ABSTRACT: Background. Preprocedual C-reactive protein (CRP) has been reported to correlate with in-stent restenosis following bare-metal stent implantation. The aim of this study was to investigate the impact of preprocedural inflammation on neointimal hyperplasia assessed by intravascular ultrasound (IVUS) following everolimus-eluting stent (EES) implantation. Methods. We identified 134 patients meeting the following criteria: 1) patients treated with EES; 2) those with stable or unstable angina; and 3) patients available for high-sensitivity (hs)-CRP before the procedure and volumetric IVUS analysis at follow up. We divided the patients into two groups on the basis of hs-CRP levels (Methods
Patients. Data were obtained from the intravascular ultrasound (IVUS) database of the Cardiovascular Core Analysis Laboratory at Stanford University. We identified patients who met the following criteria derived from the SPIRIT III randomized trial and SPIRIT Japan nonrandomized arm: 1) patients treated with EES; 2) patients with stable or unstable angina; and 3) those available for hs-CRP preprocedure and volumetric intravascular ultrasound (IVUS) analysis at 8-month follow up. We divided these patients into two groups based on hs-CRP levels: Results
We identified 134 patients with 134 vessels fulfilling the inclusion criteria for this study (77 vessels from the SPIRIT III randomized trial and 57 vessels from the SPIRIT Japan non-randomized arm). The baseline, angiographic and procedural characteristics are summarized in Tables 1 and 2. The average and median hs-CRP levels were 3.22 mg/L and 1.45 mg/L, respectively. Although there was no significant difference in age, male gender, coronary risk factors, unstable angina pectoris (AP), prevalence of prior myocardial infarction and distribution of target vessel between the two groups, the prevalence of smoking was significantly higher in the elevated CRP group (p = 0.037). For the IVUS parameters, there was no significant difference in VVI, PVI and LVI between the two groups at baseline. At 8-month follow up, there was also no significant difference in %NIV and maximum %CSN, nor in VVI, PVI and LVI between the two groups (Table 3). In addition, there was no significant correlation of hs-CRP with %NIV (r = 0.044, p = 0.610, Figure 1A) or maximum %CSN (r = 0.086, p = 0.321, Figure 1B) at 8-month follow up. There was no correlation of hs-CRP with %NIV and maximum %CSN when CRP was transformed to natural logarithms for greater symmetry of the distribution (%NIV: r = -0.053; p = 0.544, and %CSN: r = -0.011; p = 0.897). The rate of maximum %CSN ≥ 60% was low and did not differ between the two groups (Table 3). In patients with stable angina, there was no significant difference in %NIV and maximum %CSN between those with and without elevated hs-CRP levels (%NIV: 5.30 ± 5.91% for CRP Discussion
Our study showed that preprocedural vascular inflammation assessed by hs-CRP did not correlate with NIH or max % cross sectional narrowing in patients following EES implantation.
Recent studies have shown that inflammation plays a pivotal role in the pathogenesis of atherosclerosis17,18 and is associated with an increased risk of cardiovascular events.19,20 For in-stent restenosis, inflammation has been shown to contribute to NIH.21 After stent implantation, an inflammatory reaction, including recruitment of leukocytes and release of inflammatory cytokines, takes place, resulting in neointimal growth. These responses may be enhanced under conditions of preexisting inflammation.22 Luizzo et al found that CRP levels before balloon angioplasty positively correlated with peak CRP levels after the procedure.22 Thus, preprocedural inflammation has been considered to be an important factor associated with subsequent in-stent restenosis. Studies including small numbers of patients revealed conflicting results when treated with balloon angioplasty or BMS. While some studies showed a positive relationship between CRP and in-stent restenosis,10, 23–26 others did not.27–31 More recently, Ferrante et al confirmed that higher baseline CRP levels were associated with a higher risk of angiographic restenosis in patients treated with BMS in their meta-analysis, consisting of 2,747 patients.1
Our data showed that elevated preprocedural hs-CRP was not associated with increased NIH in patients following EES implantation (Table 3). This result was unchanged when we examined the correlation between hs-CRP with %NIV or maximum %CSN (Figure 1). Also, the incidence of maximum %CSN ≥ 60%, which indicates in-stent restenosis in the clinical setting, was minimal and did not differ between the two groups (Table 3). In addition, neointimal suppression in the current study using EES (4.9% at 8 months) is similar to that in SES (3.1% at 8 months)32 and may be even lower than that in other clinically available drug-eluting stents such as paclitaxel- (12.2% at 9 months)33 and zotarolimus-eluting stents (16.1% at 8 months).34 Taken together, EES may be effective in NIH suppression regardless of the presence of inflammation.
We cannot determine why the inflammation did not affect NIH following EES implantation in the current study. Apart from their antiproliferative effect, sirolimus analogs have an anti-inflammatory property through inhibition of production of cytokines including tumor necrosis factor alpha, interleukin-1β, and so forth.2–5 Furthermore, considering the observation that everolimus treatment significantly reduced inflammatory cytokines in LDL-receptor-/- mice,35 it is possible that EES have a beneficial effect on NIH through, at least in part, suppression of vascular inflammation.
More recently, Lasave et al reported that preprocedural hs-CRP correlated with NIH volume assessed by IVUS in 40 patients treated with the ZoMaxx stent system (Abbott Laboratories, Abbott Park, Illinois), a zotarolimus-eluting stent.36 In their report, multivariate linear regression analysis revealed that hs-CRP independently correlates with the neointimal hyperplasia volume.36 Neointimal hyperplasia of ZoMaxx stent at 9 months, however, was 14.6%,37 which seems to be higher compared to that of EES. Although there was no direct comparison between the ZoMaxx stent system and EES in terms of neointimal hyperplasia, strong suppression of neointimal formation from EES or its anti-inflammatory properties might have blunted the effect of inflammation.
In the current study, there was no significant difference in prevalence of unstable angina pectoris (AP) between patients with and without higher hs-CRP levels (Table 1). Some reports showed that CRP levels were higher in patients with unstable AP than those with stable AP.10,29 In contrast, other reports showed that CRP levels were similar between unstable and stable AP patients.38 Although the exact reasons why there was no difference in hs-CRP levels between unstable and stable AP are not clear in the current study, one possible explanation may include the fact that the patient population enrolled in this trial had relatively stable disease. Compared with observational studies, randomized, controlled studies are more likely to have more stable patients due to their inclusion and exclusion criteria.39 Another possibility is the underpowered analysis due to the limited number of patients with unstable AP in the current trial.
Study limitations. We should note several limitations of this study. First, patient selection may have affected our observations. Second, there was a lack of standardization of the assay used for hs-CRP, therefore differences in hs-CRP measurement methods could have confounded the results. Finally, there was insufficient patient information regarding medications following EES implantation.
Conclusions
Preprocedural inflammation was not found to affect neointimal hyperplasia as well as maximum % cross-sectional narrowing at 8 months following EES implantation. Thus, the influence of preprocedural inflammation on neointimal formation may be minimal in patients treated with EES.
Acknowledgement. We thank Heidi N. Bonneau, RN, MS, CCA for her expert review of this manuscript.
From Stanford University, Stanford, California, *Abbott Vascular, Santa Clara, California, §Columbia University, New York, New York, and †Shonan Kamakura General Hospital, Kamakura, Japan.
Disclosures: Paul G. Yock receives royalties and Fellow support from Abbott Vascular; Wesley Pierson and Krishnankutty Sudhir work as employees for Abbott Vascular. Gregg W. Stone and Peter J. Fitzgerald work as consultants for Abbott Vascular. The other authors have no conflicts of interest to report regarding the content herein.
Manuscript submitted July 6, 2009, provisional acceptance given July 28, 2009, final version accepted September 8, 2009.
Address for correspondence: Peter J. Fitzgerald, MD, PhD, Center for Research in Cardiovascular Interventions, Cardiovascular Core Analysis Laboratory, Stanford University Medical Center, 300 Pasteur Drive, Room H3554, Stanford, CA 94305. E-mail: crci-cvmed@stanford.edu
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