Preinterventional peak monocyte count and in-stent intimal hyperplasia after coronary stent implantation in human coronary arteries

BACKGROUND: The mechanism of restenosis after stent implantation principally is neointimal hyperplasia. There is evidence that monocytes play a important role in in-stent restenosis (ISR) after stent implantation. Hypothesis: This study assessed the relationship between preinterventional peak monocyte count and neointimal growth after successful stent implantation. METHODS: We performed coronary stent implantation in 85 patients (85 de novo lesions). Peripheral blood sample was obtained in all patients every 12 h before coronary angiography for measurement of peripheral monocytes. All patients received angiographic and intravascular ultrasound (IVUS) follow-up at 6 months after stenting. RESULTS: The preinterventional circulating monocyte count was significantly higher in the ISR group than that in the group without ISR (654 +/- 62/vs. 461 +/- 222/mm3, p < 0.001) and was significantly higher in the reintervention group than that in the no-reintervention group (660 +/- 72/ vs. 470 +/- 216/mm3, p< 0.001). The incidence of ISR and repeat intervention associated with preinterventional monocyte count was highest among the patients in the highest tertile, who were at a 2.64-fold increased risk of ISR and 3.22-fold increased risk of repeat intervention compared with the patients in the lowest tertile. A significant positive correlation was found between preinterventional peak monocyte count and preinterventional plaque and media cross-sectional area and follow-up neointima area (r = 0.311, p = 0.007, r = 0.465, p < 0.001, respectively). The neointima area associated with preinterventional monocyte count was largest among the patients in the highest tertile, that is, 2-fold larger than that of the patients in the lowest tertile (p < 0.001) and 1.44-fold larger than that of the patients in the middle tertile (p = 0.001). CONCLUSION: Our results suggest that circulating preinterventional monocytes play a principal role in the process of in-stent neointimal growth after successful stent implantation.     

Relation of stent design and stent surface material to subsequent in-stent intimal hyperplasia in coronary arteries determined by intravascular ultrasound

A variety of different stent designs and coatings have become available. This study sought to determine the impact of stent design and gold-coating of stents on intimal hyperplasia (IH) in human atherosclerotic coronary arteries in relation to known predictors of restenosis. Angiographic and intravascular ultrasound (IVUS) studies were performed at 6-month follow-up on 311 native coronary lesions of 311 patients treated with 99 Multi-Link stents, 74 InFlow steel stents, 73 InFlow gold-coated stents, 41 Palmaz-Schatz stents, 12 NIR steel stents, and 12 gold-coated NIR Royal stents. Lumen and stent cross-sectional area (CSA) were measured at 1-mm axial increments. Mean IH CSA (stent CSA − lumen CSA) and mean IH thickness were calculated and averaged over the total stent length. IVUS demonstrated different levels of IH for the 6 stents. Mean IH thickness ranged from 0.20 ± 0.13 mm for Multi-Link stents to 0.43 ± 0.14 mm for InFlow goal-coated stents (p <0.001). Multivariate analysis proved non–Multi-Link stent design (odds ratio 3.45, 95% confidence intervals 1.13 to 11.11, p <0.034) and gold coating (odds ratio 3.78, 95% confidence intervals 1.88 to 7.54, p <0.001) to be the only independent predictors of IH thickness >0.3 mm. In conclusion, stent design and surface material have an important impact on the IH response to stents implanted in human coronary arteries. However, the differences in IH thickness between the analyzed stents were relatively small compared with the absolute lumen dimensions.     

辛伐他丁对支架新生内膜的作用

目的观察他丁类调脂药物对支架再狭窄和支架内新生内膜的影响.方法对单支冠脉病变行支架植入术的患者随机接受或不接受调脂药物的治疗,10月后复查冠脉造影和血管内超声检查.结果 65位患者随机接受辛伐他丁10mg治疗.辛伐他丁组患者在接受降脂治疗后血清总胆固醇降低15%,低密度脂蛋白胆固醇下降了26%,高密度脂蛋白胆固醇增加12%.辛伐他丁组和对照组支架再狭窄率无差异(分别为30.3%和37.5%,P>0.05).定量冠脉造影结果两组比较,两组参考段血管直径、支架最小管腔直径以及直径狭窄率均无明显差异.血管内超声发现辛伐他丁组参考段血管内膜腔截面积、最小血管内膜腔截面积以及最小支架截面积均无显著性差异.新生内膜截面积两组比较对照组大于辛伐他丁组,但无统计学意义.结论辛伐他丁长期治疗能够有效降低血中致动脉粥样硬化的脂蛋白.但10 mg/日的辛伐他丁对支架的再狭窄率以及支架内膜增生无明显影响.     

Extent and distribution of in-stent intimal hyperplasia and edge effect in a non-radiation stent population

Intimal hyperplasia within the body of the stent is the primary mechanism for in-stent restenosis; however, stent edge restenosis has been described after brachytherapy. Our current understanding about the magnitude of in vivo intimal hyperplasia and edge restenosis is limited to data obtained primarily from select, symptomatic patients requiring repeat angiography. The purpose of this study was to determine the extent and distribution of intimal hyperplasia both within the stent and along the stent edge in relatively nonselect, asymptomatic patients scheduled for 6-month intravascular ultrasound (IVUS) as part of a multicenter trial: Heparin Infusion Prior to Stenting. Planar IVUS measurements 1 mm apart were obtained throughout the stent and over a length of 10 mm proximal and distal to the stent at index and follow-up. Of the 179 patients enrolled, 140 returned for repeat angiography and IVUS at 6.4 +/- 1.9 months and had IVUS images adequate for analysis. Patients had 1.2 +/- 0.6 Palmaz-Schatz stents per vessel. There was a wide individual variation of intimal hyperplasia distribution within the stent and no mean predilection for any location. At 6 months, intimal hyperplasia occupied 29.3 +/- 16.2% of the stent volume on average. Lumen loss within 2 mm of the stent edge was due primarily to intimal proliferation. Beyond 2 mm, negative remodeling contributed more to lumen loss. Gender, age, vessel location, index plaque burden, hypercholesterolemia, diabetes, and tobacco did not predict luminal narrowing at the stent edges, but diabetes, unstable angina at presentation, and lesion length were predictive of in-stent intimal hyperplasia. In a non-radiation stent population, 29% of the stent volume is filled with intimal hyperplasia at 6 months. Lumen loss at the stent edge is due primarily to intimal proliferation.     

Impact of preinterventional arterial remodeling on in-stent neointimal hyperplasia and in-stent restenosis after coronary stent implantation.

BACKGROUND: Patterns of arterial remodeling during the course of plaque development have been shown to play an important role in both the progression of de novo atherosclerosis and in the restenotic process following coronary intervention. The aim of the present prospective study was to evaluate the effect of pre-interventional arterial remodeling on in-stent neointimal hyperplasia (NIH) and in-stent restenosis (ISR) after stenting. METHODS AND RESULTS: Pre-interventional arterial remodeling was assessed in 85 native coronary lesions by using intravascular ultrasound (IVUS). The remodeling index (RI) was 1.09+/-0.20 in the positive remodeling (PR)/intermediate remodeling (IR) group and 0.84+/-0.12 in the negative remodeling (NR) group. The plaque plus media cross sectional area (P&M CSA) at pre-intervention and NIH CSA at follow-up in the minimal lumen CSA were significantly larger in the PR/IR group (9.2+/-2.9 mm2 vs 6.2+/-1.8 mm2, 3.3+/-1.2 mm2 vs 1.5+/-0.9 mm2; p = 0.001, p = 0.001, respectively). On 3-dimensional analysis of IVUS images at follow-up, the lumen volume was significantly smaller in the PR/IR group than that in the NR group (62+/-15 mm3 vs 75 +/-20 mm3; p = 0.001), and neointima hyperplasia volume was significantly larger in the PR/IR group than that in the NR group (46+/-15 mm3 vs 26+/-10 mm3; p = 0.001). A significant positive correlation was found between pre-interventional RI and follow-up NIH CSA (r = 0.25, p = 0.022). The incidence of ISR and repeat intervention was significantly higher in the PR/IR group (30.8% vs 18.2%, 28.8% vs 15.2%; p = 0.032, 0.035, respectively). CONCLUSION: Measuring pre-interventional arterial remodeling patterns by IVUS may be helpful to stratify lesions at high-risk of ISR.     

The genous™ endothelial progenitor cell capture stent accelerates stent re‐endothelialization but does not affect intimal hyperplasia in porcine coronary arteries

Objectives : To study the effect of endothelial progenitor cell (EPC) capture on the vascular response to coronary stenting. Background : The introduction of drug‐eluting stents has reduced the need for target lesion revascularization, but their effect on delayed healing, inflammation, and vascular dysfunction has emphasized the need to design strategies that improve current DES. One such strategy is to improve endothelialization by capturing CD34‐positive cells (EPC) by the stent surface. The first human clinical trial using coronary EPC capture stents showed stent safety but neointimal thickness (NIT) was not reduced compared to bare metal stents (BMS). To understand these responses we studied the coronary response to the EPC capture stent in swine. Methods and Results : The stent, coated with murine antihuman monoclonal CD34 antibodies, was assessed with QCA guided stent implantation in normal swine coronary arteries for early endothelialization at 2 and 5 days, and NIT at 28 and 90 days in comparison to control stents carrying a non‐specific murine antibody or to BMS. The main finding was that while the EPC capture stent significantly improved early endothelialization it did not reduce NIT at 28 and 90 days. Conclusions : The EPC capture stent improves early endothelialization in swine but this does not affect neointimal thickness as compared to control stents at 28 and 90 days. © 2011 Wiley Periodicals, Inc.     

Oral mycophenolate mofetil prevents in-stent intimal hyperplasia without edge effect

Neointimal hyperplasia is in the forefront in in-stent restenosis. Prevention of in-stent restenosis is possible by reducing and inhibiting the hyperplasia of smooth muscle cells. The authors planned this study to test the hypothesis that when administered orally, mycophenolate mofetil (MMF) could inhibit in-stent neointimal hyperplasia. The study included 14 New Zealand rabbits. The rabbits were allocated to 2 different groups: Group 1 included 7 rabbits that were given MMF, 40 mg/kg/day by oral route. Group 2 included 7 rabbits that were not given MMF after the stenting. Sampling materials were taken before and after stenting by incising the artery so as to cover a 5-mm area. The samples taken from the edge of the stent in Group 1 showed focal neointimal cell proliferation, but it was less than that from the control group. Neointimal thickness was 0.048 +/-0.009 mm and neointimal area was 0.0925 +/-0.019 mm(2). Apparent neointimal cell proliferation and thickening of the intimal layer were observed in Group 2. Neointimal thickness at the stent edge was 0.147 +/-0.051 mm and the neointimal area was 0.154 +/-0.023 mm(2). The differences between groups in terms of neointimal thickness and neointimal area were statistically significant (p=0.001 for thickness and p=0.001 for area). In-stent artery samples of Group 1 showed that some subjects had no neointimal cell proliferation, while others had very limited focal intimal thickening. Neointimal thickening was 0.071 +/-0.003 mm and neointimal area was 0.073 +/-0.003 mm(2). In Group 2 apparent, and mostly focal, neointimal cell proliferation and formation of intimal layer were observed in the stent. Neointimal thickening was 0.154 +/-0.069 mm and neointimal area was 0.279 +/-0.059 mm(2). The comparison between groups showed significant differences (p=0.011 for thickness and p=0.001 for area). It was established in the third month that endothelialization was completed in both groups. Oral MMF decreased in-stent intimal hyperplasia without edge effect. It was concluded that for the prevention of in-stent restenosis, studies should be conducted for using systemic immunosuppressive treatments in humans as well.     

Effect of Chlamydia pneumoniae infection on coronary flow reserve and intimal hyperplasia after stent implantation in patients with angina pectoris.

OBJECTIVES: Chlamydia pneumoniae (C. pneumoniae) has been detected in tissue from coronary atherosclerotic vascular lesions and may be involved in the pathogenesis of atherosclerosis. However, the effect of prior C. pneumoniae infection on coronary intimal hyperplasia after stent implantation and on coronary microvascular function is unknown. METHODS: Seventy-three patients with stable angina pectoris and a single de novo coronary lesion were studied prospectively. All patients underwent successful coronary angioplasty and stent implantation for the stenotic lesion. Blood samples were tested for prior C. pneumoniae infection before the procedure, and patients were divided into two groups: Seropositive and seronegative. Coronary flow reserve was measured in the non-stenotic coronary vessel before angioplasty, and quantitative coronary arteriography was performed at the stent implantation site before angioplasty and 6 months later in all patients. RESULTS: Coronary flow reserve in the non-stenotic vessel was significantly lower in the seropositive group than in the seronegative group (2.51 +/- 0.35 vs 2.76 +/- 0.43, p < 0.05). The minimum luminal diameter was smaller and late loss was greater in the seropositive group than in the seronegative group (minimum luminal diameter: 1.52 +/- 0.59 vs 1.91 +/- 0.79 mm, p < 0.05, late loss: 1.17 +/- 0.55 vs 0.76 +/- 0.67, p < 0.05). However, there was no significant difference in the restenosis rate or target lesion revascularization rate between the two groups. CONCLUSIONS: Prior C. pneumoniae infection may accelerate intimal hyperplasia after stent implantation and impair coronary microvascular function in the non-stenotic coronary vessels.     

Diffuse intimal thickening of coronary arteries in slow coronary flow

Intravascular ultrasound imaging can detect intimal thickening and is suitable for detection of early atherosclerosis, which cannot be detected by conventional angiography. The aim of the present study was to investigate the epicardial coronary morphology and intracoronary pressure in relation to slow coronary flow (SCF). The study population consisted of 19 patients with SCF [11 (57.9%) females; 55.95 +/- 9.42 years]. Proximal, middle, distal and mean total vessel area, lumen area, intima + media area (IMA), percent IMA, and maximal intima + media (I + M) thickness were calculated and compared to healthy subjects. Proximal, middle, distal and mean I + M thickness, IMA, and % IMA of patients with SCF were found to be significantly higher than those of control subjects. Longitudinally extended massive calcification throughout the epicardial arteries was found in 13 (68.49%) patients with SCF and regional calcification was found in 6 (31.6%) patients with SCF. Proximal and distal pressure gradients of patients with SCF were determined to be 15.84 +/- 12.11 mmHg in the intracoronary pressure measurements. Fractional flow reserve values were significantly lower than the normal population (0.83 +/- 0.13, P < 0.0001). This study indicates that patients with SCF have diffuse intimal thickening, widespread calcification along the vessel wall and atheroma which does not cause luminal irregularities in coronary angiography, and a pressure gradient between proximal and distal segments of epicardial coronary arteries with SCF. Based on these results, we believe that SCF may be a form of diffuse atherosclerosis involving both the microvascular system and epicardial coronary arteries.     

Effect of preintervention plaque burden on subsequent intimal hyperplasia in stented coronary artery lesions

We sought to determine if axial and circumferential distribution of plaque before stenting determines the axial and circumferential distribution of subsequent intimal hyperplasia (IH). We studied 22 patients with a single Palmaz-Schatz stent implanted in a native coronary artery, who underwent intravascular ultrasound (IVUS) imaging before intervention, after stenting, and at 6-month follow-up. For each lesion, 7 locations were analyzed: proximal and distal reference, proximal and distal edge of the stent, proximal and distal location within the body of the stent, and the articulation. Pre- and postintervention and follow-up image slices were precisely aligned and analyzed for pre- and postintervention plaque area and follow-up IH area and thickness. The location of maximal IH area was at or adjacent to the location of maximal preintervention plaque in 17 of 22 of the patients (77%). Similiarly, the circumferential distribution of IH at follow-up paralleled the eccentricity pattern of the native plaque burden in 69% (24 of 35 slices). Using multivariant analysis, the strongest predictor of IH was preintervention plaque area (p = 0.001). IH accumulates axially and circumferentially preferentially at the site of maximal preintervention plaque.     

Efficacy and safety of oral sirolimus to inhibit in-stent intimal hyperplasia.

Sirolimus systemic administration has shown marked inhibition of neointimal hyperplasia (NIH) after balloon angioplasty in porcine models. In this pilot study, we tested the hypothesis that oral sirolimus is safe and effective to inhibit in-stent NIH and therefore to prevent and treat in-stent restenosis (ISR). Twelve patients (18 lesions) with high risk for ISR, including 8 ISR lesions, were admitted. One day before the procedure, patients were given a 15 mg loading dose of oral sirolimus, followed by 5 mg daily for 28 days, with weekly whole blood level measurements. The daily dose was adjusted to keep the concentration at 10-15 ng/ml. Sirolimus was well tolerated by all patients but one, who died at the end of the third week of treatment. The 4- and 8-month follow-up revealed an angiographic late loss of 0.40 +/- 0.24 and 0.67 +/- 0.45 mm (P < 0.01), respectively. At the same time points, the intravascular ultrasound in in-stent relative volumetric obstruction was 14.4% +/- 9.1% and 23.2% +/- 10.1% (P < 0.01), respectively. At 24-month clinical follow-up, adverse events were one (8.3%) death, two (11.1%) target lesion, and four (22.2%) target vessel revascularizations. In conclusion, in this small group of high-risk ISR patients, oral sirolimus inhibited NIH and therefore may be an effective strategy for the prevention and treatment of ISR.