INTRODUCTION: The pathophysiology and mechanism of in-stent restenosis (ISR) after implantation of second-generation drug-eluting stents (DESs) are not fully clear. We compared the morphological characteristics of ISR between first- and second-generation DESs using frequency domain optical coherence tomography (OCT). METHODS: Patients who underwent follow-up coronary angiography (CAG) after first-generation (CYPHER™ and TAXUS™) and second-generation (Nobori®, PROMUS Element™, Resolute Integrity and XIENCE) DES implantations were examined. ISR was defined as lesions of over 50% diameter stenosis at follow-up CAG. Frequency domain OCT was performed at the time of revascularisation of ISR. Tissue morphology was assessed at minimum lumen area. OCT images of DESs at both early (≤ 1 year) and late (> 1 year) phase follow-up were compared. RESULTS: On qualitative OCT assessment, the ratios of homogeneous, layered, heterogeneous without-attenuation and heterogeneous with-attenuation morphologies were 57.1%, 17.1%, 20.0% and 5.7%, respectively, for second-generation DES ISR (n = 35), and 16.7%, 25.0%, 25.0% and 33.3%, respectively, for first-generation DES ISR (n = 36). At late phase follow-up, homogeneous morphology was significantly more common for second-generation DES ISR compared to first-generation DES ISR (first-generation: 8.0% vs. second-generation: 50.0%; p < 0.01) while heterogeneous with-attenuation morphology was significantly more common for first-generation DES ISR (first-generation: 44.0% vs. second-generation: 5.6%; p < 0.01). CONCLUSION Homogeneous tissue morphology was more frequently found for second-generation than first-generation DES ISR, especially in the late phase. This suggested that neointimal hyperplasia was the main mechanism in second-generation DES ISR, and that the neointima was stabilised, much like in bare metal stent implantation.
Aged ; Constriction, Pathologic ; pathology ; Coronary Angiography ; Coronary Restenosis ; diagnostic imaging ; pathology ; Coronary Vessels ; diagnostic imaging ; pathology ; surgery ; Drug-Eluting Stents ; adverse effects ; Female ; Humans ; Incidence ; Male ; Metals ; Middle Aged ; Neointima ; Retrospective Studies ; Tomography, Optical Coherence

BACKGROUNDPeri-strut low-intensity area (PLIA) is a typical image pattern of neointima detected by optical coherence tomography (OCT) after stent implantation. However, few studies evaluated the predictors and prognosis of the PLIA; therefore, we aimed to explore the genesis and prognosis of PLIA detected by OCT in this study.

METHODSPatients presenting neointimal hyperplasia documented by OCT reexamination after percutaneous coronary intervention were prospectively included from 2009 to 2011. Peri-strut intensity was analyzed and classified into two patterns: Low-intensity and high-intensity. Clinical characteristics were analyzed to assess their contribution to peri-strut intensity patterns. Follow-up were performed in patients who did not receive revascularization during OCT reexamination, and the prognosis of the patients was evaluated.

RESULTSThere were 128 patients underwent OCT reexamination after stent implantation included in the study. PLIA was detected in 22 (17.2%) patients. The incidence of PLIA was positively correlated with serum triglyceride (odds ratio [OR]: 2.11, 95% confidence interval [CI]: 1.14-3.90, P = 0.017), low-density lipoprotein (OR: 2.61, 95% CI: 1.22-5.66, P = 0.015), history of cerebrovascular disease (OR: 101.11, 95% CI: 6.54-1562.13, P < 0.001), and initial clinical presentation of acute coronary syndrome (ACS, OR: 18.77, 95% CI: 2.73-128.83, P = 0.003) while negatively correlated with stent implantation time (OR: 0.57, 95% CI: 0.33-0.98, P = 0.043). The median follow-up was longer than 3.8 years. Major adverse cardiovascular events (MACEs) occurred in 7 (7.3%) patients while showed no correlation with PLIA. A total of 17 (17.7%) patients experienced unstable angina (UA) and showed significant correlation with PLIA (hazard ratio: 6.16, 95% CI: 1.25-30.33, P = 0.025).

CONCLUSIONSPLIA detected by OCT was positively correlated with higher serum lipid level, history of cerebrovascular disease and initial presentation of ACS, and negatively correlated with stent implantation time. Patients with PLIA were more likely to have UA than those with high-intensity while no significant difference was found in MACEs.

Acute Coronary Syndrome ; blood ; pathology ; physiopathology ; Aged ; Angina, Unstable ; blood ; pathology ; physiopathology ; Cross-Sectional Studies ; Female ; Humans ; Lipoproteins, LDL ; blood ; Male ; Middle Aged ; Neointima ; blood ; pathology ; physiopathology ; Prospective Studies ; Tomography, Optical Coherence ; methods ; Triglycerides ; blood

Intimal accumulation of smooth muscle cells contributes to the development and progression of atherosclerotic lesions and restenosis following endovascular procedures. Arterial smooth muscle cells display heterogeneous phenotypes in both physiological and pathological conditions. In response to injury, dedifferentiated or synthetic smooth muscle cells proliferate and migrate from the tunica media into the intima. As a consequence, smooth muscle cells in vascular lesions show a prevalent dedifferentiated phenotype compared to the contractile appearance of normal media smooth muscle cells. The discovery of abundant stem antigen-expressing cells in vascular lesions also rarely detected in the tunica media of normal adult vessels stimulated a great scientific debate concerning the possibility that proliferating vascular wall-resident stem cells accumulate into the neointima and contribute to the progression of lesions. Although several experimental studies support this hypothesis, others researchers suggest a positive effect of stem cells on plaque stabilization. So, the real contribute of vascular wall-resident stem cells to pathological vascular remodelling needs further investigation. This review will examine the evidence and the contribution of vascular wall-resident stem cells to arterial pathobiology, in order to address future investigations as potential therapeutic target to prevent the progression of vascular diseases.
Adult ; Endovascular Procedures ; Humans ; Myocytes, Smooth Muscle ; Neointima ; Pathology* ; Phenotype ; Stem Cells* ; Tunica Media ; Vascular Diseases

BACKGROUNDEndothelial cell damage is an important pathophysiological step of restenosis after angioplasty and stenting. Cell transplantation has great therapeutic potential for endothelial recovery. We investigated the effect of transplanting endothelial progenitor cells (EPCs) derived from human early fetal aortas in rat injured arteries.

METHODSThe carotid arterial endothelium of Sprague-Dawley rats was damaged by dilatation with a 1.5 F balloon catheter, and then EPCs derived from human early fetal aortas (<14 weeks) were injected into the lumen of the injured artery in transplanted rats, with an equal volume of normal saline injected into control rats. Rats were sacrificed at 2 and 4 weeks after treatment and transplanted cells were identified by immunohistochemical staining with anti-human CD31 and anti-human mitochondria antibodies. Arterial cross-sections were analyzed by pathology, immunohistochemistry, and morphometry.

RESULTSGreen fluorescence-labeled EPCs could be seen in the endovascular surface of balloon-injured vessels after transplantation. The intimal area and intimal/medial area ratio were significantly smaller in the transplanted group than in the control (P < 0.05) and the residual lumen area was larger (P < 0.05). After EPC transplantation, a complete vascular endothelial layer was formed, which was positive for human von Willebrand factor after immunohistochemical staining, and immunohistochemical staining revealed many CD31- and mitochondria-positive cells in the re-endothelialized endothelium with EPC transplantation but not control treatment.

CONCLUSIONEPCs derived from human early fetal aorta were successfully transplanted into injured vessels and might inhibit neointimal hyperplasia after vascular injury.

Animals ; Carotid Arteries ; pathology ; Cell Adhesion ; physiology ; Cell Survival ; physiology ; Cell Transplantation ; Endothelial Progenitor Cells ; cytology ; physiology ; Humans ; Immunohistochemistry ; Microscopy, Fluorescence ; Neointima ; therapy ; Rats ; Rats, Sprague-Dawley

BACKGROUNDCell transplantation has great potential for promoting endothelial repair and reducing the complications of percutaneous coronary intervention (PCI). The aim of this study was to investigate the effect of transplantation of human umbilical cord blood endothelial progenitor cells (EPCs) on injured arteries.

METHODSUmbilical cord blood mononuclear cells were obtained from post-partum lying-in women, and EPCs were isolated, cultured, expanded and identified by immunofluorescence. The carotid arterial endothelium of New Zealand white rabbits was injured by dilatation with a 3F balloon, and the EPCs were injected into the lumen of the injured artery in the transplanted group (n = 16), while an equal volume of phosphated buffered saline (PBS) was injected into the control group after balloon injury (n = 16). The animals were sacrificed after either 2 or 4 weeks, and the grafted cells were identified by double immunofluorescence staining with human nuclear antigen (HNA) and CD31 antibodies. Arterial cross sections were analyzed by pathology, immunohistochemistry and morphometry to evaluate the reparative effects of EPCs. Proliferating cell nuclear antigen (PCNA) and transforming growth factor (TGF)-β1 mRNA expression were detected by reverse transcription-polymerase chain reaction (RT-PCR).

RESULTSFluorescence-labeled EPCs were found in the neointima. The neointimal area and the neointimal/medial area ratio were significantly lower in the transplanted group than in the control group (P < 0.05). von Willebrand factor (vWF) immunohistostaining showed more VWF-positive cells in the transplanted animals than in the controls (8.75 ± 2.92 vs. 4.50 ± 1.77, P < 0.05). Compared with the control group, the transplanted group had lower expression of PCNA mRNA (0.67 ± 0.11 vs. 1.25 ± 0.40, P < 0.01) and higher expression of TGF-β1 mRNA (1.10 ± 0.21 vs. 0.82 ± 0.07, P < 0.05).

CONCLUSIONSEPCs derived from human umbilical cord blood were successfully transplanted into injured vessels. The transplanted EPCs inhibited neointimal hyperplasia and promoted vascular re-endothelialization.

Animals ; Carotid Artery Injuries ; immunology ; pathology ; therapy ; Cell Differentiation ; Cells, Cultured ; Cytokines ; genetics ; Endothelial Cells ; cytology ; physiology ; Fetal Blood ; cytology ; Humans ; Hyperplasia ; Male ; Neointima ; pathology ; Proliferating Cell Nuclear Antigen ; genetics ; RNA, Messenger ; analysis ; Rabbits ; Stem Cell Transplantation ; Transforming Growth Factor beta1 ; genetics

OBJECTIVETo examine the effect of the zedoary essential component-eluting stent (ZES) on a porcine coronary neointimal formation.

METHODSZES, sirolimus-eluting stents (SES), and bare metal stents (BMS) were randomly implanted in three different major epicardial vessels in 36 balloon-injured pigs. Coronary angiography, optical coherence tomography, and histomorphological analysis were used to determine antihyperplasia effects.

RESULTSZES and SES had a significantly larger lumen diameter and area, and reduced diameter and area of stenosis in arteries at 30 and 90 days compared with arteries implanted with BMS (P<0.01). Histomorphometric analysis showed moderate inflammatory responses, such as infiltration of mononuclear cells, lymphocytes, and multinucleated giant cells in some arteries with SES compared with ZES (P<0.05). Injury scores were not different among the three groups at 30 and 90 days. The endothelialization score in the SES group was 2.69 ± 0.42 at 30 days and 2.83 ± 0.39 at 90 days compared with the ZES and BMS groups (both were 3.00 ± 0.00 at either 30 or 90 days, P<0.05). Well developed endothelium was observed in the ZES group, while incomplete endothelium and inflammatory cells were observed with stent struts partly naked at the vessel lumen in the SES group.

CONCLUSIONThe ZES inhibits neointimal hyperplasia with good endothelia coverage in the porcine balloon injury coronary model.

Animals ; Coated Materials, Biocompatible ; pharmacology ; Coronary Stenosis ; pathology ; Coronary Vessels ; drug effects ; pathology ; Curcuma ; chemistry ; Endothelium, Vascular ; drug effects ; pathology ; Inflammation ; pathology ; Microscopy, Electron, Scanning ; Neointima ; pathology ; Prosthesis Implantation ; Stents ; Sus scrofa ; Time Factors

BACKGROUNDStent-based delivery of sirolimus has been shown to reduce neointimal hyperplasia significantly. However, the long-term effect of the polymer is thought to initiate and sustain an inflammatory response and contribute to the occurrence of late complications. Our study aimed to evaluate the efficacy and safety of the BuMA biodegradable drug-coated sirolimus-eluting stent (BSES) for inhibiting neointimal hyperplasia in a porcine coronary model.

METHODSFour types of stents were implanted at random in different coronary arteries of the same pig: BSES (n = 24), bare metal stent (BMS) (n = 24), biodegradable polymer coated stent without drug (PCS) (n = 24) and only poly (n-butyl methacrylate) base layer coated stent (EGS) (n = 23). In total, 26 animals underwent successful random placement of 95 oversized stents in the coronary arteries. Coronary angiography was performed after 28 days, 90 days and 240 days of stent implantation. After 14 days, 28 days, 90 days and 240 days, 6 animals at each timepoint were sacrificed for histomorphologic analysis.

RESULTSThe 28-day, 90-day and 240-day results of quantitative coronary angiography (QCA) showed reduction in luminal loss (LL) in the BSES group when compared with the BMS group; (0.20 ± 0.35) mm vs. (0.82 ± 0.51) mm (P = 0.035), (0.20 ± 0.30) mm vs. (0.93 ± 0.51) mm (P = 0.013), and (0.18 ± 0.16) mm vs. (0.19 ± 0.24) mm (P = 0.889), respectively. By 28-day, 90-day and 240-day histomorphomeric analysis results, there was also a corresponding significant reduction in neointimal tissue proliferation with similar injury scores of BSES compared with the BMS control; average neointimal area (0.90 ± 0.49) mm(2) vs. (2.16 ± 1.29) mm(2) (P = 0.049), (1.53 ± 0.84) mm(2) vs. (3.41 ± 1.55) mm(2) (P = 0.026), and (2.43 ± 0.95) mm(2) vs. (3.12 ± 1.16) mm(2) (P = 0.228), respectively. High magnification histomorphologic examination revealed similar inflammation scores and endothelialization scores in both the BSES and BMS groups.

CONCLUSIONSThe BuMA biodegradable drug-coated sirolimus-eluting stents can significantly reduce neointimal hyperplasia and in-stent restenosis. Re-endothelialization of the BuMA stent is as good as that of the BMS in the porcine coronary model due to the reduced inflammation response to the BuMA stent.

Absorbable Implants ; Animals ; Coronary Angiography ; Drug-Eluting Stents ; Female ; Hyperplasia ; pathology ; Neointima ; prevention & control ; Polymers ; chemistry ; Sirolimus ; therapeutic use ; Swine

We investigated tissue responses to endoskeleton stent grafts for saccular abdominal aortic aneurysms (AAAs) in canines. Saccular AAAs were made with Dacron patch in 8 dogs, and were excluded by endoskeleton stent grafts composed of nitinol stent and expanded polytetrafluoroethylene graft. Animals were sacrificed at 2 months (Group 1; n = 3) or 6 months (Group 2; n = 5) after the placement, respectively. The aortas embedding stent grafts were excised en bloc for gross inspection and sliced at 5 to 8 mm intervals for histopathologic evaluation. Stent grafts were patent in all except a dog showing a thrombotic occlusion in Group 2. In the 7 dogs with patent lumen, the graft overhanging the saccular aneurysm was covered by thick or thin thrombi with no endothelial layer, and the graft over the aortic wall was completely covered by neointima with an endothelial layer. Transgraft cell migration was less active at an aneurysm than at adjacent normal aorta. In conclusion, endoskeleton stent grafts over saccular aneurysms show no endothelial coverage and poor transgraft cell migration in a canine model.
Alloys/chemistry ; Angiography ; Animals ; Aortic Aneurysm, Abdominal/*pathology/surgery/ultrasonography ; Cell Movement ; Disease Models, Animal ; Dogs ; Endothelial Cells/cytology ; Neointima/etiology ; Polytetrafluoroethylene/chemistry ; *Stents ; Thrombosis/etiology ; Tomography, X-Ray Computed

Very late stent thrombosis is a life-threatening complication of implantation of drug-eluting stent (DES). The mechanisms are still unidentified. Stent malapposition is supposed to be one debated reason. Here we report a case of 33 months after DES implanted. Observed by optical coherence tomography, we detected a lipid-rich plaque with defective fibrous cap within the neointima and many local aneurysmal dilatations between stent struts, which mimic “malapposition” on the angiogram. These indicated that vulnerable plaque hidden in the neointima at the stent segment might be a potential mechanism of very late stent thrombosis after DES implantation.
Coronary Aneurysm ; pathology ; Dilatation, Pathologic ; Drug-Eluting Stents ; adverse effects ; Humans ; Male ; Middle Aged ; Neointima ; diagnosis ; Plaque, Atherosclerotic ; diagnosis ; Tomography, Optical Coherence ; methods

PURPOSE: There is a lack of sufficient data in comparison of optical coherence tomographic (OCT) findings between first- and second-generation drug-eluting stents (DES). Compared to first-generation (i.e., sirolimus- or paclitaxel-eluting stents), second-generation DESs (i.e., everolimus- or biolinx-based zotarolimus-eluting stents) might have more favorable neointimal coverage. MATERIALS AND METHODS: Follow-up OCT findings of 103 patients (119 lesions) treated with second-generation DESs were compared with those of 139 patients (149 lesions) treated with first-generation DESs. The percentage of uncovered or malapposed struts, calculated as the ratio of uncovered or malapposed struts to total struts in all OCT cross-sections, respectively, was compared between the two groups. RESULTS: Both DES groups showed similar suppression of neointimal hyperplasia (NIH) on OCT (mean NIH cross-sectional area; second- vs. first-generation=1.1+/-0.5 versus 1.2+/-1.0 mm2, respectively, p=0.547). However, the percentage of uncovered struts of second-generation DESs was significantly smaller than that of first-generation DESs (3.8+/-4.8% vs.7.5+/-11.1%, respectively, p<0.001). The percentage of malapposed struts was also significantly smaller in second-generation DESs than in first-generation DESs (0.4+/-1.6% vs.1.4+/-3.7%, respectively, p=0.005). In addition, intra-stent thrombi were less frequently detected in second-generations DESs than in first-generation DESs (8% vs. 20%, respectively, p=0.004). CONCLUSION: This follow-up OCT study showed that second-generation DESs characteristically had greater neointimal coverage than first-generation DESs.
Aged ; Coronary Angiography ; *Drug-Eluting Stents ; Female ; Humans ; Male ; Middle Aged ; Neointima/pathology/prevention & control ; Tomography, Optical Coherence/*methods