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

OBJECTIVE: The aim of this study was to investigate the effects of 2 anti-malarial drugs, chloroquine (CQ) and hydroxychloroquine (HCQ), on inhibition of vascular smooth muscle cell (VSMC) proliferation both in vivo and in vitro via Adenosine monophosphate-activated protein kinase (AMPK) activation. METHODS: Protein and mRNA levels were determined by western blot analysis and real-time reverse transcription-polymerase chain reaction in primary rat VSMCs treated with CQ and HCQ, respectively. Cell proliferation was measured by flow cytometry and cell counting. Mice carotid arteries were ligated and treated with CQ or HCQ every other day for 3 weeks. Pathological changes of carotid arteries were visualized by both microscopy and fluorescence microscopy. RESULTS: CQ and HCQ increase AMPK phosphorylation in VSMCs. Both CQ and HCQ decrease platelet-derived growth factor-induced VSMC proliferation and cell cycle progression in an AMPK-dependent manner. In addition, CQ and HCQ inhibit Smad3 phosphorylation and VSMC proliferation induced by transforming growth factor-β1. Moreover, CQ and HCQ diminished neointimal proliferation in a mouse model of carotid artery ligation-induced neointima formation. CONCLUSION: The results demonstrated that CQ and HCQ inhibit cell proliferation and cell cycle progression in VSMCs via the AMPK-dependent signaling pathway. Carotid artery ligation-induced intima thickness was reduced in mouse arteries treated with CQ or HCQ, suggesting a role for antimalarial drugs in treating atherosclerosis and restenosis.
Adenosine ; AMP-Activated Protein Kinases ; Animals ; Antimalarials ; Arteries ; Atherosclerosis ; Blotting, Western ; Carotid Arteries ; Cell Count ; Cell Cycle ; Cell Proliferation ; Chloroquine ; Flow Cytometry ; Hydroxychloroquine ; In Vitro Techniques ; Mice ; Microscopy ; Microscopy, Fluorescence ; Muscle, Smooth, Vascular ; Neointima ; Phosphorylation ; Protein Kinases ; Rats ; RNA, Messenger

PURPOSE: This study aimed to compare the effects of ticagrelor and clopidogrel on early neointimal healing assessed with optical coherence tomography (OCT) after drug-eluting stent (DES) implantation in patients with acute myocardial infarction (AMI). MATERIALS AND METHODS: AMI patients were randomly assigned to either the ticagrelor or clopidogrel arm. After DES implantation, OCT was performed to assess the percentages of uncovered struts immediately after procedure and 3 months later. RESULTS: Due to early termination, 83 patients out of 106 initially enrolled patients (24% of planned participants) underwent 3-month OCT. Differences in vascular healing patterns between the two groups, including percentage of uncovered struts on 3-month OCT (9.6% vs. 11.7% in ticagrelor vs. clopidogrel, respectively; p=0.867), neointimal thickness, percentage of malapposed struts, and healing scores did not reach statistical significance. The predictors of uncovered strut on 3-month OCT included greater reference vessel diameter [odds ratio (OR)=1.96, p < 0.001] and more malapposed struts (OR=1.12, p=0.003). CONCLUSION: The current study did not explore favorable effect of ticagrelor on 3-month vascular healing after DES implantation. Our findings should only be considered for generating hypothesis, due to insufficient power.
Arm ; Drug-Eluting Stents ; Humans ; Myocardial Infarction* ; Neointima ; Tomography, Optical Coherence*

After coronary stent implantation, neointima formation resembles the wound healing process as it involves the sequential processes of inflammation, granulation, and remodeling. Because antiproliferative drugs and polymers of drug-eluting stents (DESs) delay vascular healing compared with bare metal stents, fibrin deposition can remain long after stent implantation, or inflammation can be excessive. Delayed vascular healing can be associated with adverse clinical outcomes including DES thrombosis or restenosis, and poor endothelization of DES neointima can accelerate neoatherosclerotic change inside the neointima, further contributing to luminal restenosis or neointimal instability. Despite the lack of correlation between pathologic and optical coherence tomography (OCT) findings, OCT assessments of neointima under various circumstances can reveal vascular responses to stent therapy. Homogeneous, heterogeneous, and layered neointima patterns can be recognized by OCT and can change with time. Homogeneous neointima might be associated with better clinical outcomes after DES implantation, whereas non-homogeneous neointima or neoatherosclerotic change can be associated with poorer clinical outcomes. However, limited data are currently available, and further studies are required to comprehensively address these questions.
Coronary Artery Disease ; Drug-Eluting Stents* ; Fibrin ; Inflammation ; Neointima* ; Phenobarbital ; Polymers ; Stents ; Thrombosis ; Tomography, Optical Coherence ; Wound Healing

PURPOSE: Inhibitory effect of paclitaxel on neointimal hyperplasia after open cutdown has not been elucidated. METHODS: For the control group (n = 16), silicone 2.7-Fr catheters were placed via the right external jugular vein with the cutdown method. For the treatment group (n = 16), a mixture of 0.65 mg of paclitaxel and 1 mL of fibrin glue was infiltrated around the exposed vein after cutdown. After scheduled intervals (1, 2, 4, and 8 weeks), the vein segment was harvested and morphometric analysis was performed on cross-sections. RESULTS: Proliferation of smooth muscle cell (SMC) was strongly suppressed in the treatment group, and the ratio of neointima to vein wall was significantly reduced in the treatment group (8 weeks; 0.63 ± 0.08 vs. 0.2 ± 0.08, P < 0.05). Luminal patency was significantly more preserved in the treatment group, and the luminal area was significantly wider in the paclitaxel-treated group compared to the control group (8 weeks; 1.91 ± 0.43 mm² vs. 5.1 ± 0.43 mm², P < 0.05). Mean SMC counts measured at 1 and 2 weeks after cutdown were significantly lower in the treatment group (2 weeks; 115 ± 22 vs. 62 ± 22). Paclitaxel was undetectable in systemic circulation (<10 ng/mL). CONCLUSION: Sustained perivascular delivery of paclitaxel with fibrin glue was effective in inhibiting neointimal hyperplasia in rat jugular vein after open cutdown.
Animals ; Catheters ; Central Venous Catheters* ; Fibrin ; Fibrin Tissue Adhesive ; Hyperplasia* ; Jugular Veins* ; Methods ; Myocytes, Smooth Muscle ; Neointima ; Paclitaxel* ; Phenobarbital ; Rats* ; Silicon ; Silicones ; Veins

BACKGROUND AND OBJECTIVES: Artemisinin and dihydroartemisinin are drugs used to treat malaria. These drugs suppress inflammatory reactions. The aim of this study was to examine the anti-intima hyperplasia effect of a novel drug-eluting stent with artemisinin or dihydroartemisinin in a porcine coronary restenosis model. MATERIALS AND METHODS: Pigs were randomized into four groups; in the first, the coronary arteries (20 pigs, a total of 40 coronary arteries, with 10 coronary arteries in each group) was implanted with bare metal stents (BMS, n=10); the second group was given polymer-coated stents (PCS, n=10); the third group was treated with artemisinin-eluting stents (AES, n=10); and the fourth group was given dihydroartemisinin-eluting stents (DAES, n=10). Histopathologic analysis was performed 28 days after stenting. RESULTS: The injury and fibrin scores among the four groups were not significantly different. However, the internal elastic lamina, lumen area, and neointima area were significantly different. Moreover, the percent area of stenosis (46.2±18.66% in BMS vs. 89.4±10.92% in PCS vs. 83.3±17.07% in AES vs. 36.7±11.20% in DAES, p<0.0001) and inflammation score (1.0 [range: 1.0-1.0] vs. 3.0 [range: 2.25-3.0] vs. 3.0 [range: 1.0-3.0] vs. 2.0 [range: 1.75-3.0] in BMS, PCS, AES, and DAES, respectively; p<0.001) were markedly decreased in the DAES group compared to the PCS group. CONCLUSION: DES, which uses a natural substance, dihydroartemisinin, showed a neointima and inflammatory suppressive effect in a porcine coronary restenosis model.
Constriction, Pathologic ; Coronary Restenosis* ; Coronary Vessels ; Drug-Eluting Stents ; Fibrin ; Hyperplasia ; Inflammation ; Malaria ; Neointima ; Stents* ; Swine

Urotensin II (UII) is a mitogenic and hypertrophic agent that can induce the proliferation of vascular cells. UII inhibition has been considered as beneficial strategy for atherosclerosis and restenosis. However, currently there is no therapeutics clinically available for atherosclerosis or restenosis. In this study, we evaluated the effects of a newly synthesized UII receptor (UT) antagonist, KR-36996, on the proliferation of SMCs in vitro and neointima formation in vivo in comparison with GSK-1440115, a known potent UT antagonist. In primary human aortic SMCs (HASMCs), UII (50 nM) induced proliferation was significantly inhibited by KR-36996 at 1, 10, and 100 nM which showed greater potency (IC₅₀: 3.5 nM) than GSK-1440115 (IC₅₀: 82.3 nM). UII-induced proliferation of HASMC cells was inhibited by U0126, an ERK1/2 inhibitor, but not by SP600125 (inhibitor of JNK) or SB202190 (inhibitor of p38 MAPK). UII increased the phosphorylation level of ERK1/2. Such increase was significantly inhibited by KR-36996. UII-induced proliferation was also inhibited by trolox, a scavenger for reactive oxygen species (ROS). UII-induced ROS generation was also decreased by KR-36996 treatment. In a carotid artery ligation mouse model, intimal thickening was dramatically suppressed by oral treatment with KR-36996 (30 mg/kg) which showed better efficacy than GSK-1440115. These results suggest that KR-36996 is a better candidate than GSK-1440115 in preventing vascular proliferation in the pathogenesis of atherosclerosis and restenosis.
Animals ; Atherosclerosis ; Carotid Arteries ; Humans ; In Vitro Techniques ; Ligation ; Mice ; Muscle, Smooth* ; Muscle, Smooth, Vascular ; Neointima ; Phosphorylation ; Reactive Oxygen Species

Urotensin II (UII) is a potent vasoactive peptide and mitogenic agent to induce proliferation of various cells including vascular smooth muscle cells (VSMCs). In this study, we examined the effects of a novel UII receptor (UT) antagonist, KR-36676, on vasoconstriction of aorta and proliferation of aortic SMCs. In rat aorta, UII-induced vasoconstriction was significantly inhibited by KR-36676 in a concentration-dependent manner. In primary human aortic SMCs (hAoSMCs), UII-induced cell proliferation was significantly inhibited by KR-36676 in a concentration-dependent manner. In addition, KR-36676 decreased UII-induced phosphorylation of ERK, and UII-induced cell proliferation was also significantly inhibited by a known ERK inhibitor U0126. In mouse carotid ligation model, intimal thickening of carotid artery was dramatically suppressed by oral treatment with KR-36676 (30 mg/ kg/day) for 4 weeks compared to vehicle-treated group. From these results, it is indicated that KR-36676 suppress UII-induced proliferation of VSMCs at least partially through inhibition of ERK activation, and that it also attenuates UII-induced vasoconstriction and vascular neointima formation. Our study suggest that KR-36676 may be an attractive candidate for the pharmacological management of vascular dysfunction.
Animals ; Aorta ; Carotid Arteries ; Cell Proliferation ; Humans ; Ligation ; Mice ; Muscle, Smooth ; Muscle, Smooth, Vascular ; Neointima ; Phosphorylation ; Rats ; Vasoconstriction

OBJECTIVETo explore the related factors of optical coherence tomography (OCT) detected in-stent heterogeneous neointimal in coronary stents.

METHODSA total of 143 cases of coronary heart disease patients with OCT detected in-stent neointimal hyperplasia in Fuwai hospital from September 2009 to April 2012 were included in this study and patients data were retrospectively analyzed. Patients were divided into heterogeneous intima group(26 cases) and homogeneous intima group(117 cases)according to neointimal characteristics. Clinical features and OCT characteristics of the 2 groups were compared and binary logistic regression analysis was performed to analyze the risk factors of in-stent heterogonous neointimal hyperplasia.

RESULTSCompared to homogeneous intima group, patients in heterogeneous intima group had significantly higher cholesterol level ((5.31±1.11)mmol/L vs.(4.70±0.94)mmol/L, P=0.005), low-density lipoprotein cholesterol level ((2.57±0.87)mmol/L vs.(2.29±0.46)mmol/L, P=0.021) and triglyceride level (2.12(1.82-2.87)mmol/L vs. 1.90(1.73-2.11)mmol/L, P=0.015). Moreover, the percent of percutaneous coronary intervention (PCI) because of acute coronary syndrome (23.1%(6/26) vs. 6.8%(8/117), P=0.022) and the thin cap neoatheroma (5.8%(28/481)vs. 3.9%(89/2 276), P=0.043) were also significantly higher in heterogeneous intima group than in homogeneous intima group. Binary logistic regression analysis showed that low-density lipoprotein cholesterol (OR=2.74, 95%CI 1.04-7.24, P=0.042), triglyceride (OR=2.88, 95%CI 1.05-7.89, P=0.040), PCI for acute coronary syndrome (OR=12.74, 95%CI 2.69-60.49, P=0.001), and cerebrovascular disease (OR=13.09, 95%CI 2.16-79.53, P=0.005) were risk factors for in-stent heterogenous intima. Time post stent implantation was protective factor for in-stent heterogenous intima (OR=0.63, 95%CI 0.42-0.96, P=0.033).

CONCLUSIONOCT detected heterogeneous intima is correlated with level of blood lipid, PCI for acute coronary syndrome and history of cerebrovascular disease, and it may lead to unstable intima.

Acute Coronary Syndrome ; Coronary Artery Disease ; Humans ; Hyperplasia ; Neointima ; Percutaneous Coronary Intervention ; Retrospective Studies ; Risk Factors ; Stents ; Tomography, Optical Coherence ; Tunica Intima

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