Genetic Basis For Inflammation

Figure 1-4. Angiogram demonstrating in-stent restenosis of a sirolimus-eluting stent in the middle left anterior descending artery (arrow).
Figure 1-5. Intravascular ultrasound (IVUS) demonstrating severe in-stent restenosis.

arterial medial fracture, particularly deep into lipid-rich plaque, is associated with a higher degree of inflammatory infiltrate, increased neointimal thickness, and neoangiogenesis.41 Clinical factors associated with restenosis, particularly in diabetics, include longer stent length, active tobacco use, smaller arterial reference diameter, and inflammatory state as determined by CRP level.42

Leukocyte infiltration as a response to injury remains an important feature of this inflammatory assault, as does leukocyte adhesion to endothelial cells and to platelets. The expression of neutrophil adhesion molecules, particularly the integrins CD11b/ CD18 (now ITGAM/ITGB2) known as the membrane attack complex (MAC-1), increases after PCI with bare metal stents (BMS) in patients with single-vessel coronary atherosclerosis and is strongly correlated with the risk of restenosis. The correlation between MAC-1 expression, as a surrogate marker of leukocyte activation, and neointimal hyperplasia has been examined in MAC-1 -/- mice. After endothelial denudation, a limited leukocyte presence and a reduction in the degree of neointimal hyperplasia were noted.43

The response-to-injury hypothesis appears to involve a complex interplay among platelets, leukocytes, fibrin, and other components. The release of a multitude of cytokine mediators, such as MCP-1, IL-6, IL-1, and TNF-a, appears to coordinate this effort. The end result is neointimal hyperplasia leading to restenosis. The potential exists to establish molecular targets, such as MAC-1, with the aim of developing specific therapies to combat inflammation.

The significance of these findings is highlighted by the influence of inflammation on clinical outcomes. Leukocytosis, a nonspecific surrogate marker of inflammatory response across the spectrum of ACS, has been demonstrated to be an ominous sign. In the setting of PCI, peak circulating monocyte count has been shown to be associated with angiographic restenosis at 6 months.44

Biomarkers of Inflammation and Percutaneous Coronary Intervention

Inflammatory biomarkers have also been used to quantify systemic inflammation to assess the relation between inflammation and restenosis in PCI. Prepro-cedural levels of sCD40L were examined prospec-tively and found to be predictors of restenosis at 6 months in patients undergoing PCI for stable angina.45 CRP elevation is more commonly used as a measure of inflammatory status after coronary stent implantation. Levels of hsCRP were shown to rise across a translesional gradient, both in patients with angina and in those who had undergone PCI, suggesting local production of CRP or increased local release of CRP-rich thrombus.46 In patients with stable coronary disease who underwent PCI, elevated postprocedural levels of CRP were noted and supported a robust inflammatory response.

The rationale of predicting outcomes using prepro-cedural measures of inflammation remains controversial, because pre-PCI levels of CRP and IL-6 have not been shown to correlate with in-stent restenosis after PCI.47 In 483 patients with stable or unstable angina who underwent coronary intervention with BMS, elevated CRP and lipoprotein(a) predicted adverse cardiac events at 1 year, but the association did not hold for in-stent restenosis.48 Prospective investigation of 276 patients who had undergone PCI with BMS for both stable angina and unstable ai


□ Upper tertile

□ Middle tertile

□ Lower tertile

Angiographic restenosis (diameter stenosis >50%)

Clinical restenosis

(target vessel revascularization)

Figure 1-6. Incidence of angiographic and clinical restenosis in three groups defined by the change in C-reactive protein (A CRP) after percutaneous coronary interventions. (Redrawn from Dibra A, Mehilli J, Braun S, et al: Inflammatory response after intervention assessed by serial C-reactive protein measurements correlates with restenosis in patients treated with coronary stenting. Am Heart J 2005;150:344-350.)

coronary syndromes demonstrated that preproce-dural CRP levels were predictive of increased rates of restenosis and worse clinical outcomes after adjusting for the presence of unstable coronary disease.49 Given the available data, it is difficult to make definitive conclusions regarding the utility of the prepro-cedural inflammatory state, particularly in the population of patients with stable angina. In ACS, however, an assessment of the baseline inflammatory state may provide valuable prognostic information.

Clinically, a rise in postprocedural CRP has been shown to correlate with in-stent restenosis at 6 months after PCI. In 1800 patients with either stable or unstable angina undergoing PCI, peak postpro-cedure CRP level strongly correlated with both angiographic and clinical restenosis (Fig. 1-6). Those patients in the highest tertile of postprocedure increase in CRP level also had higher 30-day rates of stent thrombosis, death, MI, or target vessel revascu-larization.50 Alternatively, a return of post-PCI CRP levels to baseline 72 hours after intervention was highly predictive of event-free survival over a 1-year period in a prospective study of 81 consecutive patients with one-vessel stable angina. Therefore, the postprocedural rise in CRP appears to provide a consistent correlation with future risk of restenosis.

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