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The safety and efficacy of percutaneous coronary interventions (PCI) have been drastically improved by the introduction of bare metal stent (BMSs) in clinical practice.1 However, a new pathologic entity arose with the implantation of BMSs within coronary arteries: in-stent restenosis (ISR).2 ISR can be defined as the in-stent lumen narrowing that pathobiologically relates to the phenomenon of neointimal hyperplasia (NIH).3 Biologic, mechanical, procedural, and stent-related factors interplay in determining the incidence, morphology, and clinical implications of ISR. Introduction of drug-eluting stents (DESs) in 2001 in clinical practice represented a technologic breakthrough. DESs critically improved the efficacy of percutaneous revascularization procedures by reducing the need of target lesion revascularization (TLR) and target vessel revascularization (TVR) at follow-up.4 However, a low rate of ISR after DES implantation still exists. With more than 3 million DESs implanted worldwide each year, DES-ISR represents a major public health issue. In this chapter, we comprehensively review the incidence, mechanisms, diagnosis, and potential treatment strategies of ISR, with a particular focus in the contemporary DES era.


The goal of percutaneous revascularization procedures is the relief of significant coronary artery obstructions. Effectiveness of PCI with stent implantation is expressed in terms of clinically significant restenosis assessed objectively as a requirement for ischemia-driven repeat revascularization either of the stented lesion itself (TLR) or of the stented vessels and its collateral branches (TVR). ISR can be defined as a lumen narrowing within the site of stent implantation induced by local vascular barotrauma with reactive NIH. The clinical consequence of ISR is the development of a new flow-limiting obstructive lesion and subsequent reduction of downstream myocardial perfusion.

ISRs differ in their morphologic pattern, which in turn is associated with important clinical, prognostic, and therapeutic implications. The most accepted morphologic classification of ISR is the one proposed by Mehran et al.5 Before the introduction of this classification, patterns of ISR were broadly classified as focal (in-stent lesion <10 mm in length) or diffuse (in-stent lesion >10 mm in length). The Mehran classification introduced the description of the topographic relation between NIH and the coronary stent implanted. This classification is as follows (Fig. 33-1):


Descriptive diagram of in-stent restenosis (ISR) angiographic patterns. Pattern I (focal type) is <10 mm="" in="" length="" and="" contains="" 4="" subtypes="" (types="" ia-id).="" patterns="" ii="" to="" iv="" (diffuse="" type)="" are="">10 mm in length and are distinguished according to the relation with the stent and the vessel lumen. (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;100:1872-1878.)

  • Class I, focal ISR group: Lesions are ≤10 mm in length and are placed at the unscaffolded segment (articulation or gap) (type IA), the body of the stent (type IB), the proximal or distal margin (type IC), or a combination of these sites (type ID; multifocal ISR).

  • Class II, ...

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