For most clinical trials, restenosis is defined by the binary endpoint of a reduction of 50% of the luminal diameter compared with the reference vessel (9). This is somewhat of an arbitrary definition that endeavors to separate clinically important lesions from those without sequelae. Restenosis can also be described in more continuous terms, which are helpful in understanding the pathophysiology of the process. As an example, late lumen loss (LLL) is defined as the continuous angiographic measure of lumen deterioration, and calculated by subtracting minimal lumen diameter (MLD) at immediate follow-up from late postprocedural MLD. This parameter has been used as a surrogate marker for the effects of different antirestenotic therapies and to determine outcomes in the BMS era and continued in the DES era (10, 11). One important point derived from viewing restensosis as a continuous variable is the fundamental understanding that virtually all patients suffer some degree of restenosis, which follows a typical Gaussian distribution (Fig. 2-1). However, only the few patients who have severe ISR (usually with a lesion severity of >70%) have symptoms. The average amount of LLL is 0.8 to 1.0 mm after implantation of a BMS. This amount of late loss occurs regardless of the size of the original vessel lumen. This is of critical significance, especially for smaller vessels. A 4-mm-diameter vessel would lose 44% of lumen area with the loss of 1-mm diameter. If a vessel with a 2-mm diameter experiences the same 1 mm of late loss, there is a 75% loss of lumen area and angiographic restenosis. Therefore, late loss and angiographic restenosis are related to the diameter of the reference vessel (12). One of the most important concepts to understand is that restenosis rates vary hugely, depending on the particular definition used in any given study (Table 2-1).

Discordance between late loss and binary restenosis has been observed in several trials and is probably multifactorial and has been a topic of much debate. Although late loss has been very useful as a surrogate marker for the effectiveness of a given drug to prevent clinical restenosis, the relationship between late loss and binary restenosis is nonlinear and has been characterized by a curvilinear function. This notion implies that there is a threshold for clinical significance. The argument is that below a given amount of late loss, the degree of tissue growth is immaterial as it does not reflect a worse clinical restenosis rate (Fig. 2-2). This argument is not universally supported.

The clinical sequelae of angiographic restenosis are not always in concordance with the degree of restenosis. In a meta-analysis of all patients with angiographic ISR from the BENESTENT I, BENESTENT II pilot, BENESTENT II, MUSIC, WEST 1, DUET, FINESS 2, Fluvastatin Angioplasty Restenosis (FLARE), SOPHOS, and ROSE studies, which recruited 2,690 patients who underwent percutaneous revascularization, restenosis (≥50% diameter stenosis) occurred in 607 patients and was clinically silent in almost half those patients. There are likely multiple factors that play a role in how patients present, including reference diameter and lesion severity, in follow-up (13).

Traditionally, restenosis has been viewed as a largely benign condition presenting most commonly with stable angina. However, there is substantial evidence to the contrary. Bare metal ISR had shown variability in presentation. Although the majority present with stable exertional symptoms, unstable angina is a frequent presentation (26%-53%), and acute myocardial infarction (MI) has been described in 3.5% to 20% of patients (14, 15). DESs have similar presentations. In one series, the rates of unstable angina and MI were comparable between the two groups, 18% and 2%, respectively (16). These stud ies point to the fact that ISR is not always a benign condition.

One of the special concerns regarding restenosis is the potential greater risk in the setting of left main stenting, which has been increasing in frequency in recent years, and, though it remains <1% of percutaneous coronary intervention (PCI) in the United States, is likely to increase. Despite concerns regarding the possible serious consequences of restenosis in this scenario, multiple case series such as the Rotterdam and Milan series have shown promising results of left main stenting compared with coronary artery bypass surgery. The safety of the procedure has also been well documented in randomized trials, and follow-up angiography is no longer routinely recommended after the procedure (17, 18 and 19).

Multiple studies have confirmed that compared with atherosclerosis, restenosis following balloon angioplasty or stent implantation is a relatively accelerated process. With balloon angioplasty, clinically important restenosis is almost always apparent by 6 months (20, 21). Similarly, in stents, the average time at which ISR is apparent is at 5.5 months, with some evidence that there is a shorter interval if presentation was with acute MI (22).

The three most important clinical risk factors for restenosis that have been identified are increased stent length, smaller MLD, and the presence of diabetes (23). Risk factors can be loosely identified as both biologic in nature and mechanical, although there is considerable interplay between the two.

Mehran et al. developed an angiographic classification of ISR according to the geographic distribution of intimal hyperplasia in reference to the implanted stent (48). That included four classes defined as the following (Fig. 2-3):

Class I: Focal ISR group—Lesions are 10 mm in length and are positioned at the unscaffolded segment (i.e., 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—Lesions are 10 mm in length and are confined to the stent(s), without extending outside the margins of the stent(s).

Class III: “Diffuse proliferative” ISR—Lesions are 10 mm in length and extend beyond the margin(s) of the stent(s).

Class IV: ISR with “total occlusion”—Lesions have a thrombolysis in myocardial ischemia (TIMI) flow grade of 0.

The pattern of ISR is different in BMSs and DESs: while diffuse pattern is more likely with the latter, more focal pattern is seen with the former. Of interest, patients presenting with MI are likely to present with diffuse pattern compared with those without MI (16, 22).

The pathogenesis of restenosis is significantly different from atherogenesis in both the content of the lesion and the time required for development. As discussed above, restenosis develops much more
rapidly than atherosclerosis and is sometimes referred to as an accelerated arteriopathy. Forrester proposed a paradigm for restenosis based on the vascular biology of wound healing and suggested three phases in the process: the inflammatory phase, a granulation or cellular proliferation phase, and a phase of remodeling involving extracellular matrix (ECM) protein synthesis (49). More recently, Park et al. have suggested a possible occurrence of in-stent neoatherosclerosis in selected situations, although the prevalence of these histologic findings is uncertain (50).

Before discussing the molecular and cellular mechanisms of restenosis, it is worth elucidating the important differences that exist between restenosis following balloon angioplasty alone and in-stents.

Expansion of a balloon or placement of a stent causes injury within the vessel wall, including dissection, crush injury of SMCs, and de-endothelialization. Leukocyte recruitment and infiltration occur at these sites of injury, where platelets and fibrin have been deposited. Within areas of injury such as atherosclerotic and postangioplasty restenotic lesions, and in areas of ischemia-reperfusion injury, in vivo studies have shown that leukocytes and platelets are deposited together. For the inflammatory response after angioplasty, this interaction between platelets and leukocytes appears to be important (59).

This interaction has been explained by Diacovo et al., who have put forth a paradigm of leukocyte attachment to surface-adherent platelets followed by transmigration (60). As with atherosclerosis, the initial loose association of leukocytes is mediated through the selectin class of adhesion molecules, particularly by platelet P-selectin, followed by their firm adhesion and transplatelet migration, processes that are dependent on the integrin class of adhesion molecules (60, 61). The β₂ integrin molecule Mac-1 (CD11b/CD18) is present on both neutrophils and monocytes, and appears to be of central importance in leukocyte recruitment following vascular injury. In addition to promoting the accumulation of leukocytes at sites of vascular injury, the binding of platelets to neutrophils amplifies the inflammatory response by inducing neutrophil activation, upregulating cell-adhesion-molecule expression, and generating signals that promote integrin activation and chemokine synthesis. These processes of activation may be mediated through the release of soluble CD40 ligand, a proinflam-matory molecule stored most abundantly in platelets. Bolstering these data, both neutrophil-platelet and monocyte-platelet aggregates have been identified in the peripheral blood of patients with coronary artery disease, and may be markers of disease activity and prognosis (62, 63).

In most cases, restenosis does not appear to be a case of accelerated atherosclerosis, but rather a distinct temporal and pathophysiologic process. However, inflammation is an important common link between atherogenesis and restenosis. Observations regarding restenosis have been hampered by the difficulty of obtaining human restenotic tissue. Farb et al. investigated stented arteries from pathologic samples of 116 stents from 87 patients >90 days post procedure. They found a statistically significant association between extent of medial damage, inflammation, and restenosis (64). Also linking leukocytes and restenosis is a study by Moreno et al., in which the authors present data from tissue retrieved from directional atherectomy at the time of angioplasty. They found a strong positive correlation between the number of macrophages present in the tissue at the time of angioplasty and subsequent risk of restenosis (65).

Systemic markers of inflammation following angioplasty have also provided insight into the mechanisms of restenosis. Neumann et al. investigated systemic inflammation by collecting blood samples both proximal to and just distal to the site of balloon dilatation in humans. Using flow cytometry to determine the expression of the neutrophil adhesion molecules L-selectin and CD11b, they found an upregulation of these markers of leukocyte activation after angioplasty, measured as a gradient of distal and proximal specimens (32). Mickelson et al. were able to document upregulation of CD11b on both neutrophils and monocytes using systemic venous specimens from patients undergoing angioplasty. They found that levels of CD11b had a positive correlation with adverse clinical events (33). Inoue et al. confirmed these data, demonstrating that elevated levels of neutrophil CD11b are predictive of future propensity for restenosis after balloon angioplasty and stenting (66, 67). Pietersma et al. showed that interleukin 1 production by stimulated monocytes isolated from blood before angioplasty was correlated positively with late luminal loss, while activation of granulocytes measured by CD66 levels was inversely correlated with late loss (68). Cipollone et al. demonstrated upregulated levels of MCP-1 following percutaneous intervention in humans, and found that MCP-1 levels correlate with risk for restenosis (34). Gaspardone et al. showed a positive correlation between the nonspecific inflammatory marker CRP following stent placement and propensity for restenosis (69).

Animal models have been invaluable in elucidating basic cellular and molecular mechanisms of restenosis. In several experimental animal models, cell adhesion molecules critical for leukocyte recruitment have been found to be upregulated by an atherogenic diet (70

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