclerotic Plaque. New York: Springer-Verlag; 1990:393-411, with permission of Springer.)
Early thrombolytic trials were instrumental in our current understanding of ACS. As part of these trials, patients with AMI underwent serial angiography after randomization to thrombolytics or placebo, which revealed an unexpected finding, namely that the majority of the culprit lesions had <50% in diameter stenosis (Fig. 9-5). Furthermore, in some patients, mild and moderate stenoses progressed to MI within weeks.43,44 Importantly, only 15% of AMIs arose from lesions with a coronary stenosis >60% on a prior angiogram (see Fig. 9-5).44 These finding focused future research efforts on determining the vascular biology of a vulnerable plaque and the mechanisms responsible for conversion from a stable plaque to a thrombotic lesion. Noncritical lesions are significantly more abundant than critical lesions, and compensatory enlargement of the vessel often accompanies atherosclerosis. Thus, mildly stenotic lesions can have an even larger plaque burden by volume, which may portend a higher risk for plaque rupture and thrombosis.
Compiled data from 4 thrombolytic trials showing that the majority of underlying lesions responsible for acute myocardial infarction involve less than 50% diameter stenosis. (Reproduced with permission from Smith SC. Risk-reduction therapy: the challenge to change. Circulation. 1996;93:2205-2211.)
Plaque rupture is the proximate event leading to thrombosis, which exposes the subendothelium to circulating blood. Several histologic features have been associated with plaque vulnerability, including a thin fibrous cap, a large lipid-laden necrotic core, and an accumulation of leukocytes and inflammatory cells at the shoulder regions of the plaque (Fig. 9-6).18 An important natural history study of coronary atherosclerosis was recently conducted called Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT).45 In PROSPECT, 697 patients who were stented in the setting of ACS underwent 3-vessel intravascular imaging to determine the clinical and lesion risk factors associated with future events.45 At 3 years, approximately 20% of patients experienced a major adverse cardiac event, in which nearly 50% of the adverse events were associated with nonculprit lesions.45 The majority of adverse cardiac events were in lesions that were mildly stenotic at the time of index angiography.45 Three lesions characteristics were strongly associated with a higher risk for future adverse cardiac events in nonculprit lesions; these were a plaque burden ≥70%, presence of a thin cap fibroatheroma, and a minimal lumen area ≤4 mm2.45
Characteristics of stable versus vulnerable plaques. Vulnerable plaques have thinner fibrous caps and larger, more inflammatory cell–rich lipid cores. SMC, smooth muscle cell. (Reproduced with permission from Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844-2850.)
A plaque’s structural integrity is regulated by vascular inflammation and dependent on the balance between the mass of smooth muscle cells and content of the extracellular matrix. Smooth muscle cell mass is regulated by cell migration from the media, neointimal proliferation, and cell death. The latter occurs due to cytokine release from inflammatory cells, leading to apoptosis.46 Extracellular matrix content depends on the interplay between production from smooth muscle and inflammatory cells and protease activity leading to degradation (Fig. 9-7). Within a plaque, activated T cells release IFN-γ, which inhibits smooth muscle cell collagen synthesis. Inflammatory cells also produce enzymes (eg, MMPs and cathepsins) that degrade important structural components of the extracellular matrix (ie, collagens, elastin).18 This process weakens the structural integrity of a plaque by decreasing smooth muscle cell mass and degrading the extracellular matrix.
Thickness of the fibrous cap is a balance between synthesis of extracellular matrix proteins by smooth muscle cells (SMCs) and the breakdown of these products by degradative enzymes. These processes are largely under the influence of inflammatory cells. IFN, interferon; MCP-1, monocyte chemoattractant protein-1; M-CSF, monocyte colony-stimulating factor; TNF, tumor necrosis factor. (Reproduced with permission from Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844-2850.)
Predicting how, why, and when a plaque will rupture is a subject of continuing study. An interesting historical observation is the diurnal variation in MI presentation, which peaks in the early morning hours.47 Additionally, MI rates increase during times of extreme stress (eg, earthquake).48 These observations suggest that variations in cortisol and adrenaline levels may impact plaque rupture through their systemic hemodynamic effects. The site of rupture coincides with the highest circumferential biomechanical force, which is located at the shoulder region of a plaque.49 Thus, a combination of biochemical and biophysical characteristics predispose the shoulder regions to plaque rupture, which is supported by histologic postmortem studies in patients who died from an AMI. Other processes may also be responsible for the thrombotic complications of ACS. Focal endothelial denudation can expose the internal elastic membrane to circulating blood and act as a substrate for thrombosis, which occurs more frequently in women and diabetics. Also, mechanical injury during PCI can also disrupt plaque and lead to acute thrombosis.
Atherothrombosis is the final consequence of plaque rupture or endothelial denudation that leads to acute coronary vessel occlusion. Exposing the lipid core (ie, tissue factor associated with lipid-laden and necrotic macrophages) to circulating blood is a potent stimulus for thrombus formation. Thrombus formation following plaque rupture is regulated by the blood’s tight control over the balance between procoagulant-anticoagulant and fibrinolytic-antifibrinolytic factors. In the presence of an intact and robust fibrinolytic system, a thrombus may undergo rapid lysis and manifest clinically as unstable angina or non–ST-segment elevation MI (NSTEMI). Similarly, patients on antiplatelet therapy (eg, aspirin) may be protected from platelet activation and aggregation during subendothelial exposure to blood. Conversely, the presence of prothrombotic factors (eg, fibrinogen or plasminogen activator inhibitor-1) can accelerate the growth of a thrombus, leading to coronary occlusion. Nonocclusive thrombus can also become incorporated into a plaque during the healing process and provide a mechanism for plaque expansion and lumen encroachment and be a source for angina.
Importantly, antiplatelet and lipid-lowering therapy trials have corroborated the thrombotic paradigm of ACS and demonstrated marked reductions in the morbidity and mortality associated with an acute coronary event. Furthermore, these breakthroughs have been achieved despite a lack of change in lesion severity.44 Lipids have a central role in atherosclerosis and atherothrombosis as the critical initiating and sustaining inflammatory stimulus for plaque growth and rupture. The beneficial actions of statins include not only their lipid-lowering properties, but also the reduction in inflammation, which can stabilize the fibrous cap and reduce thrombogenicity of the inner lipid-laden necrotic core. Evidence supports that lipid-lowering therapy is vital to acute and chronic therapy for patients presenting with ACS.
A major goal of vascular biologists and clinical cardiologists is to develop a more complete understanding of the mechanisms of plaque rupture and the development of novel strategies to stabilize lesions. However, many different lesions of varying vulnerability may coexist throughout the coronary tree. Novel imaging techniques are being developed to identify plaques that are the most susceptible to rupture, which may allow for better prognostication and therapeutic developments.
Andreas Gruentzig ushered in the modern era of management of obstructive CAD with the publication of his experience with coronary balloon angioplasty in a landmark study of 5 patients in 1978.50 Yet, his first angiographic follow-up study revealed that 19% of patients undergoing successful initial angioplasty suffered restenosis.51 Since the early days of balloon angioplasty, the introduction of stenting has reduced certain limitations of balloon angioplasty. However, in-stent restenosis (ISR) still remains an important limitation of coronary stents. Bare metal stents (BMS) decreased restenosis compared to balloon angioplasty, but in selected studies, ISR remained as high as 30%.52 Drug-eluting stents (DES) further reduced the rates of ISR to as low as 5% to 20%, depending on the patient population.53,54,55,56
Our understanding of the pathophysiology of restenosis has evolved considerably. Early postmortem studies revealed a fibrocellular response at sites of prior balloon angioplasty.57 Initial animal studies revealed that endothelial denudation, medial dissection, and platelet deposition contribute to an immediate response to balloon injury, whereas late restenosis is a consequence of smooth muscle cell migration and proliferation.58,59 The initial paradigm for restenosis comprised 3 phases: (1) an inflammatory phase, (2) a granulation or cellular proliferation phase, and (3) a phase of remodeling involving extracellular matrix protein synthesis (Fig. 9-8).60 As with atherosclerosis, inflammation plays a critical role in the pathogenesis of restenosis. Coronary stenting has a profound impact on the vascular biologic response to vessel injury, especially the inflammatory response and vascular remodeling following injury. The aim of this chapter is to understand the pathogenesis of restenosis and the clinical indicators and biochemical markers associated with increased risk and to introduce the concepts of antirestenotic therapy.
A. A mature atherosclerotic plaque prior to intervention. B. The immediate result of stent placement with endothelial denudation and platelet/fibrinogen deposition. C and D. Leukocyte recruitment, infiltration, and smooth muscle cell (SMC) proliferation and migration in the days following injury. E. Neointimal thickening in the weeks following injury with continued SMC proliferation and monocyte recruitment. F. The long-term (weeks to months) change from a predominantly cellular to a less cellular and more extracellular matrix (ECM)-rich plaque. FGF, fibroblast growth factor; IGF, insulin-like growth factor; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor. (Reproduced with permission from Welt FGP, Rogers C. Inflammation and restenosis in the stent era. Arterioscler Thromb Vasc Biol. 2002;22:1769-1776.)
Definitions and Clinical Sequelae of Restenosis
In clinical trials, restenosis was historically defined angiographically as a binary (ie, yes or no) reduction of ≥50% of the luminal diameter compared with the reference vessel, which does not always separate clinically relevant lesions from those without any sequelae.61 However, restenosis can also be defined by angiographic terms that are more relevant to our understanding of the pathophysiology. Late lumen loss (LLL) is the continuous measure of angiographic luminal narrowing and is calculated by subtracting minimal lumen diameter (MLD) at the time of index revascularization from postprocedural MLD at angiographic follow-up. LLL is an important surrogate marker used to assess the effectiveness of antirestenotic therapies and different stent platforms.62,63 It is important to note that virtually all patients have some degree of restenosis. In any given population, the severity of restenosis will follow a typical Gaussian distribution (Fig. 9-9), and only a minority of patients will have severe ISR (eg, diameter stenosis >70%) and anginal symptoms. On average, LLL is 0.8 to 1.0 mm following implantation of a BMS, regardless of the reference vessel diameter, and is critically important when considering revascularization of smaller vessels. For example, a 4-mm diameter vessel would lose 44% of lumen area with an LLL of 1 mm, whereas a 2-mm vessel with the same 1-mm loss would have a 75% loss in lumen area. LLL and angiographic restenosis are related to the reference vessel diameter, and restenosis is heavily dependent on the definition used in a given clinical study.64 An inventory of the wide variety of angiographic and clinical definitions used to define restenosis is shown in Table 9-2.
Table 9-2Examples of Definitions Used for Restenosis in the Medical Literature ||Download (.pdf) Table 9-2 Examples of Definitions Used for Restenosis in the Medical Literature
Histogram of percent diameter stenosis at follow-up angiography of 1445 lesions treated with percutaneous intervention. The superimposed curve represents the theoretic Gaussian distribution. SD, standard deviation. (Reproduced with permission from Rensing BJ, Hermans WR, Deckers JW, et al. Lumen narrowing after percutaneous transluminal coronary balloon angioplasty follows a near gaussian distribution: a quantitative angiographic study in 1,445 successfully dilated lesions. J Am Coll Cardiol. 1992;19:939-945.)
The discordance between LLL and binary restenosis is controversial. Late loss is a useful surrogate marker for assessing the effectiveness of therapies for restenosis. However, the relationship between late loss and binary restenosis is nonlinear and a curvilinear function (Fig. 9-10), which implies that there may be a threshold of LLL that is clinically significant. The argument is that LLL below a certain level is not clinically significant and does not portend a worse clinical restenosis rate (ie, target lesion revascularization [TLR]) (see Fig. 9-10). This argument is a contentious issue in interventional cardiology. Regardless, the clinical sequelae of angiographic restenosis are not always concordant. An example of this was observed in a meta-analysis of patients with angiographic ISR from multiple stenting trials, where ISR defined as ≥50% diameter stenosis was asymptomatic in approximately 50% of patients.65 This study highlights the multifactorial nature of restenosis and discrepancy between angiographic restenosis as a binary outcome and corresponding clinical significance.
A. Data from the TAXUS IV trial shows the in-stent late loss for the Taxus stent (Boston Scientific) and control bare metal stent. B. Probability of target lesion revascularization (TLR) as a function of in-stent late loss revealing a curvilinear distribution. Superimposed are the mean and standard deviations for the Taxus stent late loss (red) and the control bare metal stent (blue). The distribution of the Taxus stent late loss falls along the relatively flat portion of the curve, whereas the distribution for the bare metal stent falls along the steeper portion of the curve where there is greater correlation between late loss and TLR. (Reproduced with permission from Ellis SG, Popma JJ, Lasala JM, et al. Relationship between angiographic late loss and target lesion revascularization after coronary stent implantation: analysis from the TAXUS-IV trial. J Am Coll Cardiol 2005;45:1193-1200.)
Traditionally, restenosis has been viewed as a condition that clinically manifests as stable angina. However, there is substantial evidence to the contrary. Although the majority of patients present with stable exertional symptoms, unstable angina (26%-53%), and acute MI (3.5%-20%) are not uncommon.66,67 Restenosis following balloon angioplasty or stenting is an accelerated process compared with atherosclerosis. With balloon angioplasty, clinically significant restenosis is typically present by 6 months.68,69 Following stent implantation, the average time for ISR is approximately 5.5 months, with evidence that a shorter interval may be present in patients presenting with AMI.70 Taken together, these studies highlight that restenosis is not always a benign condition and is a distinct clinical entity from atherosclerosis.
Risk Factors for Restenosis
The 3 most important and historical clinical risk factors for restenosis are stent length, MLD, and diabetes mellitus.71 In conceptualizing the risk factors for restenosis, it is helpful to classify them as biologic or mechanical, although there is considerable overlap between the 2 classifications.
The risk for restenosis is high among patients with diabetes mellitus. Data from a registry involving >35,000 patients following DES (Endeavor, sirolimus-eluting stents [SES], Taxus Express, and Liberte) revealed that, at 2-year follow-up, the rates of ISR with DES implantation were significantly higher in patients with diabetes.72 Another study of 954 patients undergoing PCI revealed that TLR was also significantly higher in diabetics compared with individuals without diabetes.73 The increased risk for restenosis in diabetics is likely secondary to endothelial dysfunction, accelerated intimal hyperplasia, and increased platelet reactivity.74
Patients may also be genetically predisposed to restenosis. For example, genetic polymorphisms associated with a higher risk for restenosis include genes for angiotensin-converting enzyme inhibitor, glycoprotein receptor IIIa PLA1/2, haptoglobin 2/2.25, and IL-8.75,76 Additionally, resistance to antiproliferative drugs used in DESs has been observed in patients with genetic polymorphisms to the intracellular receptor mammalian target of rapamycin (mTOR), enzymes responsible for paclitaxel or sirolimus metabolism, and mutations of proteins in the downstream signaling of mTOR.77,78 Thus, biologic resistance to DESs may be presents in certain individuals.
Biomarkers associated with an increased risk for ISR have also been identified. Higher plasma levels of MCP-1 have been associated with a higher rate of restenosis at 6-month angiographic follow-up following balloon angioplasty.79 CRP is considered a strong risk predictor for cardiovascular disease, but the relationship between CRP and ISR remains controversial and an area of active investigation.80,81,82,83,84 Circulating MMPs have also been associated with a higher risk of developing ISR following DES implantation. MMP-2 and MMP-9 play a key role in the migration of vascular smooth muscle cells and remodeling following vascular injury. Significant elevations in MMP-2 and MMP-9 levels are strongly associated with the development of ISR following DES implantation.85
Several mechanical factors related to stent deployment may also contribute to a higher rate of restenosis. Stent underexpansion and malapposition are associated with a higher risk of ISR, which may impact effective drug delivery in DES and cause less inhibition of neointimal hyperplasia.86,87 In the era of DES, geographic miss may also be responsible for restenosis. Geographic miss typically refers to an area of the treated segment that was exposed to balloon injury but not covered with a DES. Thus, this uncovered area would not receive the benefits of the antiproliferative therapy of DES. Stent fracture may also contribute to ISR in DES and lead to ineffective drug delivery.88,89,90,91,92
Classification of Patterns of In-Stent Restenosis
An angiographic classification of ISR was developed and classifies restenosis according to the geographic distribution of intimal hyperplasia in reference to the implanted stent.93 Four classes of ISR are defined as follows (Fig. 9-11):
Patterns of in-stent restenosis (ISR). (Reproduced with permission from Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. Circulation. 1999;100(18):1872–1878.)
Class I: Focal ISR group
Lesions are ≤10 mm in length and positioned at the unscaffolded segment (ie, articulation or gap), the body of the stent, the proximal or distal margin (but not both), or a combination of these sites (multifocal ISR).
Class II: Diffuse intrastent ISR
Class III: Diffuse proliferative ISR
Class IV: ISR with total occlusion
The pattern of ISR is different between BMS and DES, where BMS tends to present as focal ISR and DES presents as a diffuse pattern. Additionally, patients with AMI are likely to have diffuse ISR compared with patients presenting without MI.70,94
Pathogenesis of Restenosis
The pathogenesis of restenosis is different than atherosclerosis. Restenosis is more rapid than atherosclerosis and sometimes referred to as an “accelerated arteriopathy.”
Differences Between Balloon Angioplasty Versus In-Stent Restenosis
In balloon angioplasty, intravascular ultrasound (IVUS) studies demonstrated that restenosis is secondary to both neointimal growth and shrinkage of the artery by acute recoil and negative remodeling. Acute elastic recoil following angioplasty is observed within a few minutes and results in vessel collapse. The amount of recoil is proportional to the extent of stretching with balloon inflation and can result in as much as 50% loss in cross-sectional area and 33% loss in lumen diameter.95 Negative remodeling is different from acute recoil. It involves contraction of the external elastic laminae and is a process that occurs over weeks to months following injury. Concurrently, neointimal proliferation is an inflammatory response to the site of injury, which leads to smooth muscle cell proliferation and excessive extracellular matrix production.96,97 In terms of their relative contribution, negative remodeling plays the largest role in restenosis following balloon injury without stent placement (Fig. 9-12).
Illustration of differences in mechanisms of restenosis between balloon angioplasty and stenting. In balloon angioplastied vessels, restenosis is caused by a combination of neointimal growth and negative remodeling. Stented arteries have lower rates of restenosis despite incurring greater neointimal growth due to their ability to achieve a larger initial lumen size and the elimination of negative remodeling. EEM, external elastic membrane.
Our understanding of the pathophysiology of restenosis relies heavily upon animal models and intravascular imaging. Initial IVUS studies determined that negative remodeling (ie, external elastic membrane area) and neointimal hyperplasia (ie, plaque plus media cross-sectional area) contributed to restenosis following vascular injury from balloon angioplasty.97 In an angiographic analysis of the first 2 large-scale coronary stent trials in humans, distinct differences were observed between the pattern of restenosis in balloon-injured compared with stented coronary arteries.98,99 Arteries that received a stent had a larger initial lumen gain, which was due to the rigid stent scaffolding that prevented acute elastic recoil and negative remodeling. Angiographic follow-up at 6 months revealed that the luminal area was greater (ie, lower restenosis) in stented vessels compared with balloon angioplasty. However, LLL was higher in stented arteries due to greater neointimal growth. These findings were later confirmed in IVUS studies.100 Thus, the benefit of stents for restenosis is largely attributable to the larger initial lumen gain and prevention of negative remodeling (see Fig. 9-12). The neointimal formation that occurs in ISR is similar to balloon angioplasty. Yet the response is exaggerated in stenting secondary to differences in vessel injury and inflammation. For example, one study demonstrated that the inflammatory response and volume of neointimal formation were increased when the stent struts perforated the internal and external elastic lamina.101 Potential contributing factors to the exaggerated inflammatory response with stenting may be related to the higher balloon pressures required for stent deployment or possibly a contact allergy to the stent metal. BMSs slowly elute metal ions and have the potential to stimulate a delayed-type hypersensitivity response within the stented vessel.102 One study of patients who underwent cutaneous patch testing for nickel and molybdenum hypersensitivity after stent placement found that patients with a positive test also had more ISR requiring revascularization.102 The data suggest that metallic hypersensitivity may account for a subset patients who presents with restenosis after stenting.
Mechanisms of Leukocyte Recruitment and Infiltration
Balloon expansion and/or stent placement causes vascular injury by dissection, crushing the smooth muscle cells, and de-endothelialization. Leukocytes are recruited to sites of injury and are deposited together with platelets. As part of the inflammatory response after angioplasty, the interaction between platelets and leukocytes is important.103,104 The initial loose attachment of leukocytes to surface-adherent platelets is mediated through the selectin class of adhesion molecules (eg, P-selectin), followed by firm adhesion and transplatelet migration via the integrin class of adhesion molecules (eg, β2 integrin Mac-1, also known as CD11b/CD18).105,106 In addition to promoting leukocyte recruitment, platelet binding to neutrophils amplifies the inflammatory response via proinflammatory molecules (eg, soluble CD40 ligand) by inducing neutrophil activation, amplifying the expression of CAMs, and enhancing signal transduction pathways that promote integrin activation and cytokine synthesis. Neutrophil-platelet and monocyte-platelet aggregates have been identified in patients with CAD and may be markers of disease activity and prognostic markers.107,108
Inflammation: A Key Role in Restenosis
Restenosis is not typically secondary to accelerated atherosclerosis, but is a distinct temporal and pathophysiologic process. However, inflammation still plays a central role in both atherosclerosis and restenosis. In a study of pathologic samples of 116 stents from 87 patients more than 90 days after procedure, the severity of restenosis was associated with the extent of medial damage and inflammation.109 An additional study of tissue samples retrieved from direct atherectomy at the time of angioplasty demonstrated a strong positive correlation between the number of inflammatory cells and the risk of restenosis.110
Inflammatory biomarkers have also provided insight into the mechanisms of restenosis. In one study, blood samples were collected from patients both proximal and distal to the site of injury following balloon dilatation, and inflammatory biomarkers of leukocyte activation (eg, neutrophil adhesion molecules L-selectin and CD11b) were upregulated after angioplasty.111 CD11b is upregulated on both neutrophils and monocytes in patients following angioplasty and is a prognostic marker for restenosis following angioplasty and stenting.112,113,114 Increased IL-1 production by monocytes isolated from blood before angioplasty was associated with LLL, whereas granulocyte activation was protective against luminal narrowing.115 Higher MCP-1 levels are associated with a risk for ISR following PCI.79 The nonspecific inflammatory marker CRP is also positively correlated with a risk for restenosis following stent placement.116
Animal models have been invaluable in elucidating the basic cellular and molecular mechanisms of restenosis. CAMs are critical for leukocyte recruitment and are upregulated by an atherogenic diet, induction of diabetes, and increased shear stress in various animal models.117,118,119,120,121 VCAM-1, ICAM-1, and major histocompatibility complex (MHC) class II antigens are upregulated following balloon endothelial denudation.122 Stents induce a potent and early inflammatory response evidenced by an abundance of surface adherent leukocytes.123,124 In the days to weeks following stent implantation, macrophages invade the forming neointima and cluster around stent struts forming giant cells. Blockade of monocyte recruitment with anti-inflammatory agents results in reduced late neointimal thickening.123,125,126 A strong correlation exists between the number of tissue monocytes and neointimal area, which suggests a causal role for monocytes in restenosis.123 Furthermore, activated macrophages influence vascular repair by production of a variety of inflammatory cytokines (eg, IL family, tumor necrosis factor-α, MCP-1) and growth factors (eg, platelet-derived, basic fibroblast, and heparin-binding epidermal growth factors).127
Vascular injury leads to neutrophil infiltration within the arterial wall.128,129,130 A reduction in accumulation of neutrophils and smooth muscle proliferation by anti-inflammatory agents results in less neointimal growth.124 The mechanisms by which neutrophils affect vascular repair are less understood compared with monocytes or macrophages. Neutrophils may cause tissue injury through the release of reactive oxygen species, proteases, or inflammatory cytokines.127,131 Vascular smooth cell proliferation can also be stimulated by neutrophils.132
Smooth Muscle Cell Proliferation
Vascular smooth muscle cell proliferation and migration are central to the development of restenosis and the target for antirestenosis therapies. Thus, it is important to understand two intracellular signaling pathways responsible for the regulation of smooth muscle cell proliferation: the tyrosine kinase cascade and the cyclic adenosine monophosphate (cAMP) pathway. Growth factors bind to the smooth muscle cell receptors and activate tyrosine kinase, which, via a phosphorylation cascade, activates the ras/raf/mitogen-activated protein kinase (MAPKK) signal transduction pathway, resulting in intranuclear activation of transcription factors that induce smooth muscle cell proliferation and migration. The cAMP pathway activates protein kinase A (PKA), which also activates the transcription factor cAMP responsive element binding protein (CREB). Additionally, PKA also phosphorylates raf, which inhibits the other major pathway involved in the activation of smooth muscle cell proliferation.133 Importantly, inactivation of ras by activation of the cAMP pathway leads to a >50% reduction in neointimal formation at 14 days following balloon injury in rat carotid arteries. Similarly, inhibition of MAPKK by a dominant inhibitor mutant gene results in a decrease in neointima formation.134,135,136
Downstream from these two important signal transduction pathways are other processes that regulate the progression of a smooth muscle cell through the cell cycle. The progression from the G0 (ie, quiescent) to G1 phase is regulated by cyclin-dependent kinases, of which several endogenous inhibitors (eg, p21cip1, p27kip1, and INK4 families) regulate the process of a smooth muscle cell entering the G1 phase. For example, vascular inflammation and injury decrease the level of p27kip1, which then promotes more cell division. However, cAMP activation leads to increased p27kip1 levels and can promote the proliferating cells to enter a quiescent phase.133 Thus, intracellular signaling regulates the conversion of smooth muscle cells to differentiate into myofibroblasts and migration to the site of vascular injury. Histologic analysis demonstrates that these cells form a cap across the site of injury, proliferate toward the tunica media, produce the constituents of the extracellular matrix, and form the neointimal mass.137 Importantly, the extent of neointimal formation is determined by the degree of the inflammatory response at the site of vascular injury.138
Remodeling is a change in vessel size following vascular injury and is responsible for luminal loss after angioplasty or stenting.97,139 Following balloon angioplasty, negative remodeling typically occurs within 1 to 6 months and accounts for up to 65% of luminal loss.97,140 The adventitia plays a critical role in both proliferation and concentric compression of the external elastic lamina (ie, negative remodeling).141 Upon injury to the vessel, inflammatory cells stimulate cell proliferation in the adventitia by converting adventitial fibroblasts to myofibroblasts, which begin to secrete components of the extracellular matrix, leading to vessel constriction and formation of a fibrotic scar within the adventitia surrounding the site of injury.141,142 Thus, the adventitia is not a passive player in the process of restenosis.
Biologic Differences Between Balloon and Stent Injury
Important differences exist between the vascular biologic responses to balloon versus stent injury. As an example, one study demonstrated a significantly higher expression of CD11b expression on neutrophils (ie, inflammatory response) following PCI compared with balloon angioplasty alone.143 An increased inflammatory response may amplify neointimal growth following stent implantation. In animal models, heparin is a well-known modulator of vascular repair and known to reduce neointimal growth following vascular injury after balloon injury or stent implantation.144,145,146,147 However, a notable difference exists between these mechanisms of vascular injury in animal models. Heparin inhibits neointimal hyperplasia in stented rabbit iliac arteries, only when given in a prolonged fashion (14 days), whereas maximal inhibition of balloon-injured arteries only requires an early and brief duration of heparin therapy (3 days).147 One explanation of this difference is suggested by immunohistologic and molecular studies, which demonstrate a distinct pattern of leukocyte infiltration that distinguishes the superficial injury from balloon-induced de-endothelialization from the deep chronic injury associated with stent implantation. In animal models, balloon injury causes early and transient infiltration of neutrophils without monocyte recruitment, whereas stenting leads to an early influx of neutrophils followed by a sustained monocyte accumulation over the ensuing weeks following implantation. These differences are mirrored by molecular studies, whereby MCP-1 and IL-8 are only transiently (ie, hours) expressed following balloon injury compared with sustained expression as late as 14 days following stenting.148
An Integrated View of the Pathophysiology of Restenosis
When a balloon is inflated and a stent deployed at the site of a mature atherosclerotic plaque, a cascade of events is initiated (see Fig. 9-8). The first event is an inflammatory phase. Stent placement causes immediate de-endothelialization, crushing of the plaque with occasional dissection into the tunica media or adventitia, and stretching of the entire artery. Due to this injury, platelets and fibrin are deposited at the injured site. Activated platelets layered on the injured surface express adhesion molecules (eg, P-selectin and glycoprotein [GP] Ibα) and bind to circulating leukocytes, which initiates leukocyte rolling along the surface. Leukocytes bind tightly to the platelet receptors through the leukocyte integrin adhesion molecules (eg, Mac-1) and stop rolling after cross-linking with fibrinogen to the GP IIb/IIIa receptor. Migration of leukocytes across the platelet-fibrin layer and diapedesis into the subendothelium are amplified by cytokines released from neighboring smooth muscle and resident cells. Following the inflammation phase, the granulation or cellular proliferation phase ensues with the release of cellular growth factors from platelets, leukocytes, and smooth muscle cells. Growth factors stimulate smooth muscle cell proliferation and migration from the media to the neointima. Thus, the resultant neointima is composed of smooth muscle cells, extracellular matrix, and macrophages that are recruited over a period of several weeks. Next, the remodeling phase is initiated over a longer period of time and involves extracellular matrix protein degradation and resynthesis and a shift from cellular accumulation to a greater production of extracellular matrix. In the balloon angioplasty era, this phase typically would result in luminal narrowing from negative remodeling. However, stented arteries are resistant to negative modeling due to the rigid scaffolding of the stent. Finally, re-endothelialization of the vessel surface occurs following balloon angioplasty or stenting.
More recently, it has been demonstrated that some cases of ISR closely resemble atherosclerosis. This process is termed neoatherosclerosis and has been identified pathologically by clusters of foam cells and true thin capped atheromas identified within stents from patients at autopsy.149 Intravascular imaging techniques have identified lesions consistent with thin-capped fibroatheroma within prior placed stents. In particular, optical coherence tomography has been used, and some studies suggest a frequency of neoatherosclerosis as high as 50%, particularly in cases of DES ISR.150
Since the advent of percutaneous revascularization, therapies for restenosis have been heavily investigated. For years, numerous preclinical studies have shown efficacy against restenosis in animal models but failed in large-scale clinical trials. Finally, agents directed against smooth muscle cell proliferation delivered locally to the site of injury resulted in significant reductions in restenosis and revolutionized current clinical practice.
Several mechanical strategies have been employed to reduce the frequency of ISR including: (1) IVUS-guided high-pressure deployment to achieve larger MLD; (2) debulking therapy with rotational atherectomy; and (3) minimizing vessel injury with the avoidance of predilation by “direct” stenting. Although each strategy reduces restenosis rates in small clinical trials, large randomized controlled trials failed to support their overall efficacy.151,152,153
BMSs were developed as mechanical scaffolding to prevent recoil and negative remodeling for the reduction of restenosis. The rates of major adverse cardiac events and restenosis were significantly lower in patients with stable coronary disease randomized to BMS compared with balloon angioplasty.52 The evidence from several early BMS trials confirmed the superiority of stenting over angioplasty alone. However, persistent high rates of ISR spurred the development of pharmacologic therapies.
Therapies directed toward the various pathways implicated in restenosis have been investigated including antithrombotic, anti-inflammatory, and antiproliferative agents. Give the breadth of agents that have been studied for their effect in restenosis, we limit our discussion to agents with established or emerging efficacy.
Cilostazol is an antiplatelet agent predominantly used for the treatment of intermittent claudication. It is a selective inhibitor of phosphodiesterase-3 (PDE-3), which is abundant in platelets and vascular smooth muscle cells. Inhibition of PDE-3 increases intracellular cAMP and PKA activation to reduce platelet activation/aggregation, increase smooth muscle cell relaxation and cardiac contractility, and inhibit smooth muscle cell proliferation.154 Nonrandomized studies demonstrated that cilostazol was associated with a reduction in restenosis in patients who underwent balloon angioplasty or stenting.155 In the Cilostazol for Restenosis (CREST) trial, patients randomized to cilostazol following BMS had significantly larger MLD and reduced ISR (>50% diameter stenosis) compared with patients randomized to placebo.156 A meta-analysis of 10 randomized studies supports the use of cilostazol for the reduction of ISR.157
Local drug delivery has important advantages for the treatment of restenosis, namely, that drugs can be delivered at high doses locally without systemic toxicity. DESs predictably elute high doses of a therapeutic agent to reduce smooth muscle proliferation that is undetectable in the peripheral blood.158 The process of local drug delivery is complex and dependent on the dose, rate of release, tissue retention, and pharmacologic properties of the drug. Lower doses can be ineffective, whereas higher doses may result in tissue death, delayed healing, and higher rates of thrombosis.159,160 Prior studies determined that faster drug release is less effective at reducing LLL compared with slower release.161 Drugs can be directly bound to the stent. However, the majority of DESs use a polymer to store and time-release the drug. Nonerodable polymers were developed for effective drug delivery over a period of time and to not, by themselves, stimulate any additional inflammation or cell proliferation. The polymer release kinetics are critical to the prevention of ISR. In the Paclitaxel In-Stent Controlled Elution Study (PISCES), 10 or 30 μg of paclitaxel released over 10 days after DES implantation had little effect on neointimal formation, whereas 10 μg released over a 30-day period significantly reduced neointimal formation and LLL.162 Early clinical studies like PISCES supported the concept of a drug threshold with delivery over a sustained period of time to inhibit inflammation and smooth muscle cell proliferation.163 DESs are the preferred treatment for ISR. Compared with angioplasty, DESs significantly reduce the rate of restenosis and LLL in patients presenting with ISR.164 An emerging device for the treatment of ISR is the use of drug-coated balloons to deliver antirestenotic pharmacotherapy without the use of a polymer or metal scaffold.165 For the purposes of this chapter, we will introduce the pharmacologic agents used in DES and their mechanisms of action. In subsequent chapters, a review of the clinical trials related to DES and emerging technologies will be described in detail.
Sirolimus (rapamycin) is a natural macrocyclic lactone with potent immunosuppressive and antimitotic action produced by a fungus, Streptomyces hygroscopicus. It binds to FK binding protein-12 (FKBP-12), forming an immunosuppressive complex that inhibits mTOR, which leads to higher levels of p27kip1, blocking the G1-S transition in the cell cycle and halting vascular smooth muscle cell proliferation.166 Several pivotal trials conducted with sirolimus-eluting stents (SESs) led to US Food and Drug Administration (FDA) approval in April 2003. In the Randomized Study With the Sirolimus-Eluting Velocity Balloon-Expandable Stent (RAVEL) trial, SES demonstrated significant reductions in LLL, neointimal hyperplasia, and ISR compared with BMS at 6-month follow-up.167 At 1 year, SES also reduced the rate of major adverse cardiac events compared with BMS.63 The Sirolimus-Eluting Stent in De Novo Native Coronary Lesions (SIRIUS) trial recruited patients with more complex CAD and a higher prevalence of diabetes mellitus.168 In SIRIUS, SES reduced the rates of LLL and ISR compared with BMS, and these finding were consistent across high-risk subgroups for restenosis including small vessels, long lesions, and diabetes mellitus.168,169
Paclitaxel is isolated from the bark of the Pacific yew tree (Taxus brevifolia) and inhibits microtubule depolymerization, resulting in inhibition of cellular replication and cytokine-mediated smooth muscle cell proliferation and migration. The efficacy of paclitaxel-eluting stents (PES) was demonstrated in the TAXUS trials, where PES reduced ISR, TLR, and adverse cardiac events compared with BMS.170,171,172,173 These benefits were maintained in specific subgroups, including patients with vessel diameters <2.5 mm, lesion lengths >20 mm, renal insufficiency, and diabetes mellitus.
Everolimus is a 40-O-(2-hydroxyethyl) derivative of sirolimus and shares the same mechanism. Abbott Vascular (Temecula, CA) produces several everolimus-eluting stent (EES) in the Xience family of DES, the latest of which are called Xience Expedition and Alpine. EESs are also produced by Boston Scientific (Marlborough, MA) as the Promus Element and Premier stent systems. In a pooled analysis of the SPIRIT (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System) and COMPARE (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice) trials, EES reduced the rates of death or MI, stent thrombosis, and ischemic-driven TLR compared with PES in patients with ACS and stable CAD at 2-year follow-up.174 EES has similar clinical outcomes (ie, major adverse cardiac events and TLR) compared with SES and a lower rate of definite stent thrombosis.175
Zotarolimus is an analogue of sirolimus with a similar mechanism of action that was initially designed to have a short half-life.176 The FDA approved the Endeavor zotarolimus-eluting stent (ZES) platform in 2008 after reviewing the Medtronic (Minneapolis, MN) ENDEAVOR clinical program. Importantly, the Endeavour ZES elutes >95% of the drug within 14 days. In a combined analysis of the ENDEAVOR trials, Endeavour ZES was associated with a significantly lower rate of adverse cardiac events (death, MI, and very late stent thrombosis) compared with a pooled cohort of SES and PES patients (ie, first-generation DES).177 Endeavour ZES did have a higher rate of angiographic restenosis compared to first-generation DES, but this did not translate into a higher rate of TLR.177 The Resolute ZES was developed by Medtronic with substantially longer polymer drug release kinetics (180 days). In the RESOLUTE All-Comers trial, the clinical outcomes were comparable between Resolute ZES and EES.178
Biolimus A9 is an analogue of rapamycin that binds to mTOR and inhibits smooth muscle cell proliferation by blocking cell cycle progression between the G1 and S phases.179 Currently, 2 stents platforms, Biomatrix and Nobori, have received approval in Europe. Unique to these stent platforms is the use of a bioabsorbable polymer that is completely dissolved by 6 to 9 months following stent implantation.
Intracoronary brachytherapy effectively reduces neointimal proliferation and rates of ISR.180,181,182,183 Since the introduction of DES, the use of brachytherapy for ISR is uncommon and only performed at specialized tertiary referral centers. The practical difficulty in scheduling the procedure between radiation oncologists and the catheterization lab, reduced availability at tertiary centers, and increased rates of subacute thrombosis have deterred widespread acceptance of intracoronary radiation into clinical practice for ISR of DES.184,185
Over the past decades, the molecular and cellular pathophysiology of atherosclerosis has been extensively studied. Our current understanding of plaque vulnerability and the mechanisms responsible for conversion from a stable plaque to plaque rupture and atherothrombosis has shaped the landscape of pharmacotherapy and interventional cardiology for the treatment of ACS. Inflammation plays a central role in the pathogenesis of atherosclerosis and restenosis. Important molecular and biologic differences exist between atherosclerosis and restenosis. Recognition of the differences in the biologic response to vascular injury between balloon angioplasty and stenting led to the development of local drug delivery and DES for the prevention of restenosis. Improved understanding of the molecular mechanisms of atherosclerosis and restenosis, identification of plaques prone to rupture, and more effective methods to treat restenosis will continue to advance the field of interventional cardiology.
R. The pathogenesis of atherosclerosis: an update. N Engl J Med
NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med
MS, Van Lente
et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med
P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol
MA Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1995;251:788–791.
PM. Intercellular adhesion molecule (ICAM-1) and the risks of developing atherosclerotic disease. Eur Heart J
et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell
M. Binding to heparan sulfate or heparin
enhances neutrophil responses to interleukin 8. Proc Natl Acad Sci USA
et al. The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium. J Clin Invest
ZQ. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res
et al. Alternatively activated macrophages differentially express fibronectin and its splice variants and the extracellular matrix protein betaIG-H3. Scand J Immunol
S. Alternatively activated antigen-presenting cells: molecular repertoire, immune regulation, and healing. Skin Pharmacol Appl Skin Physiol
S. Interleukin-4 and dexamethasone
counterregulate extracellular matrix remodelling and phagocytosis in type-2 macrophages. Scand J Immunol
P. Innate and adaptive immunity in atherosclerosis. Semin Immunopathol
P. Cytokines and growth factors positively and negatively regulate interstitial collagen
gene expression in human vascular smooth muscle cells. Arterioscler Thromb
R. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol
P. Molecular bases of the acute coronary syndromes. Circulation
et al. Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures. Biochem Biophys Res Commun
et al. A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps. Proc Natl Acad Sci USA
S. Molecular cloning and characterization of 2B7, a rat mRNA which distinguishes smooth muscle cell phenotypes in vitro and is identical to osteopontin (secreted phosphoprotein I, 2aR). Biochem Biophys Res Commun
LL. Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest
PL. High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J Clin Invest
et al. Coronary calcification improves cardiovascular risk prediction in the elderly. Circulation
KS. Plaque angiogenesis and atherosclerosis. Curr Atheroscler Rep
E. Tension in the plaque: hypoxia modulates metabolism in atheroma. Circ Res
et al. Segmental heterogeneity of vasa vasorum neovascularization in human coronary atherosclerosis. JACC Cardiovasc Imaging
Z. Matrix metalloproteinase-9 expression in post-hypoxic human brain capillary endothelial cells: H2O2 as a trigger and NF-kappaB as a signal transducer. Thromb Haemost
M. Chronic hypoxia activates the Akt and beta-catenin pathways in human macrophages. Arterioscler Thromb Vasc Biol
et al. Hypoxia-induced gene expression in human macrophages: implications for ischemic tissues and hypoxia-regulated gene therapy. Am J Pathol
M. The role of hypoxia in atherosclerosis. Curr Opin Lipidol
VJ. The emerging concept of vascular remodeling. N Engl J Med
JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res
JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med
MJ. Coronary physiology revisited: practical insights from the cardiac catheterization laboratory. Circulation
GJ, De Bruyne
et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation
PA, De Bruyne
et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med
et al. One-year outcome of patients submitted to routine fractional flow reserve assessment to determine the need for angioplasty. Eur Heart J
et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study. J Am Coll Cardiol
WF, De Bruyne
et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol
et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med
et al. Coronary angiographic morphology in myocardial infarction: a link between the pathogenesis of unstable angina and myocardial infarction. J Am Coll Cardiol
SC Jr. Risk-reduction therapy: the challenge to change. Presented at the 68th scientific sessions of the American Heart Association November 13, 1995 Anaheim, California. Circulation
et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med
et al. Activated monocytes induce smooth muscle cell death: role of macrophage colony-stimulating factor and cell contact. Circulation
et al. Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med
RA. The Northridge earthquake as a trigger for acute myocardial infarction. Am J Cardiol
P. Circumferential stress and matrix metalloproteinase 1 in human coronary atherosclerosis. Implications for plaque rupture. Arterioscler Thromb Vasc Biol
A. Transluminal dilatation of coronary-artery stenosis. Lancet
WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med
PW, de Jaegere
et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med
et al. Unrestricted use of drug-eluting stents compared with bare-metal stents in routine clinical practice: findings from the National Heart, Lung, and Blood Institute Dynamic Registry. J Am Coll Cardiol
C. A prospective randomized comparison between paclitaxel
stents in the real world of interventional cardiology: the TAXi trial. J Am Coll Cardiol
et al. Comparative clinical outcomes of paclitaxel- and sirolimus-eluting stents: results from a large prospective multicenter registry—STENT Group. J Am Coll Cardiol
et al. Comparable clinical outcomes with paclitaxel- and sirolimus-eluting stents in unrestricted contemporary practice. J Am Coll Cardiol
LD. Restenosis after successful coronary angioplasty. Pathophysiology and prevention. N Engl J Med
TJ. Acute effects of transmural angioplasty in three experimental models of atherosclerosis. Arteriosclerosis
et al. Restenosis following transluminal angioplasty in experimental atherosclerosis. Arteriosclerosis
J. A paradigm for restenosis based on cell biology: clues for the development of new preventive therapies. J Am Coll Cardiol
SB 3rd, Douglas
JS Jr. Restenosis after percutaneous transluminal coronary angioplasty: the Emory University Hospital experience. Am J Cardiol
et al. Randomized trial of a nonpolymer-based rapamycin-eluting stent versus a polymer-based paclitaxel-eluting stent for the reduction of late lumen loss. Circulation
et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med
JM. Drug-eluting stents: a mechanical and pharmacologic approach to coronary artery disease. Pharmacotherapy
MW, de Valk
et al. Clinical and angiographic factors associated with asymptomatic restenosis after percutaneous coronary intervention. Circulation
et al. In-stent restenosis: long-term outcome and predictors of subsequent target lesion revascularization after repeat balloon angioplasty. J Am Coll Cardiol
DL. Bare metal stent restenosis is not a benign clinical entity. Am Heart J
et al. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. A quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. Circulation
et al. Risk factors, time course and treatment effect for restenosis after successful percutaneous transluminal coronary angioplasty of chronic total occlusion. Am J Cardiol
et al. Myocardial infarction as a presentation of clinical in-stent restenosis. Circ J
et al. Predictive factors of restenosis after coronary stent placement. J Am Coll Cardiol
SK. Differences in restenosis rate with different drug-eluting stents in patients with and without diabetes mellitus: a report from the SCAAR (Swedish Angiography and Angioplasty Registry). J Am Coll Cardiol
et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol
EJ. Potential mechanisms promoting restenosis in diabetic patients. J Am Coll Cardiol
et al. Plasma activity and insertion/deletion polymorphism of angiotensin I-converting enzyme: a major risk factor and a marker of risk for coronary stent restenosis. Circulation
DA. Interleukin 8 gene polymorphisms and susceptibility to restenosis after percutaneous coronary intervention. J Thromb Thrombolys. 2010;29(1):134–140.
SB. Drug resistance in ovarian cancer: the emerging importance of gene transcription and spatio-temporal regulation of resistance. Drug Resist Updat
PJ. Mechanisms of resistance to rapamycins. Drug Resist Updat
et al. Elevated circulating levels of monocyte chemoattractant protein-1 in patients with restenosis after coronary angioplasty. Arterioscler Thromb Vasc Biol
et al. Comparison of effects of bare metal versus drug-eluting stent implantation on biomarker levels following percutaneous coronary intervention for non-ST-elevation acute coronary syndrome. Am J Cardiol
et al. Comparison of effects of drug-eluting stents versus bare metal stents on plasma C-reactive protein levels. Am J Cardiol
et al. Pre-procedural plasma levels of C-reactive protein and interleukin-6 do not predict late coronary angiographic restenosis after elective stenting. Eur Heart J
et al. Serum concentrations of high-sensitivity C-reactive protein predict progressively obstructive lesions rather than late restenosis in patients with unstable angina undergoing coronary artery stenting. Circ J
G. Progression of native coronary plaques and in-stent restenosis are associated and predicted by increased pre-procedural C reactive protein. Heart
et al. Increased restenosis rate after implantation of drug-eluting stents in patients with elevated serum activity of matrix metalloproteinase-2 and −9. JACC Cardiovasc Interv
et al. Nonuniform strut distribution correlates with more neointimal hyperplasia after sirolimus-eluting stent implantation. Circulation
ER. Physiological transport forces govern drug distribution for stent-based delivery. Circulation
et al. Classification and potential mechanisms of intravascular ultrasound patterns of stent fracture. Am J Cardiol
et al. Incidence and clinical impact of coronary stent fracture after sirolimus-eluting stent implantation. Catheter Cardiovasc Interv
S. Stent fracture associated with drug-eluting stents: clinical characteristics and implications. Catheter Cardiovasc Interv
et al. Frequency, predictors and outcome of stent fracture after sirolimus-eluting stent implantation. Int J Cardiol
R. In-stent restenosis in the drug-eluting stent era. J Am Coll Cardiol
et al. Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. Circulation
et al. A comparison of clinical presentations, angiographic patterns and outcomes of in-stent restenosis between bare metal stents and drug eluting stents. EuroIntervention
et al. Quantitative angiographic assessment of elastic recoil after percutaneous transluminal coronary angioplasty. Am J Cardiol
RS. Animal models of human coronary restenosis. In: Topol
EJ, ed. Textbook of Interventional Cardiology. Philadelphia, PA: W.B. Saunders; 1994:365–381.
et al. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation
et al. A randomized comparison of coronary artery-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med
PW, de Jaegere
et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med
et al. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation
MB. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol
et al. Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis. Lancet
AJ. Thrombosis and inflammation as multicellular processes: significance of cell-cell interactions. Semin Hematol
DI. Inflammation and thrombosis: the clot thickens. Circulation
TA. Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the beta 2-integrin CD11b/CD18. Blood
IA. Role of P-selectin and leukocyte activation in polymorphonuclear cell adhesion to surface adherent activated platelets under physiologic shear conditions (an injury vessel wall model). Blood
A. Increased neutrophil-platelet adhesion in patients with unstable angina. Circulation
et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol
R. Morphological predictors of restenosis after coronary stenting in humans. Circulation
et al. Macrophage infiltration predicts restenosis after coronary intervention in patients with unstable angina. Circulation
A. Neutrophil and platelet activation at balloon-injured coronary artery plaque in patients undergoing angioplasty. J Am Coll Cardiol
CW. Leukocyte activation with platelet adhesion after coronary angioplasty: a mechanism for recurrent disease. J Am Coll Cardiol
Y. Expression of polymorphonuclear leukocyte adhesion molecules and its clinical significance in patients treated with percutaneous transluminal coronary angioplasty. J Am Coll Cardiol
S. Stent-induced expression and activation of the leukocyte integrin Mac-1 is associated with neointimal thickening and restenosis. Circulation
M, de Wit
et al. Late lumen loss after coronary angioplasty is associated with the activation status of circulating phagocytes before treatment. Circulation
et al. Predictive value of C-reactive protein after successful coronary-artery stenting in patients with stable angina. Am J Cardiol
MAJ. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science
P. An atherogenic diet induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit endothelium. Arterioscler Thromb. 1992;13:197–204.
MA Jr, Libby
P. Inducible expression of vascular cell adhesion molecule-1 by vascular smooth muscle cells in vitro and within rabbit atheroma. Am J Pathol
MI. Increased expression in vivo of VCAM-1 and E-selectin by the aortic endothelium of normolipemic and hyperlipemic diabetic rabbits. Arterioscler Thromb
L. Expression of ICAM-1 and VCAM-1 and monocyte adherence in arteries exposed to altered shear stress. Arterioscler Thromb Vasc Biol
et al. Sustained activation of vascular cells and leukocytes in the rabbit aorta after balloon injury. Circulation
ER. Monocyte recruitment and neointimal hyperplasia in rabbits: coupled inhibitory effects of heparin
. Arterioscler Thromb Vasc Biol
C. Neutrophil, not macrophage, infiltration precedes neointimal thickening in balloon-injured arteries. Arterioscler Thromb Vasc Biol
DI. A mAb to the beta2-leukocyte integrin Mac-1 (CD11b/CD18) reduces intimal thickening after angioplasty or stent implantation in rabbits. Proc Natl Acad Sci USA
et al. Essential role of monocyte chemoattractant protein-1 in development of restenotic changes (neointimal hyperplasia and constrictive remodeling) after balloon angioplasty in hypercholesterolemic rabbits. Circulation
S. A cascade model for restenosis. Circulation. 1992;86:III 47–III 52.
JF. Sequence of cellular responses in rabbit aortas following one and two injuries with a balloon catheter. Br J Exp Pathol
S. Wound healing in the media of the normolipemic rabbit carotid artery injured by air drying or by balloon catheter de-endothelialization. Am J Pathol
MM, De Meyer
AG. Triphasic sequence of neointimal formation in the cuffed carotid artery of the rabbit. Arterioscler Thromb
JJ. Poly’s lament: the neglected role of the polymorphonuclear neutrophil in the afferent limb of the immune response. Immunol Today
PO. A neutrophil derived factor(s) stimulates [3H]thymidine incorporation by vascular smooth muscle cells in vitro. Clin Invest Med
D. Molecular mechanisms of in-stent restenosis and approach to therapy with eluting stents. Trends Cardiovasc Med
EV, Di Lorenzo
et al. Activation of cAMP-PKA signaling in vivo inhibits smooth muscle cell proliferation induced by vascular injury. Nat Med
et al. Inhibition of cellular ras prevents smooth muscle cell proliferation after vascular injury in vivo. Nat Med
et al. In vivo gene transfer: prevention of neointima formation by inhibition of mitogen-activated protein kinase kinase. Basic Res Cardiol
TD. Pathophysiology of coronary artery restenosis. Rev Cardiovasc Med
. 2002;3(Suppl 5):S4–S9.
KM. Acute and chronic tissue response to coronary stent implantation: pathologic findings in human specimen. J Am Coll Cardiol
et al. Remodeling after directional coronary atherectomy (with and without adjunct percutaneous transluminal coronary angioplasty): a serial angiographic and intravascular ultrasound analysis from the Optimal Atherectomy Restenosis Study. J Am Coll Cardiol
et al. Remodeling of human coronary arteries undergoing coronary angioplasty or atherectomy. Circulation
et al. Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation
NA. The role of the adventitia in the arterial response to angioplasty: the effect of intravascular radiation. Int J Radiat Oncol Biol Phys
S. Comparison of activation process of platelets and neutrophils after coronary stent implantation versus balloon angioplasty for stable angina pectoris. Am J Cardiol
MM. Kinetics of cellular proliferation after arterial injury: II. Inhibition of smooth muscle cell growth by heparin
. Lab Invest
MM. Kinetics of cellular proliferation after arterial injury: IV. Heparin
inhibits rat smooth muscle cell mitogenesis and migration. Circ Res
ER. Controlled release of heparin
reduces neointimal hyperplasia in stented rabbit arteries: ramifications for local therapy. J Intervent Cardiol
MJ. Contrasting effects of the intermittent and continuous administration of heparin
in experimental restenosis. Circulation
et al. Leukocyte recruitment and expression of chemokines following different forms of vascular injury. Vasc Med
et al. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol
Y. In-stent neoatherosclerosis: a final common pathway of late stent failure. J Am Coll Cardiol
et al. Final results of the Can Routine Ultrasound Influence Stent Expansion (CRUISE) study. Circulation
RM. Meta-analysis of randomized trials of percutaneous transluminal coronary angioplasty versus atherectomy, cutting balloon atherotomy, or laser angioplasty. J Am Coll Cardiol
et al. Direct coronary stenting versus stenting with balloon pre-dilation: immediate and follow-up results of a multicentre, prospective, randomized study. The DISCO trial. DIrect Stenting of COronary Arteries. Eur Heart J
(pletal): a dual inhibitor of cyclic nucleotide phosphodiesterase type 3 and adenosine
uptake. Cardiovasc Drug Rev
et al. Effect of cilostazol
, a novel anti-platelet drug, on restenosis after percutaneous transluminal coronary angioplasty. Jpn Circ J
JS Jr, Holmes
DR Jr, Kereiakes
et al. Coronary stent restenosis in patients treated with cilostazol
et al. Efficacy of cilostazol
in reducing restenosis in patients undergoing contemporary stent based PCI: a meta-analysis of randomised controlled trials. EuroIntervention
et al. Stent-based delivery of sirolimus
reduces neointimal formation in a porcine coronary model. Circulation
et al. Pathological analysis of local delivery of paclitaxel
via a polymer-coated stent. Circulation
et al. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med
et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation
et al. The effect of variable dose and release kinetics on neointimal hyperplasia using a novel paclitaxel-eluting stent platform: the Paclitaxel
In-Stent Controlled Elution Study (PISCES). J Am Coll Cardiol
EG. Expression of cyclin-dependent kinase inhibitors in vascular disease. Circ Res
J, von Beckerath
et al. Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial. JAMA[JAMA and JAMA Network Journals Full Text]
drug-coated balloons: a review of current status and emerging applications in native coronary artery de novo lesions. JACC Cardiovasc Interv
AR. Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest
et al. Angiographic findings of the multicenter Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent (RAVEL): sirolimus-eluting stents inhibit restenosis irrespective of the vessel size. Circulation
et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med
et al. Quantitative assessment of angiographic restenosis after sirolimus-eluting stent implantation in native coronary arteries. Circulation
et al. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation
et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med
et al. Impact of moderate renal insufficiency on restenosis and adverse clinical events after paclitaxel-eluting and bare metal stent implantation: results from the TAXUS-IV Trial. Am Heart J
et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial. Circulation
et al. Comparison of everolimus- and paclitaxel-eluting stents in patients with acute and stable coronary syndromes: pooled results from the SPIRIT (A Clinical Evaluation of the XIENCE V Everolimus
Eluting Coronary Stent System) and COMPARE (A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice) trials. JACC Cardiovasc Interv
et al. Everolimus-eluting versus sirolimus-eluting stents: an updated meta-analysis of randomized trials. Clin Res Cardiol
et al. Zotarolimus, a novel sirolimus
analogue with potent anti-proliferative activity on coronary smooth muscle cells and reduced potential for systemic immunosuppression. J Cardiovasc Pharmacol
L. Final 5-year outcomes from the Endeavor zotarolimus-eluting stent clinical trial program: comparison of safety and efficacy with first-generation drug-eluting and bare-metal stents. JACC Cardiovasc Interv
et al. Comparison of zotarolimus-eluting and everolimus-eluting coronary stents. N Engl J Med
PW. Rapamycin in cardiovascular medicine. Int Med J. 2003;33(3):103–109.
et al. Inhibition of restenosis with beta-emitting radiotherapy: report of the Proliferation Reduction with Vascular Energy Trial (PREVENT). Circulation
et al. Intracoronary brachytherapy after stenting de novo lesions in diabetic patients: results of a randomized intravascular ultrasound study. J Am Coll Cardiol
et al. Reno, a European postmarket surveillance registry, confirms effectiveness of coronary brachytherapy in routine clinical practice. Int J Radiat Oncol Biol Phys
et al. Successful reduction of in-stent restenosis in long lesions using beta-radiation–subanalysis from the RENO registry. Int J Radiat Oncol Biol Phys
LE. Dosimetric considerations for catheter-based beta and gamma emitters in the therapy of neointimal hyperplasia in human coronary arteries. Int J Radiat Oncol Biol Phys
et al. Geographic miss: a cause of treatment failure in radio-oncology applied to intracoronary radiation therapy. Circulation
MULTIPLE CHOICE QUESTIONS
1. Sectioning of atherosclerotic lesions at postmortem can reveal the architecture of atherosclerotic plaques. Which of the following would typically be present in plaques at low risk of rupture?
B. Abundant expression of collagen fibrils
C. Abundant free cholesterol esters
D. Abundant inflammatory cells
E. High concentration of matrix metalloproteinases
2. Immune cells can be divided into those involved in the adaptive response and the innate response to antigens. Which of the following cell types belongs to the innate response?
3. A 55-year-old man presents with increasing angina despite best medical therapy. A high-grade lesion is identified in the proximal left anterior descending artery (LAD) with a minimal lumen diameter of 0.5 mm. After stent placement, the diameter is increased to 3.5 mm. The patient returns at 6 months with recurrent angina, and an angiogram shows a minimal lumen diameter of 1.5 mm. What is the loss index?
4. You are performing catheterization on a 65-year-old man who is 1 year out from bare metal stent placement in the LAD in the setting of an acute anterior myocardial infarction (MI). He now presents with stable angina on a maximal medical regimen, and a recent exercise tolerance test combined with a sestamibi scan revealed ischemia in the left circumflex coronary artery (LCX) territory. Catheterization reveals 50% in-stent restenosis in the prior placed LAD stent and a new long 80% lesion in a 2.5-mm LCX artery. What is the most appropriate strategy?
A. Treat the LCX lesion with a drug-eluting stent (DES). Defer therapy of the LAD.
B. Treat the LCX lesion with DES. Treat the LAD lesion with DES as well, given the evidence of restenosis.
C. Treat the LCX lesion with DES. Treat the LAD lesion with plain balloon angioplasty (POBA) and brachytherapy, given evidence of restenosis.
D. Recommend urgent coronary artery bypass grafting (CABG) given restenosis in the LAD, marking the patient as a poor candidate for percutaneous coronary intervention (PCI).
5. The pathogenesis of atherosclerosis has many similar features to the development of restenosis. Which of the following features would help differentiate a restenotic lesion from a primary atherosclerotic lesion?
B. Inflammatory cell involvement
C. Smooth muscle cell proliferation
D. Adhesion molecule expression
Vulnerable plaques are characterized by thin fibrous caps, which are relatively poor in smooth muscle cells (SMCs) and extracellular matrix proteins (such as collagens), and large lipid-rich necrotic cores, which are abundant in inflammatory cells.
The immune response can be divided into the innate immune response, which is an immediate response to foreign antigens and injury and is largely based on phagocytic cells and preformed mediators, and the adaptive response, which is a learned response to specific antigens and involves cell-mediated and humoral immune responses. The innate immune response has traditionally been thought of as the major player in atherosclerosis, with macrophages being the predominant cell type. However, there is mounting evidence for an important role for the adaptive response as well, as evidenced by the presence of T cells within atherosclerotic plaques.
Loss index is equal to the late loss divided by acute gain. The acute gain in this example is 3 mm and the late loss is 2 mm. Therefore, the loss index is 2/3 or 0.66.
The lesion in the LCX is long and in a small-caliber vessel, marking it as high risk for restenosis when treated with either POBA or bare metal stent. Treatment with DES is appropriate. Data would suggest that most cases of restenosis will occur within the first 6 to 12 months. There is no reason to suspect that the LAD restenosis will proceed to a clinical significant degree, and there is no evidence of ischemia in that territory. Neither PCI nor CABG to address the LAD is warranted. Conservative management of this lesion is most appropriate.
As with atherosclerosis, the mechanisms of restenosis involve an inflammatory response to injury involving leukocyte recruitment amplified by the release of cytokines and growth, which eventually lead to smooth muscle cell proliferation and migration. However, in contrast to atherosclerotic plaques, restenosis is termed an accelerated arteriopathy with a time course that is measured in months as opposed to decades.