Osteopontin targeted theranostic nanoprobes for laser-induced synergistic regression of vulnerable atherosclerotic plaques

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.

PATHOLOGICAL FEATURES OF CORONARY ATHEROSCLEROTIC PLAQUES IN NONAGENARIANS

The atherosclerotic lesions from 4 major epicardial coronary arteries (left main, left anterior descending, left circumflex and right coronary arteries) of 23 nonagenarians patients were compared with that from 23 patients aged 60?9. The arteries were cut into transversely 5 mm long segments and were examined by microscope. The inside circumferences of the lumen were measured by computerized morphometric analysis. The results showed that the numbers of atherosclerotic plaques, percentages of narrowing of the coronary arterial lumen and circumferences of the arterial lumen in both groups were similar. But there were much more fibrous and resting (silent) or regressive plaques in the group aged 90-99 years as well as less lipid and active or progressive plaques than those in the group of 60-69 years. The above morphological findings may be correlated with the fact that there was a similar incidence of coronary heart disease but a less risk of acute myocardial infarction in patients aged 90?9 years than those aged 60?9 years.

Atherosclerotic aortic plaques detected by transesophageal echocardiography

Objective To evaluate the predictive value of atherosclerotic aortic plaques in coronary artery disease (CAD). Methods In 50 patients with suspected coronary artery disease, transesophageal echocardiography was performed to examine their thoracic aortas 2 weeks before or after coronary angiography. In the cases of coronary angiography studied, stenosis of the coronary artery ≥50%was considered to be due to coronary artery disease, whereas the thickness of the intima ≥1.3 mm was taken to be the criteria for the presence of an atherosclerotic aortic plaque on the transesophageal echocardiographic test. Results Among the 50 patients, 37 cases were diagnosed as CAD and 13 cases were considered to be normal. The plaques of the thoracic aorta were observed in 34 cases in the CAD group and 3 cases in the normal group. The sensitivity and specificity of aortic plaques for CAD were 91.9%and 76.9%, respectively. The positive and negative predictive values of the aortic plaques for CAD were 91.9%and 76.9%, respectively. The accuracy was 88.0%. 80 percent of the patients with single-vessel disease had thoracic aortic plaques, 92 percent of the patients with two vessel disease and 100 percent of the patients with three vessel disease had thoracic aortic plaques. There was a significant difference in the thickness of aortic intimas between the normal group and the CAD group. Conclusions Detecting atherosclerotic plaques in the thoracic aorta with transesophageal echocardiography may be of great value in predicting the presence and extent of coronary artery disease.

Evaluation of Carotid Atherosclerotic Plaque Stability with Contrast-enhanced Ultrasonography

This study was aimed to evaluate the relationship between carotid atherosclerotic plaque stability and the clinical symptoms in patients with carotid atherosclerotic plaques by using contrast-enhanced ultrasonography. Fifty patients with carotid atherosclerotic plaques were enrolled and examined with contrast-enhanced ultrasonography. The correlation of contrast agent enhancement of the carotid atherosclerotic plaques and the clinical symptoms was analyzed. The results showed that among the 50 patients, plaques were enhanced in the 23 patients with obvious clinical symptoms. In 27 patients without apparent clinical symptoms, plaques were enhanced sparsely in 15 patients and not enhanced in 12 patients. It was suggested that contrast-enhanced ultrasonography could be used for the examination of the microcirculation in carotid atherosclerotic plaques on real-time basis and serve as a new noninvasive approach for the assessment of stability of carotid atherosclerotic plaques.

Study on the relationship between Lp-PLA2, D- dimer and Galectin-3 and atherosclerotic vulnerable plaque in patients with coronary heart disease

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.

Evaluation of ^(99m)Tc Labeled Diadenosine Tetraphosphate as an Atherosclerotic Plaque Imaging Agent in Experimental Models

The potential of ^99mTc labeled P^1, P^4-di （adenosine-5 ＇ ）-tetraphosphate （Ap4A） for imaging experimental atherosclerotic plaques was evaluated in New Zealand white （NZW） rabbits. To label the ^99mTc to Ap4A, stannous tartrate solution was used. ^99mTc-Ap4A was purified on a Sephadex G-25 column. The radiochemistry purities of ^99mTc-Ap4A were 85% to 91%. Biodistribution study revealed ^99mTc-Ap4A cleared from blood rapidly. Thirty min after ^99mTc-Ap4A administrated on NZW atherosclerotic rabbits, lesion to blood （target/blood, T/B） ratio was 3. 17 ±1.27, and lesions to normal （target/non-target, T/NT） ratio was 5.23 ±1.87. Shadows of atherosclerotic plaques were clearly visible on radioautographic film. Aortas with atherosclerotic plaques also could be seen on ex vivo gamma camera images. Atherosclerotic abdominal aortas were clearly visible on in vivo images 15 min to 3 h after ^99mTc-Ap4A administration. ^99mTc-labeled Ap4A can be used for rapid noninvasive detection of experimental atherosclerotic plaque.

Effects of different statins application methods on plaques in patients with coronary atherosclerosis

BACKGROUND Discontinued application of statins may be related to adverse cardiovascular events.However,it is unclear whether different statins administration methods have effects on coronary artery plaques.AIM To evaluate the effects of different statins application methods on plaques in patients with coronary atherosclerosis.METHODS A total of 100 patients diagnosed with atherosclerotic plaque by coronary artery computed tomography were continuously selected and divided into three groups according to different statins administration methods(discontinued application group,n=32;intermittent application group,n=39;sustained application group,n=29).The effects of the different statins application methods on coronary atherosclerotic plaque were assessed.RESULTS The volume change and rate of change of the most severe plaques were significantly reduced in the sustained application group(P≤0.001).The volume change of the most severe plaques correlated positively with low-density lipoprotein(LDL-C)levels only in the sustained application group(R=0.362,P=0.013).There were no changes in plaques or LDL-C levels in the intermittent and discontinued application groups.CONCLUSION Continuous application of statins is effective for controlling plaque progression,whereas discontinued or intermittent administration of statins is not conducive to controlling plaques.Only with continuous statins administration can a reduction in LDL-C levels result in plaque volume shrinkage.

Atherosclerotic plaque burdens in type 2 diabetes

In this issue of the Journal of Geriatric Cardiology,Huang et al. have reported the detection of coronary artery disease with electron-beam computed tomography (EBCT),utilizing non-contrast and contrast imaging techniques (EBCTA) in several subgroups including type 2 diabetes mellitus (DM), impaired glucose tolerance (IGT), coronary heart disease, and normal subjects. ……

Comparison of the Values of MRI in the Differential Diagnosis of Symptomatic Carotid Stenosis and Atherosclerotic Plaque

Objective:To evaluate the values of Carotid Magnetic Resonance Imaging(MRI)in the differential diagnosis of symptomatic carotid stenosis and atherosclerotic plaque.Methods:56 patients with ischemic cerebrovascular disease admitted in our hospital from October 2018 to October 2019 were selected and treated with Carotid MRI and digital subtraction angiography(DSA)examinations.According to the two examination results recorded and the“gold standard”of DSA examination,values of Carotid MRI in the differential diagnosis of symptomatic carotid stenosis were evaluated.Results:According to the“gold standard”of DSA examination,the sensitivity and specificity of MRI examination for carotid stenosis were:Mild:92.54%and 97.78%;Moderate:85.71%and 88.78%;Severe:100.00%and 97.8%;and complete occlusion:100.00%and 100.00%;The proportions of intraplaque haemorrhage and ruptured fibrous cap in different degrees of carotid artery stenosis were:Mild:30.16%and 22.22%;Moderate:43.48%and 39.13%;And severe:57.89%and 52.63%.Conclusion:MRI examination can evaluate the degree of symptomatic carotid artery stenosis,and show the characteristics of atherosclerotic plaque at the same time to provide a reference for early clinical differential diagnosis and treatment.

Is angiography still the best method to stratify stroke risk in symptomatic atherosclerotic carotid plaque?

The degree of vessel lumen narrowing is an independent predictor of ischemic stroke. New developments in carotid plaque morphology imaging (MR, CT), may bring new insights to the relationship between carotid atherosclerotic disease and stroke risk. Our aim is to review the stroke risk in a symptomatic patient with moderate carotid stenosis by CT imaging and histopathology. A 72-year-old patient with low ABCD2 scores TIA and moderate left internal carotid stenosis (50% by carotid ultrasound), was discharged with an optimized medical therapy. Four months later, he presented an ischemic stroke in the left frontal area. Carotid angiography showed a 60% stenosis in the left-internal carotid artery with a regular surface. CT plaque imaging detected a thin fibrous cap with calcification and an intraplaque hemorrhage (high-risk plaque). These findings were confirmed in the histolopathological study of the atherosclerotic plaque performed after the endarterectomy. After 1 year of follow-up, the patient returned independently to his daily activities. We propose, in this study, the inclusion of noninvasive plaque imaging in the evaluation of acute TIA with moderate carotid stenosis to better select patients with higher risk of stroke recurrence.

Role of glycolysis in diabetic atherosclerosis

Diabetes mellitus is a kind of typical metabolic disorder characterized by elevated blood sugar levels.Atherosclerosis(AS)is one of the most common complications of diabetes.Modern lifestyles and trends that promote overconsumption and unhealthy practices have contributed to an increase in the annual incidence of diabetic AS worldwide,which has created a heavy burden on society.Several studies have shown the significant effects of glycolysis-related changes on the occurrence and development of diabetic AS,which may serve as novel therapeutic targets for diabetic AS in the future.Glycolysis is an important metabolic pathway that generates energy in various cells of the blood vessel wall.In particular,it plays a vital role in the physiological and pathological activities of the three important cells,Endothelial cells,macrophages and vascular smooth muscle cells.There are lots of similar mechanisms underlying diabetic and common AS,the former is more complex.In this article,we describe the role and mechanism underlying glycolysis in diabetic AS,as well as the therapeutic targets,such as trained immunity,microRNAs,gut microbiota,and associated drugs,with the aim to provide some new perspectives and potentially feasible programs for the treatment of diabetic AS in the foreseeable future.

Role of activin receptor-like kinase 1 in vascular development and cerebrovascular diseases

Activin receptor-like kinase 1(ALK1)is a transmembrane serine/threonine receptor kinase of the transforming growth factor beta(TGFβ)receptor superfamily.ALK1 is specifically expressed in vascular endothelial cells,and its dynamic changes are closely related to the proliferation of endothelial cells,the recruitment of pericytes to blood vessels,and functional differentiation during embryonic vascular development.The pathophysiology of many cerebrovascular diseases is today understood as a disorder of endothelial cell function and an imbalance in the proportion of vascular cells.Indeed,mutations in ALK1 and its co-receptor endoglin are major genetic risk factors for vascular arteriovenous malformation.Many studies have shown that ALK1 is closely related to the development of cerebral aneurysms,arteriovenous malformations,and cerebral atherosclerosis.In this review,we describe the various roles of ALK1 in the regulation of angiogenesis and in the maintenance of cerebral vascular homeostasis,and we discuss its relationship to functional dysregulation in cerebrovascular diseases.This review should provide new perspectives for basic research on cerebrovascular diseases and offer more effective targets and strategies for clinical diagnosis,treatment,and prevention.

Relationship between platelet-lymphocyte ratio and carotid atherosclerosis in middle-aged and elderly patients with type 2 diabetes mellitus

Objective:To investigate the relationship between platelet-lymphocyte ratio(PLR)and carotid atherosclerosis(CAS)in middle-aged and elderly patients with T2DM.Methods:A total of 420 middle-aged and elderly patients with T2DM who were hospitalized in the Endocrinology Department of our hospital from September 2018 to September 2020 and were examined by ultrasound were selected as the subjects.The carotid artery intima-media thickness(CIMT)was examined by color Doppler ultrasonography,including normal CIMT group(n=111),CIMT thickening group(n=103)and CAS plaque group(n=206).The differences of serum PLR levels among the three groups were compared.Multivariate Logistic regression was used to analyze the relationship between PLR and CAS plaque formation.The receiver operating curve(ROC)was used to evaluate the value of multivariate Logistic regression model(Logit P)in the diagnosis of CAS lesions.Results:The mean value of PLR in CAS plaque group(127.86±48.54)was significantly higher than that in CIMT normal group(109.15±48.35).Multivariate Logistic regression analysis showed that after adjusting for other confounding factors,the increase of PLR was an independent risk factor for the occurrence of CAS plaque.ROC showed that the efficacy of multivariate Logit P model in the diagnosis of CAS plaque was(AUC=0.807,95%CI=0.759-0.858).Conclusions:PLR is one of the important risk factors for the occurrence of CAS lesions.At the same time,the multivariate Logistic regression model established in this study has clinical reference value in predicting CAS lesions in middle-aged and elderly patients with T2DM.

The“two-pronged”nanosystem to precisely improve lipid metabolism and inflammatory microenvironment for atherosclerotic plaque stabilization

The rupture of atherosclerosis(AS)vulnerable plaque is the major cause of fatal arterial thrombosis related diseases.The lipid dysbolism and pro-inflammatory microenvironment are considered two main driving factors for plaque rupture.Herein,a“two-pronged”nanosystem LCS-Se/Res was designed to efficiently stabilize AS plaques,by precisely regulating lipid metabolism and inflammatory microenvironment.LCS-Se/Res was constructed with the core of resveratrol(Res)loaded selenium(Se)nanoparticles(NPs),and the shell(LCS)of targeting peptide(LSIPPKA)modified chitosan(CS).This system was stable in blood circulation.When it arrived at the plaque site,LCS-Se/Res could actively recognize the highly expressed lectin-like oxidized low-density lipoprotein receptor 1(LOX-1)receptor and accumulate there.Thereafter,Res was released from LCS-Se nanocarriers in situ by responding to acidic plaque microenvironment.On the one hand,Res increased autophagy flux in damaged endothelial cells by activating cAMP-PKA-AMPK-SIRT1 signaling pathway to promote lipid degradation.Interestingly,LCS-Se also promoted cholesterol efflux to improve lipid metabolism.On the other hand,fixed-point separated Res and LCS-Se synergistically improved plaque inflammatory microenvironment by reversing macrophage phenotype(M1 to M2)and alleviating plaque oxidative stress.Pharmacodynamics result proved that the plaque vulnerability index(VI)decreased from 1.39±0.282 to 0.108±0.02 after LCS-Se/Res treatment.In short,this study provided a new therapeutic strategy for the atherosclerosis through the two-pronged approach.

Machine learning for diagnosis of coronary artery disease in computed tomography angiography:A survey

Coronary artery disease(CAD)has become a major illness endangering human health.It mainly manifests as atherosclerotic plaques,especially vulnerable plaques without obvious symptoms in the early stage.Once a rupture occurs,it will lead to severe coronary stenosis,which in turn may trigger a major adverse cardiovascular event.Computed tomography angiography(CTA)has become a standard diagnostic tool for early screening of coronary plaque and stenosis due to its advantages in high resolution,noninvasiveness,and three-dimensional imaging.However,manual examination of CTA images by radiologists has been proven to be tedious and time-consuming,which might also lead to intra-and interobserver errors.Nowadays,many machine learning algorithms have enabled the(semi-)automatic diagnosis of CAD by extracting quantitative features from CTA images.This paper provides a survey of these machine learning algorithms for the diagnosis of CAD in CTA images,including coronary artery extraction,coronary plaque detection,vulnerable plaque identification,and coronary stenosis assessment.Most included articles were published within this decade and are found in the Web of Science.We wish to give readers a glimpse of the current status,challenges,and perspectives of these machine learning-based analysis methods for automatic CAD diagnosis.

Research Progress of Angiogenesis in Atherosclerotic Plaque in Chinese Medicine and Western Medicine

Angiogenesis in atherosclemtic plaque plays a critical role in the mechanism of atherosclerotic physiopathology. Present consensus shows that angiogenesis in atherosclerotic plaque is mainly resulted in hypoxia, inflammation and some pro-angiogenic factors. The homeostasis in plaque, which is hypoxic and infiltrated by inflammatory cells, may lead to angiogenesis, increase the plaque instability and the incidence rate of vascular events. This article reviews the progression of pathogenetic mechanism, physiopathological significance, relevant detecting technique and corresponding therapeutic methods of Chinese and Western medicine of angiogenesis in atherosclerotic plaque, so as to provide more theoretical basis for atherosclerotic clinical treatment.

Clinical Study on Effect of Garlicin in Stabilizing the Carotid Artery Atherosclerotic Plaque in Patients with Primary Hypertension and Coronary Artery Disease

Objective： To investigate the effect of garlicin in treating carotid artery atherosclerotic plaque （OAAP） in patients with primary hypertension and coronary heart disease （PHT-OHD）. Methods： Seventynine patients with PHT-OHD were randomly divided into the treated group （39 patients） treated with garlicin and fosinopril and the control group （40 patients） treated with fosinopril alone. The change of OAAP was evaluated by high frequency ultrasonic examination every six months, and the changes of intercellular adhesion molecule-1 （IOAM-1） and high sensitive O-reactive protein （hs-ORP） were measured by ELISA, with the observation proceeding for 52 weeks totally. Results： By the end of the experiment, the number of complex plaques, Orouse integrals, intima-media thickness, serum IOAM-1 and hs-ORP were significantly lower in the treated group than those in the control group with significant difference （P〈0.05）. Conclusion： Garlicin could stabilize CAAP to a certain extent and shows a definite vascular protective effect in patients with PHT-CHD.

The expression of matrix metalloproteinases-9, transforming growth factor-β1 and transforming growth factor-β receptorⅠ in human atherosclerotic plaque and their relationship with plaque stability

Background Transforming growth factor beta (TGF β) and matrix metalloproteinases 9 (MMP 9) have been implicated in the pathogenesis of human atherosclerosis but their relationship during lesion progression are poorly understood The objective of this study was to investigate the expression of MMP 9, TGF β1 and TGF β receptor Ⅰ (TβR Ⅰ) in human atherosclerotic plaque and their relationship and plaque stability Methods Specimens of human coronary artery atherosclerotic plaques were obtained from 41 patients undergoing coronary endarterectomy, and were paraffin embedded, sectioned at 4 μm intervals then stained with haematoxylin and eosin They were divided into stable (with no or only little lipid core) and unstable plaque groups (with lipid core size>40%): the immunohistochemical staining were performed for MMP 9,TGF β1 and TβR Ⅰ Results The expression of MMP 9 in the unstable plaques was much higher than in the stable ones, but the expression of TGF β1 was higher in the stable plaques There was no similar significant difference for TβR Ⅰ Correlation analysis showed that there was a negative correlation between the expression of MMP 9 and TGF β1 ( r =-0 332, P =0 034 for average areal density; r =-0 373, P = 0 016 for average optical density) Conclusions There were close relationships between MMP 9, TGF β1 and plaque stability Enhanced production of MMP 9 may participate in the formation of unstable plaque, while TGF β1 maybe an important stabilizing factor in preventing transition into an unstable plaque phenotype

Qingre Quyu Granule(清热祛瘀颗粒)Stabilizes Plaques through Inhibiting the Expression of Tenascin-C in Patients with Severe Carotid Stenosis

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.

Effect of Removing Toxic Substances Combined with Activating Blood Circulation on Stabilizing the Atherosclerotic Plaque and Unstable Angina

The therapeutic effects of activating blood circulation to remove stasis of Chinese medicine （CM） in the prevention and treatment of atherosclerotic diseases such as coronary artery disease and angina are generally acknowledged. In recent years, to further improve the therapeutic effects of those Chinese herbs on such diseases, we have carried out a series of studies of CM medications with the function of clearing heat and removing toxic substances combined with activating blood circulation to remove stasis.