Anti-inflammatory effect of abciximab-coated stent in a porcine coronary restenosis model

The aim of this study was to examine the anti-inflammatory effect of abciximab-coated stent in a porcine coronary overstretch restenosis model. Ten abciximab-coated stents, ten sirolimus-eluting stents (SES), and ten paclitaxel-eluting stents (PES) were deployed with oversizing (stent/artery ratio 1.3:1) in porcine coronary arteries, and histopathologic analysis was done at 28 days after stenting. There were no significant differences in the neointima area normalized to injury score and inflammation score among the three stent groups (1.58 +/- 0.43 mm(2), 1.57 +/-0.39 mm(2) in abciximab-coated stent group vs. 1.69 +/- 0.57 mm(2), 1.72 +/- 0.49 mm(2) in the SES group vs. 1.92 +/- 0.86 mm(2), 1.79 +/- 0.87 mm(2) in the PES group, respectively). In the neointima, most inflammatory cells were lymphohistiocytes. Significant positive correlations were found between the extent of inflammatory reaction and the neointima area (r=0.567, p<0.001) and percent area stenosis (r=0.587, p<0.001). Significant correlations were found between the injury score and neointimal area (r=0.645, p<0.001), between the injury score and the inflammation score (r=0.837, p<0.001), and between the inflammation score and neointimal area (r=0.536, p=0.001). There was no significant difference in the inflammatory cell counts normalized to injury score among the three stent groups (75.5 +/- 23.1/microL in abciximabcoated stent group vs. 78.8 +/- 33.2/microL in the SES group vs. 130.3 +/- 46.9/microL in the PES group). Abciximab-coated stent showed comparable inhibition of inflammatory cell infiltration and neointimal hyperplasia with other drug-eluting stents in a porcine coronary restenosis model.     

The degree of neointimal formation after stent placement in atherosclerotic rabbit iliac arteries is dependent on the underlying plaque.

The purpose of this study was to determine the effects of stent placement on the underlying arterial morphology and the relations of stent-vessel wall interactions with subsequent neointimal formation in an atherosclerotic artery. Seven New Zealand White rabbits with experimentally induced atherosclerosis underwent balloon angioplasty (n = 7) and stent placement after balloon angioplasty (n = 7) in the iliac arteries. Histologic analysis of the treated arteries was performed at 28 days to assess device interactions with the artery and the pattern of the neointimal response. The area within the external elastic lamina of the stented vessels was 66% greater than the arteries with balloon angioplasty alone (p = 0.001) which contributed to a significantly greater late lumen area (3.33 +/- 0.51 mm2 versus 1.33 +/- 0.20 mm2, p = 0.0028). Neointimal thickness was measured at 220 stent wire sites from 21 sections of stented arteries of which 139 (63%) had underlying plaque and 81 (37%) were adjacent to normal media. Rupture of the internal elastic lamina (IEL) occurred at only 9 (11%) of the 81 stent wire sites over normal media. The mean neointimal thickness was 0.16 +/- 0.01 mm lor all stent wire sites. The neointimal thickness was greater at the stent wire sites with underlying plaque (0.23 +/- 0.01 min) than at the stent wire sites adjacent to normal media (0.08 +/- 0.01 mm) or at sites with rupture of the internal elastic lamina (0.16 +/- 0.02 mm, p = 0.0001). The degree of neointimal formation within the stents strongly correlated with the area of the underlying atherosclerotic plaque (r = 0.76, p = 0.0007) and the extent of plaque or medial compression by the struts (r = 0.90, p = 0.006). The present study characterizes stent interactions in a model commonly employed to evaluate novel therapies for the prevention of restenosis. The neointimal response was influenced by the local arterial morphology and correlated with the extent of plaque or medial compression by the stent. These data may be useful for future studies in this model and understanding the mechanism of in-stent restenosis.     

Protective effect of hydrogen sulfide on balloon injury-induced neointima hyperplasia in rat carotid arteries

Endogenous hydrogen sulfide (H(2)S), generated from homocysteine metabolism mainly catalyzed by cystathionine gamma-lyase (CSE), possesses important functions in the cardiovascular system. In this study, we investigated the role of H(2)S during the pathogenesis of neointimal formation induced by balloon injury in rats. CSE mRNA levels were reduced by 86.5% at 1 week and 64.0% at 4 weeks after balloon injury compared with the uninjured controls. CSE activity was also correspondingly reduced. Endogenous production of H(2)S in the injured carotid artery was significantly inhibited at 1 week and 4 weeks after balloon injury. Treatment with NaHS (a donor of H(2)S) enhanced methacholine-induced vasorelaxation of balloon-injured artery. More importantly, treatment with NaHS significantly inhibited neointima formation (0.15 +/- 0.01 mm(2) versus 0.21 +/- 0.01 mm(2), P < 0.001) of the balloon-injured carotid arteries and reduced the intima/media ratio (1.05 +/- 0.07 versus 1.43 +/- 0.06, P < 0.001). A significant decrease in vascular smooth muscle cell proliferation was demonstrated by bromodeoxyuridine incorporation at day 7 after injury. In conclusion, CSE expression and H(2)S production are reduced during the development of balloon injury-induced neointimal hyperplasia, and treatment with NaHS significantly reduces neointimal lesion formation.     

Vascular wound healing and neointima formation induced by perivascular electric injury in mice.

Vascular interventions for atherothrombotic disease frequently induce neointima formation, which can contribute to restenosis of blood vessels. As the molecular mechanisms of this process remain largely unknown, quantitative models of arterial injury in transgenic animals may be useful to study this process at the genetic level. Here, an injury model is proposed in which surgically exposed femoral arteries in mice were injured perivascularly via a single delivery of an electric current. Transmission electron microscopy, light microscopy, and immunohistochemistry revealed that electric injury destroyed all medial smooth muscle cells, denuded the injured segment of intact endothelium, and transiently induced platelet-rich mural thrombosis. A vascular wound-healing response resulted that was characterized by degradation of the mural thrombus, transient infiltration of the vessel wall by inflammatory cells, and progressive removal of the necrotic debris. Topographic analysis revealed repopulation of the media and accumulation in the neointima of smooth muscle cells originating from the uninjured borders and progressing into the necrotic center. Within 3 weeks after injury, a neointima of 0.026 +/- 0.003 mm2 (n = 7 arteries) was formed that contained a maximum of 12 +/- 1 layers of smooth muscle alpha-actin-immunoreactive cells. Evans blue staining in five electrically injured arteries revealed a denuded distance of 2.8 +/- 0.2 mm immediately after injury, which became progressively re-endothelialized from the uninjured borders to 2.2 +/- 0.08 mm (P = 0.013 vs freshly injured by analysis of variance), 0.8 +/- 0.22 mm (P < 0.001), and 0.005 +/- 0.003 mm (P < 0.001) within 2, 7, and 14 days after injury, respectively. Analysis of 5'-bromo-2'-deoxyuridine incorporation revealed that a maximum of 35 +/- 10% endothelial cells proliferated within 2 days after injury and that in the media and neointima, a maximum of, respectively, 12 +/- 2% and 18 +/- 3% smooth muscle cells proliferated within 2 weeks after injury. Thus, electric injury of arteries provides a model of vascular wound healing with arterial neointima formation and re-endothelialization that may be useful for the genetic analysis of its molecular mechanisms in transgenic mice.     

Highly active antiretroviral therapy attenuates re-endothelialization and alters neointima formation in the rat carotid artery after balloon injury

Highly active antiretroviral therapy (HAART) has led to a sustained decline of HIV-associated morbidity and mortality. HAART exhibits significant side effects, however, such as hyperlipidemia and hyperglycemia, which possibly contribute to accelerated atherosclerosis in HAART-treated patients. In addition, direct effects of HAART on vascular cells have been described, which may promote atherosclerotic lesion formation. The effects of HAART on balloon-induced neointima formation have not been studied previously. The rat carotid artery balloon model was used to evaluate the effects of HAART (lopinavir, ritonavir, lamivudine, and zidovudine) on neointima formation and endothelial recovery. Furthermore, the effects of concomitant administration of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor rosuvastatin were investigated. HAART-treated animals displayed an increase in lesion size (neointima/media ratio: 1.14 +/- 0.32 vs. 1.31 +/- 0.20 in control vs. HAART; P < 0.05) and an impaired regenerative capacity of the endothelium, as indicated by reduction in endothelial regrowth from an adjacent undilated vessel segment 14 days after injury (re-endothelialization area: 8.29 +/- 1.45 mm vs. 5.09 +/- 0.53 mm in control vs. HAART; P < 0.05). When rosuvastatin was given in addition to HAART, these effects were not observed. In conclusion, HAART inhibited endothelial cell-mediated healing and promoted neointima formation after angioplasty in rats. These deleterious effects were attenuated by cotreatment with rosuvastatin, however. Our studies suggest that currently used drug regimens against HIV infection may lead to an increased risk for restenosis after percutaneous vascular interventions. Moreover, the findings indicate that the additional treatment with statins might counteract these adverse effects by HAART.     

AT2R基因在体转染抑制大鼠颈动脉新生内膜增生

目的: 探讨AngⅡ 2型受体（AT2R）基因在体转染对大鼠颈动脉球囊损伤后新生内膜增生的抑制作用。方法:大鼠颈动脉球囊损伤后，局部转染AT2R重组腺病毒载体（pAdCMV/AT2R）或空病毒载体（pAd-GFP），于术后7、14和21 d用RT-PCR、免疫组织化学及HE染色方法，进行AT2R、AngⅡ 1型受体(AT1R)、PCNA在颈动脉壁中表达的变化及定量组织形态学分析；免疫荧光双标染色和激光共聚焦技术检测血管中AT2R与PCNA表达的关系。结果: pAdCMV/AT2R转染后，大鼠颈动脉AT2R的表达水平显著高于未转染组和pAd-GFP组(P<0.01)，21 d时仍维持较强表达。在14 d时pAdCMV/AT2R组PCNA阳性表达率显著低于未转染组和pAd-GFP组［(27.29±5.81)% vs ( 72.25±4.47)%、(68.43±9.12)%，P<0.01］，在AT2R表达阳性的部位PCNA表达阴性。在21 d时，pAdCMV/AT2R组的内膜面积与中膜面积比显著低于未转染组和pAd-GFP组(0.78±0.06 vs 1.44±0.22、1.36±0.21, P<0.01)，pAd-GFP组和未转染组间无显著差异（P>0.05）；各组颈动脉AT1R表达水平无显著差异(P>0.05)。结论: AT2R基因在体转染可抑制球囊损伤后大鼠颈动脉平滑肌细胞增殖和新生内膜增生，AT2R基因转染后表达并发挥其生物学作用时，AT1R和AT2R之间不存在表达量上此起彼伏的关系，可能是建立在信号转导基础上的功能调节关系。     

Pretreatment of a Dacron graft with tissue factor pathway inhibitor decreases thrombogenicity and neointimal thickness: a preliminary animal study

The purpose of this study was to evaluate the effects of locally applied TFPI on the reduction of neointimal thickness in Dacron grafts. Seven millimeter internal diameter 5 cm lengths of albumin coated knitted Dacron grafts were interposed in the infrarenal aorta in 14 mongrel dogs. Before implantation, the grafts were immersed in saline solution containing 200 microg/ml of TFPI (TFPI group, n = 7) or 100 IU/ml of heparin (control group, n = 7) for 15 minutes at room temperature. Three months after implantation, neointimal thickness and percentage of graft stenosis were measured by computerized planimetry. All grafts were patent 3 months after implantation. Thrombus was found in one graft in the TFPI group, but observed in three of seven control grafts. Neointimal thickness in the TFPI group was significantly smaller than that in the control group (mean +/- SD, 0.26 +/- 0.1 mm vs. 0.57 +/- 0.15 mm, p < 0.001). Percentage of graft stenosis was significantly lower in the TFPI group than in the control group (13.4 +/- 5.3% vs. 26.9 +/- 7.0%, p < 0.001). Scanning electron micrographs showed that the neointima of TFPI treated grafts were completely covered by endothelial cells. The present results indicate that locally applied TFPI reduces thrombogenicity and neointimal thickness in albumin coated knitted Dacron grafts.     

Vascular delivery of c-myc antisense from cationically modified phosphorylcholine coated stents

c-Myc is involved in the formation of neointimal hyperplasia. We investigated in vitro, ex vivo and in vivo release of antisense c-myc from cationically modified phosphorylcholine-coated stents, as well as the effects on c-Myc expression and neointima formation in a porcine coronary stent model. In vitro experiments were performed to determine optimal loading of stents with antisense. Stents loaded with labelled antisense were deployed in porcine arteries ex vivo and in vivo. Antisense was detected in the vessel wall directly surrounding the stent of pig carotid and coronary artery up to 48 h after stent deployment. Nuclear uptake was observed in endothelial and vascular smooth muscle cells. Labelled antisense within peripheral tissues in vivo was <1.0% of that within stented arterial segments. Control and antisense loaded stents implanted into 10 pig coronary arteries and analysed at 28 days post-stenting showed that lumen area within the antisense stents was significantly increased (i.e. 30.5% greater, P<0.01), whilst both neointimal area and neointimal thickness were significantly reduced (17.5% and 19.5%, respectively, P<0.01) compared to control stents. Cationically modified phosphorylcholine coated stent-based delivery of c-myc antisense is feasible with minimal systemic delivery and is associated with a reduction of in-stent neointimal hyperplasia in pig coronary arteries.     

Angiographic follow-up after placement of a self-expanding coronary-artery stent

BACKGROUND. The placement of stents in coronary arteries after coronary angioplasty has been investigated as a way of treating abrupt coronary-artery occlusion related to the angioplasty and of reducing the late intimal hyperplasia responsible for gradual restenosis of the dilated lesion. METHODS. From March 1986 to January 1988, we implanted 117 self-expanding, stainless-steel endovascular stents (Wallstent) in the native coronary arteries (94 stents) or saphenous-vein bypass grafts (23 stents) of 105 patients. Angiograms were obtained immediately before and after placement of the stent and at follow-up at least one month later (unless symptoms required angiography sooner). The mortality after one year was 7.6 percent (8 patients). Follow-up angiograms (after a mean [+/- SD] of 5.7 +/- 4.4 months) were obtained in 95 patients with 105 stents and were analyzed quantitatively by a computer-assisted system of cardiovascular angiographic analysis. The 10 patients without follow-up angiograms included 4 who died. RESULTS. Complete occlusion occurred in 27 stents in 25 patients (24 percent); 21 occlusions were documented within the first 14 days after implantation. Overall, immediately after placement of the stent there was a significant increase in the minimal luminal diameter and a significant decrease in the percentage of the diameter with stenosis (changing from a mean [+/- SD] of 1.88 +/- 0.43 to 2.48 +/- 0.51 mm and from 37 +/- 12 to 21 +/- 10 percent, respectively; P less than 0.0001). Later, however, there was a significant decrease in the minimal luminal diameter and a significant increase in the stenosis of the segment with the stent (1.68 +/- 1.78 mm and 48 +/- 34 percent at follow-up). Significant restenosis, as indicated by a reduction of 0.72 mm in the minimal luminal diameter or by an increase in the percentage of stenosis to greater than or equal to 50 percent, occurred in 32 percent and 14 percent of patent stents, respectively. CONCLUSIONS. Early occlusion remains an important limitation of this coronary-artery stent. Even when the early effects are beneficial, there are frequently late occlusions or restenosis. The place of this form of treatment for coronary artery disease remains to be determined.     

QT interval dispersion changes according to the vessel involved during percutaneous coronary angioplasty

Increased QT dispersion (QTd) is a noninvasive marker of an electrophysiologic abnormality associated with high mortality in coronary artery disease. The purposes of this study were to measure changes in QTd and ST-segment changes immediately before, during and after intracoronary balloon inflation and to determine whether the coronary artery vessel involved and/or the duration of inflation affect(s) QTd. A total of 45 patients (32 men, 13 women, mean age 58 +/- 11 years) who were referred for elective percutaneous transluminal coronary angioplasty were included. The mean QT interval dispersions for all patients before the inflation, during the balloon inflation at 60 sec and after the balloon deflation at 5 min were 68 +/- 13 ms, 82 +/- 16 ms and 71 +/- 13 ms, respectively. There was no significant difference between baseline and 5 min after deflation. The increase in QTd during the balloon inflation was significant (p<0.01). There was no significant QTd change in patients with left circumflex artery (Cx) lesions during inflation and after deflation compared with baseline. The differences were statistically significant only in patients with left anterior descending (LAD) lesions and right coronary artery (RCA) lesions at 60 sec during balloon inflation (p=0.001 vs. p=0.04). Acute reversible myocardial ischemia induced by balloon inflation causes an increase in QTd limited to the LAD and RCA vessels. Therefore, when using QTd as a marker of myocardial repolarization abnormality due to acute reversible ischemia, the involved coronary artery vessel must be taken into account.     

Neointimal formation in the porcine aortic organ culture. I. Cellular dynamics over 1 month

Since intimal smooth muscle cells (SMC) are an important feature of atherosclerotic fibrofatty plaques, we tested the hypothesis that endothelial cells (EC) regulate SMC proliferation in the process of neointimal formation. Using a porcine thoracic aortic organ culture (OC) system, we previously showed in a preliminary study that short-term porcine aortic explants incubated in 5% fetal bovine serum for 7 days promote neointimal formation only in the presence of endothelium or in conditioned media collected from proliferating OC with endothelium present. We now report that these organ cultures can be maintained in culture for up to 4 weeks. The surface cells stained positively for dil-acetylated-low-density lipoprotein throughout the 4-week period indicating the continued presence of EC while the neointimal cells stained positively for the smooth muscle actin-specific monoclonal antibodies alpha-SM1 and HHF-35 indicating their smooth muscle nature. The number of EC did not change during the 4-week incubation period, however, EC turnover peaked at 5 days and remained elevated but constant throughout. The number of intimal SMC doubled between day 0 (18.4 +/- 0.2 cells/field) and day 7 (41.5 +/- 0.9) and between day 7 and day 14 (75.8 +/- 10.1). The intimal SMC number then stabilized thereafter (day 21: 79.5 +/- 7.8, day 28: 73.8 +/- 12.1). Cell proliferation played a large part since autoradiography studies using nondenuded OC showed that intimal SMC thymidine index on day 0 was 1.4% +/- 0.4, peaked at the end of day 5 (25.7% +/- 4.1) and gradually decreased thereafter. The peak in the intimal SMC thymidine index occurred during a period of high EC turnover (maximum EC thymidine index on day 5: 21.8% +/- 2.1), and the stabilization of intimal SMC number observed beyond 2 weeks of incubation occurred when EC replication was reduced (day 14: 6.7% +/- 0.21). Incubation of organ cultures denuded of their endothelium in 5% fetal bovine serum showed a marked decrease in neointimal formation. However, denuded OC when incubated in conditioned medium collected from 4-day-old nondenuded OC (4DCM) enhanced neointimal formation of denuded OC. In contrast, the neointima of denuded OC incubated in 24-day-old nondenuded OC conditioned medium was similar to that of controls. The thymidine index of intimal SMC of denuded OC treated with 4DCM was markedly higher than that found with the control treatment at all time points.(ABSTRACT TRUNCATED AT 400 WORDS)     

Endothelialization and in-stent restenosis on the surface of glycoprotein IIIa monoclonal antibody eluting stent

Since the percutaneous transtuminal coronary angioplasty was introduced into China in 1984, this procedure has become widely accepted as an important step in coronary revascularization. This study shows the effect of the monoclonal antibody (mAb) on the platelet glycoprotein IIIa receptor during endothelialization and in-stent restenosis by implanting the mAb-eluting stents into iliac arteries of rabbits. The hard tissue cross sections of the stent-implanted arterial segments were made by polymethylmethacrylate embedding. Arterial intima proliferation was observed and analyzed. The endothelialization of the stent surface was observed using scanning electron microscope, whereas the ultrastructure of the neointima was observed using transmission electron microscope. After one month of stent implantation, the surfaces of both groups were covered by intact endothelial layers, but the neointimal areas and the ratio of stenosis were significantly lesser in the mAb-eluting stent group (p < 0.01). After 3 months, the ratio of stenosis in the mAb-eluting stent group was 14.67 ± 0.79, whereas that of the bare stent group was 21.58 ± 1.76 (p < 0.01). Therefore, the mAb eluting from the stent surface has the potential to accelerate endothelialization, prevent thrombosis formation due to the interaction of stent with blood, and decrease the stenosis ratio by inhibiting neointima proliferation.     

大鼠血管球囊损伤促进血小板活化、凝血酶受体及血管紧张素Ⅱ1型受体的mRNA表达

目的该研究通过建立大鼠主动脉内皮球囊损伤模型，观察血小板活化、凝血酶受体及血管紧张素Ⅱ1型受体的变化。方法将大鼠随机分为对照组(n=24)和手术组(n=24)，并于术后3、7、14和28d取主动脉，通过组织学检查、放射免疫法和反转录聚合酶链反应(RT-PCR)技术检测血管球囊损伤后内膜增生的过程、血小板表面GMP-140的数目、血管AT1受体和凝血酶受体mRNA表达的变化。结果①凝血酶受体mRNA在正常血管组织表达极弱，球囊损伤术后3d已显著增加，术后14d达峰值，术后28d开始下降。②AT1受体mRNA于术后3d明显增高，并持续至术后14d，术后28d恢复至对照水平。③GMP-140于术后3d明显升高，术后7d开始下降。④内皮损伤术后3d已有增殖的血管平滑肌细胞(VSMC)移行至内膜层，术后7d内膜开始增生，术后14d VSMC的增殖及内膜增生更为明显，术后28d VSMC的增殖明显减弱，细胞外基质增加，内膜继续增生。结论血小板活化、凝血酶受体和AT。受体mRNA表达增加参与了血管内皮损伤后内膜增生的过程。     

MT1‐MMP evaluation in neointimal hyperplasia in the late follow‐up after prosthesis implantation

Vascular surgical interventions are often burdened with late complications, including thrombosis or restenosis. The latter is generally caused by neointimal hyperplasia. Although extracellular matrix (ECM) remodelling is an important part of neointima formation, this process is not clearly understood. The aim of the study was to assess the content and activity of membrane‐type 1 matrix metalloproteinase in human neointima in the late stages of its development. Matrix metalloproteinase‐2 and tissue inhibitor of matrix metalloproteinase‐2 were also evaluated. The research was performed on neointima samples collected during secondary vascular interventions from patients with chronic limb ischaemia who developed vascular occlusion at 6‐18 months after aorto/ilio‐femoral bypass grafting. The control material consisted of segments of femoral arteries collected from organ donors. Western blot and/or ELISA were used for the determination of MT1‐MMP and TIMP‐2 expression. The activity of MT1‐MMP was measured by fluorometric assay and that of MMP‐2 by zymography. We demonstrated significantly increased MT1‐MMP protein content in neointima when compared to normal arteries. However, the activity of MT1‐MMP was significantly lower in neointima than in control samples. The decreased MT1‐MMP activity was concomitant with reduced activity of MMP‐2. The TIMP‐2 protein levels in neointima and normal arteries were not significantly different. The results of our study suggest that the reduced activity of MT1‐MMP and consequently MMP‐2 in human neointima may play a role in decreased degradation of ECM components and thus promote neointimal overgrowth.     

Urinary trypsin inhibitor reduced inflammatory response after stent injury in minipig

This study investigated whether urinary trypsin inhibitor (UTI) inhibits neointimal formation by reducing inflammatory response after stent injury. Twenty minipigs having undergone oversized bare material stent implantation in the left anterior descending artery were randomly subdivided into two groups: a UTI group (n=10) and a control group (n=10). Two systemic markers of inflammation (serum macrophage chemoattractant protein-1 and interleukin-6 levels measured by ELISA) were increased after stent implantation, and two days after stem implantation, their levels were positively correlated with the maximal percentage of area stenosis on day 28 (r(2)=0.889 and 0.743, respectively). This effect was abolished by UTI administration. Twenty-eight days after implantation, morphometric analysis of the stented arteries revealed significantly reduced luminal stenosis (38±6% vs. 64±12%, P<0.05), a neointimal area (3.22±0.57 mm(2) vs. 5.21±1.04 mm(2), P<0.05), neointimal thickness (0.31±0.13 mm vs. 0.46±0.16 mm, P<0.05), and an inflammatory score of 1.02±0.05 vs. 1.30±0.08 in UTI-treated animals as compared with controls. Twenty-eight days after stenting, arterial nuclear factor-κB expression was 36.93±7.16% in all of the cells in controls and 23.32±4.54% in UTI-treated minipigs. UTI could reduce neointimal formation after stenting by inhibiting the local and the systemic inflammatory response. Percutaneous coronary intervention could benefit from precocious anti-inflammatory treatment.     

Suppressor of cytokine signaling-3 and intimal hyperplasia in porcine coronary arteries following coronary intervention

Aims

The growth and differentiation of cells is regulated by cytokines by binding to cell-surface receptors and activating intracellular signal transduction cascade. Suppressor of cytokine signaling (SOCS)-3 is a negative regulator of cytokines. In this study we examined the expression of SOCS-3 in porcine coronary artery smooth muscle cells (PCASMCs) in vitro and in proliferating smooth muscle cells of neointimal lesions after coronary artery intervention in a swine model.

Methods and results

PCASMCs were cultured and stimulated with TNF-α and/or IGF-1 individually or in combination. Protein expression of SOCS-3 was examined using Western blot. For in vivo studies, six female Yucatan miniswine were fed with special high cholesterol diet for 8 months. At 4 months of high cholesterol diet, animals underwent coronary balloon angioplasty. At the end of 8 months animals were euthanized, coronary arteries were isolated and morphological and histological studies were performed. Western blot data revealed significantly high SOCS-3 expression in PCASMCs in the presence of either TNF-α or IGF-1 (5–6 fold) alone. However, in the presence of both TNF-α and IGF-1 the SOCS-3 expression was significantly decreased (4–5 fold). Results from morphological studies including, H&E and Masson's trichrome stain showed typical lesions with significant neointimal proliferation. Histological evaluation showed expression of smooth muscle α-actin and significantly increased proliferating cell nuclear antigen (PCNA) in neointimal lesion. Interestingly, there was significantly decreased expression of SOCS-3 in smooth muscle cells of neointima as compared to control.

Conclusions

These data suggest that SOCS-3 expression is decreased in proliferating smooth muscle cells of neointimal lesions. This leads to uncontrolled growth of vascular smooth muscle cells in injured arteries leading to restenosis. Therefore, local delivery of SOCS-3 gene at the site of injury after coronary artery intervention could regulate the proliferation of vascular smooth muscle cells and help in preventing the neointimal hyperplasia and restenosis.     

小型猪冠状动脉球囊扩张术后MAPKs活性及c-fos mRNA增加

目的:观察小型猪冠状动脉球囊扩张术后丝裂素活化蛋白激酶(MAPKs)活性及c-fosmRNA的变化。方法:小型猪17头,6头作为正常对照,其余小型猪左冠状动脉前降支和回旋支行球囊过度扩张术。静脉麻醉处死动物,通过病理染色切片分析目标血管组织的形态学变化;采用反转录-聚合酶链反应(RT-PCR)方法,定量检测目标血管组织c-fosmRNA的表达;并测定血管组织MAPKs活性。结果:球囊扩张术后3天血管组织MAPKs活性及c-fosmRNA的表达均明显增加(51.5%,P＜0.01;318.7%,P＜0.01),术后30d出现新生内膜的增厚和管腔狭窄。结论:早期MAPKs活性升高和c-fos表达增加可能参与球囊扩张术后再狭窄过程。     

Decreased rate of coronary restenosis after lowering of plasma homocysteine levels.

BACKGROUND: We have previously demonstrated an association between elevated total plasma homocysteine levels and restenosis after percutaneous coronary angioplasty. We designed this study to evaluate the effect of lowering plasma homocysteine levels on restenosis after coronary angioplasty. METHODS: A combination of folic acid (1 mg), vitamin B12 (400 microg), and pyridoxine (10 mg)--referred to as folate treatment--or placebo was administered to 205 patients (mean [+/-SD] age, 61+/-11 years) for six months after successful coronary angioplasty in a prospective, double-blind, randomized trial. The primary end point was restenosis within six months as assessed by quantitative coronary angiography. The secondary end point was a composite of major adverse cardiac events. RESULTS: Base-tine characteristics and initial angiographic results after coronary angioplasty were similar in the two study groups. Folate treatment significantly lowered plasma homocysteine levels from 11.1+/-4.3 to 7.2+/-2.4 micromol per liter (P<0.001). At follow-up, the minimal luminal diameter was significantly larger in the group assigned to folate treatment (1.72+/-0.76 vs. 1.45+/-0.88 mm, P=0.02), and the degree of stenosis was less severe (39.9+/-20.3 vs. 48.2+/-28.3 percent, P=0.01). The rate of restenosis was significantly lower in patients assigned to folate treatment (19.6 vs. 37.6 percent, P=0.01), as was the need for revascularization of the target lesion (10.8 vs. 22.3 percent, P=0.047). CONCLUSIONS: Treatment with a combination of folic acid, vitamin B12, and pyridoxine significantly reduces homocysteine levels and decreases the rate of restenosis and the need for revascularization of the target lesion after coronary angioplasty. This inexpensive treatment, which has minimal side effects, should be considered as adjunctive therapy for patients undergoing coronary angioplasty.     

Repeated stent thrombosis after DES implantation and localized hypersensitivity to a stent implanted in the distal portion of a coronary aneurysm thought to be a sequela of Kawasaki disease: Autopsy report

The patient was a 40‐year‐old Japanese woman. At 37 years of age she underwent stent implantation in LAD#7 for an acute myocardial infarction. Subsequently, coronary intervention was performed four times because of occlusion of the stent. Sudden death occurred at 40 years of age due to ventricular tachycardia. Clinically, the patient had had no history of collagen disease, anti‐phospholipid antibody syndrome or coagulation disorder. The autopsy revealed only very mild atherosclerotic changes in the aorta and various other organs, but concentric thickening of the intima was observed in all three branches of the coronary arteries. Also, aneurysms accompanied by calcification were observed at each of LAD #6, LCx #11 and RCA #4PD. The stent was occluded with a thrombus, and the vascular walls showed infiltration by lymphocytes, plasma cells and numerous eosinophils. The eosinophil infiltration was confined to the site of the stent. It was surmised that the patient had experienced late stent thrombosis due to a hypersensitivity reaction to the DES on the basis of a development of a state of high susceptibility to thrombus formation because of a coronary aneurysm. The aneurysm was suspected of being a post‐inflammatory change of Kawasaki disease.     

低浓度脂多糖加速大鼠颈动脉球囊损伤后新生内膜的形成

目的：探讨低浓度脂多糖（LPS）刺激机体免疫系统对血管损伤后加速血管新生内膜增生的影响。方法：选用健康Wistar大鼠，静脉注入LPS后，行颈动脉球囊损伤术，建立血管内膜损伤模型。采用免疫荧光或组织化学染色观察内膜增生变化。Western blot 分析损伤组织特异性平滑肌细胞标志物和细胞凋亡表达。用ELISA测定血清白介素-1β(IL-1β)含量和流式细胞术分析CD14阳性细胞表达水平。结果：每只鼠注入LPS(50 ng)后循环血中单核细胞和IL-1β水平显著升高。血管损伤7 d后中膜平滑肌细胞增殖, 转化为合成表型，新生内膜逐渐形成，随时间延长，内膜增生加速，内膜厚度由(151.2±14.5)μm2增至(173.9±15.3)μm2。免疫荧光染色观察到增殖细胞核抗原及核因子-κB分别定位于新生内膜和外膜。Western blot分析显示新生内膜形成早期LPS组平滑肌特异性标志蛋白α-肌动蛋白多于对照组，caspase-3表达持续上调，细胞凋亡多于对照组。结论：炎症介质LPS刺激全身免疫系统导致血管损伤后新生内膜暂时性增生，表明炎症介质可以加剧血管损伤后再狭窄的形成。