Background

When a vessel is dilated by percutaneous transluminal angioplasty (PTA) or stenting, there is an “initial gain” in lumen size. Restenosis, an iatrogenic “disease,” is defined as a reduction in luminal size due to a “loss of gain.” Restenosis has been defined in several ways. Greater than 50% stenosis at follow-up angiography or duplex ultrasonography has become the most frequently used definition in recent trials. In-stent restenosis (ISR) is usually defined as 50% stenosis at the stented site or at a proximal or distal site adjacent to a segment without stenosis. Clinical patency and clinical restenosis are other terms used to describe the clinical outcome of vascular intervention. The clinical patency rate is the percentage of patients who have undergone an initially successful procedure, with the symptomatic improvements being uninterrupted in any specified period. Clinical patency is ended when symptoms recur to the same degree as present before the intervention. Clinical restenosis is defined as the need for target lesion revascularization (TLR), which is any clinically driven repeat percutaneous intervention of the target lesion or bypass surgery of the target vessel performed for a clinical indication. Clinical indications refer to ischemic symptoms or greater than 50% in-lesion stenosis, or both, by quantitative angiography or ultrasound. The period from primary percutaneous intervention to repeat intervention is defined as “freedom from TLR.”

Restenosis is a multifactorial process involving three major mechanisms: remodeling, neointimal hyperplasia, and thrombosis. In vascular remodeling, arteries structurally adapt in size and composition. Using serial intravascular ultrasound imaging to observe the coronary artery after percutaneous transluminal coronary angioplasty (PTCA), Mintz et al.¹ demonstrated that remodeling was a bidirectional phenomenon. Of 212 native coronary lesions in 209 patients after PTCA, 22% of the lesions showed positive remodeling (adaptive or expansive remodeling), and 78% of the lesions exhibited negative remodeling (constrictive or restrictive remodeling) with a decrease in lumen area (from 6.6 ± 2.5 mm² to 4.0 ± 3.7 mm²; P < 0.0001). The SURE (Serial Ultrasound Restenosis) study² examined the time course of this phenomenon by performing serial intravascular ultrasonography and revealed that the decrease in lumen and external elastic membrane volume occurred between 1 and 6 months after PTCA. The remodeling event was related to the adventitial fibrosis. Preliminary animal studies have demonstrated that arterial injury triggers the differentiation of adventitial fibroblasts into activated myofibroblasts by day 3 after injury.³ Myofibroblasts have both synthetic capability (type I collagen) and the ability to translocate to the vessel intima.⁴ They contribute to restenosis by proliferating, forming a fibrotic scar around the injury site, and migrating into the neointima.⁵ The source of the early proliferating cells causing stenosis formation is likely to be derived from the adventitia and media.⁶

Neointimal hyperplasia has been extensively investigated and described. First, the interventional damage to the endothelium and the subsequent exposure of subintimal collagen and tissue factors lead to loss of nitric oxide,⁷ prostacyclin,⁸ tissue plasminogen activator,⁹ heparan sulfate proteoglycans,¹⁰ and endothelial-derived hyperpolarizing factor.¹¹ This process results in thrombosis, vasoconstriction, inflammation, and cellular activation and growth. Second, dysfunctional endothelial cells overexpress plasminogen activator inhibitor (PAI)-1, fibronectin, thrombospondin, integrins, selectins, angiotensinogen, angiotensin-converting enzyme, endothelin, and several growth factors, thereby leading to smooth muscle cell activation and growth.¹² Proliferation plus migration of smooth muscle cells from the adventitial and medial layers of the vessel wall to the intima is a universal phenomenon in animal models of restenosis. However, the bulk of neointimal tissue is composed not primarily of smooth muscle cells themselves but of the fibrocollagenous extracellular matrix they secreted after activation. In human neointima, only 11% of the neointimal tissue mass is composed of cellular elements.¹³ The cytokines and growth factors released have the ability to promote proto-oncogene expression (e.g., c-myc, c-myb, c-fos), believed to regulate transformation of smooth muscle cells from a contractile phenotype to a secretory phenotype.¹⁴ The secretory phenotype of smooth muscle cells produces a loose extracellular matrix that represents the major portion of neointimal hyperplasia. Meanwhile, the whole process leads not only to tissue growth but also to fibrotic constriction of the adventitia, also responsible for constrictive remodeling.¹⁵

Mural thrombosis is a fundamental participant in the restenosis process. Immediately after vascular injury, circulating platelets adhere to exposed subintimal elements such as collagen, von Willebrand factor, fibronectin, and laminin via a number of glycoprotein membrane receptors. Platelet adhesion in turn promotes release of cytokines and growth factors, including platelet-derived growth factor, transforming growth factor (TGF)-β, and basic fibroblast growth factor, which can result in smooth muscle cell proliferation and, ultimately, neointima formation.16,17 Thrombus formation also acts as a scaffold for vascular smooth muscle cell migration, proliferation, and synthesis of matrix. The role of thrombosis in the restenosis process is supported by a clinical study by Bauters et al.¹⁸ In 117 consecutive patients who underwent successful PTCA and coronary angioscopy before/immediately after the procedure and at 6 months’ follow-up, they found that an angioscopically protruding thrombus at the PTCA site was associated with significantly greater loss of luminal diameter.

Elastic recoil is a direct result of the elastic properties of the vessel wall, and it occurs immediately at the site of PTA. Ardissino et al.¹⁹ demonstrated that mean elastic recoil averaged 17.7% ± 16% in a study involving 98 consecutive patients and was correlated to the degree of residual stenosis immediately after coronary angioplasty (r = 0.64; P < 0.001). During 8 to 12 months of follow-up, no correlation was observed between the degree of elastic recoil and changes in minimal lesion diameter, but a positive correlation between the amount of elastic recoil and the incidence of restenosis was documented (r = 0.84; P < 0.05). Stenting virtually eliminates vessel elastic recoil and negative remodeling, the mechanical component of restenosis, but it also stimulates the cellular mechanisms that result in neointimal hyperplasia and subsequent ISR.²⁰

Clinical Relevance

Restenosis remains the major limitation of many endovascular interventions, despite new technologies and devices. In noncoronary vessels, restenosis is seen mainly in small and medium-sized arteries.

Prevention of Restenosis

Physician knowledge of appropriate endovascular interventions is crucial. Appropriate indications and accurate balloon or stent placement and expansion may help prevent restenosis. Various pharmacologic strategies have been shown to modulate the restenotic processes in vitro and have been efficient in reducing restenosis in animal models. Still, in clinical trials most of these attempts did not successfully limit neointima formation.

Systemic pharmacotherapies have targeted different mechanisms that have been identified as potential participants in the development of restenosis. Antithrombotic agents were associated with improved outcomes, especially cilostazol. In a study of 141 consecutive patients scheduled for PTA in the femoropopliteal artery, the incidence of TLR was significantly lower in the cilostazol-treated than in the non–cilostazol-treated patients (12% vs. 32%; P < 0.01).⁴⁶

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