Objective: To explore the relationship and clinical value of serum phospholipase A2 (Lp-PLA2), d-dimers, and serum galectin-3 (galectin-3) with atherosclerotic vulnerable plaques in coronary artery patients with coron...Objective: To explore the relationship and clinical value of serum phospholipase A2 (Lp-PLA2), d-dimers, and serum galectin-3 (galectin-3) with atherosclerotic vulnerable plaques in coronary artery patients with coronary heart disease. Methods: A total of 248 patients who underwent coronary angiography (CAG) and intravascular ultrasound (IVUS) in our hospital from June 2017 to September 2018 were selected and divided into vulnerable plaque group (89), stable plaque group (89) and control group (70) according to the examination results. The serum levels of Lp-PLA2, d-dimer and galectin-3 in three groups were compared, as well as their correlation with the detection parameters. To evaluate the clinical value of Lp-PLA2, d-dimer and galectin-3 in patients with coronary heart disease (CHD) with atherosclerotic vulnerable plaque. Results: Serum Lp-PLA2, d-dimer and galectin-3 levels were significantly different from the three groups (P<0.05), and the control group < stable plaque group <vulnerable plaque group (P<0.05). Correlation analysis showed that Lp-PLA2, d-dimer and galectin-3 were significantly positively correlated with plaque area, plaque load, necrotic core and calcified tissue (P<0.01), and negatively correlated with fibrous lipid and fibrous tissue (P<0.01). ROC curve showed that Lp-PLA2, d-dimer and galectin-3 had certain predictive value for vulnerable coronary atherosclerotic plaques (AUC=0.939, 0.977, 0.920, P<0.01), and the three combinations (AUC=0.986, P<0.01) had higher predictive value. Conclusion: Serum Lp-PLA2, d-dimer and galectin-3 are significantly correlated with coronary atherosclerotic vulnerable plaques in patients with coronary heart disease, with high sensitivity and specificity, which can be used for the diagnosis and treatment of early atherosclerotic vulnerable plaques.展开更多
Background The association between vulnerability of plaque assessed with intravascular ultrasound （IVUS） and plasma levels of fibrinolytic biomarkers was determined in patients with acute coronary syndrome （ACS）. ...Background The association between vulnerability of plaque assessed with intravascular ultrasound （IVUS） and plasma levels of fibrinolytic biomarkers was determined in patients with acute coronary syndrome （ACS）. However, few data are available on the relationship between the levels of tissue type plasminogen activator （t-PA） and virtual histological intravascular ultrasound （VH-IVUS） signs of plaque instability. Methods Eighty-nine patients with ACS were enrolled in the study. Blood was collected to measure t-PA levels by liquid phase bead flow cytometry. Eighty-nine nonbifurcate lesions （identified by coronary angiography and ECG） were investigated using IVUS before catheterization. IVUS radiofrequency data obtained with a 20 MHz catheter were analyzed with IVUS virtual histological software. The areas of plaque and media were calculated and lesions were classified into two groups： VH-IVUS derived thin cap fibroatheroma （VH-TCFA） and non-VH-TCFA plaque. Results Plasma t-PA level in the patients with TCFA was significantly lower than that with non-TCFA （（1489 ± 715） pg/ml vs （2163 ± 1004） pg/ml）. Decreased plasma levels of t-PA were associated with plaque vulnerability. Plasma levels of t-PA correlated negatively with plaque plus media and necrotic core in plaque in patients with ACS. Conclusions t-PA is an independent risk factor and a powerful predictor of vulnerable plaques. Decreased levels of t-PA may reflect instability of atherosclerotic plaques and might therefore serve as noninvasive determinants of those at high risk for consequent adverse events.展开更多
Rupture of atherosclerotic plaques causing thrombosis is the main cause of acute coronary syndrome and ischemic strokes.Inhibition of thrombosis is one of the important tasks developing biomedical materials such as in...Rupture of atherosclerotic plaques causing thrombosis is the main cause of acute coronary syndrome and ischemic strokes.Inhibition of thrombosis is one of the important tasks developing biomedical materials such as intravascular stents and vascular grafts.Shear stress(SS)influences the formation and development of atherosclerosis.The current review focuses on the vulnerable plaques observed in the high shear stress(HSS)regions,which localizes at the proximal region of the plaque intruding into the lumen.The vascular outward remodelling occurs in the HSS region for vascular compensation and that angiogenesis is a critical factor for HSS which induces atherosclerotic vulnerable plaque formation.These results greatly challenge the established belief that low shear stress is important for expansive remodelling,which provides a new perspective for preventing the transition of stable plaques to high-risk atherosclerotic lesions.展开更多
Background:Acute coronary syndromes mainly result from abrupt thrombotic occlusion caused by atherosclerotic vulnerable plaques (VPs) that suddenly rupture or erosion. Fibrous cap thickness (FCT) is a major determinan...Background:Acute coronary syndromes mainly result from abrupt thrombotic occlusion caused by atherosclerotic vulnerable plaques (VPs) that suddenly rupture or erosion. Fibrous cap thickness (FCT) is a major determinant of the propensity of a VP to rupture and is recognized as a key factor. The intensive use of statins is known to have the ability to increase FCT;however, there is a risk of additional adverse effects. However, lower dose statin with ezetimibe is known to be tolerable by patients. The present study aimed to investigate the effect of intensive statin vs. low-dose stain + ezetimibe therapy on FCT, as evaluated using optical coherence tomography. Method:Patients who had VPs (minimum FCT <65 μm and lipid core >90°) and deferred from intervention in our single center from January 2014 to December 2018 were included in the trial. They were divided into the following two groups: intensive statin group (rosuvastatin 15-20 mg or atorvastatin 30-40 mg) and combination therapy group (rosuvastatin 5-10 mg or atorvastatin 10-20 mg + ezetimibe 10 mg). At the 12-month follow-up, we compared the change in the FCT (ΔFCT%) between the two groups and analyzed the association of ΔFCT% with risk factors. Fisher exact test was used for all categorical variables. Student’s t test or Mann-Whitney U-test was used for analyzing the continuous data. The relationship between ΔFCT% and risk factors was analyzed using linear regression analysis. Result:Total 53 patients were finally enrolled, including 26 patients who were in the intensive statin group and 27 who were in the combination therapy group. At the 12-month follow-up, the serum levels of total cholesterol (TC), total triglyceride, low-density lipoprotein (LDL-C), hypersensitive C-reactive protein (hs-CRP), and lipoprotein-associated phospholipase A2 (Lp-PLA2) levels were reduced in both the groups. The ΔTC%, ΔLDL-C%, and ΔLp-PLA2% were decreased further in the combination therapy group. FCT was increased in both the groups (combination treatment group vs. intensive statin group: 128.89 ± 7.64 vs. 110.19 ± 7.00 μm, t = -9.282, P < 0.001) at the 12-month follow-up. The increase in ΔFCT% was more in the combination therapy group (123.46% ± 14.05% vs. 91.14% ± 11.68%, t = -9.085, P < 0.001). Based on the multivariate linear regression analysis, only the serum Lp-PLA2 at the 12-month follow-up ( B = -0.203, t = -2.701, P = 0.010), ΔTC% ( B = -0.573, t = -2.048, P = 0.046), and Δhs-CRP% ( B = -0.302, t = -2.963, P = 0.005) showed an independent association with ΔFCT%. Conclusions:Low-dose statin combined with ezetimibe therapy maybe provide a profound and significant increase in FCT as compared to intensive statin monotherapy. The reductions in Lp-PLA2, ΔTC%, and Δhs-CRP% are independently associated with an increase in FCT.展开更多
Objective This coronary artery spasm review aimed to explore the most possible pathogenic trigger mechanism of vulnerable plaque rupture. Data sources Data used in this coronary artery spasm review were mainly from Me...Objective This coronary artery spasm review aimed to explore the most possible pathogenic trigger mechanism of vulnerable plaque rupture. Data sources Data used in this coronary artery spasm review were mainly from Medline and Pubmed in English. Study selection These reports from major review on coronary artery spasm .and these research included coronary artery conception, pathogenesis of spasm, mechanisms of plaque rupture, epidemiological evidence, clinical manifestation and the relationship between coronary artery spasm and vulnerable plaque rupture. Results Coronary artery spasm is somehow related to the presence of atherosclerotic intima disease in the coronary artery. However, chronic low-grade inflammation causes coronary vessel smooth muscle cell hypersensitivity, which can directely cause coronary artery spasm. Myocardial infarction and sudden cardiac death may be initiated by a sudden intense localized contraction of coronary artery smooth muscle. Conclusion Coronary artery spasm may be one trigger that can initiate and exacerbate vulnerable plaque rupture.展开更多
Background Noninvasive detection of vulnerable plaque has a significant implication for prevention and treatment of atherosclerotic disea±ses. The aim of this study is to investigate the difference between vulner...Background Noninvasive detection of vulnerable plaque has a significant implication for prevention and treatment of atherosclerotic disea±ses. The aim of this study is to investigate the difference between vulnerable plaques and stable plaques in magnetic resonance （MR） images. Methods Atherosclerosis was induced in twenty male New Zealand white rabbits by high cholesterol diet and balloon injury of the abdominal aorta. After baseline （pre-triggering） MR imaging （MRI） scan, the rabbits underwent pharmaceutical triggering with Russell＇s viper venom and histamine to induce atherothrombosis, followed by another MRI scan 48 hours later （post-triggering）. Rabbits were euthanized to obtain pathological and histological data. The results of MRI were compared with those of pathology and histology. Results MRI showed that abdominal aorta of the rabbits had pathological change of atherosclerosis in different degrees. Seventy-five plaques were analysed, among which 14 had vulnerable thrombi and 61 stable. Thrombosis was identified in 7 of 11 rabbits by post-triggering MRI, the sensitivity and K value of MR in detection of vulnerable plaque was 71% and 0.803 （P 〈0.05）. MRI data significantly correlated with the histopathological data in fibrous cap thickness （t=0.749） plaque area （t=0.853）, lipid core area （r=0.900）. Compared with stable plaques, vulnerable plaques had a significantly thinner fibrous cap （（0.58±0.27） mm vs. （0.95±0.22） mm）, larger lipid core area （（7.56±2.78） mm2 vs. （3.29±1.75） mm2）, and a higher ratio of lipid core area/plaque area （（55±16）% vs. （27±17）%）, but plaque area was comparable in two groups on MRI. The ratio of lipid core area/plaque area was a strong predictor of vulnerable plaques. Conclusion MRI could distinguish vulnerable plaques from stable plaques in a rabbit model of atherothrombosis and may thus be useful as a noninvasive modality for detection of vulnerable plaques in humans.展开更多
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 rep...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.展开更多
Objectives:To evaluate the efficacy of 18F-FDG-PET/CT in detection toward the vulnerabilities of carotid plaque and review systematically best evidence to prevent acute stroke from unstable carotid plaque.Methods:A se...Objectives:To evaluate the efficacy of 18F-FDG-PET/CT in detection toward the vulnerabilities of carotid plaque and review systematically best evidence to prevent acute stroke from unstable carotid plaque.Methods:A search was conducted on Medline(PubMed),Web of science,Cochrane and WHIC using the search terms‘PET/CT’AND‘18F-FDG’AND‘fluorodeoxyglucose’AND‘carotid plaque’,from 2013/01/01 to now.Two authors will independently extract data following the study characteristics,eligibility criteria,interventions,outcome measurements,duration,adverse events,results and the type of needle used.All searched articles were inserted into in EndNote software that can automatically save,manage,and delete duplicate documents.Results:There were 3 articles included in the systematic review finally and form the study population analysis.The total 89 patients(64 males and 25 females)identified from the included studies.The mean 18F-FDG injected dose was 4.58 MBq/kg.The last three articles have demonstrated that 18F-FDG can accurately identify the stability of carotid plaques and can accurately locate and identify high-inflammation areas by histological analysis.Conclusions:18F-FDG-PET/CT is very efficient and practical for the identification of carotid vulnerable plaques.TBR(max and mean values)as a parameter for identifying inflammatory plaques is more reliable than SUV.展开更多
This study investigated the relationship between carotid plaque neovascularization and diabetes mellitus（DM） by using contrast-enhanced ultrasonography. Contrast-enhanced ultrasonography was performed in 104 patient...This study investigated the relationship between carotid plaque neovascularization and diabetes mellitus（DM） by using contrast-enhanced ultrasonography. Contrast-enhanced ultrasonography was performed in 104 patients with carotid plaque thicker than 2.0 mm. There were 36 patients with DM and 68 patients without DM. The enhanced intensity in the plaque and the ratio of enhanced intensity in the plaque to that in the lumen of the carotid artery in patients with DM were significantly greater than those in patients without DM. Our study demonstrated that the enhanced intensity in patients with DM is greater than that their counterparts without DM, suggesting that carotid plaque in DM patients may have more neovessels and may be more vulnerable.展开更多
Objective：To evaluate the clinical value with positron emission tomography/computerized tomography（PET/CT） imaging for the detection of vulnerable plaque in atherosclerotic lesions. Methods：Sixty people with a age...Objective：To evaluate the clinical value with positron emission tomography/computerized tomography（PET/CT） imaging for the detection of vulnerable plaque in atherosclerotic lesions. Methods：Sixty people with a age of over 60[mean age （69.2 ± 7.1）years] underwent three dimension（3D） whole-body fluorine-18-2-fluoro-2-deoxy-D-glucose（^18F-FDG） PET/CT imaging and were evaluated retrospectively, including 6 cases assessed as normal and 54 cases with active atherosclerotic plaque. Fifty-four cases with SUVs and CT values in the aortic wall of high-FDG-uptake were measured retrospectively. These high-FDG-uptake cases in the aortic wall were divided into three groups according their CT value. Cases in group 1 had high uptake in atherosclerotic lesions of the aortic wall with CT value of less than 60 Hu（soft plaque）. Cases in group 2 had high uptake with CT value between 60-100 Hu （intermediate plaque）, Cases in group 3 had high uptake with CT value more than 100 Hu（calcified plaque）, Group 4 was normal. Results： In group 1, there were 42 high-FDG-uptake sites （average SUV 1.553 ± 0.486）. In group 2, there were 30 high-FDG-uptake sites（average SUV 1.393 ± 0.296）. In group 3, there were 36 high-FDG-uptake sites（average SUV 1.354 ± 0.189）. In group 4, there were 33 normal-FDG-uptake sites （average SUV was 1.102 ± 0.141）, The SUVs showed significant difference among the four groups（F = 678.909, P = 0.000）. There were also significant difference found between the normal-FDG-uptake group and the high-FDG-uptake groups（P = 0.000, 0.000, 0.001, respectively）. Conclusion：Different degrees of ^18F-FDG uptake in active large atherosclerotic plaque were shown in different stages of atherosclerotic plaque formation. The soft plaque had the highest FDG uptake in this study. This suggested that ^18F- FDG PET/CT imaging may be of great potential value in early diagnosis and monitoring of vulnerable soft plaque in atherosclerotic lesions.展开更多
Due to the high risk of tearing and rupture,vulnerable atherosclerotic plaques would induce serious cardiovascular and cerebrovascular diseases.Despite the available clinical methods can evaluate the vulnerability of ...Due to the high risk of tearing and rupture,vulnerable atherosclerotic plaques would induce serious cardiovascular and cerebrovascular diseases.Despite the available clinical methods can evaluate the vulnerability of plaques and specifically treat vulnerable plaques before a cardiovascular event,but the efficiency is still low and undesirable.Herein,we rationally design and engineer the low-intensity focused ultrasound(LIFU)-responsive FPD@CD nanomedicine for the highly efficient treatment of vulnerable plaques by facilely loading phase transition agent perfluorohexane(PFH)into biocompatible PLGA-PEG-PLGA nanoparticles(PPP NPs)and then attaching dextran sulphate(DS)onto the surface of PPP NPs for targeting delivery.DS,as a typical macrophages-targeted molecule,can achieve the precise vaporization of NPs and subsequently controllable apoptosis of RAW 264.7 macrophages as induced by acoustic droplet vaporization(ADV)effect.In addition,the introduction of DiR and Fe3O4 endows nanomedicine with near-infrared fluorescence(NIRF)and magnetic resonance(MR)imaging capabilities.The engineered FPD@CD nanomedicine that uses macrophages as therapeutic targets achieve the conspicuous therapeutic effect of shrinking vulnerable plaques based on in vivo and in vitro evaluation outcomes.A reduction of 49.4%of vascular stenosis degree in gross pathology specimens were achieved throughout the treatment period.This specific,efficient and biosafe treatment modality potentiates the biomedical application in patients with cardiovascular and cerebrovascular diseases based on the relief of the plaque rupture concerns.展开更多
Vulnerable atherosclerotic plaque rupture lead-ing to thrombosis is the major cause of acute coronary syndrome(ACS).Studies on the pathophysiologic mechanism of both ACS and plaque stabilizing treatment are driving th...Vulnerable atherosclerotic plaque rupture lead-ing to thrombosis is the major cause of acute coronary syndrome(ACS).Studies on the pathophysiologic mechanism of both ACS and plaque stabilizing treatment are driving the development of animal models of vulnerable plaque.In our laboratory,we established animal models of plaque rupture and thrombosis in rabbits and mice that are similar to human plaque rupture.Potential mechanisms involved in plaque vulnerability were studied from the inflammation-immunity,proliferation-apoptosis,oxidative stress and biomechanics aspects.Imaging markers and biomarkers were used to detect vulnerable plaques,including high frequency duplex ultrasound,intravascular ultrasound(IVUS),intravascular ultrasound elastography,magnetic resonance imaging(MRI)and inflammatory markers.Effective gene and drug strategies to treat vulnerable plaques were explored.展开更多
Vulnerable atherosclerotic plaque(VASPs)is the major pathological cause of acute cardiovascular event.Early detection and precise intervention of VASP hold great clinical significance,yet remain a major challenge.Phot...Vulnerable atherosclerotic plaque(VASPs)is the major pathological cause of acute cardiovascular event.Early detection and precise intervention of VASP hold great clinical significance,yet remain a major challenge.Photodynamic therapy(PDT)realizes potent ablation efficacy under precise manipulation of laser irradiation.In this study,we constructed theranostic nanoprobes(NPs),which could precisely regress VASPs through a cascade of synergistic events triggered by local irradiation of lasers under the guidance of fluorescence/MR imaging.The NPs were formulated from human serum albumin(HSA)conjugated with a high affinity-peptide targeting osteopontin(OPN)and encapsulated with photosensitizer IR780 and hypoxia-activatable tirapazamine(TPZ).After intravenous injection into atherosclerotic mice,the OPN-targeted NPs demonstrated high specific accumulation in VASPs due to the overexpression of OPN in activated foamy macrophages in the carotid artery.Under the visible guidance of fluorescence and MR dual-model imaging,the precise near-infrared(NIR)laser irradiation generated massive reactive oxygen species(ROS),which resulted in efficient plaque ablation and amplified hypoxia within VASPs.In response to the elevated hypoxia,the initially inactive TPZ was successively boosted to present potent biological suppression of foamy macrophages.After therapeutic administration of the NPs for 2 weeks,the plaque area and the degree of carotid artery stenosis were markedly reduced.Furthermore,the formulated NPs displayed excellent biocompatibility.In conclusion,the developed HSA-based NPs demonstrated appreciable specific identification ability of VASPs and realized precise synergistic regression of atherosclerosis.展开更多
Background Cathepsin S and its endogenous inhibitor cystatin C are implicated in the pathogenesis of atherosclerosis, especially in the plaque destabilization and rupture leading to acute coronary syndrome. However, w...Background Cathepsin S and its endogenous inhibitor cystatin C are implicated in the pathogenesis of atherosclerosis, especially in the plaque destabilization and rupture leading to acute coronary syndrome. However, whether circulating cathepsin S and cystatin C also change in association with coronary plaque morphology is unknown yet. Methods We recruited 98 patients with unstable angina （UA, n=56） or stable angina （SA, n=-42） who had a segmental stenosis resulting in 〉20% and 〈70% diameter reduction in one major coronary artery on coronary angiography. Thirty-one healthy subjects served as controls. Intravascular ultrasound （IVUS） was used to evaluate plaque morphology. Plasma cathepsin S and cystatin C were measured as well. Results At the culprit lesion site, plaque area （（7.85±2.83） mm^2 vs （6.53±2.92） mm^2, P=0.027）, plaque burden （（60.92±11.04）% vs （53.87±17.52）%, P=0.025）, remodeling index （0.93±0.16 vs 0.86±0.10, P=0.004） and eccentricity index （0.74±0.17 vs 0.66±0.21, P=0.038） were bigger in UA group than in SA group. Plasma cathepsin S and cystatin C were significantly higher in patients than in controls （P〈0.01）. Plasma cathepsin S was higher in UA group （（0.411±0.121） nmol/L） than in SA group （（0.355±0.099） nmol/L, P=0.007）, so did the plasma cystatin C （（0.95±0.23） mg/L in UA group, （0.84±0.22） mg/L in SA group; P=0.009）. Plasma cathepsin S positively correlated with remodeling index （r=0.402, P=0.002） and eccentricity index （r=0.441, P=0.001）, and plasma cystatin C positively correlated with plaque area （r=0.467, P 〈0.001） and plaque burden （r=0.395, P=0.003） in UA group but not in SA group. Conclusions Plasma cathepsin S and cystatin C increased significantly in UA patients. In angina patients, higher plasma cathepsin S may suggest the presence of vulnerable plaque, and higher plasma cystatin C may be a clue for larger atherosclerotic coronary plaque.展开更多
Background Vasoactive factors have been reported to correlate with vulnerable plaque and acute coronary syndrome （ACS）. This study aimed to investigate the relationship between vasoactive factors and plaque morpholo...Background Vasoactive factors have been reported to correlate with vulnerable plaque and acute coronary syndrome （ACS）. This study aimed to investigate the relationship between vasoactive factors and plaque morphology in patients suffering from non-ST-segment elevated ACS. Methods From April 2007 to April 2009, 124 consecutive patients suffering from non-ST-segment elevated ACS who had received coronary angiography （CAG） and intravascular ultrasound （IVUS） in the People＇s Liberation Army General Hospital and Beijing Anzhen Hospital were enrolled in this study. Three serum vasoactive factors, plasma soluble vascular endothelial growth factor receptor-1 （sFIt-1）, placental growth factor （PLGF） and interleukin-18 （IL-18）, were measured by enzyme-linked-immunosorbent serologic assay of the patients. The levels of vasoactive factors were compared between vulnerable plaque group and stable plaque group, and between unstable angina pectoris （UAP） group and non-ST-segment elevation acute myocardial infarction （NSTE-AMI） group. The relationship between the plaque morphology and levels of vasoactive factors was analyzed. Results The levels of vasoactive factors were similar between the UAP group （69 patients） and NSTE-AMI group （55 patients）. The levels of sFIt-1 and PLGF in the vulnerable plaque group were significantly higher than those in the stable plaque group. The level of IL-18 was correlated positively with plaque morphology. Multivariate Logistic regression analysis showed that the level of PLGF was an independent risk factor for vulnerable plaque （OR=2.115, 95%Cl 1.415-5.758, P=0.018）. Using the ROC curve, PLGF was a significant factor for the diagnosis of vulnerable plaque （the diagnostic point was 26.3 ng/L, the proportion of square area under the ROC curve was 0.799, 95%C/0.758-0.839, P 〈0.001 ; the sensitivity of PLGF under the ROC curve was 86%, and the specificity 63%）. Conclusion Both IL-18 and PLGF are biomarkers for vulnerable plaques and helpful to predict vulnerable plaque.展开更多
Background Vulnerable plaques play an important role in the onset of sudden cardiac events and strokes. How to stabilize vulnerable plaques is still a challenge to medical science. Alprostadil is a biologically active...Background Vulnerable plaques play an important role in the onset of sudden cardiac events and strokes. How to stabilize vulnerable plaques is still a challenge to medical science. Alprostadil is a biologically active substance with strong activity on vessel. Our study assessed the stabilizing effects of an alprostadil liposome microsphere preparation （ALMP） on vulnerable plaques in the brachiocephalic artery of apolipoprotein E （Apo E） knockout mice. Methods Seventy-two male Apo E-knockout mice were fed a high-fat diet beginning at eight weeks of age. At week 17, they were divided randomly into groups for treatment with a high dose （3.6 μg, kg-1. d-1） or low dose （1.8 μg. kg-1 . d-1） of an ALMP, or 0.2 ml/d normal saline （control group）, The drug was administered using a micro-capsule pump. Twenty weeks after drug administration, pathological changes in the vulnerable plaques within the brachiocephalic artery were assessed, and levels of anti-mouse monocyte/macrophage monoclonal antibody （MOMA-2） and superoxide anions in the plaques were detected using immunofluorescence. The soluble intercellular adhesion molecule-1 （ICAM-1） expression was measured by ELISA, and the expression of matrix metalloproteinase-9 （MMP-9） and CD40 mRNA was measured using RT-PCR. Thrombospindin-1 （TSP-1） expression was detected using Western blotting. Results Compared with the control group, ALMP treatment significantly reduced the plaque area in the brachiocephalic artery （P 〈0.01）, significantly lowered the contents of the lipid core （P 〈0.01 ）, significantly reduced the number of ruptured fibrous caps （P 〈0.05）, and increased the thickness of the fibrous cap and significantly reduced the incidence of intra-plaque hemorrhage （P 〈0.05）. ALMP treatment significantly reduced the expression of MOMA-2, superoxide anion, MMP-9, ICAM-1 and CD40 in the plaques （P 〈0.01）, decreased plasma ICAM-1 expression （P 〈0.01 ）, and increased the expression of TSP-1. Conclusions Treatment with ALMP can stabilize vulnerable plaques by inhibiting inflammation.展开更多
Abstract：Background Atherosclerotic plaque rupture is the primary mechanism of thrombosis which plays a key role in the onset of acute coronary syndromes. Detection of these plaques prone to rupture （vulnerable pla...Abstract：Background Atherosclerotic plaque rupture is the primary mechanism of thrombosis which plays a key role in the onset of acute coronary syndromes. Detection of these plaques prone to rupture （vulnerable plaque） could be clinically significant for prevention of cardiac events. It has been shown that high metabolism cells have a high uptake of fluorine-18 fluorodeoxyglucose （18F-FDG）. The objective of this study was to investigate the correlation of FDG uptake and the immuno-histochemistry parameters of plaques, and the effect of atorvastatin on vulnerable atherosclerotic plaque in a rabbit model.Methods Ten male New Zealand White rabbits were divided into three groups as follows： （1） normal control group （n=2,C group）： the animals were fed a standard diet at 120 g/d and were given water ad labium; （2） atherosclerosis group （n=4,As group）： animals were fed with high fat diet for 5 months after aortic endothelia damage; （3） treatment group （atherosclerosis ＋ atorvastatin, n=4, Statin group）： animals were fed with high fat diet for 5 months and then changed into normal chow plus atorvastatin （2.5 mg·d-1·kg-1） treatment for another 4 months. Then these four rabbits were imaged with fluorine-18 fluorodexyglucose positron emission tomography/computed tomography （PET/CT） and sacrificed for pathohistologic studies. FDG uptake by the aorta was expressed as target-to-background ratio （TBR）. Maximal standardized uptake value （SUV） was measured over the thoracic and abdominal aortas. The aortic smooth muscle cell （SMC） number, CD-14 antibody positive cell （macrophage） number and the ratio of the thickness of fibrous cap to the thickness of lipid core （cap-to-core ratio） in atherosclerotic plaques were analyzed.Results As group showed significantly higher uptake of FDG than C group （SUVs： 0.746±0.172 vs. 0.286±0.073, P 〈0.001）. After 4 months of atorvastatin treatment and the modification of diet, SUVs decreased significantly （Statin group：0.550±0.134, compared to As group, P 〈0.001）. However, no marked difference was found in TBR, the number of macrophages, the number of SMC and the cap-to-core ratio in the aortic segments between Statin group and As group.The correlation of aortic FDG uptake with SMC assessed by histopathology was negatively significant （r=0.57, P〈0.001）. When aortic FDG uptake was expressed as TBR, it correlated significantly （r=0.69, P 〈0.001） with the macrophage number, and also correlated significantly （r=0.78, P 〈0.001） with the cap-to-core ratio.Conclusion 18F-FDG PET/CT might serve as a useful non-invasive imaging technique for detection of atherosclerotic plaque and potentially permit monitoring of relative changes in inflammation within the atherosclerotic lesion.展开更多
Objective： To investigate the effect of Qingre Quyu Granule （清热祛瘀颗粒, QRQYG） on stabilizing vulnerable plaques in apolipoprotein E （ApoE） defficient mice. Methods： Seventy-two male ApoE defficient mice were...Objective： To investigate the effect of Qingre Quyu Granule （清热祛瘀颗粒, QRQYG） on stabilizing vulnerable plaques in apolipoprotein E （ApoE） defficient mice. Methods： Seventy-two male ApoE defficient mice were given a high-fat diet from 6 weeks of age. At the 16th week, all the mice were randomized into 3 groups： the QRQYG group, the simvastatin group, and the control group. Sixteen weeks after administration of 0.9 g/kg QRQYG, 3 mg/kg simvastatin or 10 mg/kg sodium chloride per day to the respective groups, the animals were euthanized. The pathological morphologic changes in the vulnerable plaques were evaluated, the matrix metalloprotease-9 （MMP-9） expression was measured by immunohistofluorescence, the soluble intercellular adhesion molecule 1 （ICAM-1） was determined by ELISA, the nuclear factor kappaB （NF-κB） subunit p65 was measured by quantitative RT-PCR, and, finally, thrombospondin-1 （TSP-1） was determined by the immunohistochemical method. Results： The plaque cross-sectional area in the brachiocephalic artery （23.7%, P0.01）, the lipid core of the plaque （43.1%±3.1%）, and the number of buried ？brotic caps of the plaque were significantly decreased in the QRQYG group compared to the control group （both P0.01）; furthermore, the thickness of the ？brotic cap of the plaque increased and the intra-plaque hemorrhage of the plaque decreased. The serum soluble ICAM-1 （27.1±5.1 μg/mL）, the protein expression of MMP-9 and TSP-1 and the p65 mRNA expression increased in the QRQYG group in comparison with the control group （P0.05 or P0.01）. Conclusion： QRQYG could stabilize the vulnerable plaque through inhibition of the inflammatory response.展开更多
To evaluate the effect of atrovastatin therapy on borderline vulnerable lesions in patients with acute coronary syndrome (ACS) .Methods Patients with ACS underwent coronary angiography (CAG) and intravascular ultrasou...To evaluate the effect of atrovastatin therapy on borderline vulnerable lesions in patients with acute coronary syndrome (ACS) .Methods Patients with ACS underwent coronary angiography (CAG) and intravascular ultrasound (IVUS) investigation.Patients with culprit vulnerable borderline lesions were enrolled.No coronary inter-vention was performed on these lesions.All the patients received atrovastatin therapy for 12 months and underwent clin-ical follow-up along with IVUS follow-up.Cross section area (CSA) of the targeted lesion,CSA of the reference arter-ies (extra elastic membrane) ,minimal lumen CSA,and plaque area were measured at baseline and follow-ups.Ad-verse events included recurrent angina,recurrent myocardial infarction,revascularization and death.Results No ad-verse events was reported during follow-up period.Compared with baseline data,the level of ApoB decreased signifi-cantly at the end of the study (0.589 ± 0.136 g /L vs 0.681 ± 0.132 g /L,P = 0.03) .Both the percent diameter steno-sis and the percent area stenosis detected by CAG displayed minimal change ((62.50 ± 10.21) % vs (54.79 ± 12.35) % ,P = 0.48 and (58.61 ± 8.36) % vs (48.18 + 10.56) % ,P = 0.78) .Detected by IVUS,the minimal lu-minal CSA of the targeted lesion increased significantly (6.32 ± 2.42 mm2 vs 5.63 ± 2.51 mm2,P < 0.01) ,the plaque area and CSA stenosis decreased (7.70 ± 2.19 mm2 vs 8.17 ± 2.55 mm2,P < 0.05 and 56.94 ± 8.47% vs 61.4 ± 110.34% ,P < 0.01) .A total of 25 soft plaques (50% ) transformed into fibrous plaque.Conclusions Atro-vastatin therapy stabilizes borderline vulnerable plaque and reverses atherosclerosis progression in patients with ACS.展开更多
Objective： To investigate the therapeutic effects of Qingre Quyu Granule （请热祛瘀颗粒, QQG） on the patients with severe carotid stenosis, and to explore the mechanism of it. Methods： Ninety-six patients with seve...Objective： To investigate the therapeutic effects of Qingre Quyu Granule （请热祛瘀颗粒, QQG） on the patients with severe carotid stenosis, and to explore the mechanism of it. Methods： Ninety-six patients with severe carotid stenosis were enrolled in the study and were classified into a QQG group （n=48） and a control group （n=48） randomly using consecutively numbered envelopes. The patients in the QQG group were given QQG and Western medicine, those in the control group were given Western medicine merely, the course of treatment was 16 weeks. All patients went through endarterectomy after treatment. Plaques were subjected to the analysis of CD3, CD68, soluble intercellular adhesion molecule 1 （ICAM-1）, matrix metalloprotease-9 （MMP-9）, CD40L, tenascin-C, and collagen content lipid content by immunohistochemistry or polarized light analysis. Results： By the end of experiment, the expressions of CD3, CD68, ICAM-1, MMP9, CD40L and tenascin-C on the plaques were statistically significant lower in the QQG group compared with the control group （P〈0.01）, The lipid content of the plaque was also significantly lower in the QQG group compared with the control group （P〈O.01）, The interstitial collagen in the tissue sections of the plaques was also significantly higher in the QQG group in comparison with the control group （P〈0.01）. Conclusion： QQG could stabilize carotid artery plaques through inhibiting pro-inflammation factors and restraining the tenascin-C and MMP9 pathway.展开更多
文摘Objective: To explore the relationship and clinical value of serum phospholipase A2 (Lp-PLA2), d-dimers, and serum galectin-3 (galectin-3) with atherosclerotic vulnerable plaques in coronary artery patients with coronary heart disease. Methods: A total of 248 patients who underwent coronary angiography (CAG) and intravascular ultrasound (IVUS) in our hospital from June 2017 to September 2018 were selected and divided into vulnerable plaque group (89), stable plaque group (89) and control group (70) according to the examination results. The serum levels of Lp-PLA2, d-dimer and galectin-3 in three groups were compared, as well as their correlation with the detection parameters. To evaluate the clinical value of Lp-PLA2, d-dimer and galectin-3 in patients with coronary heart disease (CHD) with atherosclerotic vulnerable plaque. Results: Serum Lp-PLA2, d-dimer and galectin-3 levels were significantly different from the three groups (P<0.05), and the control group < stable plaque group <vulnerable plaque group (P<0.05). Correlation analysis showed that Lp-PLA2, d-dimer and galectin-3 were significantly positively correlated with plaque area, plaque load, necrotic core and calcified tissue (P<0.01), and negatively correlated with fibrous lipid and fibrous tissue (P<0.01). ROC curve showed that Lp-PLA2, d-dimer and galectin-3 had certain predictive value for vulnerable coronary atherosclerotic plaques (AUC=0.939, 0.977, 0.920, P<0.01), and the three combinations (AUC=0.986, P<0.01) had higher predictive value. Conclusion: Serum Lp-PLA2, d-dimer and galectin-3 are significantly correlated with coronary atherosclerotic vulnerable plaques in patients with coronary heart disease, with high sensitivity and specificity, which can be used for the diagnosis and treatment of early atherosclerotic vulnerable plaques.
文摘Background The association between vulnerability of plaque assessed with intravascular ultrasound （IVUS） and plasma levels of fibrinolytic biomarkers was determined in patients with acute coronary syndrome （ACS）. However, few data are available on the relationship between the levels of tissue type plasminogen activator （t-PA） and virtual histological intravascular ultrasound （VH-IVUS） signs of plaque instability. Methods Eighty-nine patients with ACS were enrolled in the study. Blood was collected to measure t-PA levels by liquid phase bead flow cytometry. Eighty-nine nonbifurcate lesions （identified by coronary angiography and ECG） were investigated using IVUS before catheterization. IVUS radiofrequency data obtained with a 20 MHz catheter were analyzed with IVUS virtual histological software. The areas of plaque and media were calculated and lesions were classified into two groups： VH-IVUS derived thin cap fibroatheroma （VH-TCFA） and non-VH-TCFA plaque. Results Plasma t-PA level in the patients with TCFA was significantly lower than that with non-TCFA （（1489 ± 715） pg/ml vs （2163 ± 1004） pg/ml）. Decreased plasma levels of t-PA were associated with plaque vulnerability. Plasma levels of t-PA correlated negatively with plaque plus media and necrotic core in plaque in patients with ACS. Conclusions t-PA is an independent risk factor and a powerful predictor of vulnerable plaques. Decreased levels of t-PA may reflect instability of atherosclerotic plaques and might therefore serve as noninvasive determinants of those at high risk for consequent adverse events.
基金This research program was supported by grants from the National Natural Science Foundation of China(31370949,11332003,81400329 and 11372364)Chongqing Science and Technology Commission(cstc2013kjrc-ljrccj10003)as well as the Public Experiment Center of State Bioindustrial Base(Chongqing),China.
文摘Rupture of atherosclerotic plaques causing thrombosis is the main cause of acute coronary syndrome and ischemic strokes.Inhibition of thrombosis is one of the important tasks developing biomedical materials such as intravascular stents and vascular grafts.Shear stress(SS)influences the formation and development of atherosclerosis.The current review focuses on the vulnerable plaques observed in the high shear stress(HSS)regions,which localizes at the proximal region of the plaque intruding into the lumen.The vascular outward remodelling occurs in the HSS region for vascular compensation and that angiogenesis is a critical factor for HSS which induces atherosclerotic vulnerable plaque formation.These results greatly challenge the established belief that low shear stress is important for expansive remodelling,which provides a new perspective for preventing the transition of stable plaques to high-risk atherosclerotic lesions.
基金a grant from the Nanjing Medical Science and Technology Development Foundation,Nanjing Department of Health(No.201803008).
文摘Background:Acute coronary syndromes mainly result from abrupt thrombotic occlusion caused by atherosclerotic vulnerable plaques (VPs) that suddenly rupture or erosion. Fibrous cap thickness (FCT) is a major determinant of the propensity of a VP to rupture and is recognized as a key factor. The intensive use of statins is known to have the ability to increase FCT;however, there is a risk of additional adverse effects. However, lower dose statin with ezetimibe is known to be tolerable by patients. The present study aimed to investigate the effect of intensive statin vs. low-dose stain + ezetimibe therapy on FCT, as evaluated using optical coherence tomography. Method:Patients who had VPs (minimum FCT <65 μm and lipid core >90°) and deferred from intervention in our single center from January 2014 to December 2018 were included in the trial. They were divided into the following two groups: intensive statin group (rosuvastatin 15-20 mg or atorvastatin 30-40 mg) and combination therapy group (rosuvastatin 5-10 mg or atorvastatin 10-20 mg + ezetimibe 10 mg). At the 12-month follow-up, we compared the change in the FCT (ΔFCT%) between the two groups and analyzed the association of ΔFCT% with risk factors. Fisher exact test was used for all categorical variables. Student’s t test or Mann-Whitney U-test was used for analyzing the continuous data. The relationship between ΔFCT% and risk factors was analyzed using linear regression analysis. Result:Total 53 patients were finally enrolled, including 26 patients who were in the intensive statin group and 27 who were in the combination therapy group. At the 12-month follow-up, the serum levels of total cholesterol (TC), total triglyceride, low-density lipoprotein (LDL-C), hypersensitive C-reactive protein (hs-CRP), and lipoprotein-associated phospholipase A2 (Lp-PLA2) levels were reduced in both the groups. The ΔTC%, ΔLDL-C%, and ΔLp-PLA2% were decreased further in the combination therapy group. FCT was increased in both the groups (combination treatment group vs. intensive statin group: 128.89 ± 7.64 vs. 110.19 ± 7.00 μm, t = -9.282, P < 0.001) at the 12-month follow-up. The increase in ΔFCT% was more in the combination therapy group (123.46% ± 14.05% vs. 91.14% ± 11.68%, t = -9.085, P < 0.001). Based on the multivariate linear regression analysis, only the serum Lp-PLA2 at the 12-month follow-up ( B = -0.203, t = -2.701, P = 0.010), ΔTC% ( B = -0.573, t = -2.048, P = 0.046), and Δhs-CRP% ( B = -0.302, t = -2.963, P = 0.005) showed an independent association with ΔFCT%. Conclusions:Low-dose statin combined with ezetimibe therapy maybe provide a profound and significant increase in FCT as compared to intensive statin monotherapy. The reductions in Lp-PLA2, ΔTC%, and Δhs-CRP% are independently associated with an increase in FCT.
文摘Objective This coronary artery spasm review aimed to explore the most possible pathogenic trigger mechanism of vulnerable plaque rupture. Data sources Data used in this coronary artery spasm review were mainly from Medline and Pubmed in English. Study selection These reports from major review on coronary artery spasm .and these research included coronary artery conception, pathogenesis of spasm, mechanisms of plaque rupture, epidemiological evidence, clinical manifestation and the relationship between coronary artery spasm and vulnerable plaque rupture. Results Coronary artery spasm is somehow related to the presence of atherosclerotic intima disease in the coronary artery. However, chronic low-grade inflammation causes coronary vessel smooth muscle cell hypersensitivity, which can directely cause coronary artery spasm. Myocardial infarction and sudden cardiac death may be initiated by a sudden intense localized contraction of coronary artery smooth muscle. Conclusion Coronary artery spasm may be one trigger that can initiate and exacerbate vulnerable plaque rupture.
基金This study is supported by grants from the National Natural Science Foundation of China （No. 30972810 and No. 81101173）.
文摘Background Noninvasive detection of vulnerable plaque has a significant implication for prevention and treatment of atherosclerotic disea±ses. The aim of this study is to investigate the difference between vulnerable plaques and stable plaques in magnetic resonance （MR） images. Methods Atherosclerosis was induced in twenty male New Zealand white rabbits by high cholesterol diet and balloon injury of the abdominal aorta. After baseline （pre-triggering） MR imaging （MRI） scan, the rabbits underwent pharmaceutical triggering with Russell＇s viper venom and histamine to induce atherothrombosis, followed by another MRI scan 48 hours later （post-triggering）. Rabbits were euthanized to obtain pathological and histological data. The results of MRI were compared with those of pathology and histology. Results MRI showed that abdominal aorta of the rabbits had pathological change of atherosclerosis in different degrees. Seventy-five plaques were analysed, among which 14 had vulnerable thrombi and 61 stable. Thrombosis was identified in 7 of 11 rabbits by post-triggering MRI, the sensitivity and K value of MR in detection of vulnerable plaque was 71% and 0.803 （P 〈0.05）. MRI data significantly correlated with the histopathological data in fibrous cap thickness （t=0.749） plaque area （t=0.853）, lipid core area （r=0.900）. Compared with stable plaques, vulnerable plaques had a significantly thinner fibrous cap （（0.58±0.27） mm vs. （0.95±0.22） mm）, larger lipid core area （（7.56±2.78） mm2 vs. （3.29±1.75） mm2）, and a higher ratio of lipid core area/plaque area （（55±16）% vs. （27±17）%）, but plaque area was comparable in two groups on MRI. The ratio of lipid core area/plaque area was a strong predictor of vulnerable plaques. Conclusion MRI could distinguish vulnerable plaques from stable plaques in a rabbit model of atherothrombosis and may thus be useful as a noninvasive modality for detection of vulnerable plaques in humans.
文摘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.
文摘Objectives:To evaluate the efficacy of 18F-FDG-PET/CT in detection toward the vulnerabilities of carotid plaque and review systematically best evidence to prevent acute stroke from unstable carotid plaque.Methods:A search was conducted on Medline(PubMed),Web of science,Cochrane and WHIC using the search terms‘PET/CT’AND‘18F-FDG’AND‘fluorodeoxyglucose’AND‘carotid plaque’,from 2013/01/01 to now.Two authors will independently extract data following the study characteristics,eligibility criteria,interventions,outcome measurements,duration,adverse events,results and the type of needle used.All searched articles were inserted into in EndNote software that can automatically save,manage,and delete duplicate documents.Results:There were 3 articles included in the systematic review finally and form the study population analysis.The total 89 patients(64 males and 25 females)identified from the included studies.The mean 18F-FDG injected dose was 4.58 MBq/kg.The last three articles have demonstrated that 18F-FDG can accurately identify the stability of carotid plaques and can accurately locate and identify high-inflammation areas by histological analysis.Conclusions:18F-FDG-PET/CT is very efficient and practical for the identification of carotid vulnerable plaques.TBR(max and mean values)as a parameter for identifying inflammatory plaques is more reliable than SUV.
基金supported by the Natural Science Founda-tion of Zhejiang Province,China(No.LY13H180007)
文摘This study investigated the relationship between carotid plaque neovascularization and diabetes mellitus（DM） by using contrast-enhanced ultrasonography. Contrast-enhanced ultrasonography was performed in 104 patients with carotid plaque thicker than 2.0 mm. There were 36 patients with DM and 68 patients without DM. The enhanced intensity in the plaque and the ratio of enhanced intensity in the plaque to that in the lumen of the carotid artery in patients with DM were significantly greater than those in patients without DM. Our study demonstrated that the enhanced intensity in patients with DM is greater than that their counterparts without DM, suggesting that carotid plaque in DM patients may have more neovessels and may be more vulnerable.
文摘Objective：To evaluate the clinical value with positron emission tomography/computerized tomography（PET/CT） imaging for the detection of vulnerable plaque in atherosclerotic lesions. Methods：Sixty people with a age of over 60[mean age （69.2 ± 7.1）years] underwent three dimension（3D） whole-body fluorine-18-2-fluoro-2-deoxy-D-glucose（^18F-FDG） PET/CT imaging and were evaluated retrospectively, including 6 cases assessed as normal and 54 cases with active atherosclerotic plaque. Fifty-four cases with SUVs and CT values in the aortic wall of high-FDG-uptake were measured retrospectively. These high-FDG-uptake cases in the aortic wall were divided into three groups according their CT value. Cases in group 1 had high uptake in atherosclerotic lesions of the aortic wall with CT value of less than 60 Hu（soft plaque）. Cases in group 2 had high uptake with CT value between 60-100 Hu （intermediate plaque）, Cases in group 3 had high uptake with CT value more than 100 Hu（calcified plaque）, Group 4 was normal. Results： In group 1, there were 42 high-FDG-uptake sites （average SUV 1.553 ± 0.486）. In group 2, there were 30 high-FDG-uptake sites（average SUV 1.393 ± 0.296）. In group 3, there were 36 high-FDG-uptake sites（average SUV 1.354 ± 0.189）. In group 4, there were 33 normal-FDG-uptake sites （average SUV was 1.102 ± 0.141）, The SUVs showed significant difference among the four groups（F = 678.909, P = 0.000）. There were also significant difference found between the normal-FDG-uptake group and the high-FDG-uptake groups（P = 0.000, 0.000, 0.001, respectively）. Conclusion：Different degrees of ^18F-FDG uptake in active large atherosclerotic plaque were shown in different stages of atherosclerotic plaque formation. The soft plaque had the highest FDG uptake in this study. This suggested that ^18F- FDG PET/CT imaging may be of great potential value in early diagnosis and monitoring of vulnerable soft plaque in atherosclerotic lesions.
基金support from the National Natural Science Foundation of China(Grant Nos.81701650,81971608,and 82172092)the Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University(Grant No.2020-7)the Science&Technology Commission Foundation of Chongqing(Grant No.cstc2017jcyjAX0444).
文摘Due to the high risk of tearing and rupture,vulnerable atherosclerotic plaques would induce serious cardiovascular and cerebrovascular diseases.Despite the available clinical methods can evaluate the vulnerability of plaques and specifically treat vulnerable plaques before a cardiovascular event,but the efficiency is still low and undesirable.Herein,we rationally design and engineer the low-intensity focused ultrasound(LIFU)-responsive FPD@CD nanomedicine for the highly efficient treatment of vulnerable plaques by facilely loading phase transition agent perfluorohexane(PFH)into biocompatible PLGA-PEG-PLGA nanoparticles(PPP NPs)and then attaching dextran sulphate(DS)onto the surface of PPP NPs for targeting delivery.DS,as a typical macrophages-targeted molecule,can achieve the precise vaporization of NPs and subsequently controllable apoptosis of RAW 264.7 macrophages as induced by acoustic droplet vaporization(ADV)effect.In addition,the introduction of DiR and Fe3O4 endows nanomedicine with near-infrared fluorescence(NIRF)and magnetic resonance(MR)imaging capabilities.The engineered FPD@CD nanomedicine that uses macrophages as therapeutic targets achieve the conspicuous therapeutic effect of shrinking vulnerable plaques based on in vivo and in vitro evaluation outcomes.A reduction of 49.4%of vascular stenosis degree in gross pathology specimens were achieved throughout the treatment period.This specific,efficient and biosafe treatment modality potentiates the biomedical application in patients with cardiovascular and cerebrovascular diseases based on the relief of the plaque rupture concerns.
文摘Vulnerable atherosclerotic plaque rupture lead-ing to thrombosis is the major cause of acute coronary syndrome(ACS).Studies on the pathophysiologic mechanism of both ACS and plaque stabilizing treatment are driving the development of animal models of vulnerable plaque.In our laboratory,we established animal models of plaque rupture and thrombosis in rabbits and mice that are similar to human plaque rupture.Potential mechanisms involved in plaque vulnerability were studied from the inflammation-immunity,proliferation-apoptosis,oxidative stress and biomechanics aspects.Imaging markers and biomarkers were used to detect vulnerable plaques,including high frequency duplex ultrasound,intravascular ultrasound(IVUS),intravascular ultrasound elastography,magnetic resonance imaging(MRI)and inflammatory markers.Effective gene and drug strategies to treat vulnerable plaques were explored.
基金This work was supported by the National Nature Science Foundation of China(Nos.81820108019,91939303 and 31971302)the National Key Research and Development Program of China(2018YFC0116305)the Science Foundation of PLA General Hospital(2018XXFC-9,CX19028,China).
文摘Vulnerable atherosclerotic plaque(VASPs)is the major pathological cause of acute cardiovascular event.Early detection and precise intervention of VASP hold great clinical significance,yet remain a major challenge.Photodynamic therapy(PDT)realizes potent ablation efficacy under precise manipulation of laser irradiation.In this study,we constructed theranostic nanoprobes(NPs),which could precisely regress VASPs through a cascade of synergistic events triggered by local irradiation of lasers under the guidance of fluorescence/MR imaging.The NPs were formulated from human serum albumin(HSA)conjugated with a high affinity-peptide targeting osteopontin(OPN)and encapsulated with photosensitizer IR780 and hypoxia-activatable tirapazamine(TPZ).After intravenous injection into atherosclerotic mice,the OPN-targeted NPs demonstrated high specific accumulation in VASPs due to the overexpression of OPN in activated foamy macrophages in the carotid artery.Under the visible guidance of fluorescence and MR dual-model imaging,the precise near-infrared(NIR)laser irradiation generated massive reactive oxygen species(ROS),which resulted in efficient plaque ablation and amplified hypoxia within VASPs.In response to the elevated hypoxia,the initially inactive TPZ was successively boosted to present potent biological suppression of foamy macrophages.After therapeutic administration of the NPs for 2 weeks,the plaque area and the degree of carotid artery stenosis were markedly reduced.Furthermore,the formulated NPs displayed excellent biocompatibility.In conclusion,the developed HSA-based NPs demonstrated appreciable specific identification ability of VASPs and realized precise synergistic regression of atherosclerosis.
文摘Background Cathepsin S and its endogenous inhibitor cystatin C are implicated in the pathogenesis of atherosclerosis, especially in the plaque destabilization and rupture leading to acute coronary syndrome. However, whether circulating cathepsin S and cystatin C also change in association with coronary plaque morphology is unknown yet. Methods We recruited 98 patients with unstable angina （UA, n=56） or stable angina （SA, n=-42） who had a segmental stenosis resulting in 〉20% and 〈70% diameter reduction in one major coronary artery on coronary angiography. Thirty-one healthy subjects served as controls. Intravascular ultrasound （IVUS） was used to evaluate plaque morphology. Plasma cathepsin S and cystatin C were measured as well. Results At the culprit lesion site, plaque area （（7.85±2.83） mm^2 vs （6.53±2.92） mm^2, P=0.027）, plaque burden （（60.92±11.04）% vs （53.87±17.52）%, P=0.025）, remodeling index （0.93±0.16 vs 0.86±0.10, P=0.004） and eccentricity index （0.74±0.17 vs 0.66±0.21, P=0.038） were bigger in UA group than in SA group. Plasma cathepsin S and cystatin C were significantly higher in patients than in controls （P〈0.01）. Plasma cathepsin S was higher in UA group （（0.411±0.121） nmol/L） than in SA group （（0.355±0.099） nmol/L, P=0.007）, so did the plasma cystatin C （（0.95±0.23） mg/L in UA group, （0.84±0.22） mg/L in SA group; P=0.009）. Plasma cathepsin S positively correlated with remodeling index （r=0.402, P=0.002） and eccentricity index （r=0.441, P=0.001）, and plasma cystatin C positively correlated with plaque area （r=0.467, P 〈0.001） and plaque burden （r=0.395, P=0.003） in UA group but not in SA group. Conclusions Plasma cathepsin S and cystatin C increased significantly in UA patients. In angina patients, higher plasma cathepsin S may suggest the presence of vulnerable plaque, and higher plasma cystatin C may be a clue for larger atherosclerotic coronary plaque.
文摘Background Vasoactive factors have been reported to correlate with vulnerable plaque and acute coronary syndrome （ACS）. This study aimed to investigate the relationship between vasoactive factors and plaque morphology in patients suffering from non-ST-segment elevated ACS. Methods From April 2007 to April 2009, 124 consecutive patients suffering from non-ST-segment elevated ACS who had received coronary angiography （CAG） and intravascular ultrasound （IVUS） in the People＇s Liberation Army General Hospital and Beijing Anzhen Hospital were enrolled in this study. Three serum vasoactive factors, plasma soluble vascular endothelial growth factor receptor-1 （sFIt-1）, placental growth factor （PLGF） and interleukin-18 （IL-18）, were measured by enzyme-linked-immunosorbent serologic assay of the patients. The levels of vasoactive factors were compared between vulnerable plaque group and stable plaque group, and between unstable angina pectoris （UAP） group and non-ST-segment elevation acute myocardial infarction （NSTE-AMI） group. The relationship between the plaque morphology and levels of vasoactive factors was analyzed. Results The levels of vasoactive factors were similar between the UAP group （69 patients） and NSTE-AMI group （55 patients）. The levels of sFIt-1 and PLGF in the vulnerable plaque group were significantly higher than those in the stable plaque group. The level of IL-18 was correlated positively with plaque morphology. Multivariate Logistic regression analysis showed that the level of PLGF was an independent risk factor for vulnerable plaque （OR=2.115, 95%Cl 1.415-5.758, P=0.018）. Using the ROC curve, PLGF was a significant factor for the diagnosis of vulnerable plaque （the diagnostic point was 26.3 ng/L, the proportion of square area under the ROC curve was 0.799, 95%C/0.758-0.839, P 〈0.001 ; the sensitivity of PLGF under the ROC curve was 86%, and the specificity 63%）. Conclusion Both IL-18 and PLGF are biomarkers for vulnerable plaques and helpful to predict vulnerable plaque.
文摘Background Vulnerable plaques play an important role in the onset of sudden cardiac events and strokes. How to stabilize vulnerable plaques is still a challenge to medical science. Alprostadil is a biologically active substance with strong activity on vessel. Our study assessed the stabilizing effects of an alprostadil liposome microsphere preparation （ALMP） on vulnerable plaques in the brachiocephalic artery of apolipoprotein E （Apo E） knockout mice. Methods Seventy-two male Apo E-knockout mice were fed a high-fat diet beginning at eight weeks of age. At week 17, they were divided randomly into groups for treatment with a high dose （3.6 μg, kg-1. d-1） or low dose （1.8 μg. kg-1 . d-1） of an ALMP, or 0.2 ml/d normal saline （control group）, The drug was administered using a micro-capsule pump. Twenty weeks after drug administration, pathological changes in the vulnerable plaques within the brachiocephalic artery were assessed, and levels of anti-mouse monocyte/macrophage monoclonal antibody （MOMA-2） and superoxide anions in the plaques were detected using immunofluorescence. The soluble intercellular adhesion molecule-1 （ICAM-1） expression was measured by ELISA, and the expression of matrix metalloproteinase-9 （MMP-9） and CD40 mRNA was measured using RT-PCR. Thrombospindin-1 （TSP-1） expression was detected using Western blotting. Results Compared with the control group, ALMP treatment significantly reduced the plaque area in the brachiocephalic artery （P 〈0.01）, significantly lowered the contents of the lipid core （P 〈0.01 ）, significantly reduced the number of ruptured fibrous caps （P 〈0.05）, and increased the thickness of the fibrous cap and significantly reduced the incidence of intra-plaque hemorrhage （P 〈0.05）. ALMP treatment significantly reduced the expression of MOMA-2, superoxide anion, MMP-9, ICAM-1 and CD40 in the plaques （P 〈0.01）, decreased plasma ICAM-1 expression （P 〈0.01 ）, and increased the expression of TSP-1. Conclusions Treatment with ALMP can stabilize vulnerable plaques by inhibiting inflammation.
基金This study was supported by a grant from the National Natural Science Foundation of China （No. 30972810）.
文摘Abstract：Background Atherosclerotic plaque rupture is the primary mechanism of thrombosis which plays a key role in the onset of acute coronary syndromes. Detection of these plaques prone to rupture （vulnerable plaque） could be clinically significant for prevention of cardiac events. It has been shown that high metabolism cells have a high uptake of fluorine-18 fluorodeoxyglucose （18F-FDG）. The objective of this study was to investigate the correlation of FDG uptake and the immuno-histochemistry parameters of plaques, and the effect of atorvastatin on vulnerable atherosclerotic plaque in a rabbit model.Methods Ten male New Zealand White rabbits were divided into three groups as follows： （1） normal control group （n=2,C group）： the animals were fed a standard diet at 120 g/d and were given water ad labium; （2） atherosclerosis group （n=4,As group）： animals were fed with high fat diet for 5 months after aortic endothelia damage; （3） treatment group （atherosclerosis ＋ atorvastatin, n=4, Statin group）： animals were fed with high fat diet for 5 months and then changed into normal chow plus atorvastatin （2.5 mg·d-1·kg-1） treatment for another 4 months. Then these four rabbits were imaged with fluorine-18 fluorodexyglucose positron emission tomography/computed tomography （PET/CT） and sacrificed for pathohistologic studies. FDG uptake by the aorta was expressed as target-to-background ratio （TBR）. Maximal standardized uptake value （SUV） was measured over the thoracic and abdominal aortas. The aortic smooth muscle cell （SMC） number, CD-14 antibody positive cell （macrophage） number and the ratio of the thickness of fibrous cap to the thickness of lipid core （cap-to-core ratio） in atherosclerotic plaques were analyzed.Results As group showed significantly higher uptake of FDG than C group （SUVs： 0.746±0.172 vs. 0.286±0.073, P 〈0.001）. After 4 months of atorvastatin treatment and the modification of diet, SUVs decreased significantly （Statin group：0.550±0.134, compared to As group, P 〈0.001）. However, no marked difference was found in TBR, the number of macrophages, the number of SMC and the cap-to-core ratio in the aortic segments between Statin group and As group.The correlation of aortic FDG uptake with SMC assessed by histopathology was negatively significant （r=0.57, P〈0.001）. When aortic FDG uptake was expressed as TBR, it correlated significantly （r=0.69, P 〈0.001） with the macrophage number, and also correlated significantly （r=0.78, P 〈0.001） with the cap-to-core ratio.Conclusion 18F-FDG PET/CT might serve as a useful non-invasive imaging technique for detection of atherosclerotic plaque and potentially permit monitoring of relative changes in inflammation within the atherosclerotic lesion.
基金Supported by the Capital Medical Development Scientific Research Foundation (No. SF-2007-Ⅲ-41)
文摘Objective： To investigate the effect of Qingre Quyu Granule （清热祛瘀颗粒, QRQYG） on stabilizing vulnerable plaques in apolipoprotein E （ApoE） defficient mice. Methods： Seventy-two male ApoE defficient mice were given a high-fat diet from 6 weeks of age. At the 16th week, all the mice were randomized into 3 groups： the QRQYG group, the simvastatin group, and the control group. Sixteen weeks after administration of 0.9 g/kg QRQYG, 3 mg/kg simvastatin or 10 mg/kg sodium chloride per day to the respective groups, the animals were euthanized. The pathological morphologic changes in the vulnerable plaques were evaluated, the matrix metalloprotease-9 （MMP-9） expression was measured by immunohistofluorescence, the soluble intercellular adhesion molecule 1 （ICAM-1） was determined by ELISA, the nuclear factor kappaB （NF-κB） subunit p65 was measured by quantitative RT-PCR, and, finally, thrombospondin-1 （TSP-1） was determined by the immunohistochemical method. Results： The plaque cross-sectional area in the brachiocephalic artery （23.7%, P0.01）, the lipid core of the plaque （43.1%±3.1%）, and the number of buried ？brotic caps of the plaque were significantly decreased in the QRQYG group compared to the control group （both P0.01）; furthermore, the thickness of the ？brotic cap of the plaque increased and the intra-plaque hemorrhage of the plaque decreased. The serum soluble ICAM-1 （27.1±5.1 μg/mL）, the protein expression of MMP-9 and TSP-1 and the p65 mRNA expression increased in the QRQYG group in comparison with the control group （P0.05 or P0.01）. Conclusion： QRQYG could stabilize the vulnerable plaque through inhibition of the inflammatory response.
基金supported by Key Research Projectof Guang Dong Province(2007B031507004)by Science and Technology Planning Project of Guangdong Province(2006B36008007)
文摘To evaluate the effect of atrovastatin therapy on borderline vulnerable lesions in patients with acute coronary syndrome (ACS) .Methods Patients with ACS underwent coronary angiography (CAG) and intravascular ultrasound (IVUS) investigation.Patients with culprit vulnerable borderline lesions were enrolled.No coronary inter-vention was performed on these lesions.All the patients received atrovastatin therapy for 12 months and underwent clin-ical follow-up along with IVUS follow-up.Cross section area (CSA) of the targeted lesion,CSA of the reference arter-ies (extra elastic membrane) ,minimal lumen CSA,and plaque area were measured at baseline and follow-ups.Ad-verse events included recurrent angina,recurrent myocardial infarction,revascularization and death.Results No ad-verse events was reported during follow-up period.Compared with baseline data,the level of ApoB decreased signifi-cantly at the end of the study (0.589 ± 0.136 g /L vs 0.681 ± 0.132 g /L,P = 0.03) .Both the percent diameter steno-sis and the percent area stenosis detected by CAG displayed minimal change ((62.50 ± 10.21) % vs (54.79 ± 12.35) % ,P = 0.48 and (58.61 ± 8.36) % vs (48.18 + 10.56) % ,P = 0.78) .Detected by IVUS,the minimal lu-minal CSA of the targeted lesion increased significantly (6.32 ± 2.42 mm2 vs 5.63 ± 2.51 mm2,P < 0.01) ,the plaque area and CSA stenosis decreased (7.70 ± 2.19 mm2 vs 8.17 ± 2.55 mm2,P < 0.05 and 56.94 ± 8.47% vs 61.4 ± 110.34% ,P < 0.01) .A total of 25 soft plaques (50% ) transformed into fibrous plaque.Conclusions Atro-vastatin therapy stabilizes borderline vulnerable plaque and reverses atherosclerosis progression in patients with ACS.
基金Supported by the Capital Medical Development Scientific Research Foundation(No.SF-2007-Ⅲ-41)National Nature Science Foundation(No.81173420)
文摘Objective： To investigate the therapeutic effects of Qingre Quyu Granule （请热祛瘀颗粒, QQG） on the patients with severe carotid stenosis, and to explore the mechanism of it. Methods： Ninety-six patients with severe carotid stenosis were enrolled in the study and were classified into a QQG group （n=48） and a control group （n=48） randomly using consecutively numbered envelopes. The patients in the QQG group were given QQG and Western medicine, those in the control group were given Western medicine merely, the course of treatment was 16 weeks. All patients went through endarterectomy after treatment. Plaques were subjected to the analysis of CD3, CD68, soluble intercellular adhesion molecule 1 （ICAM-1）, matrix metalloprotease-9 （MMP-9）, CD40L, tenascin-C, and collagen content lipid content by immunohistochemistry or polarized light analysis. Results： By the end of experiment, the expressions of CD3, CD68, ICAM-1, MMP9, CD40L and tenascin-C on the plaques were statistically significant lower in the QQG group compared with the control group （P〈0.01）, The lipid content of the plaque was also significantly lower in the QQG group compared with the control group （P〈O.01）, The interstitial collagen in the tissue sections of the plaques was also significantly higher in the QQG group in comparison with the control group （P〈0.01）. Conclusion： QQG could stabilize carotid artery plaques through inhibiting pro-inflammation factors and restraining the tenascin-C and MMP9 pathway.
