Overexpression of TGF-ß1 in Macrophages Reduces and Stabilizes Atherosclerotic Plaques in ApoE-Deficient Mice

PubMed Central

Orning, Carolin; Crain, Jeanine; Küpper, Ines; Wiese, Elena; Protschka, Martina; Blessing, Manfred; Lackner, Karl J.; Torzewski, Michael

2012-01-01

Although macrophages represent the hallmark of both human and murine atherosclerotic lesions and have been shown to express TGF-ß1 (transforming growth factor β1) and its receptors, it has so far not been experimentally addressed whether the pleiotropic cytokine TGF-ß1 may influence atherogenesis by a macrophage specific mechanism. We developed transgenic mice with macrophage specific TGF-ß1 overexpression, crossed the transgenics to the atherosclerotic ApoE (apolipoprotein E) knock-out strain and quantitatively analyzed both atherosclerotic lesion development and composition of the resulting double mutants. Compared with control ApoE−/− mice, animals with macrophage specific TGF-ß1 overexpression developed significantly less atherosclerosis after 24 weeks on the WTD (Western type diet) as indicated by aortic plaque area en face (p<0.05). Reduced atherosclerotic lesion development was associated with significantly less macrophages (p<0.05 after both 8 and 24 weeks on the WTD), significantly more smooth muscle cells (SMCs; p<0.01 after 24 weeks on the WTD), significantly more collagen (p<0.01 and p<0.05 after 16 and 24 weeks on the WTD, respectively) without significant differences of inner aortic arch intima thickness or the number of total macrophages in the mice pointing to a plaque stabilizing effect of macrophage-specific TGF-ß1 overexpression. Our data shows that macrophage specific TGF-ß1 overexpression reduces and stabilizes atherosclerotic plaques in ApoE-deficient mice. PMID:22829904

Linkages between oral commensal bacteria and atherosclerotic plaques in coronary artery disease patients.

PubMed

Chhibber-Goel, Jyoti; Singhal, Varsha; Bhowmik, Debaleena; Vivek, Rahul; Parakh, Neeraj; Bhargava, Balram; Sharma, Amit

2016-01-01

Coronary artery disease is an inflammatory disorder characterized by narrowing of coronary arteries due to atherosclerotic plaque formation. To date, the accumulated epidemiological evidence supports an association between oral bacterial diseases and coronary artery disease, but has failed to prove a causal link between the two. Due to the recent surge in microbial identification and analyses techniques, a number of bacteria have been independently found in atherosclerotic plaque samples from coronary artery disease patients. In this study, we present meta-analysis from published studies that have independently investigated the presence of bacteria within atherosclerotic plaque samples in coronary artery disease patients. Data were collated from 63 studies covering 1791 patients spread over a decade. Our analysis confirms the presence of 23 oral commensal bacteria, either individually or in co-existence, within atherosclerotic plaques in patients undergoing carotid endarterectomy, catheter-based atherectomy, or similar procedures. Of these 23 bacteria, 5 ( Campylobacter rectus , Porphyromonas gingivalis , Porphyromonas endodontalis , Prevotella intermedia , Prevotella nigrescens ) are unique to coronary plaques, while the other 18 are additionally present in non-cardiac organs, and associate with over 30 non-cardiac disorders. We have cataloged the wide spectrum of proteins secreted by above atherosclerotic plaque-associated bacteria, and discuss their possible roles during microbial migration via the bloodstream. We also highlight the prevalence of specific poly-microbial communities within atherosclerotic plaques. This work provides a resource whose immediate implication is the necessity to systematically catalog landscapes of atherosclerotic plaque-associated oral commensal bacteria in human patient populations.

In vivo magnetic resonance imaging of atherosclerotic lesions with a newly developed Evans blue-DTPA-gadolinium contrast medium in apolipoprotein-E-deficient mice.

PubMed

Yasuda, Satoshi; Ikuta, Kenjiro; Uwatoku, Toyokazu; Oi, Keiji; Abe, Kohtaro; Hyodo, Fuminori; Yoshimitsu, Kengo; Sugimura, Kohtaro; Utsumi, Hideo; Katayama, Yoshiki; Shimokawa, Hiroaki

2008-01-01

Magnetic resonance imaging (MRI) contrast agents that specifically detect atherosclerotic plaque may be useful for the noninvasive detection of the plaque. We have recently developed a new contrast agent, Evans blue-DTPA-gadolinium (EB-DTPA-Gd), which selectively accumulates vascular lesions with endothelial removal. In this study, we examined whether EB-DTPA-Gd is also useful for in vivo imaging of atherosclerotic plaques. We used male apolipoprotein-E-deficient (ApoE-/-) mice of different ages (3, 6 and 12 months old) and age-matched male wild-type mice. After a single intravenous administration of EB-DTPA-Gd (160 microM/kg body weight), MRI T(1) signal was obtained in vivo. Increased signal intensity in the aortic wall was noted within 10-20 min after intravenous injection of EB-DTPA-Gd and was maintained for 30 min. The MRI enhancement in the aorta of ApoE-/- mice was increased in accordance with age, whereas no such enhancement was noted in wild-type mice. Histological examination demonstrated that there was a topological correlation between the site of MRI enhancement and that of atherosclerotic plaque. These results indicate that EB-DTPA-Gd is a useful MRI contrast medium for the in vivo detection of atherosclerotic plaques. Copyright (c) 2007 S. Karger AG, Basel.

Matrix vesicles in the fibrous cap of atherosclerotic plaque: possible contribution to plaque rupture.

PubMed

Bobryshev, Y V; Killingsworth, M C; Lord, R S A; Grabs, A J

2008-10-01

Plaque rupture is the most common type of plaque complication and leads to acute ischaemic events such as myocardial infarction and stroke. Calcification has been suggested as a possible indicator of plaque instability. Although the role of matrix vesicles in the initial stages of arterial calcification has been recognized, no studies have yet been carried out to examine a possible role of matrix vesicles in plaque destabilization. Tissue specimens selected for the present study represented carotid specimens obtained from patients undergoing carotid endarterectomy. Serial frozen cross-sections of the tissue specimens were cut and mounted on glass slides. The thickness of the fibrous cap (FCT) in each advanced atherosclerotic lesion, containing a well developed lipid/necrotic core, was measured at its narrowest sites in sets of serial sections. According to established criteria, atherosclerotic plaque specimens were histologically subdivided into two groups: vulnerable plaques with thin fibrous caps (FCT <100 microm) and presumably stable plaques, in which fibrous caps were thicker than 100 microm. Twenty-four carotid plaques (12 vulnerable and 12 presumably stable plaques) were collected for the present analysis of matrix vesicles in fibrous caps. In order to provide a sufficient number of representative areas from each plaque, laser capture microdissection (LCM) was carried out. The quantification of matrix vesicles in ultrathin sections of vulnerable and stable plaques revealed that the numbers of matrix vesicles were significantly higher in fibrous caps of vulnerable plaques than those in stable plaques (8.908+0.544 versus 6.208+0.467 matrix vesicles per 1.92 microm2 standard area; P= 0.0002). Electron microscopy combined with X-ray elemental microanalysis showed that some matrix vesicles in atherosclerotic plaques were undergoing calcification and were characterized by a high content of calcium and phosphorus. The percentage of calcified matrix vesicles/microcalcifications was significantly higher in fibrous caps in vulnerable plaques compared with that in stable plaques (6.705+/-0.436 versus 5.322+/-0494; P= 0.0474). The findings reinforce a view that the texture of the extracellular matrix in the thinning fibrous cap of atherosclerotic plaque is altered and this might contribute to plaque destabilization.

Development of an aptamer-conjugated fluorescent nanoprobe for MMP2

NASA Astrophysics Data System (ADS)

Han, Myoung-Eun; Baek, Sungmin; Kim, Hyun-Jung; Lee, Jung Hwan; Ryu, Sung-Ho; Oh, Sae-Ock

2014-03-01

Matrix metalloproteinase 2 (MMP2) plays critical roles in various diseases, such as atherosclerosis and cancer, and has been suggested to contribute to the instability of atherosclerotic plaque. To visualize MMP2 in pathologic tissues, we developed an aptamer targeting MMP2 protein by performing eight rounds of modified DNA systematic evolution of ligands by exponential enrichment (SELEX). The aptamer showed high affinity for MMP2 ( K d = 5.59 nM), precipitated MMP2, and detected MMP2 protein in pathological tissues such as atherosclerotic plaque and gastric cancer tissues. Furthermore, a MMP2 aptamer-conjugated fluorescent nanoprobe successfully visualized atherosclerotic plaques in apolipoprotein E (ApoE) knockout mice. These results suggest that the devised MMP2 aptamer could be useful for the development of various diagnostic tools.

Emerging Technology Update Intravascular Photoacoustic Imaging of Vulnerable Atherosclerotic Plaque.

PubMed

Wu, Min; Fw van der Steen, Antonius; Regar, Evelyn; van Soest, Gijs

2016-10-01

The identification of vulnerable atherosclerotic plaques in the coronary arteries is emerging as an important tool for guiding atherosclerosis diagnosis and interventions. Assessment of plaque vulnerability requires knowledge of both the structure and composition of the plaque. Intravascular photoacoustic (IVPA) imaging is able to show the morphology and composition of atherosclerotic plaque. With imminent improvements in IVPA imaging, it is becoming possible to assess human coronary artery disease in vivo . Although some challenges remain, IVPA imaging is on its way to being a powerful tool for visualising coronary atherosclerotic features that have been specifically associated with plaque vulnerability and clinical syndromes, and thus such imaging might become valuable for clinical risk assessment in the catheterisation laboratory.

Diagnosis of vulnerable atherosclerotic plaques by time-resolved fluorescence spectroscopy and ultrasound imaging.

PubMed

Jo, J A; Fang, Q; Papaioannou, T; Qiao, J H; Fishbein, M C; Beseth, B; Dorafshar, A H; Reil, T; Baker, D; Freischlag, J; Shung, K K; Sun, L; Marcu, L

2006-01-01

In this study, time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) and ultrasonography were applied to detect vulnerable (high-risk) atherosclerotic plaque. A total of 813 TR-LIFS measurements were taken from carotid plaques of 65 patients, and subsequently analyzed using the Laguerre deconvolution technique. The investigated spots were classified by histopathology as thin, fibrotic, calcified, low-inflamed, inflamed and necrotic lesions. Spectral and time-resolved parameters (normalized intensity values and Laguerre expansion coefficients) were extracted from the TR-LIFS data. Feature selection for classification was performed by either analysis of variance (ANOVA) or principal component analysis (PCA). A stepwise linear discriminant analysis algorithm was developed for detecting inflamed and necrotic lesion, representing the most vulnerable plaques. These vulnerable plaques were detected with high sensitivity (>80%) and specificity (>90%). Ultrasound (US) imaging was obtained in 4 carotid plaques in addition to TR-LIFS examination. Preliminary results indicate that US provides important structural information of the plaques that could be combined with the compositional information obtained by TR-LIFS, to obtain a more accurate diagnosis of vulnerable atherosclerotic plaque.

Molecular magnetic resonance imaging of atherosclerotic vessel wall disease.

PubMed

Nörenberg, Dominik; Ebersberger, Hans U; Diederichs, Gerd; Hamm, Bernd; Botnar, René M; Makowski, Marcus R

2016-03-01

Molecular imaging aims to improve the identification and characterization of pathological processes in vivo by visualizing the underlying biological mechanisms. Molecular imaging techniques are increasingly used to assess vascular inflammation, remodeling, cell migration, angioneogenesis and apoptosis. In cardiovascular diseases, molecular magnetic resonance imaging (MRI) offers new insights into the in vivo biology of pathological vessel wall processes of the coronary and carotid arteries and the aorta. This includes detection of early vascular changes preceding plaque development, visualization of unstable plaques and assessment of response to therapy. The current review focuses on recent developments in the field of molecular MRI to characterise different stages of atherosclerotic vessel wall disease. A variety of molecular MR-probes have been developed to improve the non-invasive detection and characterization of atherosclerotic plaques. Specifically targeted molecular probes allow for the visualization of key biological steps in the cascade leading to the development of arterial vessel wall lesions. Early detection of processes which lead to the development of atherosclerosis and the identification of vulnerable atherosclerotic plaques may enable the early assessment of response to therapy, improve therapy planning, foster the prevention of cardiovascular events and may open the door for the development of patient-specific treatment strategies. Targeted MR-probes allow the characterization of atherosclerosis on a molecular level. Molecular MRI can identify in vivo markers for the differentiation of stable and unstable plaques. Visualization of early molecular changes has the potential to improve patient-individualized risk-assessment.

Numerical simulation of haemodynamics and low-density lipoprotein transport in the rabbit aorta and their correlation with atherosclerotic plaque thickness

PubMed Central

Liu, Xiao; Zhang, Peng; Feng, Chenglong; Sun, Anqiang; Kang, Hongyan; Deng, Xiaoyan; Fan, Yubo

2017-01-01

Two mechanisms of shear stress and mass transport have been recognized to play an important role in the development of localized atherosclerosis. However, their relationship and roles in atherogenesis are still obscure. It is necessary to investigate quantitatively the correlation among low-density lipoproteins (LDL) transport, haemodynamic parameters and plaque thickness. We simulated blood flow and LDL transport in rabbit aorta using computational fluid dynamics and evaluated plaque thickness in the aorta of a high-fat-diet rabbit. The numerical results show that regions with high luminal LDL concentration tend to have severely negative haemodynamic environments (HEs). However, for regions with moderately and slightly high luminal LDL concentration, the relationship between LDL concentration and the above haemodynamic indicators is not clear cut. Point-by-point correlation with experimental results indicates that severe atherosclerotic plaque corresponds to high LDL concentration and seriously negative HEs, less severe atherosclerotic plaque is related to either moderately high LDL concentration or moderately negative HEs, and there is almost no atherosclerotic plaque in regions with both low LDL concentration and positive HEs. In conclusion, LDL distribution is closely linked to blood flow transport, and the synergetic effects of luminal surface LDL concentration and wall shear stress-based haemodynamic indicators may determine plaque thickness. PMID:28424305

Early changes in vascular reactivity in response to 56Fe irradiation in ApoE-/- mice

NASA Astrophysics Data System (ADS)

White, C. Roger; Yu, Tao; Gupta, Kiran; Babitz, Stephen K.; Black, Leland L.; Kabarowski, Janusz H.; Kucik, Dennis F.

2015-03-01

Epidemiological studies have established that radiation from a number of terrestrial sources increases the risk of atherosclerosis. The accelerated heavy ions in the galacto-cosmic radiation (GCR) that astronauts will encounter on in space, however, interact very differently with tissues than most types of terrestrial radiation, so the health consequences of exposure on deep-space missions are not clear. We demonstrated earlier that 56Fe, an important component of cosmic radiation, accelerates atherosclerotic plaque development. In the present study, we examined an earlier, pro-atherogenic event that might be predictive of later atherosclerotic disease. Decreased endothelium-dependent vasodilation is a prominent manifestation of vascular dysfunction that is thought to predispose humans to the development of structural vascular changes that precede the development of atherosclerotic plaques. To test the effect of heavy-ion radiation on endothelium-dependent vasodilation, we used the same ApoE-/- mouse model in which we previously demonstrated the pro-atherogenic effect of 56Fe on plaque development. Ten week old male ApoE mice (an age at which there is little atherosclerotic plaque in the descending aorta) were exposed to 2.6 Gy 56Fe. The mice were then fed a normal diet and housed under standard conditions. At 4-5 weeks post-irradiation, aortic rings were isolated and endothelial-dependent relaxation was measured. Relaxation in response to acetylcholine was significantly impaired in irradiated mice compared to age-matched, un-irradiated mice. This decrease in vascular reactivity following 56Fe irradiation occurred eight weeks prior to the development of statistically significant exacerbation of aortic plaque formation and may contribute to the formation of later atherosclerotic lesions.

Mechanical properties of human atherosclerotic intima tissue.

PubMed

Akyildiz, Ali C; Speelman, Lambert; Gijsen, Frank J H

2014-03-03

Progression and rupture of atherosclerotic plaques in coronary and carotid arteries are the key processes underlying myocardial infarctions and strokes. Biomechanical stress analyses to compute mechanical stresses in a plaque can potentially be used to assess plaque vulnerability. The stress analyses strongly rely on accurate representation of the mechanical properties of the plaque components. In this review, the composition of intima tissue and how this changes during plaque development is discussed from a mechanical perspective. The plaque classification scheme of the American Heart Association is reviewed and plaques originating from different vascular territories are compared. Thereafter, an overview of the experimental studies on tensile and compressive plaque intima properties are presented and the results are linked to the pathology of atherosclerotic plaques. This overview revealed a considerable variation within studies, and an enormous dispersion between studies. Finally, the implications of the dispersion in experimental data on the clinical applications of biomechanical plaque modeling are presented. Suggestions are made on mechanical testing protocol for plaque tissue and on using a standardized plaque classification scheme. This review identifies the current status of knowledge on plaque mechanical properties and the future steps required for a better understanding of the plaque type specific material properties. With this understanding, biomechanical plaque modeling may eventually provide essential support for clinical plaque risk stratification. Copyright © 2014 Elsevier Ltd. All rights reserved.

Quantification In Situ of Crystalline Cholesterol and Calcium Phosphate Hydroxyapatite in Human Atherosclerotic Plaques by Solid-State Magic Angle Spinning NMR

PubMed Central

Guo, Wen; Morrisett, Joel D.; DeBakey, Michael E.; Lawrie, Gerald M.; Hamilton, James A.

2010-01-01

Because of renewed interest in the progression, stabilization, and regression of atherosclerotic plaques, it has become important to develop methods for characterizing structural features of plaques in situ and noninvasively. We present a nondestructive method for ex vivo quantification of 2 solid-phase components of plaques: crystalline cholesterol and calcium phosphate salts. Magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectra of human carotid endarterectomy plaques revealed 13C resonances of crystalline cholesterol monohydrate and a 31P resonance of calcium phosphate hydroxyapatite (CPH). The spectra were obtained under conditions in which there was little or no interference from other chemical components and were suitable for quantification in situ of the crystalline cholesterol and CPH. Carotid atherosclerotic plaques showed a wide variation in their crystalline cholesterol content. The calculated molar ratio of liquid-crystalline cholesterol to phospholipid ranged from 1.1 to 1.7, demonstrating different capabilities of the phospholipids to reduce crystallization of cholesterol. The spectral properties of the phosphate groups in CPH in carotid plaques were identical to those of CPH in bone. 31P MAS NMR is a simple, rapid method for quantification of calcium phosphate salts in tissue without extraction and time-consuming chemical analysis. Crystalline phases in intact atherosclerotic plaques (ex vivo) can be quantified accurately by solid-state 13C and 31PMAS NMR spectroscopy. PMID:10845882

The NF-κB pathway: regulation of the instability of atherosclerotic plaques activated by Fg, Fb, and FDPs.

PubMed

Cao, Yongjun; Zhou, Xiaomei; Liu, Huihui; Zhang, Yanlin; Yu, Xiaoyan; Liu, Chunfeng

2013-11-01

Recently, the molecular mechanism responsible for the instability of atherosclerotic plaques has gradually become a hot topic among researchers and clinicians. Matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) play an important role in the processes of formation and development of atherosclerosis. In this study, we established and employed the transwell co-culture system of rabbit aortic endothelial cells and smooth muscle cells to explore the relationship between fibrin (Fb), fibrinogen (Fg), and/or their degradation products (FDPs) in relation to the instability of atherosclerotic plaques; meanwhile, we observed the effects of Fg, Fb, and FDPs on the mRNA levels of MMPs and VEGF as well as on the activation of nuclear factor-kappa B (NF-κB). We concluded that Fb, Fg, and FDPs are involved in the progression of the instability of atherosclerotic plaques via increasing the expression of MMPs and VEGF. This effect might be mediated by the NF-кB pathway.

Complement factor C5a induces atherosclerotic plaque disruptions

PubMed Central

Wezel, Anouk; de Vries, Margreet R; Lagraauw, H Maxime; Foks, Amanda C; Kuiper, Johan; Quax, Paul HA; Bot, Ilze

2014-01-01

Complement factor C5a and its receptor C5aR are expressed in vulnerable atherosclerotic plaques; however, a causal relation between C5a and plaque rupture has not been established yet. Accelerated atherosclerosis was induced by placing vein grafts in male apoE−/− mice. After 24 days, when advanced plaques had developed, C5a or PBS was applied locally at the lesion site in a pluronic gel. Three days later mice were killed to examine the acute effect of C5a on late stage atherosclerosis. A significant increase in C5aR in the plaque was detectable in mice treated with C5a. Lesion size and plaque morphology did not differ between treatment groups, but interestingly, local treatment with C5a resulted in a striking increase in the amount of plaque disruptions with concomitant intraplaque haemorrhage. To identify the potential underlying mechanisms, smooth muscle cells and endothelial cells were treated in vitro with C5a. Both cell types revealed a marked increase in apoptosis after stimulation with C5a, which may contribute to lesion instability in vivo. Indeed, apoptosis within the plaque was seen to be significantly increased after C5a treatment. We here demonstrate a causal role for C5a in atherosclerotic plaque disruptions, probably by inducing apoptosis. Therefore, intervention in complement factor C5a signalling may be a promising target in the prevention of acute atherosclerotic complications. PMID:25124749

Matrix vesicles in the fibrous cap of atherosclerotic plaque: possible contribution to plaque rupture

PubMed Central

Bobryshev, Y V; Killingsworth, M C; Lord, R S A; Grabs, A J

2008-01-01

Plaque rupture is the most common type of plaque complication and leads to acute ischaemic events such as myocardial infarction and stroke. Calcification has been suggested as a possible indicator of plaque instability. Although the role of matrix vesicles in the initial stages of arterial calcification has been recognized, no studies have yet been carried out to examine a possible role of matrix vesicles in plaque destabilization. Tissue specimens selected for the present study represented carotid specimens obtained from patients undergoing carotid endarterectomy. Serial frozen cross-sections of the tissue specimens were cut and mounted on glass slides. The thickness of the fibrous cap (FCT) in each advanced atherosclerotic lesion, containing a well developed lipid/necrotic core, was measured at its narrowest sites in sets of serial sections. According to established criteria, atherosclerotic plaque specimens were histologically subdivided into two groups: vulnerable plaques with thin fibrous caps (FCT <100 μm) and presumably stable plaques, in which fibrous caps were thicker than 100 μm. Twenty-four carotid plaques (12 vulnerable and 12 presumably stable plaques) were collected for the present analysis of matrix vesicles in fibrous caps. In order to provide a sufficient number of representative areas from each plaque, laser capture microdissection (LCM) was carried out. The quantification of matrix vesicles in ultrathin sections of vulnerable and stable plaques revealed that the numbers of matrix vesicles were significantly higher in fibrous caps of vulnerable plaques than those in stable plaques (8.908±0.544 versus 6.208±0.467 matrix vesicles per 1.92 μm2 standard area; P= 0.0002). Electron microscopy combined with X-ray elemental microanalysis showed that some matrix vesicles in atherosclerotic plaques were undergoing calcification and were characterized by a high content of calcium and phosphorus. The percentage of calcified matrix vesicles/microcalcifications was significantly higher in fibrous caps in vulnerable plaques compared with that in stable plaques (6.705±0.436 versus 5.322±0A94; P= 0.0474). The findings reinforce a view that the texture of the extracellular matrix in the thinning fibrous cap of atherosclerotic plaque is altered and this might contribute to plaque destabilization. PMID:18194456

Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation[S

PubMed Central

Bot, Martine; de Jager, Saskia C. A.; MacAleese, Luke; Lagraauw, H. Maxime; van Berkel, Theo J. C.; Quax, Paul H. A.; Kuiper, Johan; Heeren, Ron M. A.; Biessen, Erik A. L.; Bot, Ilze

2013-01-01

Lysophosphatidic acid (LPA), a bioactive lysophospholipid, accumulates in the atherosclerotic plaque. It has the capacity to activate mast cells, which potentially exacerbates plaque progression. In this study, we thus aimed to investigate whether LPA contributes to plaque destabilization by modulating mast cell function. We here show by an imaging mass spectrometry approach that several LPA species are present in atherosclerotic plaques. Subsequently, we demonstrate that LPA is a potent mast cell activator which, unlike other triggers, favors release of tryptase. Local perivascular administration of LPA to an atherosclerotic carotid artery segment increases the activation status of perivascular mast cells and promotes intraplaque hemorrhage and macrophage recruitment without impacting plaque cell apoptosis. The mast cell stabilizer cromolyn could prevent intraplaque hemorrhage elicited by LPA-mediated mast cell activation. Finally, the involvement of mast cells in these events was further emphasized by the lack of effect of perivascular LPA administration in mast cell deficient animals. We demonstrate that increased accumulation of LPA in plaques induces perivascular mast cell activation and in this way contributes to plaque destabilization in vivo. This study points to local LPA availability as an important factor in atherosclerotic plaque stability. PMID:23396975

Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation.

PubMed

Bot, Martine; de Jager, Saskia C A; MacAleese, Luke; Lagraauw, H Maxime; van Berkel, Theo J C; Quax, Paul H A; Kuiper, Johan; Heeren, Ron M A; Biessen, Erik A L; Bot, Ilze

2013-05-01

Lysophosphatidic acid (LPA), a bioactive lysophospholipid, accumulates in the atherosclerotic plaque. It has the capacity to activate mast cells, which potentially exacerbates plaque progression. In this study, we thus aimed to investigate whether LPA contributes to plaque destabilization by modulating mast cell function. We here show by an imaging mass spectrometry approach that several LPA species are present in atherosclerotic plaques. Subsequently, we demonstrate that LPA is a potent mast cell activator which, unlike other triggers, favors release of tryptase. Local perivascular administration of LPA to an atherosclerotic carotid artery segment increases the activation status of perivascular mast cells and promotes intraplaque hemorrhage and macrophage recruitment without impacting plaque cell apoptosis. The mast cell stabilizer cromolyn could prevent intraplaque hemorrhage elicited by LPA-mediated mast cell activation. Finally, the involvement of mast cells in these events was further emphasized by the lack of effect of perivascular LPA administration in mast cell deficient animals. We demonstrate that increased accumulation of LPA in plaques induces perivascular mast cell activation and in this way contributes to plaque destabilization in vivo. This study points to local LPA availability as an important factor in atherosclerotic plaque stability.

Globular domain of adiponectin: promising target molecule for detection of atherosclerotic lesions

PubMed Central

Almer, Gunter; Saba-Lepek, Matthias; Haj-Yahya, Samih; Rohde, Eva; Strunk, Dirk; Fröhlich, Eleonore; Prassl, Ruth; Mangge, Harald

2011-01-01

Background: Adiponectin, an adipocyte-specific plasma protein, has been shown to accumulate in injured endothelial cells during development of atherosclerotic lesions. In this study, we investigated the potential of different adiponectin subfractions with special emphasis on globular adiponectin (gAd) to recognize and visualize atherosclerotic lesions. Methods: Recombinant mouse gAd and subfractions of full-length adiponectin (ie, trimeric, hexameric, and oligomeric forms) were fluorescence-labeled. Aortas of wild-type and apoprotein E-deficient mice fed a high cholesterol diet were dissected and incubated with the labeled biomarkers. Imaging was performed using confocal laser scanning microscopy. Results: Confocal laser scanning microscopic images showed that gAd binds more strongly to atherosclerotic plaques than full-length adiponectin subfractions. Further, we showed that gAd accumulates preferentially in endothelial cells and the fibrous cap area of plaques. Here we demonstrate for the first time that gAd recognizes atherosclerotic plaques on aortic sections of apoprotein E-deficient mice. Conclusion: These results suggest that gAd, in addition to its physiological properties, is also suitable as a target molecule for prospective diagnostic strategies in imaging atherosclerotic lesions. PMID:22022204

SRXRF Study of Chemical Elements Content in the Atherosclerotic Plaque of Heart Vessels

NASA Astrophysics Data System (ADS)

Zhuravskaya, E. Ya.; Savchenko, T. I.; Chankina, O. V.; Polonskaya, Ya. V.; Chernyavskii, A. M.; Ragino, Yu. I.; Shcherbakova, L. V.

The SRXRF method has made it possible, for the first time, to determine the multielement composition in the atherosclerotic substrates of heart vessels after surgical interventions. The main advantage of the method is the possibility to analyze small samples without their destruction. As the amount of material to test is insufficient, we have developed a special technique for sample preparation. The concentrations of K, Ca, Cr, Mn, Fe, Co, Ni, Cu, Zn, Br, Sr, Zr, and Pb were measured in stable and unstable plaques. In all the samples studied, Ca is dominating, particularly, in the unstable plaque. No reliable difference was established for other elements measured. A high degree of the association of Ca with Fe, Zn and Sr has been revealed in the atherosclerotic plaques. Measurements were performed using SR from the VEPP-3 storage ring.

High-Risk Carotid Plaques Identified by CT-Angiogram can Predict Acute Myocardial Infarction

PubMed Central

Mosleh, Wassim; Adib, Keenan; Natdanai, Punnanithinont; Carmona-Rubio, Andres; Karki, Roshan; Paily, Jacienta; Ahmed, Mohamed Abdel-Aal; Vakkalanka, Sujit; Madam, Narasa; Gudleski, Gregory D; Chung, Charles; Sharma, Umesh C

2016-01-01

Purpose Prior studies identified the incremental value of non-invasive imaging by CT-angiogram (CTA) to detect high-risk coronary atherosclerotic plaques. Due to their superficial locations, larger calibers and motion-free imaging, the carotid arteries provide the best anatomic access for the non-invasive characterization of atherosclerotic plaques. We aim to assess the ability of predicting obstructive coronary artery disease (CAD) or acute myocardial infarction (MI) based on high-risk carotid plaque features identified by CTA. Methods We retrospectively examined carotid CTAs of 492 patients that presented with acute stroke to characterize the atherosclerotic plaques of the carotid arteries and examined development of acute MI and obstructive CAD within 12-months. Carotid lesions were defined in terms of calcifications (large or speckled), presence of low-attenuation plaques, positive remodeling, and presence of napkin ring sign (NRS). Adjusted relative risks were calculated for each plaque features. Results Patients with speckled (<3mm) calcifications and/or larger calcifications on CTA had a higher risk of developing an MI and/or obstructive CAD within one year compared to patients without [adjusted RR of 7.51, 95%CI 1.26 to 73.42, P= 0.001]. Patients with low-attenuation plaques on CTA had a higher risk of developing an MI and/or obstructive CAD within one year than patients without [adjusted RR of 2.73, 95%CI 1.19 to 8.50, P= 0.021]. Presence of carotid calcifications and low-attenuation plaques also portended higher sensitivity (100% and 79.17%, respectively) for the development of acute MI. Conclusions Presence of carotid calcifications and low-attenuation plaques can predict the risk of developing acute MI and/or obstructive CAD within 12-months. Given their high sensitivity, their absence can reliably exclude 12-month events. PMID:27866279

High-risk carotid plaques identified by CT-angiogram can predict acute myocardial infarction.

PubMed

Mosleh, Wassim; Adib, Keenan; Natdanai, Punnanithinont; Carmona-Rubio, Andres; Karki, Roshan; Paily, Jacienta; Ahmed, Mohamed Abdel-Aal; Vakkalanka, Sujit; Madam, Narasa; Gudleski, Gregory D; Chung, Charles; Sharma, Umesh C

2017-04-01

Prior studies identified the incremental value of non-invasive imaging by CT-angiogram (CTA) to detect high-risk coronary atherosclerotic plaques. Due to their superficial locations, larger calibers and motion-free imaging, the carotid arteries provide the best anatomic access for the non-invasive characterization of atherosclerotic plaques. We aim to assess the ability of predicting obstructive coronary artery disease (CAD) or acute myocardial infarction (MI) based on high-risk carotid plaque features identified by CTA. We retrospectively examined carotid CTAs of 492 patients that presented with acute stroke to characterize the atherosclerotic plaques of the carotid arteries and examined development of acute MI and obstructive CAD within 12-months. Carotid lesions were defined in terms of calcifications (large or speckled), presence of low-attenuation plaques, positive remodeling, and presence of napkin ring sign. Adjusted relative risks were calculated for each plaque features. Patients with speckled (<3 mm) calcifications and/or larger calcifications on CTA had a higher risk of developing an MI and/or obstructive CAD within 1 year compared to patients without (adjusted RR of 7.51, 95%CI 1.26-73.42, P = 0.001). Patients with low-attenuation plaques on CTA had a higher risk of developing an MI and/or obstructive CAD within 1 year than patients without (adjusted RR of 2.73, 95%CI 1.19-8.50, P = 0.021). Presence of carotid calcifications and low-attenuation plaques also portended higher sensitivity (100 and 79.17%, respectively) for the development of acute MI. Presence of carotid calcifications and low-attenuation plaques can predict the risk of developing acute MI and/or obstructive CAD within 12-months. Given their high sensitivity, their absence can reliably exclude 12-month events.

Particulate matter air pollution exposure promotes recruitment of monocytes into atherosclerotic plaques.

PubMed

Yatera, Kazuhiro; Hsieh, Joanne; Hogg, James C; Tranfield, Erin; Suzuki, Hisashi; Shih, Chih-Horng; Behzad, Ali R; Vincent, Renaud; van Eeden, Stephan F

2008-02-01

Epidemiologic studies have shown an association between exposure to ambient particulate air pollution <10 microm in diameter (PM(10)) and increased cardiovascular morbidity and mortality. We previously showed that PM(10) exposure causes progression of atherosclerosis in coronary arteries. We postulate that the recruitment of monocytes from the circulation into atherosclerotic lesions is a key step in this PM(10)-induced acceleration of atherosclerosis. The study objective was to quantify the recruitment of circulating monocytes into vessel walls and the progression of atherosclerotic plaques induced by exposure to PM(10). Female Watanabe heritable hyperlipidemic rabbits, which naturally develop systemic atherosclerosis, were exposed to PM(10) (EHC-93) or vehicle by intratracheal instillation twice a week for 4 wk. Monocytes, labeled with 5-bromo-2'-deoxyuridine (BrdU) in donors, were transfused to recipient rabbits as whole blood, and the recruitment of BrdU-labeled cells into vessel walls and plaques in recipients was measured by quantitative histological methodology. Exposure to PM(10) caused progression of atherosclerotic lesions in thoracic and abdominal aorta. It also decreased circulating monocyte counts, decreased circulating monocytes expressing high levels of CD31 (platelet endothelial cell adhesion molecule-1) and CD49d (very late antigen-4 alpha-chain), and increased expression of CD54 (ICAM-1) and CD106 (VCAM-1) in plaques. Exposure to PM(10) increased the number of BrdU-labeled monocytes adherent to endothelium over plaques and increased the migration of BrdU-labeled monocytes into plaques and smooth muscle underneath plaques. We conclude that exposure to ambient air pollution particles promotes the recruitment of circulating monocytes into atherosclerotic plaques and speculate that this is a critically important step in the PM(10)-induced progression of atherosclerosis.

Atherosclerotic plaque characterization by spatial and temporal speckle pattern analysis

NASA Astrophysics Data System (ADS)

Tearney, Guillermo J.; Bouma, Brett E.

2002-04-01

Improved methods are needed to identify the vulnerable coronary plaques responsible for acute myocardial infraction or sudden cardiac death. We describe a method for characterizing the structure and biomechanical properties of atherosclerotic plaques based on speckle pattern fluctuations. Near-field speckle images were acquired from five human aortic specimens ex vivo. The speckle decorrelation time constant varied significantly for vulnerable aortic plaques (τ = 40 ms) versus stable plaques (τ = 400 ms) and normal aorta (τ = 500 ms). These initial results indicate that different atherosclerotic plaque types may be distinguished by analysis of temporal and spatial speckle pattern fluctuations.

Ghrelin inhibits atherosclerotic plaque angiogenesis and promotes plaque stability in a rabbit atherosclerotic model.

PubMed

Wang, Li; Chen, Qingwei; Ke, Dazhi; Li, Guiqiong

2017-04-01

Intraplaque angiogenesis associates with the instability of atherosclerotic plaques. In the present study, we investigated the effects of ghrelin on intraplaque angiogenesis and plaque instability in a rabbit model of atherosclerosis. The rabbits were randomly divided into three groups, namely, the control group, atherosclerotic model group, and ghrelin-treated group, with treatments lasting for 4 weeks. We found that the thickness ratio of the intima to media in rabbits of the ghrelin-treated group was significantly lower than that in rabbits of the atherosclerotic model group. The number of neovessels and the levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) decreased dramatically in rabbits of the ghrelin-treated group compared to those of the atherosclerotic model group. Ghrelin significantly decreased the plaque content of macrophages, matrix metalloproteinase (MMP)-2, and MMP-9, in a rabbit model of atherosclerosis. In addition, the level of the pro-inflammatory factor monocyte chemoattractant protein (MCP)-1 was significantly lower in rabbits of the ghrelin-treated group than in rabbits of the atherosclerotic model group. In summary, ghrelin can inhibit intraplaque angiogenesis and promote plaque stability by down-regulating VEGF and VEGFR2 expression, inhibiting the plaque content of macrophages, and reducing MCP-1 expression at an advanced stage of atherosclerosis in rabbits. Copyright © 2017 Elsevier Inc. All rights reserved.

Modeling of Mechanical Stress Exerted by Cholesterol Crystallization on Atherosclerotic Plaques.

PubMed

Luo, Yuemei; Cui, Dongyao; Yu, Xiaojun; Chen, Si; Liu, Xinyu; Tang, Hongying; Wang, Xianghong; Liu, Linbo

2016-01-01

Plaque rupture is the critical cause of cardiovascular thrombosis, but the detailed mechanisms are not fully understood. Recent studies have found abundant cholesterol crystals in ruptured plaques, and it has been proposed that the rapid expansion of cholesterol crystals in a limited space during crystallization may contribute to plaque rupture. To evaluate the effect of cholesterol crystal growth on atherosclerotic plaques, we modeled the expansion of cholesterol crystals during the crystallization process in the necrotic core and estimated the stress on the thin cap with different arrangements of cholesterol crystals. We developed a two-dimensional finite element method model of atherosclerotic plaques containing expanding cholesterol crystals and investigated the effect of the magnitude and distribution of crystallization on the peak circumferential stress born by the cap. Using micro-optical coherence tomography (μOCT), we extracted the cross-sectional geometric information of cholesterol crystals in human atherosclerotic aorta tissue ex vivo and applied the information to the model. The results demonstrate that (1) the peak circumference stress is proportionally dependent on the cholesterol crystal growth; (2) cholesterol crystals at the cap shoulder impose the highest peak circumference stress; and (3) spatial distributions of cholesterol crystals have a significant impact on the peak circumference stress: evenly distributed cholesterol crystals exert less peak circumferential stress on the cap than concentrated crystals.

Haemodynamical stress in mouse aortic arch with atherosclerotic plaques: Preliminary study of plaque progression

PubMed Central

Assemat, P.; Siu, K.K.; Armitage, J.A.; Hokke, S.N.; Dart, A.; Chin-Dusting, J.; Hourigan, K.

2014-01-01

Atherosclerotic plaques develop at particular sites in the arterial tree, and this regional localisation depends largely on haemodynamic parameters (such as wall shear stress; WSS) as described in the literature. Plaque rupture can result in heart attack or stroke and hence understanding the development and vulnerability of atherosclerotic plaques is critically important. The purpose of this study is to characterise the haemodynamics of blood flow in the mouse aortic arch using numerical modelling. The geometries are digitalised from synchrotron imaging and realistic pulsatile blood flow is considered under rigid wall assumptions. Two cases are considered; arteries with and without plaque. Mice that are fed under fat diet present plaques in the aortic arch whose size is dependent on the number of weeks under the diet. The plaque distribution in the region is however relatively constant through the different samples. This result underlines the influence of the geometry and consequently of the wall shear stresses for plaque formation with plaques growing in region of relative low shear stresses. A discussion of the flow field in real geometry in the presence and absence of plaques is conducted. The presence of plaques was shown to alter the blood flow and hence WSS distribution, with regions of localised high WSS, mainly on the wall of the brachiocephalic artery where luminal narrowing is most pronounced. In addition, arch plaques are shown to induce recirculation in the blood flow, a phenomenon with potential influence on the progression of the plaques. The oscillatory shear index and the relative residence time have been calculated on the geometry with plaques to show the presence of this recirculation in the arch, an approach that may be useful for future studies on plaque progression. PMID:25349678

Ursodeoxycholic acid impairs atherogenesis and promotes plaque regression by cholesterol crystal dissolution in mice.

PubMed

Bode, Niklas; Grebe, Alena; Kerksiek, Anja; Lütjohann, Dieter; Werner, Nikos; Nickenig, Georg; Latz, Eicke; Zimmer, Sebastian

2016-09-09

Atherosclerosis is a chronic inflammatory disease driven primarily by a continuous retention of cholesterol within the subendothelial space where it precipitates to form cholesterol crystals (CC). These CC trigger a complex inflammatory response through activation of the NLRP3 inflammasome and promote lesion development. Here we examined whether increasing cholesterol solubility with ursodeoxycholic acid (UDCA) affects vascular CC formation and ultimately atherosclerotic lesion development. UDCA mediated intracellular CC dissolution in macrophages and reduced IL-1β production. In ApoE(-/-) mice, UDCA treatment not only impaired atherosclerotic plaque development but also mediated regression of established vascular lesions. Importantly, mice treated with UDCA had decreased CC-depositions in atherosclerotic plaques compared to controls. Together, our data demonstrate that UDCA impaired CC and NLRP3 dependent inflammation by increasing cholesterol solubility and diminished atherosclerosis in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Near-infrared hyperspectral imaging of atherosclerotic plaque in WHHLMI rabbit artery

NASA Astrophysics Data System (ADS)

Ishii, Katsunori; Kitayabu, Akiko; Omiya, Kota; Honda, Norihiro; Awazu, Kunio

2013-03-01

Hyperspectral imaging (HSI) of rabbit atherosclerotic plaque in near-infrared (NIR) range from 1150 to 2400 nm was demonstrated. A method to identify vulnerable plaques that are likely to cause acute coronary events has been required. The object of this study is identifying vulnerable plaques by NIR-HSI for an angioscopic application. In this study, we observed the hyperspectral images of the atherosclerotic plaque in WHHLMI rabbit (atherosclerotic rabbit) artery under simulated angioscopic conditions by NIR-HSI. NIR-HSI system was constructed by a NIR super continuum light and a mercury-cadmium-telluride camera. Spectral absorbance values (log (1/R) data) were obtained in the wavelength range from 1150 to 2400 nm at 10 nm intervals. The hyperspectral images were constructed with spectral angle mapper algorithm. As a result, the detections of atherosclerotic plaque under angioscopic observation conditions were achieved especially in the wavelength around 1200 nm, which corresponds to the second overtone of CH stretching vibration mode. The NIR-HSI was considered to serve as an angioscopic diagnosis technique to identify vulnerable plaques without clamping and saline injection.

Spatio-temporal texture (SpTeT) for distinguishing vulnerable from stable atherosclerotic plaque on dynamic contrast enhancement (DCE) MRI in a rabbit model

PubMed Central

Wan, Tao; Madabhushi, Anant; Phinikaridou, Alkystis; Hamilton, James A.; Hua, Ning; Pham, Tuan; Danagoulian, Jovanna; Kleiman, Ross; Buckler, Andrew J.

2014-01-01

Purpose: To develop a new spatio-temporal texture (SpTeT) based method for distinguishing vulnerable versus stable atherosclerotic plaques on DCE-MRI using a rabbit model of atherothrombosis. Methods: Aortic atherosclerosis was induced in 20 New Zealand White rabbits by cholesterol diet and endothelial denudation. MRI was performed before (pretrigger) and after (posttrigger) inducing plaque disruption with Russell's-viper-venom and histamine. Of the 30 vascular targets (segments) under histology analysis, 16 contained thrombus (vulnerable) and 14 did not (stable). A total of 352 voxel-wise computerized SpTeT features, including 192 Gabor, 36 Kirsch, 12 Sobel, 52 Haralick, and 60 first-order textural features, were extracted on DCE-MRI to capture subtle texture changes in the plaques over the course of contrast uptake. Different combinations of SpTeT feature sets, in which the features were ranked by a minimum-redundancy-maximum-relevance feature selection technique, were evaluated via a random forest classifier. A 500 iterative 2-fold cross validation was performed for discriminating the vulnerable atherosclerotic plaque and stable atherosclerotic plaque on per voxel basis. Four quantitative metrics were utilized to measure the classification results in separating between vulnerable and stable plaques. Results: The quantitative results show that the combination of five classes of SpTeT features can distinguish between vulnerable (disrupted plaques with an overlying thrombus) and stable plaques with the best AUC values of 0.9631 ± 0.0088, accuracy of 89.98% ± 0.57%, sensitivity of 83.71% ± 1.71%, and specificity of 94.55% ± 0.48%. Conclusions: Vulnerable and stable plaque can be distinguished by SpTeT based features. The SpTeT features, following validation on larger datasets, could be established as effective and reliable imaging biomarkers for noninvasively assessing atherosclerotic risk. PMID:24694153

Intra-plaque production of platelet-activating factor correlates with neoangiogenesis in human carotid atherosclerotic lesions.

PubMed

Lupia, Enrico; Pucci, Angela; Peasso, Paolo; Merlo, Maurizio; Baron, Paolo; Zanini, Cristina; Del Sorbo, Lorenzo; Rizea-Savu, Simona; Silvestro, Luigi; Forni, Marco; Emanuelli, Giorgio; Camussi, Giovanni; Montrucchio, Giuseppe

2003-09-01

Platelet-activating factor (PAF) is a phospholipid mediator synthesized by activated inflammatory and endothelial cells. Recently PAF has been shown to contribute to neoangiogenesis in several experimental models. Here we evaluated the presence of PAF and its potential role in neovascularization within human atherosclerotic plaques. The amount of PAF extracted from 18 carotid plaques (266.65+/-40.07 pg/100 mg dry tissue; mean +/- SE) was significantly higher than that extracted from 18 normal arterial specimens (6 from carotid artery and 12 from aorta) (4.72+/-2.31 pg/100 mg dry tissue; mean +/- SE). The levels of PAF significantly correlated with the infiltration of CD68-positive monocytes and the extent of neovascularization, detected as von Willebrand Factor-positive cells. The amount of PAF also correlated with the area occupied by TNF-alpha-expressing cells. The absence of enhanced level of PAF in the circulation of atherosclerotic patients suggests a local production of this mediator within the plaque. The lipid extracts of atherosclerotic plaques containing high levels of PAF-bioactivity, but not those of control arteries, were angiogenic in a murine Matrigel model. WEB 2170, a specific PAF receptor antagonist, significantly prevented angiogenesis induced by the lipid extracts of atherosclerotic plaques. Our results indicate a local production of PAF within the atherosclerotic plaques and suggest that it may contribute to intra-plaque neoangiogenesis.

Optimization of dual-wavelength intravascular photoacoustic imaging of atherosclerotic plaques using Monte Carlo optical modeling

NASA Astrophysics Data System (ADS)

Dana, Nicholas; Sowers, Timothy; Karpiouk, Andrei; Vanderlaan, Donald; Emelianov, Stanislav

2017-10-01

Coronary heart disease (the presence of coronary atherosclerotic plaques) is a significant health problem in the industrialized world. A clinical method to accurately visualize and characterize atherosclerotic plaques is needed. Intravascular photoacoustic (IVPA) imaging is being developed to fill this role, but questions remain regarding optimal imaging wavelengths. We utilized a Monte Carlo optical model to simulate IVPA excitation in coronary tissues, identifying optimal wavelengths for plaque characterization. Near-infrared wavelengths (≤1800 nm) were simulated, and single- and dual-wavelength data were analyzed for accuracy of plaque characterization. Results indicate light penetration is best in the range of 1050 to 1370 nm, where 5% residual fluence can be achieved at clinically relevant depths of ≥2 mm in arteries. Across the arterial wall, fluence may vary by over 10-fold, confounding plaque characterization. For single-wavelength results, plaque segmentation accuracy peaked at 1210 and 1720 nm, though correlation was poor (<0.13). Dual-wavelength analysis proved promising, with 1210 nm as the most successful primary wavelength (≈1.0). Results suggest that, without flushing the luminal blood, a primary and secondary wavelength near 1210 and 1350 nm, respectively, may offer the best implementation of dual-wavelength IVPA imaging. These findings could guide the development of a cost-effective clinical system by highlighting optimal wavelengths and improving plaque characterization.

Vulnerable atherosclerotic plaque detection by resonance Raman spectroscopy

NASA Astrophysics Data System (ADS)

Liu, Cheng-hui; Boydston-White, Susie; Weisberg, Arel; Wang, Wubao; Sordillo, Laura A.; Perotte, Adler; Tomaselli, Vincent P.; Sordillo, Peter P.; Pei, Zhe; Shi, Lingyan; Alfano, Robert R.

2016-12-01

A clear correlation has been observed between the resonance Raman (RR) spectra of plaques in the aortic tunica intimal wall of a human corpse and three states of plaque evolution: fibrolipid plaques, calcified and ossified plaques, and vulnerable atherosclerotic plaques (VPs). These three states of atherosclerotic plaque lesions demonstrated unique RR molecular fingerprints from key molecules, rendering their spectra unique with respect to one another. The vibrational modes of lipids, cholesterol, carotenoids, tryptophan and heme proteins, the amide I, II, III bands, and methyl/methylene groups from the intrinsic atherosclerotic VPs in tissues were studied. The salient outcome of the investigation was demonstrating the correlation between RR measurements of VPs and the thickness measurements of fibrous caps on VPs using standard histopathology methods, an important metric in evaluating the stability of a VP. The RR results show that VPs undergo a structural change when their caps thin to 66 μm, very close to the 65-μm empirical medical definition of a thin cap fibroatheroma plaque, the most unstable type of VP.

Near-infrared autofluorescence induced by intraplaque hemorrhage and heme degradation as marker for high-risk atherosclerotic plaques.

PubMed

Htun, Nay Min; Chen, Yung Chih; Lim, Bock; Schiller, Tara; Maghzal, Ghassan J; Huang, Alex L; Elgass, Kirstin D; Rivera, Jennifer; Schneider, Hans G; Wood, Bayden R; Stocker, Roland; Peter, Karlheinz

2017-07-13

Atherosclerosis is a major cause of mortality and morbidity, which is mainly driven by complications such as myocardial infarction and stroke. These complications are caused by thrombotic arterial occlusion localized at the site of high-risk atherosclerotic plaques, of which early detection and therapeutic stabilization are urgently needed. Here we show that near-infrared autofluorescence is associated with the presence of intraplaque hemorrhage and heme degradation products, particularly bilirubin by using our recently created mouse model, which uniquely reflects plaque instability as seen in humans, and human carotid endarterectomy samples. Fluorescence emission computed tomography detecting near-infrared autofluorescence allows in vivo monitoring of intraplaque hemorrhage, establishing a preclinical technology to assess and monitor plaque instability and thereby test potential plaque-stabilizing drugs. We suggest that near-infrared autofluorescence imaging is a novel technology that allows identification of atherosclerotic plaques with intraplaque hemorrhage and ultimately holds promise for detection of high-risk plaques in patients.Atherosclerosis diagnosis relies primarily on imaging and early detection of high-risk atherosclerotic plaques is important for risk stratification of patients and stabilization therapies. Here Htun et al. demonstrate that vulnerable atherosclerotic plaques generate near-infrared autofluorescence that can be detected via emission computed tomography.

Detection of High-Risk Atherosclerotic Plaque

PubMed Central

Fleg, Jerome L.; Stone, Gregg W.; Fayad, Zahi A.; Granada, Juan F.; Hatsukami, Thomas S.; Kolodgie, Frank D.; Ohayon, Jacques; Pettigrew, Roderic; Sabatine, Marc S.; Tearney, Guillermo; Waxman, Sergio; Domanski, Michael J.; Srinivas, Pothur R.; Narula, Jagat

2013-01-01

The leading cause of major morbidity and mortality in most countries around the world is atherosclerotic cardiovascular disease, most commonly caused by thrombotic occlusion of a high-risk coronary plaque resulting in myocardial infarction or cardiac death, or embolization from a high-risk carotid plaque resulting in stroke. The lesions prone to result in such clinical events are termed vulnerable or high-risk plaques, and their identification may lead to the development of pharmacological and mechanical intervention strategies to prevent such events. Autopsy studies from patients dying of acute myocardial infarction or sudden death have shown that such events typically arise from specific types of atherosclerotic plaques, most commonly the thin-cap fibroatheroma. However, the search in human beings for vulnerable plaques before their becoming symptomatic has been elusive. Recently, the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study demonstrated that coronary plaques that are likely to cause future cardiac events, regardless of angiographic severity, are characterized by large plaque burden and small lumen area and/or are thin-cap fibroatheromas verified by radiofrequency intravascular ultrasound imaging. This study opened the door to identifying additional invasive and noninvasive imaging modalities that may improve detection of high-risk atherosclerotic lesions and patients. Beyond classic risk factors, novel biomarkers and genetic profiling may identify those patients in whom noninvasive imaging for vulnerable plaque screening, followed by invasive imaging for risk confirmation is warranted, and in whom future pharmacological and/or device-based focal or regional therapies may be applied to improve long-term prognosis. PMID:22974808

Evaluation of 99mTc labeled diadenosine tetraphosphate as an atherosclerotic plaque imaging agent in experimental models.

PubMed

Cao, Wei; Zhang, Yongxue; An, Rui

2006-01-01

The potential of 99mTc labeled P1, P4-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.

EphA2 Expression Regulates Inflammation and Fibroproliferative Remodeling in Atherosclerosis.

PubMed

Finney, Alexandra C; Funk, Steven D; Green, Jonette M; Yurdagul, Arif; Rana, Mohammad Atif; Pistorius, Rebecca; Henry, Miriam; Yurochko, Andrew; Pattillo, Christopher B; Traylor, James G; Chen, Jin; Woolard, Matthew D; Kevil, Christopher G; Orr, A Wayne

2017-08-08

Atherosclerotic plaque formation results from chronic inflammation and fibroproliferative remodeling in the vascular wall. We previously demonstrated that both human and mouse atherosclerotic plaques show elevated expression of EphA2, a guidance molecule involved in cell-cell interactions and tumorigenesis. Here, we assessed the role of EphA2 in atherosclerosis by deleting EphA2 in a mouse model of atherosclerosis (Apoe - /- ) and by assessing EphA2 function in multiple vascular cell culture models. After 8 to 16 weeks on a Western diet, male and female mice were assessed for atherosclerotic burden in the large vessels, and plasma lipid levels were analyzed. Despite enhanced weight gain and plasma lipid levels compared with Apoe -/- controls, EphA2 -/- Apoe -/- knockout mice show diminished atherosclerotic plaque formation, characterized by reduced proinflammatory gene expression and plaque macrophage content. Although plaque macrophages express EphA2, EphA2 deletion does not affect macrophage phenotype, inflammatory responses, and lipid uptake, and bone marrow chimeras suggest that hematopoietic EphA2 deletion does not affect plaque formation. In contrast, endothelial EphA2 knockdown significantly reduces monocyte firm adhesion under flow. In addition, EphA2 -/- Apoe -/- mice show reduced progression to advanced atherosclerotic plaques with diminished smooth muscle and collagen content. Consistent with this phenotype, EphA2 shows enhanced expression after smooth muscle transition to a synthetic phenotype, and EphA2 depletion reduces smooth muscle proliferation, mitogenic signaling, and extracellular matrix deposition both in atherosclerotic plaques and in vascular smooth muscle cells in culture. Together, these data identify a novel role for EphA2 in atherosclerosis, regulating both plaque inflammation and progression to advanced atherosclerotic lesions. Cell culture studies suggest that endothelial EphA2 contributes to atherosclerotic inflammation by promoting monocyte firm adhesion, whereas smooth muscle EphA2 expression may regulate the progression to advanced atherosclerosis by regulating smooth muscle proliferation and extracellular matrix deposition. © 2017 American Heart Association, Inc.

Treatment with a GnRH receptor agonist, but not the GnRH receptor antagonist degarelix, induces atherosclerotic plaque instability in ApoE(-/-) mice.

PubMed

Knutsson, Anki; Hsiung, Sabrina; Celik, Selvi; Rattik, Sara; Mattisson, Ingrid Yao; Wigren, Maria; Scher, Howard I; Nilsson, Jan; Hultgårdh-Nilsson, Anna

2016-05-18

Androgen-deprivation therapy (ADT) for prostate cancer has been associated with increased risk for development of cardiovascular events and recent pooled analyses of randomized intervention trials suggest that this primarily is the case for patients with pre-existing cardiovascular disease treated with gonadotropin-releasing hormone receptor (GnRH-R) agonists. In the present study we investigated the effects of the GnRH-R agonist leuprolide and the GnRH-R antagonist degarelix on established atherosclerotic plaques in ApoE(-/-) mice. A shear stress modifier was used to produce both advanced and more stable plaques in the carotid artery. After 4 weeks of ADT, increased areas of necrosis was observed in stable plaques from leuprolide-treated mice (median and IQR plaque necrotic area in control, degarelix and leuprolide-treated mice were 0.6% (IQR 0-3.1), 0.2% (IQR 0-4.4) and 11.0% (IQR 1.0-19.8), respectively). There was also evidence of increased inflammation as assessed by macrophage immunohistochemistry in the plaques from leuprolide-treated mice, but we found no evidence of such changes in plaques from control mice or mice treated with degarelix. Necrosis destabilizes plaques and increases the risk for rupture and development of acute cardiovascular events. Destabilization of pre-existing atherosclerotic plaques could explain the increased cardiovascular risk in prostate cancer patients treated with GnRH-R agonists.

Chronic miR-29 antagonism promotes favorable plaque remodeling in atherosclerotic mice.

PubMed

Ulrich, Victoria; Rotllan, Noemi; Araldi, Elisa; Luciano, Amelia; Skroblin, Philipp; Abonnenc, Mélanie; Perrotta, Paola; Yin, Xiaoke; Bauer, Ashley; Leslie, Kristen L; Zhang, Pei; Aryal, Binod; Montgomery, Rusty L; Thum, Thomas; Martin, Kathleen; Suarez, Yajaira; Mayr, Manuel; Fernandez-Hernando, Carlos; Sessa, William C

2016-06-01

Abnormal remodeling of atherosclerotic plaques can lead to rupture, acute myocardial infarction, and death. Enhancement of plaque extracellular matrix (ECM) may improve plaque morphology and stabilize lesions. Here, we demonstrate that chronic administration of LNA-miR-29 into an atherosclerotic mouse model improves indices of plaque morphology. This occurs due to upregulation of miR-29 target genes of the ECM (col1A and col3A) resulting in reduced lesion size, enhanced fibrous cap thickness, and reduced necrotic zones. Sustained LNA-miR-29 treatment did not affect circulating lipids, blood chemistry, or ECM of solid organs including liver, lung, kidney, spleen, or heart. Collectively, these data support the idea that antagonizing miR-29 may promote beneficial plaque remodeling as an independent approach to stabilize vulnerable atherosclerotic lesions. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Spatial distribution of osteoblast-specific transcription factor Cbfa1 and bone formation in atherosclerotic arteries.

PubMed

Bobryshev, Yuri V; Killingsworth, Murray C; Lord, Reginald S A

2008-08-01

The mechanisms of ectopic bone formation in arteries are poorly understood. Osteoblasts might originate either from stem cells that penetrate atherosclerotic plaques from the blood stream or from pluripotent mesenchymal cells that have remained in the arterial wall from embryonic stages of the development. We have examined the frequency of the expression and spatial distribution of osteoblast-specific factor-2/core binding factor-1 (Osf2/Cbfa1) in carotid and coronary arteries. Cbfa1-expressing cells were rarely observed but were found in all tissue specimens in the deep portions of atherosclerotic plaques under the necrotic cores. The deep portions of atherosclerotic plaques under the necrotic cores were characterized by the lack of capillaries of neovascularization. In contrast, plaque shoulders, which were enriched by plexuses of neovascularization, lacked Cbfa1-expressing cells. No bone formation was found in any of the 21 carotid plaques examined and ectopic bone was observed in only two of 12 coronary plaques. We speculate that the sparse invasion of sprouts of neovascularization into areas underlying the necrotic cores, where Cbfa1-expressing cells reside, might explain the rarity of events of ectopic bone formation in the arterial wall. This study has also revealed that Cbfa1-expressing cells contain alpha-smooth muscle actin and myofilaments, indicating their relationship with arterial smooth muscle cells.

Usefulness of automatic measurement of contrast flow intensity: an innovative tool in contrast-enhanced ultrasound imaging of atherosclerotic carotid plaque neovascularization. A pilot study.

PubMed

Lisowska, A; Knapp, M; Tycinska, A; Sawicki, R; Kralisz, P; Lisowski, P; Sobkowicz, B; Musial, W I

2014-02-01

Contrast-enhanced ultrasound imaging of the carotid arteries (CECU) permits direct, real-time visualization of neovascularization in atherosclerotic plaques and is a confirmed predictor of unstable atheromatous lesions. The aim of the study was the assessment of a new, automatically measured index of intensity in quantitative estimation of the contrast flow through the carotid plaque (till now assessed only visually). Forty-four patients (mean age 70.4±11.4) with ultrasound diagnosed significant stenosis of internal carotid artery (ICA), after cerebrovascular or cardiovascular events, qualified for carotid artery stenting (CAS) were examined. The carotid ultrasound examinations with contrast agent Sonovue were performed. Visually in 22 patients (50%) contrast flow through the atherosclerotic plaques was found. In 17 patients (38.6%) massive, calcified atherosclerotic plaques were present. Patients with preserved contrast flow through the plaque more frequently had a history of cerebral stroke (P=0.04). Massive calcifications of atherosclerotic plaques correlated with a previous MI (P=0.03) and the degree of advancement of coronary artery disease (P=0.04), but not with a previous cerebral stroke. Contrast flow through the atherosclerotic plaque positively correlated with values of the index of intensity (r=0.69, P<0.00001). In patients with preserved contrast flow the mean value of the index of intensity was 22.24±3.55 dB as compared with 12.37±7.67 dB - a value present in patients without preserved contrast flow. No significant relation for the degree of calcifications and the value of the index of intensity was found. The assessment of the index of intensity is a novel, simple and automatic method to estimate the degree of contrast flow through the carotid plaque. The values of the index of intensity correlate with the contrast flow through the atherosclerotic plaque, but not with its calcification.

Developing a Reliable Mouse Model for Cancer Therapy-Induced Cardiovascular Toxicity in Cancer Patients and Survivors.

PubMed

Ko, Kyung Ae; Wang, Yin; Kotla, Sivareddy; Fujii, Yuka; Vu, Hang Thi; Venkatesulu, Bhanu P; Thomas, Tamlyn N; Medina, Jan L; Gi, Young Jin; Hada, Megumi; Grande-Allen, Jane; Patel, Zarana S; Milgrom, Sarah A; Krishnan, Sunil; Fujiwara, Keigi; Abe, Jun-Ichi

2018-01-01

The high incidence of cardiovascular events in cancer survivors has long been noted, but the mechanistic insights of cardiovascular toxicity of cancer treatments, especially for vessel diseases, remain unclear. It is well known that atherosclerotic plaque formation begins in the area exposed to disturbed blood flow, but the relationship between cancer therapy and disturbed flow in regulating plaque formation has not been well studied. Therefore, we had two goals for this study; (1) Generate an affordable, reliable, and reproducible mouse model to recapitulate the cancer therapy-induced cardiovascular events in cancer survivors, and (2) Establish a mouse model to investigate the interplay between disturbed flow and various cancer therapies in the process of atherosclerotic plaque formation. We examined the effects of two cancer drugs and ionizing radiation (IR) on disturbed blood flow-induced plaque formation using a mouse carotid artery partial ligation (PCL) model of atherosclerosis. We found that doxorubicin and cisplatin, which are commonly used anti-cancer drugs, had no effect on plaque formation in partially ligated carotid arteries. Similarly, PCL-induced plaque formation was not affected in mice that received IR (2 Gy) and PCL surgery performed one week later. In contrast, when PCL surgery was performed 26 days after IR treatment, not only the atherosclerotic plaque formation but also the necrotic core formation was significantly enhanced. Lastly, we found a significant increase in p90RSK phosphorylation in the plaques from the IR-treated group compared to those from the non-IR treated group. Our results demonstrate that IR not only increases atherosclerotic events but also vulnerable plaque formation. These increases were a somewhat delayed effect of IR as they were observed in mice with PCL surgery performed 26 days, but not 10 days, after IR exposure. A proper animal model must be developed to study how to minimize the cardiovascular toxicity due to cancer treatment.

Positron emission tomography of the vulnerable atherosclerotic plaque in man – a contemporary review

PubMed Central

Pedersen, Sune F; Hag, Anne Mette F; Klausen, Thomas L; Ripa, Rasmus S; Bodholdt, Rasmus P; Kjær, Andreas

2014-01-01

Atherosclerosis is the primary underlying cause of cardiovascular disease (CVD). It is the leading cause of morbidity and mortality in the Western world today and is set to become the prevailing disease and major cause of death worldwide by 2020. In the 1950s surgical intervention was introduced to treat symptomatic patients with high-grade carotid artery stenosis due to atherosclerosis – a procedure known as carotid endarterectomy (CEA). By removing the atherosclerotic plaque from the affected carotid artery of these patients, CEA is beneficial by preventing subsequent ipsilateral ischemic stroke. However, it is known that patients with low to intermediate artery stenosis may still experience ischemic events, leading clinicians to consider plaque composition as an important feature of atherosclerosis. Today molecular imaging can be used for characterization, visualization and quantification of cellular and subcellular physiological processes as they take place in vivo; using this technology we can obtain valuable information on atherosclerostic plaque composition. Applying molecular imaging clinically to atherosclerotic disease therefore has the potential to identify atherosclerotic plaques vulnerable to rupture. This could prove to be an important tool for the selection of patients for CEA surgery in a health system increasingly focused on individualized treatment. This review focuses on current advances and future developments of in vivo atherosclerosis PET imaging in man. PMID:24289282

Advances in the development of an imaging device for plaque measurement in the area of the carotid artery.

PubMed

Ličev, Lačezar; Krumnikl, Michal; Škuta, Jaromír; Babiuch, Marek; Farana, Radim

2014-03-04

This paper describes the advances in the development and subsequent testing of an imaging device for three-dimensional ultrasound measurement of atherosclerotic plaque in the carotid artery. The embolization from the atherosclerotic carotid plaque is one of the most common causes of ischemic stroke and, therefore, we consider the measurement of the plaque as extremely important. The paper describes the proposed hardware for enhancing the standard ultrasonic probe to provide a possibility of accurate probe positioning and synchronization with the cardiac activity, allowing the precise plaque measurements that were impossible with the standard equipment. The synchronization signal is derived from the output signal of the patient monitor (electrocardiogram (ECG)), processed by a microcontroller-based system, generating the control commands for the linear motion moving the probe. The controlling algorithm synchronizes the movement with the ECG waveform to obtain clear images not disturbed by the heart activity.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waksman, Ron; Pakala, Rajbabu; Burnett, Mary S.

Introduction: Inflammatory and immunological responses of vascular cells are known to play significant roles in atherosclerotic plaque development. Rapamycin with antiinflammatory, immunosuppressive and antiproliferative properties has been shown to reduce neointima formation when coated on stents. This study is designed to test the potential of oral rapamycin to inhibit atherosclerotic plaque development. Methods: Eight-week-old apoE knock-out mice were fed with 0.25% cholesterol supplemented diet (control diet), control diet containing 50 {mu}g/kg rapamycin (low-dose rapamycin) or 100 {mu}g/kg rapamycin (high-dose rapamycin) for 4 or 8 weeks. Subsets of mice from each group (n=10) were weighed and euthanized. Whole blood rapamycin levelsmore » were determined using HPLC-MS/MS, and histological analyses of atherosclerotic lesions in the aortic root were performed. Results: Mice fed with high-dose rapamycin did not gain weight (18.5{+-}1.5 vs. 20.6{+-}0.9 g, P=.01). Blood levels of rapamycin 117{+-}7 pg/ml were detected in the blood of mice fed with high-dose rapamycin for 8 weeks. The plaque area in mice fed with high dose oral rapamycin is significantly less as compared to control (0.168{+-}0.008 vs. 0.326{+-}0.013 mm{sup 2}, P=.001 at 4 weeks; 0.234{+-}0.013 vs. 0.447{+-}0.011 mm{sup 2}, P=.001 at 8 weeks). Lumen area was inversely proportional to the plaque area. Conclusions: The results indicate that oral rapamycin is effective in attenuating the progression of atherosclerotic plaque in the mice.« less

Application of the laguerre deconvolution method for time-resolved fluorescence spectroscopy to the characterization of atherosclerotic plaques.

PubMed

Jo, J A; Fang, Q; Papaioannou, T; Qiao, J H; Fishbein, M C; Beseth, B; Dorafshar, A H; Reil, T; Baker, D; Freischlag, J; Marcu, L

2005-01-01

This study investigates the ability of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) to detect inflammation in atherosclerotic lesion, a key feature of plaque vulnerability. A total of 348 TR-LIFS measurements were taken from carotid plaques of 30 patients, and subsequently analyzed using the Laguerre deconvolution technique. The investigated spots were classified as Early, Fibrotic/Calcified or Inflamed lesions. A stepwise linear discriminant analysis algorithm was developed using spectral and TR features (normalized intensity values and Laguerre expansion coefficients at discrete emission wavelengths, respectively). Features from only three emission wavelengths (390, 450 and 500 nm) were used in the classifier. The Inflamed lesions were discriminated with sensitivity > 80% and specificity > 90 %, when the Laguerre expansion coefficients were included in the feature space. These results indicate that TR-LIFS information derived from the Laguerre expansion coefficients at few selected emission wavelengths can discriminate inflammation in atherosclerotic plaques. We believe that TR-LIFS derived Laguerre expansion coefficients can provide a valuable additional dimension for the detection of vulnerable plaques.

Correlations between gene expression highlight a different activation of ACE/TLR4/PTGS2 signaling in symptomatic and asymptomatic plaques in atherosclerotic patients.

PubMed

Ferronato, Silvia; Scuro, Alberto; Gomez-Lira, Macarena; Mazzucco, Sara; Olivato, Silvia; Turco, Alberto; Elisa, Orlandi; Malerba, Giovanni; Romanelli, Maria Grazia

2018-06-19

Inflammation has a key role and translates the effects of many known risk factors for the disease in atherosclerotic vulnerable plaques. Aiming to look into the elements that induce the development of either a vulnerable or stable atherosclerotic plaque, and considering that inflammation has a central role in the progression of lesions, we analyzed the expression of genes involved in the ACE/TLR4/PTGS2 signaling in carotid plaques of symptomatic and asymptomatic patients. Patients with internal carotid artery stenosis undergoing carotid endarterectomy at Verona University Hospital were included in this study. A total of 71 patients was considered for gene expression analysis (29 atherothrombotic stroke patients and 42 asymptomatic patients). Total RNA was extracted from the excised plaques and expression of PTGS2, ACE, TLR4, PTGER4, PTGER3, EPRAP and ACSL4 genes was analyzed by real-time PCR. The correlation between the pair of genes was studied by Spearman coefficient. From the analyzed genes, we did not observe any individual difference in gene expression but the network of co-expressed genes suggests a different activation of pathways in the two groups of plaques.

TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE−/− mice

PubMed Central

Prasad, Sakamuri Siva Sankara Vara; Higashi, Yusuke; Sukhanov, Sergiy; Siddesha, Jalahalli M; Delafontaine, Patrice; Siebenlist, Ulrich; Chandrasekar, Bysani

2016-01-01

Background and aims Atherosclerosis is a major cause of heart attack and stroke. Inflammation plays a critical role in the development of atherosclerosis. Since the cytoplasmic adaptor molecule TRAF3IP2 (TRAF3-Interacting Protein 2) plays a causal role in various autoimmune and inflammatory diseases, we hypothesized that TRAF3IP2 mediates atherosclerotic plaque development. Methods TRAF3IP2/ApoE double knockout (DKO) mice were generated by crossing TRAF3IP2−/− and ApoE−/− mice. ApoE−/− mice served as controls. Both DKO and control mice were fed a high-fat diet for 12 weeks. Plasma lipids were measured by ELISA, atherosclerosis by en face analysis of aorta and plaque cross-section measurements at the aortic valve region, plaque necrotic core area, collagen and smooth muscle cell content by histomorphometry, and aortic gene expression by RT-qPCR. Results The plasma lipoprotein profile was not altered by TRAF3IP2 gene deletion in ApoE−/− mice. While total aortic plaque area was decreased in DKO female, but not male mice, the plaque necrotic area was significantly decreased in DKO mice of both genders. Plaque collagen and smooth muscle cell contents were increased significantly in both female and male DKO mice compared to respective controls. Aortic expression of proinflammatory cytokine (Tumor necrosis factor α, TNFα), chemokine (Chemokine (C-X-C motif) Ligand 1, CXCL1) and adhesion molecule (Vascular cell adhesion molecule 1, VCAM1; and Intercellular adhesion molecule 1, ICAM1) gene expression were decreased in both male and female DKO mice. In addition, the male DKO mice showed a markedly reduced expression of extracellular matrix (ECM)-related genes, including TIMP1 (Tissue inhibitor of metalloproteinase 1), RECK (Reversion-Inducing- Cysteine-Rich Protein with Kazal Motifs) and ADAM17 (A Disintegrin And Metalloproteinase 17). Conclusions TRAF3IP2 plays a causal role in atherosclerotic plaque development and vulnerability, possibly by inducing the expression of multiple proinflammatory mediators. TRAF3IP2 could be a potential therapeutic target in atherosclerotic vascular diseases. PMID:27237075

Ex vivo detection of macrophages in atherosclerotic plaques using intravascular ultrasonic-photoacoustic imaging

NASA Astrophysics Data System (ADS)

Quang Bui, Nhat; Hlaing, Kyu Kyu; Lee, Yong Wook; Kang, Hyun Wook; Oh, Junghwan

2017-01-01

Macrophages are excellent imaging targets for detecting atherosclerotic plaques as they are involved in all the developmental stages of atherosclerosis. However, no imaging technique is currently capable of visualizing macrophages inside blood vessel walls. The current study develops an intravascular ultrasonic-photoacoustic (IVUP) imaging system combined with indocyanine green (ICG) as a contrast agent to provide morphological and compositional information about the targeted samples. Both tissue-mimicking vessel phantoms and atherosclerotic plaque-mimicking porcine arterial tissues are used to demonstrate the feasibility of mapping macrophages labeled with ICG by endoscopically applying the proposed hybrid technique. A delay pulse triggering technique is able to sequentially acquire photoacoustic (PA) and ultrasound (US) signals from a single scan without using any external devices. The acquired PA and US signals are used to reconstruct 2D cross-sectional and 3D volumetric images of the entire tissue with the ICG-loaded macrophages injected. Due to high imaging contrast and sensitivity, the IVUP imaging vividly reveals structural information and detects the spatial distribution of the ICG-labeled macrophages inside the samples. ICG-assisted IVUP imaging can be a feasible imaging modality for the endoscopic detection of atherosclerotic plaques.

What We Have Learned from the Recent Meta-analyses on Diagnostic Methods for Atherosclerotic Plaque Regression.

PubMed

Biondi-Zoccai, Giuseppe; Mastrangeli, Simona; Romagnoli, Enrico; Peruzzi, Mariangela; Frati, Giacomo; Roever, Leonardo; Giordano, Arturo

2018-01-17

Atherosclerosis has major morbidity and mortality implications globally. While it has often been considered an irreversible degenerative process, recent evidence provides compelling proof that atherosclerosis can be reversed. Plaque regression is however difficult to appraise and quantify, with competing diagnostic methods available. Given the potential of evidence synthesis to provide clinical guidance, we aimed to review recent meta-analyses on diagnostic methods for atherosclerotic plaque regression. We identified 8 meta-analyses published between 2015 and 2017, including 79 studies and 14,442 patients, followed for a median of 12 months. They reported on atherosclerotic plaque regression appraised with carotid duplex ultrasound, coronary computed tomography, carotid magnetic resonance, coronary intravascular ultrasound, and coronary optical coherence tomography. Overall, all meta-analyses showed significant atherosclerotic plaque regression with lipid-lowering therapy, with the most notable effects on echogenicity, lipid-rich necrotic core volume, wall/plaque volume, dense calcium volume, and fibrous cap thickness. Significant interactions were found with concomitant changes in low density lipoprotein cholesterol, high density lipoprotein cholesterol, and C-reactive protein levels, and with ethnicity. Atherosclerotic plaque regression and conversion to a stable phenotype is possible with intensive medical therapy and can be demonstrated in patients using a variety of non-invasive and invasive imaging modalities.

Exposure to Cigarette Smoke and the Morphology of Atherosclerotic Plaques in the Extracranial Arteries Assessed by Computed Tomography Angiography in Patients with Essential Hypertension.

PubMed

Gać, Paweł; Jaźwiec, Przemysław; Mazur, Grzegorz; Poręba, Rafał

2017-01-01

The aim of the study was to determine the relationship between exposure to cigarette smoke and the morphology of atherosclerotic plaques in the extracranial arteries assessed by computed tomography angiography in patients with hypertension. The study included 61 hypertensive patients: 17 active smokers (group A), 18 non-smokers, declaring environmental exposure to tobacco smoke (group B), and 26 non-smokers, not declaring exposure to cigarette smoke (group C). The number of segments with plaques was significantly higher in group A compared to groups B and C. The number of segments with non-calcified and mixed plaques was significantly higher in group A and group B than in group C. A positive correlation between cigarette-years and the number of segments with atherosclerotic plaques was noted. In summary, both active smoking and environmental exposure to tobacco smoke appear to increase the number of segments of the extracranial arteries with non-calcified and mixed atherosclerotic plaques.

A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation

NASA Astrophysics Data System (ADS)

Duivenvoorden, Raphaël; Tang, Jun; Cormode, David P.; Mieszawska, Aneta J.; Izquierdo-Garcia, David; Ozcan, Canturk; Otten, Maarten J.; Zaidi, Neeha; Lobatto, Mark E.; van Rijs, Sarian M.; Priem, Bram; Kuan, Emma L.; Martel, Catherine; Hewing, Bernd; Sager, Hendrik; Nahrendorf, Matthias; Randolph, Gwendalyn J.; Stroes, Erik S. G.; Fuster, Valentin; Fisher, Edward A.; Fayad, Zahi A.; Mulder, Willem J. M.

2014-01-01

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

64Cu-Labeled Divalent Cystine Knot Peptide for Imaging Carotid Atherosclerotic Plaques.

PubMed

Jiang, Lei; Tu, Yingfeng; Kimura, Richard H; Habte, Frezghi; Chen, Hao; Cheng, Kai; Shi, Hongcheng; Gambhir, Sanjiv Sam; Cheng, Zhen

2015-06-01

The rupture of vulnerable atherosclerotic plaques that lead to stroke and myocardial infarction may be induced by macrophage infiltration and augmented by the expression of integrin αvβ3. Indeed, atherosclerotic angiogenesis may be a promising marker of inflammation. In this study, an engineered integrin αvβ3-targeting PET probe, (64)Cu-NOTA-3-4A, derived from a divalent knottin miniprotein was evaluated in a mouse model for carotid atherosclerotic plaques. Atherosclerotic plaques in BALB/C mice, maintained on a high-fat diet, were induced with streptozotocin injection and carotid artery ligation and verified by MR imaging. Knottin 3-4A was synthesized by solid-phase peptide synthesis chemistry and coupled to 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) before radiolabeling with (64)Cu. PET probe stability in mouse serum was evaluated. Mice with carotid atherosclerotic plaques were injected via the tail vein with (64)Cu-NOTA-3-4A or (18)F-FDG, followed by small-animal PET/CT imaging at different time points. Receptor targeting specificity of the probe was verified by coinjection of c(RGDyK) administered in molar excess. Subsequently, carotid artery dissection and immunofluorescence staining were performed to evaluate target expression. (64)Cu-NOTA-3-4A was synthesized in high radiochemical purity and yield and demonstrated molecular stability in both phosphate-buffered saline and mouse serum at 4 h. Small-animal PET/CT showed that (64)Cu-NOTA-3-4A accumulated at significantly higher levels in the neovasculature of carotid atherosclerotic plaques (7.41 ± 1.44 vs. 0.67 ± 0.23 percentage injected dose/gram, P < 0.05) than healthy or normal vessels at 1 h after injection. (18)F-FDG also accumulated in atherosclerotic lesions at 0.5 and 1 h after injection but at lower plaque-to-normal tissue ratios than (64)Cu-NOTA-3-4A. For example, plaque-to-normal carotid artery ratios for (18)F-FDG and (64)Cu-NOTA-3-4A at 1 h after injection were 3.75 and 14.71 (P < 0.05), respectively. Furthermore, uptake of (64)Cu-NOTA-3-4A in atherosclerotic plaques was effectively blocked (∼90% at 1 h after injection) by coinjection of c(RGDyK). Immunostaining confirmed integrin αvβ3 expression in both the infiltrating macrophages and the neovasculature of atherosclerotic plaques. (64)Cu-NOTA-3-4A demonstrates specific accumulation in carotid atherosclerotic plaques in which macrophage infiltration and angiogenesis are responsible for elevated integrin αvβ3 levels. Therefore, (64)Cu-NOTA-3-4A may demonstrate clinical utility as a PET probe for atherosclerosis imaging or for the evaluation of therapies used to treat atherosclerosis. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Short communication: Dating components of human atherosclerotic plaques.

PubMed

Gonçalves, Isabel; Stenström, Kristina; Skog, Göran; Mattsson, Sören; Nitulescu, Mihaela; Nilsson, Jan

2010-04-02

Atherosclerotic plaques that give rise to acute clinical symptoms are typically characterized by degradation of the connective tissue and plaque rupture. Experimental studies have shown that mechanisms to repair vulnerable lesions exist, but the rate of remodeling of human plaque tissue has not been studied. In the present study, we determined the biological age of different components of advanced human atherosclerotic plaques by analyzing tissue levels of (14)C released into the atmosphere during the nuclear weapons tests in the late 1950s and early 1960s. Atherosclerotic plaques were obtained from 10 patients (age 46 to 80 years) undergoing carotid surgery. Different regions of the plaques were dissected and analyzed for (14)C content using accelerator mass spectrometry. At the time of surgery, the mean biological age of the cap region was 6.4+/-3.2 years, which was significantly lower than that of the shoulder region (12.9+/-3.0 years, P<0.01), the interface toward the media (12.4+/-3.3 years, P<0.01), and the core (9.8+/-4.5 years, P<0.05). Analysis of proliferative activity and rate of apoptosis showed no signs of increased cellular turnover in the cap, suggesting that the lower (14)C content reflected a more recent time of formation. These results show that the turnover time of human plaque tissue is very long and may explain why regression of atherosclerotic plaque size rarely is observed in cardiovascular intervention trials.

Genesis and growth of extracellular vesicle-derived microcalcification in atherosclerotic plaques

PubMed Central

Hutcheson, Joshua D.; Goettsch, Claudia; Bertazzo, Sergio; Maldonado, Natalia; Ruiz, Jessica L.; Goh, Wilson; Yabusaki, Katsumi; Faits, Tyler; Bouten, Carlijn; Franck, Gregory; Quillard, Thibaut; Libby, Peter; Aikawa, Masanori; Weinbaum, Sheldon; Aikawa, Elena

2015-01-01

Clinical evidence links arterial calcification and cardiovascular risk. Finite-element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown. Here, by using three-dimensional collagen hydrogels that mimic structural features of the atherosclerotic fibrous cap, and high-resolution microscopic and spectroscopic analyses of both the hydrogels and of calcified human plaques, we demonstrate that calcific mineral formation and maturation results from a series of events involving the aggregation of calcifying extracellular vesicles, and the formation of microcalcifications and ultimately large calcification zones. We also show that calcification morphology and the plaque’s collagen content – two determinants of atherosclerotic plaque stability - are interlinked. PMID:26752654

A fluorescence lifetime spectroscopy study of matrix metalloproteinases -2 and -9 in human atherosclerotic plaque

PubMed Central

Phipps, Jennifer E.; Hatami, Nisa; Galis, Zorina S.; Baker, J. Dennis; Fishbein, Michael C.; Marcu, Laura

2011-01-01

Matrix metalloproteinase (MMP) -2 and -9 play important roles in the progression of atherosclerosis. This study aims to determine whether MMP-2 and -9 content in the fibrotic caps of atherosclerotic plaque is correlated with plaque autofluorescence. A time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) system was used to measure the autofluorescence and assess the biochemical composition of human plaques obtained from carotid endarterectomy. Results presented here demonstrate for the first time the ability to characterize the biochemical composition as it relates to MMP-2 and -9 content in the atherosclerotic plaque cap using a label-free imaging technique implemented with a fiberoptic TR-LIFS system. PMID:21770037

Label-free imaging of atherosclerotic plaques using third-harmonic generation microscopy

PubMed Central

Small, David M.; Jones, Jason S.; Tendler, Irwin I.; Miller, Paul E.; Ghetti, Andre; Nishimura, Nozomi

2017-01-01

Multiphoton microscopy using laser sources in the mid-infrared range (MIR, 1,300 nm and 1,700 nm) was used to image atherosclerotic plaques from murine and human samples. Third harmonic generation (THG) from atherosclerotic plaques revealed morphological details of cellular and extracellular lipid deposits. Simultaneous nonlinear optical signals from the same laser source, including second harmonic generation and endogenous fluorescence, resulted in label-free images of various layers within the diseased vessel wall. The THG signal adds an endogenous contrast mechanism with a practical degree of specificity for atherosclerotic plaques that complements current nonlinear optical methods for the investigation of cardiovascular disease. Our use of whole-mount tissue and backward scattered epi-detection suggests THG could potentially be used in the future as a clinical tool. PMID:29359098

Smooth muscle cells healing atherosclerotic plaque disruptions are of local, not blood, origin in apolipoprotein E knockout mice.

PubMed

Bentzon, Jacob F; Sondergaard, Claus S; Kassem, Moustapha; Falk, Erling

2007-10-30

Signs of preceding episodes of plaque rupture and smooth muscle cell (SMC)-mediated healing are common in atherosclerotic plaques, but the source of the healing SMCs is unknown. Recent studies suggest that activated platelets adhering to sites of injury recruit neointimal SMCs from circulating bone marrow-derived progenitor cells. Here, we analyzed the contribution of this mechanism to plaque healing after spontaneous and mechanical plaque disruption in apolipoprotein E knockout (apoE-/-) mice. To determine the origin of SMCs after spontaneous plaque disruption, irradiated 18-month-old apoE-/- mice were reconstituted with bone marrow cells from enhanced green fluorescent protein (eGFP) transgenic apoE-/- mice and examined when they died up to 9 months later. Plaque hemorrhage, indicating previous plaque disruption, was widely present, but no bone marrow-derived eGFP+ SMCs were detected. To examine the origin of healing SMCs in a model that recapitulates more features of human plaque rupture and healing, we developed a mechanical technique that produced consistent plaque disruption, superimposed thrombosis, and SMC-mediated plaque healing in apoE-/- mice. Mechanical plaque disruption was produced in irradiated apoE-/- mice reconstituted with eGFP+ apoE-/- bone marrow cells and in carotid bifurcations cross-grafted between apoE-/- and eGFP+ apoE-/- mice. Apart from few non-graft-derived SMCs near the anastomosis site in 1 transplanted carotid bifurcation, no SMCs originating from outside the local arterial segment were detected in healed plaques. Healing SMCs after atherosclerotic plaque disruption are derived entirely from the local arterial wall and not circulating progenitor cells in apoE-/- mice.

Proliferating macrophages prevail in atherosclerosis.

PubMed

Randolph, Gwendalyn J

2013-09-01

Macrophages accumulate in atherosclerotic lesions during the inflammation that is part of atherosclerosis development and progression. A new study in mice indicates that the accumulation of macrophages in atherosclerotic plaques depends on local macrophage proliferation rather than the recruitment of circulating monocytes.

Atherosclerotic Plaque in Patients with Zero Calcium Score at Coronary Computed Tomography Angiography.

PubMed

Gabriel, Fabíola Santos; Gonçalves, Luiz Flávio Galvão; Melo, Enaldo Vieira de; Sousa, Antônio Carlos Sobral; Pinto, Ibraim Masciarelli Francisco; Santana, Sara Melo Macedo; Matos, Carlos José Oliveira de; Souto, Maria Júlia Silveira; Conceição, Flávio Mateus do Sacramento; Oliveira, Joselina Luzia Menezes

2018-05-03

In view of the high mortality for cardiovascular diseases, it has become necessary to stratify the main risk factors and to choose the correct diagnostic modality. Studies have demonstrated that a zero calcium score (CS) is characteristic of a low risk for cardiovascular events. However, the prevalence of individuals with coronary atherosclerotic plaques and zero CS is conflicting in the specialized literature. To evaluate the frequency of patients with coronary atherosclerotic plaques, their degree of obstruction and associated factors in patients with zero CS and indication for coronary computed tomography angiography (CCTA). This is a cross-sectional, prospective study with 367 volunteers with zero CS at CCTA in four diagnostic imaging centers in the period from 2011 to 2016. A significance level of 5% and 95% confidence interval were adopted. The frequency of atherosclerotic plaque in the coronary arteries in 367 patients with zero CS was 9.3% (34 individuals). In this subgroup, mean age was 52 ± 10 years, 18 (52.9%) were women and 16 (47%) had significant coronary obstructions (> 50%), with involvement of two or more segments in 4 (25%) patients. The frequency of non-obese individuals (90.6% vs 73.9%, p = 0.037) and alcohol drinkers (55.9% vs 34.8%, p = 0.015) was significantly higher in patients with atherosclerotic plaques, with an odds ratio of 3.4 for each of this variable. The frequency of atherosclerotic plaque with zero CS was relatively high, indicating that the absence of calcification does not exclude the presence of plaques, many of which obstructive, especially in non-obese subjects and alcohol drinkers.

In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activity†

PubMed Central

Olson, Emilia S.; Whitney, Michael A.; Friedman, Beth; Aguilera, Todd A.; Crisp, Jessica L.; Baik, Fred M.; Jiang, Tao; Baird, Stephen M.; Tsimikas, Sotirios; Tsien, Roger Y.

2012-01-01

Thrombin and other coagulation enzymes have been shown to be important during atherosclerotic disease development. Study of these proteases is currently limited because of lack of robust molecular imaging agents for imaging protease activity in vivo. Activatable cell penetrating peptides (ACPPs) have been used to monitor MMP activity in tumors and, in principle, can be modified to detect other proteases. We have developed a probe that incorporates the peptide sequence DPRSFL from the proteinase activated receptor 1 (PAR-1) into an ACPP and shown that it is preferentially cleaved by purified thrombin. Active thrombin in serum cleaves DPRSFL–ACPP with >90% inhibition by lepirudin or argatroban. The DPRSFL–ACPP cleavage product accumulated in advanced atherosclerotic lesions in living mice, with 85% reduction in retention upon pre-injection of mice with hirudin. Uptake of the ACPP cleavage product was highest in plaques with histological features associated with more severe disease. Freshly resected human atheromas bathed in DPRSFL–ACPP retained 63% greater cleavage product compared to control ACPP. In conclusion, DPRSFL–ACPP can be used to study thrombin activity in coagulation and atherosclerosis with good spatial and temporal resolution. Thrombin-sensitive ACPPs may be developed into probes for early detection and intraoperative imaging of high risk atherosclerotic plaques. PMID:22534729

In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activity.

PubMed

Olson, Emilia S; Whitney, Michael A; Friedman, Beth; Aguilera, Todd A; Crisp, Jessica L; Baik, Fred M; Jiang, Tao; Baird, Stephen M; Tsimikas, Sotirios; Tsien, Roger Y; Nguyen, Quyen T

2012-06-01

Thrombin and other coagulation enzymes have been shown to be important during atherosclerotic disease development. Study of these proteases is currently limited because of lack of robust molecular imaging agents for imaging protease activity in vivo. Activatable cell penetrating peptides (ACPPs) have been used to monitor MMP activity in tumors and, in principle, can be modified to detect other proteases. We have developed a probe that incorporates the peptide sequence DPRSFL from the proteinase activated receptor 1 (PAR-1) into an ACPP and shown that it is preferentially cleaved by purified thrombin. Active thrombin in serum cleaves DPRSFL-ACPP with >90% inhibition by lepirudin or argatroban. The DPRSFL-ACPP cleavage product accumulated in advanced atherosclerotic lesions in living mice, with 85% reduction in retention upon pre-injection of mice with hirudin. Uptake of the ACPP cleavage product was highest in plaques with histological features associated with more severe disease. Freshly resected human atheromas bathed in DPRSFL-ACPP retained 63% greater cleavage product compared to control ACPP. In conclusion, DPRSFL-ACPP can be used to study thrombin activity in coagulation and atherosclerosis with good spatial and temporal resolution. Thrombin-sensitive ACPPs may be developed into probes for early detection and intraoperative imaging of high risk atherosclerotic plaques.

Dual-wavelength multifrequency photothermal wave imaging combined with optical coherence tomography for macrophage and lipid detection in atherosclerotic plaques using gold nanoparticles

PubMed Central

Wang, Tianyi; Jacob Mancuso, J.; Sapozhnikova, Veronika; Dwelle, Jordan; Ma, Li L.; Willsey, Brian; Shams Kazmi, S. M.; Qiu, Jinze; Li, Xiankai; Asmis, Reto; Johnston, Keith P.; Feldman, Marc D.

2012-01-01

Abstract. The objective of this study was to assess the ability of combined photothermal wave (PTW) imaging and optical coherence tomography (OCT) to detect, and further characterize the distribution of macrophages (having taken up plasmonic gold nanorose as a contrast agent) and lipid deposits in atherosclerotic plaques. Aortas with atherosclerotic plaques were harvested from nine male New Zealand white rabbits divided into nanorose- and saline-injected groups and were imaged by dual-wavelength (800 and 1210 nm) multifrequency (0.1, 1 and 4 Hz) PTW imaging in combination with OCT. Amplitude PTW images suggest that lateral and depth distribution of nanorose-loaded macrophages (confirmed by two-photon luminescence microscopy and RAM-11 macrophage stain) and lipid deposits can be identified at selected modulation frequencies. Radiometric temperature increase and modulation amplitude of superficial nanoroses in response to 4 Hz laser irradiation (800 nm) were significantly higher than native plaque (P<0.001). Amplitude PTW images (4 Hz) were merged into a coregistered OCT image, suggesting that superficial nanorose-loaded macrophages are distributed at shoulders on the upstream side of atherosclerotic plaques (P<0.001) at edges of lipid deposits. Results suggest that combined PTW-OCT imaging can simultaneously reveal plaque structure and composition, permitting characterization of nanorose-loaded macrophages and lipid deposits in atherosclerotic plaques. PMID:22502567

A fluorescence lifetime spectroscopy study of matrix metalloproteinases-2 and -9 in human atherosclerotic plaque.

PubMed

Phipps, Jennifer E; Hatami, Nisa; Galis, Zorina S; Baker, J Dennis; Fishbein, Michael C; Marcu, Laura

2011-09-01

Matrix metalloproteinase (MMP)-2 and -9 play important roles in the progression of atherosclerosis. This study aims to determine whether MMP-2 and -9 content in the fibrotic caps of atherosclerotic plaque is correlated with plaque autofluorescence. A time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) system was used to measure the autofluorescence and assess the biochemical composition of human plaques obtained from carotid endarterectomy. Results presented here demonstrate for the first time the ability to characterize the biochemical composition as it relates to MMP-2 and -9 content in the atherosclerotic plaque cap using a label-free imaging technique implemented with a fiberoptic TR-LIFS system. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Quantitative analysis of the polarization characteristics of atherosclerotic plaques

NASA Astrophysics Data System (ADS)

Gubarkova, Ekaterina V.; Kirillin, Michail Y.; Dudenkova, Varvara V.; Kiseleva, Elena B.; Moiseev, Alexander A.; Gelikonov, Grigory V.; Timofeeva, Lidia B.; Fiks, Ilya I.; Feldchtein, Felix I.; Gladkova, Natalia D.

2016-04-01

In this study we demonstrate the capability of cross-polarization optical coherence tomography (CP OCT) to assess collagen and elastin fibers condition in atherosclerotic plaques basing on ratio of the OCT signal levels in cross- and co- polarizations. We consider the depolarization factor (DF) and the effective birefringence (Δn) as quantitative characteristics of CP OCT images. We revealed that calculation of both DF and Δn in the region of interest (fibrous cap) yields a statistically significant difference between stable and unstable plaques (0.46+/-0.21 vs 0.09+/-0.04 for IDF; (4.7+/-1.0)•10-4 vs (2.5+/-0.7)•10-4 for Δn p<0.05). In parallel with CP OCT we used the nonlinear microscopy for analysis of thin cross-section of atherosclerotic plaque, revealing the different average isotropy index of collagen and elastin fibers for stable and unstable plaques (0.30 +/- 0.10 vs 0.70 +/- 0.08; p<0.001). The proposed approach for quantitative assessment of CP OCT images allows cross-scattering and birefringence characterization of stable and unstable atherosclerotic plaques.

In vivo MRI-based simulation of fatigue process: a possible trigger for human carotid atherosclerotic plaque rupture.

PubMed

Huang, Yuan; Teng, Zhongzhao; Sadat, Umar; He, Jing; Graves, Martin J; Gillard, Jonathan H

2013-04-23

Atherosclerotic plaque is subjected to a repetitive deformation due to arterial pulsatility during each cardiac cycle and damage may be accumulated over a time period causing fibrous cap (FC) fatigue, which may ultimately lead to rupture. In this study, we investigate the fatigue process in human carotid plaques using in vivo carotid magnetic resonance (MR) imaging. Twenty seven patients with atherosclerotic carotid artery disease were included in this study. Multi-sequence, high-resolution MR imaging was performed to depict the plaque structure. Twenty patients were found with ruptured FC or ulceration and 7 without. Modified Paris law was used to govern crack propagation and the propagation direction was perpendicular to the maximum principal stress at the element node located at the vulnerable site. The predicted crack initiations from 20 patients with FC defect all matched with the locations of the in vivo observed FC defect. Crack length increased rapidly with numerical steps. The natural logarithm of fatigue life decreased linearly with the local FC thickness (R(2) = 0.67). Plaques (n=7) without FC defect had a longer fatigue life compared with those with FC defect (p = 0.03). Fatigue process seems to explain the development of cracks in FC, which ultimately lead to plaque rupture.

Identification of Mature Atherosclerotic Plaque Proteome Signatures Using Data-Independent Acquisition Mass Spectrometry.

PubMed

Hansmeier, Nicole; Buttigieg, Josef; Kumar, Pankaj; Pelle, Shaneen; Choi, Kyoo Yoon; Kopriva, David; Chao, Tzu-Chiao

2018-01-05

Atherosclerosis is a chronic inflammatory disease with complex pathobiology and one of the most common causes of cardiovascular events. The process is characterized by complex vascular remodeling processes that require the actions of numerous proteins. The composition of atherosclerotic plaque is increasingly recognized as a major factor governing the occurrence of cardiovascular or neurological symptoms. To gain deeper insights into the composition of atherosclerotic plaques, we created quantitative proteome profiles of advanced plaque tissues of six male patients undergoing carotid endarterectomy for stroke prevention. Using a quantitative, data-independent proteome approach, we identified 4181 proteins with an average protein coverage of 45%. An analysis of the quantitative composition of the tissue revealed key players of vascular remodeling processes. Moreover, compared with proximal arterial tissue, 20 proteins in mature plaques were enriched, whereas 52 proteins were found in lower quantities. Among the proteins with increased abundance were prominent extracellular matrix proteins such as biglycan and lumican, whereas cytoskeletal markers for contractile smooth muscle cells (SMCs) were decreased. Taken together, this study provides the most comprehensive quantitative assessment of mature human plaque tissue to date, which indicates a central role of SMCs in the structure of advanced atherosclerotic plaques.

Molecular Imaging of Vulnerable Atherosclerotic Plaques in Animal Models

PubMed Central

Gargiulo, Sara; Gramanzini, Matteo; Mancini, Marcello

2016-01-01

Atherosclerosis is characterized by intimal plaques of the arterial vessels that develop slowly and, in some cases, may undergo spontaneous rupture with subsequent heart attack or stroke. Currently, noninvasive diagnostic tools are inadequate to screen atherosclerotic lesions at high risk of acute complications. Therefore, the attention of the scientific community has been focused on the use of molecular imaging for identifying vulnerable plaques. Genetically engineered murine models such as ApoE−/− and ApoE−/−Fbn1C1039G+/− mice have been shown to be useful for testing new probes targeting biomarkers of relevant molecular processes for the characterization of vulnerable plaques, such as vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, intercellular adhesion molecule (ICAM)-1, P-selectin, and integrins, and for the potential development of translational tools to identify high-risk patients who could benefit from early therapeutic interventions. This review summarizes the main animal models of vulnerable plaques, with an emphasis on genetically altered mice, and the state-of-the-art preclinical molecular imaging strategies. PMID:27618031

Activation of activator protein 2 alpha by aspirin alleviates atherosclerotic plaque growth and instability in vivo

PubMed Central

Yang, Jing-Jing; Li, Peng; Wang, Fu; Liang, Wen-Jing; Ma, Hui; Chen, Yuan; Ma, Zhi-Min; Li, Quan-Zhong; Peng, Qi-Sheng; Zhang, Yun; Wang, Shuang-Xi

2016-01-01

Aims Aspirin has been used for the secondary prevention and treatment of cardiovascular disease for several decades. We investigated the roles of transcriptional factor activator protein 2α (AP-2α) in the beneficial effects of aspirin in the growth and vulnerability of atherosclerotic plaque. Methods and Results In mice deficient of apolipoprotein E (Apoe-/-), aspirin (20, 50 mg/kg/day) suppressed the progression of atherosclerosis in aortic roots and increased the plaque stability in carotid atherosclerotic plaques induced by collar-placement. In vivo lentivirus-mediated RNA interference of AP-2α reversed the inhibitory effects of aspirin on atherosclerosis in Apoe-/- mice. Mechanically, aspirin increased AP-2α phosphorylation and its activity, upregulated IkBα mRNA and protein levels, and reduced oxidative stress in cultured vascular smooth muscle cells. Furthermore, deficiency of AP-2α completely abolished aspirin-induced upregulation of IkBα levels and inhibition of oxidative stress in Apoe-/- mice. Clinically, conventional doses of aspirin increased AP-2α phosphorylation and IkBα protein expression in humans subjects. Conclusion Aspirin activates AP-2α to upregulate IkBα gene expression, resulting in attenuations of plaque development and instability in atherosclerosis. PMID:27391154

Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoEnull Mice

PubMed Central

Chukkapalli, Sasanka S.; Velsko, Irina M.; Rivera-Kweh, Mercedes F.; Zheng, Donghang; Lucas, Alexandra R.; Kesavalu, Lakshmyya

2015-01-01

Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoEnull mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoEnull hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoEnull mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model. PMID:26619277

Polymicrobial Oral Infection with Four Periodontal Bacteria Orchestrates a Distinct Inflammatory Response and Atherosclerosis in ApoE null Mice.

PubMed

Chukkapalli, Sasanka S; Velsko, Irina M; Rivera-Kweh, Mercedes F; Zheng, Donghang; Lucas, Alexandra R; Kesavalu, Lakshmyya

2015-01-01

Periodontal disease (PD) develops from a synergy of complex subgingival oral microbiome, and is linked to systemic inflammatory atherosclerotic vascular disease (ASVD). To investigate how a polybacterial microbiome infection influences atherosclerotic plaque progression, we infected the oral cavity of ApoE null mice with a polybacterial consortium of 4 well-characterized periodontal pathogens, Porphyromonas gingivalis, Treponema denticola, Tannerealla forsythia and Fusobacterium nucleatum, that have been identified in human atherosclerotic plaque by DNA screening. We assessed periodontal disease characteristics, hematogenous dissemination of bacteria, peripheral T cell response, serum inflammatory cytokines, atherosclerosis risk factors, atherosclerotic plaque development, and alteration of aortic gene expression. Polybacterial infections have established gingival colonization in ApoE null hyperlipidemic mice and displayed invasive characteristics with hematogenous dissemination into cardiovascular tissues such as the heart and aorta. Polybacterial infection induced significantly higher levels of serum risk factors oxidized LDL (p < 0.05), nitric oxide (p < 0.01), altered lipid profiles (cholesterol, triglycerides, Chylomicrons, VLDL) (p < 0.05) as well as accelerated aortic plaque formation in ApoE null mice (p < 0.05). Periodontal microbiome infection is associated with significant decreases in Apoa1, Apob, Birc3, Fga, FgB genes that are associated with atherosclerosis. Periodontal infection for 12 weeks had modified levels of inflammatory molecules, with decreased Fas ligand, IL-13, SDF-1 and increased chemokine RANTES. In contrast, 24 weeks of infection induced new changes in other inflammatory molecules with reduced KC, MCSF, enhancing GM-CSF, IFNγ, IL-1β, IL-13, IL-4, IL-13, lymphotactin, RANTES, and also an increase in select inflammatory molecules. This study demonstrates unique differences in the host immune response to a polybacterial periodontal infection with atherosclerotic lesion progression in a mouse model.

Fluorescence lifetime in cardiovascular diagnostics

NASA Astrophysics Data System (ADS)

Marcu, Laura

2010-01-01

We review fluorescence lifetime techniques including time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) and fluorescence lifetime imaging microscopy (FLIM) instrumentation and associated methodologies that allow for characterization and diagnosis of atherosclerotic plaques. Emphasis is placed on the translational research potential of TR-LIFS and FLIM and on determining whether intrinsic fluorescence signals can be used to provide useful contrast for the diagnosis of high-risk atherosclerotic plaque. Our results demonstrate that these techniques allow for the discrimination of important biochemical features involved in atherosclerotic plaque instability and rupture and show their potential for future intravascular applications.

Fluorescence lifetime in cardiovascular diagnostics.

PubMed

Marcu, Laura

2010-01-01

We review fluorescence lifetime techniques including time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) and fluorescence lifetime imaging microscopy (FLIM) instrumentation and associated methodologies that allow for characterization and diagnosis of atherosclerotic plaques. Emphasis is placed on the translational research potential of TR-LIFS and FLIM and on determining whether intrinsic fluorescence signals can be used to provide useful contrast for the diagnosis of high-risk atherosclerotic plaque. Our results demonstrate that these techniques allow for the discrimination of important biochemical features involved in atherosclerotic plaque instability and rupture and show their potential for future intravascular applications.

Recent Advances in Fluorescent Angioscopy for Molecular Imaging of Human Atherosclerotic Coronary Plaque

PubMed Central

2017-01-01

Purpose of Review: In vivo imaging of the native substances, including lipoproteins, that comprise human atherosclerotic plaques is currently beyond the scope of any available imaging techniques. Color and near-infrared fluorescent angioscopy (CFA and NIRFA, respectively) systems have been recently developed for molecular imaging of lipoproteins within the human coronary arterial wall ex vivo and/or in vivo. The author reviews recent findings on lipoprotein deposition in human coronary plaques obtained by these imaging techniques. Recent Findings: Using specific biomarkers, native pro-atherogenic substances such as oxidized low-density lipoprotein (ox-LDL), LDL, triglycerides (TG), apolipoprotein B-100 (ApoB-100), and lysophosphatidylcholine (LPC), and the anti-atherogenic substance such as high-density lipoprotein (HDL) were visualized by CFA, and LDL and cholesterol by NIRFA, in coronary plaques obtained from autopsy subjects. The relationship between incidence and plaque morphology differed for each substance. The incidence of ox-LDL and LDL on color fluorescence microscopy correlated well with that observed using immunohistochemical techniques. During coronary catheterization in patients, ox-LDL, LDL, and HDL in coronary plaques were visualized by CFA or NIRFA. Conclusions: Using CFA or NIRFA, the distribution of the major native pro-atherogenic and antiatherogenic lipoproteins and their components within human coronary plaques can be evaluated ex vivo and/or in vivo. Fluorescent angioscopy could help our understanding of the molecular mechanisms of coronary atherosclerosis and in the evaluation of the effects of therapy targeting the substances comprising atherosclerotic coronary plaques. PMID:28381766

Atherosclerotic Plaque in Patients with Zero Calcium Score at Coronary Computed Tomography Angiography

PubMed Central

Gabriel, Fabíola Santos; Gonçalves, Luiz Flávio Galvão; de Melo, Enaldo Vieira; Sousa, Antônio Carlos Sobral; Pinto, Ibraim Masciarelli Francisco; Santana, Sara Melo Macedo; de Matos, Carlos José Oliveira; Souto, Maria Júlia Silveira; Conceição, Flávio Mateus do Sacramento; Oliveira, Joselina Luzia Menezes

2018-01-01

Background In view of the high mortality for cardiovascular diseases, it has become necessary to stratify the main risk factors and to choose the correct diagnostic modality. Studies have demonstrated that a zero calcium score (CS) is characteristic of a low risk for cardiovascular events. However, the prevalence of individuals with coronary atherosclerotic plaques and zero CS is conflicting in the specialized literature. Objective To evaluate the frequency of patients with coronary atherosclerotic plaques, their degree of obstruction and associated factors in patients with zero CS and indication for coronary computed tomography angiography (CCTA). Methods This is a cross-sectional, prospective study with 367 volunteers with zero CS at CCTA in four diagnostic imaging centers in the period from 2011 to 2016. A significance level of 5% and 95% confidence interval were adopted. Results The frequency of atherosclerotic plaque in the coronary arteries in 367 patients with zero CS was 9.3% (34 individuals). In this subgroup, mean age was 52 ± 10 years, 18 (52.9%) were women and 16 (47%) had significant coronary obstructions (> 50%), with involvement of two or more segments in 4 (25%) patients. The frequency of non-obese individuals (90.6% vs 73.9%, p = 0.037) and alcohol drinkers (55.9% vs 34.8%, p = 0.015) was significantly higher in patients with atherosclerotic plaques, with an odds ratio of 3.4 for each of this variable. Conclusions The frequency of atherosclerotic plaque with zero CS was relatively high, indicating that the absence of calcification does not exclude the presence of plaques, many of which obstructive, especially in non-obese subjects and alcohol drinkers. PMID:29723329

Subject-Specific Fully-Coupled and One-Way Fluid-Structure Interaction Models for Modeling of Carotid Atherosclerotic Plaques in Humans

PubMed Central

Tao, Xiaojuan; Gao, Peiyi; Jing, Lina; Lin, Yan; Sui, Binbin

2015-01-01

Background Hemodynamics play an important role in the development and progression of carotid atherosclerosis, and may be important in the assessment of plaque vulnerability. The aim of this study was to develop a system to assess the hemodynamics of carotid atherosclerotic plaques using subject-specific fluid-structure interaction (FSI) models based on magnetic resonance imaging (MRI). Material/Methods Models of carotid bifurcations (n=86 with plaques from 52 patients, n=14 normal carotids from 12 participants) were obtained at the Department of Radiology, Beijing Tian Tan Hospital between 2010 and 2013. The maximum von Mises stress, minimum pressure, and flow velocity values were assessed at the most stenotic site in patients, or at the carotid bifurcations in healthy volunteers. Results of one-way FSI were compared with fully-coupled FSI for the plaques of 19 randomly selected models. Results The maximum von Mises stress and the minimum pressure and velocity were significantly increased in the stenosis group compared with controls based on one-way FSI (all P<0.05). The maximum von Mises stress and the minimum pressure were significantly higher and the velocity was significantly lower based on fully coupled FSI compared with on-way FSI (all P<0.05). Although there were differences in numerical values, both methods were equivalent. The maximum von Mises stress of vulnerable plaques was significantly higher than stable plaques (P<0.001). The maximum von Mises stress of the group with fibrous cap defect was significantly higher than the group without fibrous cap defect (P=0.001). Conclusions The hemodynamics of atherosclerotic plaques can be assessed noninvasively using subject-specific models of FSI based on MRI. PMID:26510514

Valsartan Promoting Atherosclerotic Plaque Stabilization by Upregulating Renalase: A Potential-Related Gene of Atherosclerosis.

PubMed

Zhou, Mingxue; Ma, Chao; Liu, Weihong; Liu, Hongxu; Wang, Ning; Kang, Qunfu; Li, Ping

2015-09-01

Renalase is a protein that can regulate sympathetic nerve activity by metabolizing catecholamines, while redundant catecholamines are thought to contribute to atherosclerosis (As). Catecholamine release can be facilitated by angiotensin (Ang) II by binding to Ang II type 1 (AT1) receptors. Valsartan, a special AT1 antagonist, can dilate blood vessels and reduce blood pressure, but it remained unclear whether valsartan can promote the stability of atherosclerotic plaque by affecting renalase. This study examined the tissue distribution of renalase in ApoE(-/-) mice fed with a high-fat diet and the effect of valsartan on expression of renalase. ApoE(-/-) mice were fed with a high-fat diet for 13 or 26 weeks. As a control, 10 C57BL mice were fed with a standard chow diet. After 13 weeks on the high-fat diet, the ApoE(-/-) mice were randomized (10 mice/group) and treated with valsartan, simvastatin, or distilled water (control group) for an additional 13 weeks accompanied by a high-fat diet. Knockout of ApoE caused a dramatic increase in expression of renalase in mice adipose tissue. With the disturbance of lipid metabolism induced by a high-fat diet, renalase expression decreased in the liver. Renalase can be expressed in smooth muscle cells and M2 macrophages in atherosclerotic plaque, and its expression gradually decreases in the fibrous cap during the transition from stable to vulnerable atherosclerotic plaque. Valsartan, an AT1 receptor antagonist, promotes the stabilization of atherosclerotic plaque by increasing the levels of renalase in serum and the expression of renalase in the fibrous cap of atherosclerotic plaque. It also reduces triglyceride levels in serum and increases the expression of renalase in the liver. Renalase may be a potential-related gene of lipid metabolism and As, and it may be the possible molecular target of valsartan to help stabilize atherosclerotic plaque. © The Author(s) 2015.

Genetic Evidence Supports a Major Role for Akt1 in VSMCs During Atherogenesis

PubMed Central

Rotllan, Noemi; Wanschel, Amarylis C.; Fernandez-Hernando, Ana; Salerno, Alessandro G.; Offermanns, Stefan; Sessa, William C.; Fernández-Hernando, Carlos

2015-01-01

Rationale Coronary artery disease (CAD), the direct result of atherosclerosis, is the most common cause of death in Western societies. Vascular smooth muscle cell (VSMC) apoptosis occurs during the progression of atherosclerosis and in advanced lesions, promotes plaque necrosis, a common feature of high-risk/vulnerable atherosclerotic plaques. Akt1, a serine-threonine protein kinase, regulates several key endothelial cell (EC) and VSMC functions including cell growth, migration, survival and vascular tone. While global deficiency of Akt1 results in impaired angiogenesis and massive atherosclerosis, the specific contribution of VSMC Akt1 remains poorly characterized. Objective To investigate the contribution of VSMC Akt1 during atherogenesis and in established atherosclerotic plaques. Methods and Results We generated two mouse models in which Akt1 expression can be suppressed specifically in VSCMs before (Apoe−/−Akt1fl/flSm22αCRE) and after (Apoe−/−Akt1fl/flSM-MHC-CreERT2E) the formation of atherosclerotic plaques. This approach allows us to interrogate the role of Akt1 during the initial and late steps of atherogenesis. Absence of Akt1 in VSMCs during the progression of atherosclerosis results in larger atherosclerotic plaques characterized by bigger necrotic core areas, enhanced VSMC apoptosis and reduced fibrous cap and collagen content. In contrast, VSMC Akt1 inhibition in established atherosclerotic plaques does not influence lesion size but markedly reduces the relative fibrous cap area in plaques and increases VSMC apoptosis. Conclusions Akt1 expression in VSMCs influences early and late stages of atherosclerosis. Absence of Akt1 in VSMCs induces features of plaque vulnerability including fibrous cap thinning and extensive necrotic core areas. These observations suggest that interventions enhancing Akt1 expression specifically in VSMCs may lessen plaque progression. PMID:25868464

Atherectomy devices: technology update

PubMed Central

Akkus, Nuri I; Abdulbaki, Abdulrahman; Jimenez, Enrique; Tandon, Neeraj

2015-01-01

Atherectomy is a procedure which is performed to remove atherosclerotic plaque from diseased arteries. Atherosclerotic plaques are localized in either coronary or peripheral arterial vasculature and may have different characteristics depending on the texture of the plaque. Atherectomy has been used effectively in treatment of both coronary and peripheral arterial disease. Atherectomy devices are designed differently to either cut, shave, sand, or vaporize these plaques and have different indications. In this article, current atherectomy devices are reviewed. PMID:25565904

Imaging of lipids in atherosclerotic lesion in aorta from ApoE/LDLR-/- mice by FT-IR spectroscopy and Hierarchical Cluster Analysis.

PubMed

P Wrobel, Tomasz; Mateuszuk, Lukasz; Chlopicki, Stefan; Malek, Kamilla; Baranska, Malgorzata

2011-12-21

Spectroscopy-based approaches can provide an insight into the biochemical composition of a tissue sample. In the present work Fourier transform infrared (FT-IR) spectroscopy was used to develop a reliable methodology to study the content of free fatty acids, triglycerides, cholesteryl esters as well as cholesterol in aorta from mice with atherosclerosis (ApoE/LDLR(-/-) mice). In particular, distribution and concentration of palmitic, oleic and linoleic acid derivatives were analyzed. Spectral analysis of pure compounds allowed for clear discrimination between free fatty acids and other similar moieties based on the carbonyl band position (1699-1710 cm(-1) range). In order to distinguish cholesteryl esters from triglycerides a ratio of carbonyl band to signal at 1010 cm(-1) was used. Imaging of lipids in atherosclerotic aortic lesions in ApoE/LDLR(-/-) mice was followed by Hierarchical Cluster Analysis (HCA). The aorta from C57Bl/6J control mice (fed with chow diet) was used for comparison. The measurements were completed with an FT-IR spectrometer equipped with a 128 × 128 FPA detector. In cross-section of aorta from ApoE/LDLR(-/-) mice a region of atherosclerotic plaque was clearly identified by HCA, which was later divided into 2 sub-regions, one characterized by the higher content of cholesterol, while the other by higher contents of cholesteryl esters. HCA of tissues deposited on normal microscopic glass, hence limited to the 2200-3800 cm(-1) spectral range, also identified a region of atherosclerotic plaque. Importantly, this region correlates with the area stained by standard histological staining for atherosclerotic plaque (Oil Red O). In conclusion, the use of FT-IR and HCA may provide a novel tool for qualitative and quantitative analysis of contents and distribution of lipids in atherosclerotic plaque.

In vitro quantitation of human femoral artery atherosclerosis using near-infrared Raman spectroscopy

NASA Astrophysics Data System (ADS)

Dykes, Ava C.; Anastasiadis, Pavlos; Allen, John S., III; Sharma, Shiv K.

2012-06-01

Near-infrared Raman spectroscopy has been used in vitro to identify calcified atherosclerotic plaques in human femoral arteries. Raman techniques allow for the identification of these plaques in a nondestructive manner, which may allow for the diagnosis of coronary artery disease in cardiac patients in the future. As Raman spectroscopy also reveals chemical information about the composition of the arteries, it can also be used as a prognostic tool. The in vivo detection of atherosclerotic plaques at risk for rupture in cardiac patients will enhance treatment methods while improving clinical outcomes for these procedures. Raman spectra were excited by an Invictus 785-nm NIR laser and measured with a fiber-coupled micro-Raman RXN system (Kaiser Optical Systems, Inc., Ann Arbor, MI) equipped with a 785 nm CW laser and CCD detector. Chemical mapping of arteries obtained post mortem allowed for the discrete location of atherosclerotic plaques. Raman peaks at 961 and 1073 cm-1 reveal the presence of calcium hydroxyapatite and carbonate apatite, which are known to be present in calcified plaques. By mapping the locations of these peaks the boundaries of the plaques can be precisely determined. Areas of varying degrees of calcification were also identified. Because this can be useful in determining the degree of plaque calcification and vessel stenosis, this may have a significant impact on the clinical treatment of atherosclerotic plaques in the future.

Symptomatic and asymptomatic carotid artery plaque

PubMed Central

Mughal, Majid M; Khan, Mohsin K; DeMarco, J Kevin; Majid, Arshad; Shamoun, Fadi; Abela, George S

2011-01-01

Carotid atherosclerotic plaques represent both stable and unstable atheromatous lesions. Atherosclerotic plaques that are prone to rupture owing to their intrinsic composition such as a large lipid core, thin fibrous cap and intraplaque hemorrhage are associated with subsequent thromboembolic ischemic events. At least 15–20% of all ischemic strokes are attributable to carotid artery atherosclerosis. Characterization of plaques may enhance the understanding of natural history and ultimately the treatment of atherosclerotic disease. MRI of carotid plaque and embolic signals during transcranial Doppler have identified features beyond luminal stenosis that are predictive of future transient ischemic attacks and stroke. The value of specific therapies to prevent stroke in symptomatic and asymptomatic patients with severe carotid artery stenosis are the subject of current research and analysis of recently published clinical trials that are discussed in this article. PMID:21985544

Intravascular photoacoustic imaging of exogenously labeled atherosclerotic plaque through luminal blood

NASA Astrophysics Data System (ADS)

Yeager, Doug; Karpiouk, Andrei; Wang, Bo; Amirian, James; Sokolov, Konstantin; Smalling, Richard; Emelianov, Stanislav

2012-10-01

Combined intravascular ultrasound and intravascular photoacoustic (IVUS/IVPA) imaging has been previously established as a viable means for assessing atherosclerotic plaque morphological and compositional characteristics using both endogenous and exogenous contrast. In this study, IVUS/IVPA imaging of atherosclerotic rabbit aortas following systemic injection of gold nanorods (AUNRs) with peak absorbance within the tissue optical window is performed. Ex vivo imaging results reveal a high photoacoustic signal from localized AUNRs in regions with atherosclerotic plaques. Corresponding histological staining further confirms the preferential extravasation of AUNRs in atherosclerotic regions with compromised luminal endothelium and acute inflammation. The ability to detect AUNRs using combined IVUS and photoacoustic imaging in the presence of luminal saline and luminal blood is evaluated using both spectroscopic and single wavelength IVPA imaging techniques. Results demonstrate that AUNR detection within the arterial wall can be achieved using both methods, even in the case of imaging through luminal blood.

Fluorescence lifetime in cardiovascular diagnostics

PubMed Central

Marcu, Laura

2010-01-01

We review fluorescence lifetime techniques including time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) and fluorescence lifetime imaging microscopy (FLIM) instrumentation and associated methodologies that allow for characterization and diagnosis of atherosclerotic plaques. Emphasis is placed on the translational research potential of TR-LIFS and FLIM and on determining whether intrinsic fluorescence signals can be used to provide useful contrast for the diagnosis of high-risk atherosclerotic plaque. Our results demonstrate that these techniques allow for the discrimination of important biochemical features involved in atherosclerotic plaque instability and rupture and show their potential for future intravascular applications. PMID:20210432

Toll-like receptor 7 stimulation by imiquimod induces macrophage autophagy and inflammation in atherosclerotic plaques.

PubMed

De Meyer, Inge; Martinet, Wim; Schrijvers, Dorien M; Timmermans, Jean-Pierre; Bult, Hidde; De Meyer, Guido R Y

2012-05-01

Atherosclerotic plaques tend to rupture as a consequence of a weakened fibrous cap, particularly in the shoulder regions where most macrophages reside. Macrophages express Toll-like receptors to recognize pathogens and eliminate intracellular pathogens by inducing autophagy. Because Toll-like receptor 7 (TLR7) is thought to be expressed in macrophages but not in smooth muscle cells (SMCs), we investigated whether induction of macrophage autophagic death by TLR7 ligand imiquimod can affect the composition of atherosclerotic plaques in favor of their stability. Immunohistochemical staining of human carotid plaques as well as Western blotting of cultured macrophages and SMCs confirmed that TLR7 was expressed in macrophages, but not in SMCs. In vitro experiments showed that only TLR7 expressing cells underwent imiquimod-induced cell death, which was characterized by autophagosome formation. Imiquimod-treated macrophages activated nuclear factor-κB (NF-κB) and released pro-inflammatory cytokines and chemokines. This effect was inhibited by the glucocorticoid dexamethasone. Imiquimod-induced cytokine release was significantly decreased in autophagy-deficient macrophages because these cells died by necrosis at an accelerated pace. Local in vivo administration of imiquimod to established atherosclerotic lesions in rabbit carotid arteries induced macrophage autophagy without induction of cell death, and triggered cytokine production, upregulation of vascular adhesion molecule-1, infiltration of T-lymphocytes, accumulation of macrophages and enlargement of plaque area. Treatment with dexamethasone suppressed these pro-inflammatory effects in vivo. SMCs and endothelial cells in imiquimod-treated plaques were not affected. In conclusion, imiquimod induces macrophage autophagy in atherosclerotic plaques, but stimulates plaque progression through cytokine release and enhanced infiltration of inflammatory cells.

Progress in atherosclerotic plaque imaging

PubMed Central

Soloperto, Giulia; Casciaro, Sergio

2012-01-01

Cardiovascular diseases are the primary cause of mortality in the industrialized world, and arterial obstruction, triggered by rupture-prone atherosclerotic plaques, lead to myocardial infarction and cerebral stroke. Vulnerable plaques do not necessarily occur with flow-limiting stenosis, thus conventional luminographic assessment of the pathology fails to identify unstable lesions. In this review we discuss the currently available imaging modalities used to investigate morphological features and biological characteristics of the atherosclerotic plaque. The different imaging modalities such as ultrasound, magnetic resonance imaging, computed tomography, nuclear imaging and their intravascular applications are illustrated, highlighting their specific diagnostic potential. Clinically available and upcoming methodologies are also reviewed along with the related challenges in their clinical translation, concerning the specific invasiveness, accuracy and cost-effectiveness of these methods. PMID:22937215

Automated tissue characterization of in vivo atherosclerotic plaques by intravascular optical coherence tomography images

PubMed Central

Ughi, Giovanni Jacopo; Adriaenssens, Tom; Sinnaeve, Peter; Desmet, Walter; D’hooge, Jan

2013-01-01

Intravascular optical coherence tomography (IVOCT) is rapidly becoming the method of choice for the in vivo investigation of coronary artery disease. While IVOCT visualizes atherosclerotic plaques with a resolution <20µm, image analysis in terms of tissue composition is currently performed by a time-consuming manual procedure based on the qualitative interpretation of image features. We illustrate an algorithm for the automated and systematic characterization of IVOCT atherosclerotic tissue. The proposed method consists in a supervised classification of image pixels according to textural features combined with the estimated value of the optical attenuation coefficient. IVOCT images of 64 plaques, from 49 in vivo IVOCT data sets, constituted the algorithm’s training and testing data sets. Validation was obtained by comparing automated analysis results to the manual assessment of atherosclerotic plaques. An overall pixel-wise accuracy of 81.5% with a classification feasibility of 76.5% and per-class accuracy of 89.5%, 72.1% and 79.5% for fibrotic, calcified and lipid-rich tissue respectively, was found. Moreover, measured optical properties were in agreement with previous results reported in literature. As such, an algorithm for automated tissue characterization was developed and validated using in vivo human data, suggesting that it can be applied to clinical IVOCT data. This might be an important step towards the integration of IVOCT in cardiovascular research and routine clinical practice. PMID:23847728

Correlation of collagen synthesis with polarization-sensitive optical coherence tomography imaging of in vitro human atherosclerosis

NASA Astrophysics Data System (ADS)

Kuo, Wen-Chuan; Shyu, Jeou-Jong; Chou, Nai-Kuan; Lai, Chih-Ming; Tien, En-Kuang; Huang, Huan-Jang; Chou, Chien; Jan, Gwo-Jen

2005-04-01

Atherosclerosis is unquestionably the leading cause of morbidity and mortality in developed countries. In the mean time, the worldwide importance of acute vascular syndromes is increasing. Because collagen fiber is a critical component of atherosclerotic lesions; it constitutes up to 60% of the total atherosclerotic plaque protein. The uncontrolled collagen accumulation leads to arterial stenosis, whereas excessive collagen breakdown weakens plaques thereby making them prone to rupture finally. Thus, in this study, we present the first application, to our knowledge, of using polarization-sensitive optical coherence tomography (PS-OCT) in human atherosclerosis. We demonstrate this technique for imaging of intensity, birefringence, and fast-axis orientation simultaneously in atherosclerotic plaques. This in vitro study suggests that the birefringence change in plaque is due to the prominent deposition of collagen according to the correlation of PS-OCT images with histological counterpart. Moreover, we can acquire quantitative criteria based on the change of polarization of incident beam to estimate whether the collagen synthesized is "too much" or "not enough". Thus by combining of high resolution intensity imaging and birefringence detection makes PS-OCT could be a potentially powerful tool for early assessment of atherosclerosis appearance and the prediction of plaque rupture in clinic.

Myeloperoxidase-oxidized high density lipoprotein impairs atherosclerotic plaque stability by inhibiting smooth muscle cell migration.

PubMed

Zhou, Boda; Zu, Lingyun; Chen, Yong; Zheng, Xilong; Wang, Yuhui; Pan, Bing; Dong, Min; Zhou, Enchen; Zhao, Mingming; Zhang, Youyi; Zheng, Lemin; Gao, Wei

2017-01-10

High density lipoprotein (HDL) has been proved to be a protective factor for coronary heart disease. Notably, HDL in atherosclerotic plaques can be nitrated (NO 2 -oxHDL) and chlorinated (Cl-oxHDL) by myeloperoxidase (MPO), likely compromising its cardiovascular protective effects. Here we determined the effects of NO 2 -oxHDL and Cl-oxHDL on SMC migration using wound healing and transwell assays, proliferation using MTT and BrdU assays, and apoptosis using Annexin-V assay in vitro, as well as on atherosclerotic plaque stability in vivo using a coratid artery collar implantation mice model. Our results showed that native HDL promoted SMC proliferation and migration, whereas NO 2 -oxHDL and Cl-oxHDL inhibited SMC migration and reduced capacity of stimulating SMC proliferation as well as migration, respectively. OxHDL had no significant influence on SMC apoptosis. In addition, we found that ERK1/2-phosphorylation was significantly lower when SMCs were incubated with NO 2 -oxHDL and Cl-oxHDL. Furthermore, transwell experiments showed that differences between native HDL, NO 2 -oxHDL and Cl-oxHDL was abolished after PD98059 (MAPK kinase inhibitor) treatment. In aortic SMCs from scavenger receptor BI (SR-BI) deficient mice, differences between migration of native HDL, NO 2 -oxHDL and Cl-oxHDL treated SMCs vanished, indicating SR-BI's possible role in HDL-associated SMC migration. Importantly, NO 2 -oxHDL and Cl-oxHDL induced neointima formation and reduced SMC positive staining cells in atherosclerotic plaque, resulting in elevated vulnerable index of atherosclerotic plaque. These findings implicate MPO-catalyzed oxidization of HDL may contribute to atherosclerotic plaque instability by inhibiting SMC proliferation and migration through MAPK-ERK pathway which was dependent on SR-BI.

Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque

PubMed Central

Khambata, Rayomand S.; Ghosh, Suborno M.; Rathod, Krishnaraj S.; Thevathasan, Tharssana; Filomena, Federica; Xiao, Qingzhong; Ahluwalia, Amrita

2017-01-01

Reduced bioavailable nitric oxide (NO) plays a key role in the enhanced leukocyte recruitment reflective of systemic inflammation thought to precede and underlie atherosclerotic plaque formation and instability. Recent evidence demonstrates that inorganic nitrate (NO3−) through sequential chemical reduction in vivo provides a source of NO that exerts beneficial effects upon the cardiovascular system, including reductions in inflammatory responses. We tested whether the antiinflammatory effects of inorganic nitrate might prove useful in ameliorating atherosclerotic disease in Apolipoprotein (Apo)E knockout (KO) mice. We show that dietary nitrate treatment, although having no effect upon total plaque area, caused a reduction in macrophage accumulation and an elevation in smooth muscle accumulation within atherosclerotic plaques of ApoE KO mice, suggesting plaque stabilization. We also show that in nitrate-fed mice there is reduced systemic leukocyte rolling and adherence, circulating neutrophil numbers, neutrophil CD11b expression, and myeloperoxidase activity compared with wild-type littermates. Moreover, we show in both the ApoE KO mice and using an acute model of inflammation that this effect upon neutrophils results in consequent reductions in inflammatory monocyte expression that is associated with elevations of the antiinflammatory cytokine interleukin (IL)-10. In summary, we demonstrate that inorganic nitrate suppresses acute and chronic inflammation by targeting neutrophil recruitment and that this effect, at least in part, results in consequent reductions in the inflammatory status of atheromatous plaque, and suggest that this effect may have clinical utility in the prophylaxis of inflammatory atherosclerotic disease. PMID:28057862

A Framework for Local Mechanical Characterization of Atherosclerotic Plaques: Combination of Ultrasound Displacement Imaging and Inverse Finite Element Analysis.

PubMed

Akyildiz, Ali C; Hansen, Hendrik H G; Nieuwstadt, Harm A; Speelman, Lambert; De Korte, Chris L; van der Steen, Antonius F W; Gijsen, Frank J H

2016-04-01

Biomechanical models have the potential to predict plaque rupture. For reliable models, correct material properties of plaque components are a prerequisite. This study presents a new technique, where high resolution ultrasound displacement imaging and inverse finite element (FE) modeling is combined, to estimate material properties of plaque components. Iliac arteries with plaques were excised from 6 atherosclerotic pigs and subjected to an inflation test with pressures ranging from 10 to 120 mmHg. The arteries were imaged with high frequency 40 MHz ultrasound. Deformation maps of the plaques were reconstructed by cross correlation of the ultrasound radiofrequency data. Subsequently, the arteries were perfusion fixed for histology and structural components were identified. The histological data were registered to the ultrasound data to construct FE model of the plaques. Material properties of the arterial wall and the intima of the atherosclerotic plaques were estimated using a grid search method. The computed displacement fields showed good agreement with the measured displacement fields, implying that the FE models were able to capture local inhomogeneities within the plaque. On average, nonlinear stiffening of both the wall and the intima was observed, and the wall of the atheroslcerotic porcine iliac arteries was markedly stiffer than the intima (877 ± 459 vs. 100 ± 68 kPa at 100 mmHg). The large spread in the data further illustrates the wide variation of the material properties. We demonstrated the feasibility of a mixed experimental-numerical framework to determine the material properties of arterial wall and intima of atherosclerotic plaques from intact arteries, and concluded that, due to the observed variation, plaque specific properties are required for accurate stress simulations.

How does juxtaluminal calcium affect critical mechanical conditions in carotid atherosclerotic plaque? An exploratory study.

PubMed

Zhongzhao Teng; Jing He; Sadat, Umar; Mercer, John R; Xiaoyan Wang; Bahaei, Nasim S; Thomas, Owen M; Gillard, Jonathan H

2014-01-01

The impact of calcification on the carotid atherosclerotic plaque vulnerability remains controversial and unclear. This study assesses the critical mechanical conditions induced by the calcium at the lumen surface, i.e., juxtaluminal calcification (JLCa), within human carotid atherosclerotic plaque. Eleven patients with evidence of JLCa were included for the analysis. The plaque geometry was reconstructed based on computed tomography and magnetic resonance images and 3-D fluid-structure interaction simulation was used for mechanical analysis. The presence of JLCa increased local stresses compared to when calcification was artificially covered with a 0.2-mm-thick fibrous cap (107.87 kPa [76.99, 129.14] versus 63.17 kPa [34.55, 75.13]; Median, [interquartile range]; ). Stretch ratio decreased from 1.18 [1.07, 1.27] to 1.13 [1.10, 1.18] (p = 0.03). The presence of JLCa significantly elevates local stress and stretch level. Further exploration of this plaque feature is warranted as a possible risk factor causing plaque vulnerability.

Cadmium exposure and atherosclerotic carotid plaques –Results from the Malmö diet and Cancer study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fagerberg, Björn, E-mail: bjorn.fagerberg@wlab.gu.se; Barregard, Lars, E-mail: lars.barregard@amm.gu.se; Sallsten, Gerd, E-mail: gerd.sallsten@amm.gu.se

Background: Epidemiological studies indicate that cadmium exposure through diet and smoking is associated with increased risk of cardiovascular disease. There are few data on the relationship between cadmium and plaques, the hallmark of underlying atherosclerotic disease. Objectives: To examine the association between exposure to cadmium and the prevalence and size of atherosclerotic plaques in the carotid artery. Methods: A population sample of 4639 Swedish middle-aged women and men was examined in 1991–1994. Carotid plaque was determined by B-mode ultrasound. Cadmium in blood was analyzed by inductively coupled plasma mass spectrometry. Results: Comparing quartile 4 with quartile 1 of blood cadmium,more » the odds ratio (OR) for prevalence of any plaque was 1.9 (95% confidence interval 1.6–2.2) after adjustment for sex and, age; 1.4 (1.1–1.8) after additional adjustment for smoking status; 1.4 (1.1–1.7) after the addition of education level and life style factors; 1.3 (1.03–1.8) after additional adjustment for risk factors and predictors of cardiovascular disease. No effect modification by sex was found in the cadmium-related prevalence of plaques. Similarly, ORs for the prevalence of small and large plaques were after full adjustment 1.4 (1.0–2.1) and 1.4 (0.9–2.0), respectively. The subgroup of never smokers showed no association between cadmium and atherosclerotic plaques. Conclusions: These results extend previous studies on cadmium exposure and clinical cardiovascular events by adding data on the association between cadmium and underlying atherosclerosis in humans. The role of smoking remains unclear. It may both cause residual confounding and be a source of pro-atherogenic cadmium exposure. - Highlights: • Blood cadmium level is associated with atherosclerotic plaques in the carotid artery. • The results extend previous knowledge of cadmium exposure and clinical events. • The role of smoking remains unclear.« less

Quantification of plaque area and characterization of plaque biochemical composition with atherosclerosis progression in ApoE/LDLR(-/-) mice by FT-IR imaging.

PubMed

Wrobel, Tomasz P; Mateuszuk, Lukasz; Kostogrys, Renata B; Chlopicki, Stefan; Baranska, Malgorzata

2013-11-07

In this work the quantitative determination of atherosclerotic lesion area (ApoE/LDLR(-/-) mice) by FT-IR imaging is presented and validated by comparison with atherosclerotic lesion area determination by classic Oil Red O staining. Cluster analysis of FT-IR-based measurements in the 2800-3025 cm(-1) range allowed for quantitative analysis of the atherosclerosis plaque area, the results of which were highly correlated with those of Oil Red O histological staining (R(2) = 0.935). Moreover, a specific class obtained from a second cluster analysis of the aortic cross-section samples at different stages of disease progression (3, 4 and 6 months old) seemed to represent the macrophages (CD68) area within the atherosclerotic plaque.

Increase in the adhesion molecule P-selectin in endothelium overlying atherosclerotic plaques. Coexpression with intercellular adhesion molecule-1.

PubMed Central

Johnson-Tidey, R. R.; McGregor, J. L.; Taylor, P. R.; Poston, R. N.

1994-01-01

P-selectin (GMP-140) is an adhesion molecule present within endothelial cells that is rapidly translocated to the cell membrane upon activation, where it mediates endothelial-leukocyte interactions. Immunohistochemical analysis of human atherosclerotic plaques has shown strong expression of P-selectin by the endothelium overlying active atherosclerotic plaques. P-selectin is not, however, detected in normal arterial endothelium or in endothelium overlying inactive fibrous plaques. Color image analysis was used to quantitate the degree of P-selectin expression in the endothelium and demonstrates a statistically significant increase in P-selectin expression by atherosclerotic endothelial cells. Double immunofluorescence shows that some of this P-selectin is expressed on the luminal surface of the endothelial cells. Previous work has demonstrated a significant up-regulation in the expression of the intercellular adhesion molecule-1 in atherosclerotic endothelium and a study on the expression of intercellular adhesion molecule-1 and P-selectin in atherosclerosis shows a highly positive correlation. These results suggest that the selective and cooperative expression of P-selectin and intercellular adhesion molecule-1 may be involved in the recruitment of monocytes into sites of atherosclerosis. Images Figure 1 Figure 3 Figure 4 Figure 5 PMID:7513951

[Diabetes and type of diet as determinant factor in the progression of atherosclerosis].

PubMed

Perales-Torres, Adriana Leticia; Castillo-Ruíz, Octelina; Castañeda Licón, María Teresa; Alemán-Castillo, Sanjuana E; Jiménez Andrade, Juan Miguel

The purpose of this review is to analyze the biochemical progression of atherosclerotic plaque and its association with diet and diabetes. This study shows the scientific evidence of demonstrating that diabetic patients present high levels of fatty acids like palmitic acid and linoleic acid in their atheroma plaques in comparison with non-diabetic patients. This study also establishes how patients with diabetes mellitus have a higher prevalence of atherosclerotic heart diseases in the form of Coronary Thrombosis and have different anatomopathological appearance like higher necrotic core and thin fibrotic layer than the general population. Furthermore this review describes the different anatomopathological appearance and cellular changes involved in the formation of these plaques and how diet can affect the development of these plaques. Copyright © 2016 Instituto Nacional de Cardiología Ignacio Chávez. Publicado por Masson Doyma México S.A. All rights reserved.

Quantitative assessment of atherosclerotic plaques on (18)F-FDG PET/MRI: comparison with a PET/CT hybrid system.

PubMed

Li, Xiang; Heber, Daniel; Rausch, Ivo; Beitzke, Dietrich; Mayerhoefer, Marius E; Rasul, Sazan; Kreissl, Michael; Mitthauser, Markus; Wadsak, Wolfgang; Hartenbach, Markus; Haug, Alexander; Zhang, Xiaoli; Loewe, Christian; Beyer, Thomas; Hacker, Marcus

2016-07-01

PET with (18)F-FDG has the potential to assess vascular macrophage metabolism. (18)F-FDG is most often used in combination with contrast-enhanced CT to localize increased metabolism to specific arterial lesions. Novel (18)F-FDG PET/MRI hybrid imaging shows high potential for the combined evaluation of atherosclerotic plaques, due to the superior morphological conspicuity of plaque lesions. The purpose of this study was to evaluate the reliability and accuracy of (18)F-FDG PET/MRI uptake quantification compared to PET/CT as a reference standard in patients with carotid atherosclerotic plaques. The study group comprised 34 consecutive oncological patients with carotid plaques who underwent both PET/CT and PET/MRI with (18)F-FDG on the same day. The presence of atherosclerotic plaques was confirmed by 3 T MRI scans. Maximum standardized uptake values (SUVmax) for carotid plaque lesions and the average SUV of the blood pool within the adjacent internal jugular vein were determined and target-to-blood ratios (TBRs, plaque to blood pool) were calculated. Atherosclerotic lesions with maximum colocalized focal FDG uptake were assessed in each patient. SUVmax values of carotid plaque lesions were significantly lower on PET/MRI than on PET/CT (2.3 ± 0.6 vs. 3.1 ± 0.6; P < 0.01), but were significantly correlated between PET/CT and PET/MRI (Spearman's r = 0.67, P < 0.01). In contrast, TBRmax values of plaque lesions were similar on PET/MRI and on PET/CT (2.2 ± 0.3 vs. 2.2 ± 0.3; P = 0.4), and again were significantly correlated between PET/MRI and PET/CT (Spearman's r = 0.73, P < 0.01). Considering the increasing trend in SUVmax and TBRmax values from early to delayed imaging time-points on PET/CT and PET/MRI, respectively, with continuous clearance of radioactivity from the blood, a slight underestimation of TBRmax values may also be expected with PET/MRI compared with PET/CT. SUVmax and TBRmax values are widely accepted reference parameters for estimation of the radioactivity of atherosclerotic plaques on PET/CT. However, due to a systematic underestimation of SUVmax and TBRmax with PET/MRI, the optimal cut-off values indicating the presence of inflamed plaque tissue need to be newly defined for PET/MRI.

Evaluation of the radiolabeled boronic acid-based FAP inhibitor MIP-1232 for atherosclerotic plaque imaging.

PubMed

Meletta, Romana; Müller Herde, Adrienne; Chiotellis, Aristeidis; Isa, Malsor; Rancic, Zoran; Borel, Nicole; Ametamey, Simon M; Krämer, Stefanie D; Schibli, Roger

2015-01-27

Research towards the non-invasive imaging of atherosclerotic plaques is of high clinical priority as early recognition of vulnerable plaques may reduce the incidence of cardiovascular events. The fibroblast activation protein alpha (FAP) was recently proposed as inflammation-induced protease involved in the process of plaque vulnerability. In this study, FAP mRNA and protein levels were investigated by quantitative polymerase chain reaction and immunohistochemistry, respectively, in human endarterectomized carotid plaques. A published boronic-acid based FAP inhibitor, MIP-1232, was synthetized and radiolabeled with iodine-125. The potential of this radiotracer to image plaques was evaluated by in vitro autoradiography with human carotid plaques. Specificity was assessed with a xenograft with high and one with low FAP level, grown in mice. Target expression analyses revealed a moderately higher protein level in atherosclerotic plaques than normal arteries correlating with plaque vulnerability. No difference in expression was determined on mRNA level. The radiotracer was successfully produced and accumulated strongly in the FAP-positive SK-Mel-187 melanoma xenograft in vitro while accumulation was negligible in an NCI-H69 xenograft with low FAP levels. Binding of the tracer to endarterectomized tissue was similar in plaques and normal arteries, hampering its use for atherosclerosis imaging.

Icaritin Inhibits Collagen Degradation-Related Factors and Facilitates Collagen Accumulation in Atherosclerotic Lesions: A Potential Action for Plaque Stabilization

PubMed Central

Zhang, Zong-Kang; Li, Jie; Yan, De-Xin; Leung, Wing-Nang; Zhang, Bao-Ting

2016-01-01

Most acute coronary syndromes result from rupture of vulnerable atherosclerotic plaques. The collagen content of plaques may critically affect plaque stability. This study tested whether Icaritin (ICT), an intestinal metabolite of Epimedium-derived flavonoids, could alter the collagen synthesis/degradation balance in atherosclerotic lesions. Rabbits were fed with an atherogenic diet for four months. Oral administration of ICT (10 mg·kg−1·day−1) was started after two months of an atherogenic diet and lasted for two months. The collagen degradation-related parameters, including macrophages accumulation, content and activity of interstitial collagenase-1 (MMP-1), and the collagen synthesis-related parameters, including amount and distribution of smooth muscle cells (SMC) and collagen mRNA/protein levels, were evaluated in the aorta. ICT reduced plasma lipid levels, inhibited macrophage accumulation, lowered MMP-1 mRNA and protein expression, and suppressed proteolytic activity of pro-MMP-1 and MMP-1 in the aorta. ICT changed the distribution of the SMCs towards the fibrous cap of lesions without increasing the amount of SMCs. Higher collagen protein content in lesions and aorta homogenates was observed with ICT treatment compared with the atherogenic diet only, without altered collagen mRNA level. These results suggest that ICT could inhibit the collagen degradation-related factors and facilitate collagen accumulation in atherosclerotic lesions, indicating a new potential of ICT in atherosclerotic plaques. PMID:26828485

Assessment of atherosclerotic plaque activity in patients with sleep apnea using hybrid positron emission tomography/magnetic resonance imaging (PET/MRI): a feasibility study.

PubMed

Kundel, Vaishnavi; Trivieri, Maria Giovanna; Karakatsanis, Nicolas A; Robson, Phillip M; Mani, Venkatesh; Kizer, Jorge R; Kaplan, Robert; Fayad, Zahi; Shah, Neomi

2018-03-05

Evidence suggests that the inflammatory state of an atherosclerotic plaque is important in predicting future risk of plaque rupture. This study aims to investigate the feasibility of measuring plaque inflammation in patients with obstructive sleep apnea (OSA) utilizing advanced vascular imaging - hybrid positron-emission tomography/magnetic resonance imaging (PET/MRI) with fluorodeoxyglucose (FDG) tracer-before and after continuous positive airway pressure (CPAP). Patients with newly diagnosed moderate to severe OSA underwent baseline PET/MRI for assessment of vascular inflammation of the carotid arteries and thoracic aorta prior to initiation of CPAP. Those adherent to CPAP returned for repeat imaging after 3-6 months of CPAP use. Atherosclerotic plaque activity, as measured by arterial wall FDG uptake, was calculated using target-to-background ratios (TBR) before and after CPAP. Five patients were recruited as part of a focused project. Mean age was 52 years (80% male), and mean apnea-hypopnea index (AHI) was 33. Three patients were objectively adherent with CPAP. In the pre-CPAP phase, all patients had focal FDG uptake in the carotid arteries and aorta. After CPAP, there was an average reduction in TBR of 5.5% (TBR mean ) and 6.2% (TBR max ) in carotid and aortic plaque inflammation, similar in magnitude to the reduction observed with statin therapy alone in non-OSA patients (previously reported by others). We demonstrate the feasibility of using hybrid PET/MRI to assess atherosclerotic plaque inflammation in patients with OSA before and after CPAP. Use of the vascular PET/MRI platform in patients with OSA may provide better insight into the role of OSA and its treatment in reducing atherosclerotic inflammation.

Laguerre-based method for analysis of time-resolved fluorescence data: application to in-vivo characterization and diagnosis of atherosclerotic lesions.

PubMed

Jo, Javier A; Fang, Qiyin; Papaioannou, Thanassis; Baker, J Dennis; Dorafshar, Amir H; Reil, Todd; Qiao, Jian-Hua; Fishbein, Michael C; Freischlag, Julie A; Marcu, Laura

2006-01-01

We report the application of the Laguerre deconvolution technique (LDT) to the analysis of in-vivo time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) data and the diagnosis of atherosclerotic plaques. TR-LIFS measurements were obtained in vivo from normal and atherosclerotic aortas (eight rabbits, 73 areas), and subsequently analyzed using LDT. Spectral and time-resolved features were used to develop four classification algorithms: linear discriminant analysis (LDA), stepwise LDA (SLDA), principal component analysis (PCA), and artificial neural network (ANN). Accurate deconvolution of TR-LIFS in-vivo measurements from normal and atherosclerotic arteries was provided by LDT. The derived Laguerre expansion coefficients reflected changes in the arterial biochemical composition, and provided a means to discriminate lesions rich in macrophages with high sensitivity (>85%) and specificity (>95%). Classification algorithms (SLDA and PCA) using a selected number of features with maximum discriminating power provided the best performance. This study demonstrates the potential of the LDT for in-vivo tissue diagnosis, and specifically for the detection of macrophages infiltration in atherosclerotic lesions, a key marker of plaque vulnerability.

Laguerre-based method for analysis of time-resolved fluorescence data: application to in-vivo characterization and diagnosis of atherosclerotic lesions

NASA Astrophysics Data System (ADS)

Jo, Javier A.; Fang, Qiyin; Papaioannou, Thanassis; Baker, J. Dennis; Dorafshar, Amir; Reil, Todd; Qiao, Jianhua; Fishbein, Michael C.; Freischlag, Julie A.; Marcu, Laura

2006-03-01

We report the application of the Laguerre deconvolution technique (LDT) to the analysis of in-vivo time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) data and the diagnosis of atherosclerotic plaques. TR-LIFS measurements were obtained in vivo from normal and atherosclerotic aortas (eight rabbits, 73 areas), and subsequently analyzed using LDT. Spectral and time-resolved features were used to develop four classification algorithms: linear discriminant analysis (LDA), stepwise LDA (SLDA), principal component analysis (PCA), and artificial neural network (ANN). Accurate deconvolution of TR-LIFS in-vivo measurements from normal and atherosclerotic arteries was provided by LDT. The derived Laguerre expansion coefficients reflected changes in the arterial biochemical composition, and provided a means to discriminate lesions rich in macrophages with high sensitivity (>85%) and specificity (>95%). Classification algorithms (SLDA and PCA) using a selected number of features with maximum discriminating power provided the best performance. This study demonstrates the potential of the LDT for in-vivo tissue diagnosis, and specifically for the detection of macrophages infiltration in atherosclerotic lesions, a key marker of plaque vulnerability.

Laguerre-based method for analysis of time-resolved fluorescence data: application to in-vivo characterization and diagnosis of atherosclerotic lesions

PubMed Central

Jo, Javier A.; Fang, Qiyin; Papaioannou, Thanassis; Baker, J. Dennis; Dorafshar, Amir H.; Reil, Todd; Qiao, Jian-Hua; Fishbein, Michael C.; Freischlag, Julie A.; Marcu, Laura

2007-01-01

We report the application of the Laguerre deconvolution technique (LDT) to the analysis of in-vivo time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) data and the diagnosis of atherosclerotic plaques. TR-LIFS measurements were obtained in vivo from normal and atherosclerotic aortas (eight rabbits, 73 areas), and subsequently analyzed using LDT. Spectral and time-resolved features were used to develop four classification algorithms: linear discriminant analysis (LDA), stepwise LDA (SLDA), principal component analysis (PCA), and artificial neural network (ANN). Accurate deconvolution of TR-LIFS in-vivo measurements from normal and atherosclerotic arteries was provided by LDT. The derived Laguerre expansion coefficients reflected changes in the arterial biochemical composition, and provided a means to discriminate lesions rich in macrophages with high sensitivity (>85%) and specificity (>95%). Classification algorithms (SLDA and PCA) using a selected number of features with maximum discriminating power provided the best performance. This study demonstrates the potential of the LDT for in-vivo tissue diagnosis, and specifically for the detection of macrophages infiltration in atherosclerotic lesions, a key marker of plaque vulnerability. PMID:16674179

Comparison of Gadofluorine-M and Gd-DTPA for Non-Invasive Staging of Atherosclerotic Plaque Stability Using MRI

PubMed Central

Ronald, John A.; Chen, Yuanxin; Belisle, Andre J.-L.; Hamilton, Amanda M.; Rogers, Kem A.; Hegele, Robert A.; Misselwitz, Bernd; Rutt, Brian K.

2009-01-01

Background Inflammation and neovascularization play critical roles in the stability of atherosclerotic plaques. Whole-body quantitative assessment of these plaque features may improve patient risk-stratification for life-threatening thromboembolic events and direct appropriate intervention. Here we determined the utility of the MR contrast agent Gadofluorine-M (GdF) for staging plaque stability and compared this to the conventional agent Gd-DTPA. Methods and Results 5 control and 7 atherosclerotic rabbits were sequentially imaged following administration of Gd-DTPA (0.2 mmol/kg) and GdF (0.1 mmol/kg) using a T1-weighted pulse sequence on a 3T MRI scanner. Diseased aortic wall could be distinguished from normal wall based on wall-to-muscle contrast-to-noise values following GdF administration. RAM-11 (macrophages) and CD-31 (endothelial cells) immunostaining of MR-matched histological sections revealed that GdF accumulation was related to the degree of inflammation at the surface of plaques and the extent of core neovascularization. Importantly, an MR measure of GdF accumulation at both 1 and 24 hours post-injection, but not Gd-DTPA at peak enhancement, was shown to correlate with a quantitative histological morphology index related to these two plaque features. Conclusions GdF-enhanced MRI of atherosclerotic plaques allows non-invasive quantitative information about plaque composition to be acquired at multiple time points post-injection (within 1 and up to 24 hours post-injection). This dramatically widens the imaging window for assessing plaque stability that is currently attainable with clinically approved MR agents, therefore opening the possibility of whole-body (including coronary) detection of unstable plaques in the future and potentially improved mitigation of cataclysmic cardiovascular events. PMID:19808597

Rationale, Design, and Methodological Aspects of the BUDAPEST-GLOBAL Study (Burden of Atherosclerotic Plaques Study in Twins-Genetic Loci and the Burden of Atherosclerotic Lesions).

PubMed

Maurovich-Horvat, Pál; Tárnoki, Dávid L; Tárnoki, Ádám D; Horváth, Tamás; Jermendy, Ádám L; Kolossváry, Márton; Szilveszter, Bálint; Voros, Viktor; Kovács, Attila; Molnár, Andrea Á; Littvay, Levente; Lamb, Hildo J; Voros, Szilard; Jermendy, György; Merkely, Béla

2015-12-01

The heritability of coronary atherosclerotic plaque burden, coronary geometry, and phenotypes associated with increased cardiometabolic risk are largely unknown. The primary aim of the Burden of Atherosclerotic Plaques Study in Twins-Genetic Loci and the Burden of Atherosclerotic Lesions (BUDAPEST-GLOBAL) study is to evaluate the influence of genetic and environmental factors on the burden of coronary artery disease. By design this is a prospective, single-center, classical twin study. In total, 202 twins (61 monozygotic pairs, 40 dizygotic same-sex pairs) were enrolled from the Hungarian Twin Registry database. All twins underwent non-contrast-enhanced computed tomography (CT) for the detection and quantification of coronary artery calcium and for the measurement of epicardial fat volumes. In addition, a single non-contrast-enhanced image slice was acquired at the level of L3-L4 to assess abdominal fat distribution. Coronary CT angiography was used for the detection and quantification of plaque, stenosis, and overall coronary artery disease burden. For the primary analysis, we will assess the presence and volume of atherosclerotic plaques. Furthermore, the 3-dimensional coronary geometry will be assessed based on the coronary CT angiography datasets. Additional phenotypic analyses will include per-patient epicardial and abdominal fat quantity measurements. Measurements obtained from monozygotic and dizygotic twin pairs will be compared to evaluate the genetic or environmental effects of the given phenotype. The BUDAPEST-GLOBAL study provides a unique framework to shed some light on the genetic and environmental influences of cardiometabolic disorders. © 2015 Wiley Periodicals, Inc.

Fluorescence spectroscopic detection of virus-induced atherosclerosis

NASA Astrophysics Data System (ADS)

Yan, Wei-dong; Perk, Masis; Nation, Patric N.; Power, Robert F.; Liu, Liying; Jiang, Xiuyan; Lucas, Alexandra

1994-07-01

Laser-induced fluorescence (LF) has been developed as a diagnostic tool for the detection of atherosclerosis. We have examined the use of LF for the identification of accelerated atherosclerotic plaque growth induced by Marek's Disease Virus (MDV) infection in White Leghorn rooster chicks (R) as well as plaque regression after treatment. Twenty-eight newborn R were infected with 12,000 cfu of MDV. Twelve parallel control R had saline injection. LF spectra were recorded from the arteries in vitro with a CeramOptec laser angioplasty catheter during 308 nm XeCl excimer laser excitation. Significant differences were detected at 440 to 475, 525, 550, 600, and 650 nm in MDV-R (p<0.05). In a subsequent study, 60 R were infected with 5,000 cfu of MDV, and were then treated with either Pravastatin (PRV) or placebo at 3 months post infection. These PRV-R were followed for 6 months to detect changes in atherosclerotic plaque development. PRV reduced intimal proliferation produced by MDV infection on histological examination (PRV-R 128.0+/- 44.0 micrometers , placebo-R 412.2+/- 91.5 micrometers , pequals0.007). MDV infected, PRV treated R were examined for LF changes that correlated with decreased atherosclerosis. There was an associated significant increase in LF intensity in PRV-R at 405 to 425 nm (p<0.001). In conclusion, LF can detect intimal proliferation in virus- induced atherosclerosis and atherosclerotic plaque regression after PRV therapy.

Vulnerable atherosclerotic plaque morphology in apolipoprotein E-deficient mice unable to make ascorbic Acid.

PubMed

Nakata, Yukiko; Maeda, Nobuyo

2002-03-26

Oxidative stress is thought to play an important role in atherogenesis, suggesting that antioxidants could prevent coronary artery disease. However, the efficacy of vitamin C in reducing atherosclerosis is debatable in humans and has not been tested rigorously in animals. Gulo(-/-)Apoe(-/-) mice were used to test a hypothesis that chronic vitamin C deficiency enhances the initiation and development of atherosclerosis. These mice are dependent on dietary vitamin C because of the lack of L-gulonolactone-gamma-oxidase and are prone to develop atherosclerosis because of lacking apolipoprotein E. Beginning at 6 weeks of age, the Gulo(-/-)Apoe(-/-) mice were fed regular chow or Western-type diets containing high fat and supplemented with either 0.033 g or 3.3 g/L of vitamin C in their drinking water. This regimen produced mice with chronically low vitamin C (average 1.5 microg/mL in plasma) or high vitamin C (average 10 to 30 microg/mL in plasma). Morphometric analysis showed that within each sex, age, and diet group, the sizes of the atherosclerotic plaques were not different between low vitamin C mice and high vitamin C mice. However, advanced plaques in the low vitamin C mice had significantly reduced amounts of Sirius red-staining collagen (36.4+/-2.2% versus 54.8+/-2.3%, P<0.0001), larger necrotic cores within the plaques, and reduced fibroproliferation and neovascularization in the aortic adventitia. Chronic vitamin C deficiency does not influence the initiation or progression of atherosclerotic plaques but severely compromises collagen deposition and induces a type of plaque morphology that is potentially vulnerable to rupture.

Alternation of histone and DNA methylation in human atherosclerotic carotid plaques.

PubMed

Greißel, A; Culmes, M; Napieralski, R; Wagner, E; Gebhard, H; Schmitt, M; Zimmermann, A; Eckstein, H-H; Zernecke, A; Pelisek, J

2015-08-01

Little is known about epigenetics and its possible role in atherosclerosis. We here analysed histone and DNA methylation and the expression of corresponding methyltransferases in early and advanced human atherosclerotic carotid lesions in comparison to healthy carotid arteries. Western Blotting was performed on carotid plaques from our biobank with early (n=60) or advanced (n=60) stages of atherosclerosis and healthy carotid arteries (n=12) to analyse di-methylation patterns of histone H3 at positions K4, K9 and K27. In atherosclerotic lesions, di-methylation of H3K4 was unaltered and that of H3K9 and H3K27 significantly decreased compared to control arteries. Immunohistochemistry revealed an increased appearance of di-methylated H3K4 in smooth muscle cells (SMCs), a decreased expression of di-methylated H3K9 in SMCs and inflammatory cells, and reduced di-methylated H3K27 in inflammatory cells in advanced versus early atherosclerosis. Expression of corresponding histone methyltransferases MLL2 and G9a was increased in advanced versus early atherosclerosis. Genomic DNA hypomethylation, as determined by PCR for methylated LINE1 and SAT-alpha, was observed in early and advanced plaques compared to control arteries and in cell-free serum of patients with high-grade carotid stenosis compared to healthy volunteers. In contrast, no differences in DNA methylation were observed in blood cells. Expression of DNA-methyltransferase DNMT1 was reduced in atherosclerotic plaques versus controls, DNMT3A was undetectable, and DNMT3B not altered. DNA-demethylase TET1 was increased in atherosclerosisc plaques. The extent of histone and DNA methylation and expression of some corresponding methyltransferases are significantly altered in atherosclerosis, suggesting a possible contribution of epigenetics in disease development.

Dietary micronutrient intake and atherosclerosis in systemic lupus erythematosus.

PubMed

Lourdudoss, C; Elkan, A-C; Hafström, I; Jogestrand, T; Gustafsson, T; van Vollenhoven, R; Frostegård, J

2016-12-01

The aim of this study was to investigate the role of dietary micronutrient intake in systemic lupus erythematosus (SLE). This study included 111 SLE patients and 118 age and gender-matched controls. Data on diet (food frequency questionnaires) were linked with data on Systemic Lupus Activity Measure, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and carotid atherosclerotic/echolucent plaque (B-mode ultrasound). Dietary micronutrient intake were compared between SLE patients and controls and in relation to lupus activity and atherosclerosis in SLE. Associations between micronutrient intake and plaque were analyzed through logistic regression, adjusted for potential confounders. Micronutrient intake did not differ between patients and controls, and between lower and higher lupus activity, apart from the fact that phosphorus was associated with SLEDAI > 6. In SLE patients, some micronutrients were associated with atherosclerotic plaque, left side. Lower intake of riboflavin and phosphorus was associated with atherosclerotic plaque, left side (odds ratio (OR) 3.06, 95% confidence interval (CI) 1.12-8.40 and OR 4.36, 95% CI 1.53-12.39, respectively). Higher intake of selenium and thiamin was inversely associated with atherosclerotic plaque, left side (OR 0.28, 95% CI 0.09-0.89 and OR 0.26, 95% CI 0.08-0.80, respectively). In addition, higher intake of thiamin was inversely associated with echolucent plaque, left side (OR 0.22, 95% CI 0.06-0.84). Lower intake of folate was inversely associated with bilateral echolucent plaque (OR 0.36, 95% CI 0.13-0.99). SLE patients did not have different dietary micronutrient intake compared to controls. Phosphorus was associated with lupus activity. Riboflavin, phosphorus, selenium and thiamin were inversely associated with atherosclerotic plaque, left side in SLE patients, but not in controls. Dietary micronutrients may play a role in atherosclerosis in SLE. © The Author(s) 2016.

Classification of human coronary atherosclerotic plaques using ex vivo high-resolution multicontrast-weighted MRI compared with histopathology.

PubMed

Li, Tao; Li, Xin; Zhao, Xihai; Zhou, Weihua; Cai, Zulong; Yang, Li; Guo, Aitao; Zhao, Shaohong

2012-05-01

The objective of our study was to evaluate the feasibility of ex vivo high-resolution multicontrast-weighted MRI to accurately classify human coronary atherosclerotic plaques according to the American Heart Association classification. Thirteen human cadaver heart specimens were imaged using high-resolution multicontrast-weighted MR technique (T1-weighted, proton density-weighted, and T2-weighted). All MR images were matched with histopathologic sections according to the landmark of the bifurcation of the left main coronary artery. The sensitivity and specificity of MRI for the classification of plaques were determined, and Cohen's kappa analysis was applied to evaluate the agreement between MRI and histopathology in the classification of atherosclerotic plaques. One hundred eleven MR cross-sectional images obtained perpendicular to the long axis of the proximal left anterior descending artery were successfully matched with the histopathologic sections. For the classification of plaques, the sensitivity and specificity of MRI were as follows: type I-II (near normal), 60% and 100%; type III (focal lipid pool), 80% and 100%; type IV-V (lipid, necrosis, fibrosis), 96.2% and 88.2%; type VI (hemorrhage), 100% and 99.0%; type VII (calcification), 93% and 100%; and type VIII (fibrosis without lipid core), 100% and 99.1%, respectively. Isointensity, which indicates lipid composition on histopathology, was detected on MRI in 48.8% of calcified plaques. Agreement between MRI and histopathology for plaque classification was 0.86 (p < 0.001). Ex vivo high-resolution multicontrast-weighted MRI can accurately classify advanced atherosclerotic plaques in human coronary arteries.

Apoptosis does not mediate macrophage depletion in rabbit atherosclerotic plaques after dietary lipid lowering.

PubMed

Martinet, Wim; Croons, Valerie; Herman, Arnold G; De Meyer, Guido R Y

2009-08-01

Unstable atherosclerotic plaques are characterized by a thin fibrous cap that contains few smooth muscle cells (SMCs) and numerous foam cells of macrophage origin. Previously we and others demonstrated that macrophages disappear from atherosclerotic plaques after dietary lipid lowering. However, it remains unclear whether loss of macrophages after lipid lowering occurs via increased apoptosis, decreased macrophage replication and/or recruitment, or via a combination of both. Rabbits were fed a diet supplemented with cholesterol (0.3%) for 24 weeks followed by a normal diet for 4, 12, or 24 weeks. After 24 weeks of cholesterol supplement, plaques showed apoptosis in both macrophages and SMCs, as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Cell replication (Ki-67 immunolabeling) was predominantly present in macrophages. After 24 weeks of cholesterol withdrawal, the thickness and areas of the plaques were unchanged. Nevertheless, plaques showed a considerable loss of macrophages. This event was associated with a reduced immunoreactivity for vascular cell adhesion molecule-1 (VCAM-1) in the endothelial cells starting 4 weeks after cholesterol withdrawal. Apoptosis did not increase after lipid lowering but showed a steady decline. Apart from decreased VCAM-1 expression, a strong decrease in Ki-67 immunolabeling was observed after 12 weeks of cholesterol withdrawal. Our findings suggest that loss of macrophages in atherosclerotic plaques after dietary lipid lowering is not related to induction of macrophage apoptosis but mainly a consequence of impaired monocyte recruitment followed by decreased macrophage replication. This information is essential for understanding the effects of aggressive lipid lowering on plaque stability.

Quantitative T1 and T2* carotid atherosclerotic plaque imaging using a three-dimensional multi-echo phase-sensitive inversion recovery sequence: a feasibility study.

PubMed

Fujiwara, Yasuhiro; Maruyama, Hirotoshi; Toyomaru, Kanako; Nishizaka, Yuri; Fukamatsu, Masahiro

2018-06-01

Magnetic resonance imaging (MRI) is widely used to detect carotid atherosclerotic plaques. Although it is important to evaluate vulnerable carotid plaques containing lipids and intra-plaque hemorrhages (IPHs) using T 1 -weighted images, the image contrast changes depending on the imaging settings. Moreover, to distinguish between a thrombus and a hemorrhage, it is useful to evaluate the iron content of the plaque using both T 1 -weighted and T 2 *-weighted images. Therefore, a quantitative evaluation of carotid atherosclerotic plaques using T 1 and T 2 * values may be necessary for the accurate evaluation of plaque components. The purpose of this study was to determine whether the multi-echo phase-sensitive inversion recovery (mPSIR) sequence can improve T 1 contrast while simultaneously providing accurate T 1 and T 2 * values of an IPH. T 1 and T 2 * values measured using mPSIR were compared to values from conventional methods in phantom and in vivo studies. In the phantom study, the T 1 and T 2 * values estimated using mPSIR were linearly correlated with those of conventional methods. In the in vivo study, mPSIR demonstrated higher T 1 contrast between the IPH phantom and sternocleidomastoid muscle than the conventional method. Moreover, the T 1 and T 2 * values of the blood vessel wall and sternocleidomastoid muscle estimated using mPSIR were correlated with values measured by conventional methods and with values reported previously. The mPSIR sequence improved T 1 contrast while simultaneously providing accurate T 1 and T 2 * values of the neck region. Although further study is required to evaluate the clinical utility, mPSIR may improve carotid atherosclerotic plaque detection and provide detailed information about plaque components.

[Expression and antagonist role of endothelin and nitric oxide synthase in atherosclerotic plaque].

PubMed

Song, L; Wang, D; Wang, T

1997-02-01

To study the pathogenetic mechanism of atherosclerotic plaque, the action of mediation and antagonism of endothelin (ET) and nitric oxide synthase (NOS) was investigated. In situ hybridization, RT-PCR on endothelin and NOS, cytochemistry on NOS were measured using the rabbit atherosclerosis model and cultured vascular smooth muscle cells (VSMC) from normal rabbit. Transcription of endothelin mRNA increased and transcription of NOS mRNA decreased in astherosclerotic plaque: compared with normal aorta, expression of ET gene in plaque was increased by 1.2 times and the expression of NOS gene was decreased by 22.2%; cytochemistry combined with image pattern analysis showed that ET could inhibit NOS protien synthesis in VSMC; type A receptor antagonist of ET could inhibit the role of ET which causes a decrease of NOS protein in VSMC. The imbalance between NOS and ET, namely abnormal increase of ET and/or obvious decrease of NOS, is related to atherosclerotic plaque formation.

Imaging of the Fibrous Cap in Atherosclerotic Carotid Plaque

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saba, Luca, E-mail: lucasaba@tiscali.i; Potters, Fons; Lugt, Aad van der

2010-08-15

In the last two decades, a substantial number of articles have been published to provide diagnostic solutions for patients with carotid atherosclerotic disease. These articles have resulted in a shift of opinion regarding the identification of stroke risk in patients with carotid atherosclerotic disease. In the recent past, the degree of carotid artery stenosis was the sole determinant for performing carotid intervention (carotid endarterectomy or carotid stenting) in these patients. We now know that the degree of stenosis is only one marker for future cerebrovascular events. If one wants to determine the risk of these events more accurately, other parametersmore » must be taken into account; among these parameters are plaque composition, presence and state of the fibrous cap (FC), intraplaque haemorrhage, plaque ulceration, and plaque location. In particular, the FC is an important structure for the stability of the plaque, and its rupture is highly associated with a recent history of transient ischaemic attack or stroke. The subject of this review is imaging of the FC.« less

Gold nanoparticles based imaging technique and drug delivery for the detection and treatment of atherosclerotic vascular disease

NASA Astrophysics Data System (ADS)

Ankri, Rinat; Leshem-Lev, Dorit; Lev, Eli I.; Motiei, Menachem; Hochhauser, Edith; Fixler, Dror

2016-03-01

In our study we aim to develop a new, simple and non-invasive method to detect and to treat atherosclerosis. We use gold nanoparticles (GNPs) combined with the diffusion reflection (DR) method to demonstrate the detection of vulnerable atherosclerotic plaques. Our method is based on the fact that macrophages are a major component in the vulnerable plaque and are able to uptake metal nanoparticles that can be discovered by the DR system. Moreover, it is well known that high density lipoprotein (HDL) reduces ASVD by inhibiting pro-inflammatory factors, enabling the specific treatment of atherosclerosis.

Reversal of coronary atherosclerosis: Role of life style and medical management.

PubMed

Parsons, Christine; Agasthi, Pradyumna; Mookadam, Farouk; Arsanjani, Reza

2018-05-17

Atherosclerotic coronary artery disease continues to be a major global health burden in developing and developed nations. Newer imaging techniques afford an accurate assessment of plaque burden and characteristics as well as the effects of treatment. Lifestyle interventions and pharmacotherapy remain the mainstay of non-interventional treatment of coronary atherosclerosis, with reversal seen in many studies. In addition, control of modifiable risk factors can be beneficial. As a better understanding of atherosclerosis pathophysiology is achieved, new therapeutic targets and combination therapies may join the armamentarium that promotes regression of atherosclerotic plaque. We present a review of the literature regarding lifestyle and medical therapies that can promote the reversal of coronary atherosclerosis. Copyright © 2018. Published by Elsevier Inc.

The values of wall shear stress, turbulence kinetic energy and blood pressure gradient are associated with atherosclerotic plaque erosion in rabbits.

PubMed

Sameshima, Naoki; Yamashita, Atsushi; Sato, Shinya; Matsuda, Shuntaro; Matsuura, Yunosuke; Asada, Yujiro

2014-01-01

To clarify the contribution of hemodynamic factors to the onset of plaque erosion in smooth muscle cell (SMC)-rich atherosclerotic plaque. We developed a rabbit model of SMC-rich atherosclerotic plaque with various degree of stenosis induced by incomplete ligation and generated three-dimensional models of five rabbit femoral arteries based on 130-162 serial histological cross-sections at 100-μm intervals per artery. We performed a computational blood flow simulation using the Reynolds-averaged Navier-Stokes model and calculated the wall shear stress (WSS), turbulence kinetic energy (TKE), blood pressure (BP) and blood pressure gradients (BPG) in eight sections (the inlet, the stenotic portion and areas 1, 2 and 5mm from the stenotic portion) in each rabbit. We also investigated whether the magnitude of WSS or TKE was related to the presence or absence of erosive injury by evaluating six points (the locally highest, median and lowest of WSS or TKE) in each section. The magnitudes of WSS, TKE and BPG, but not BP, correlated significantly with the extent of histologically-defined plaque erosion (WSS, r=0.55, p＜0.001; TKE, r=0.53, p＜0.001; BPG, r=0.61, p＜0.0001, n=40). The values for WSS and TKE were significantly larger at sites with, compared to without, erosive injury (n=107 and n=119 points, respectively; both p＜0.0001). These results suggest that increased values of WSS, TKE and BPG considerably contribute to the onset of plaque erosion.

Mathematical Modeling of Intravascular Blood Coagulation under Wall Shear Stress

PubMed Central

Rukhlenko, Oleksii S.; Dudchenko, Olga A.; Zlobina, Ksenia E.; Guria, Georgy Th.

2015-01-01

Increased shear stress such as observed at local stenosis may cause drastic changes in the permeability of the vessel wall to procoagulants and thus initiate intravascular blood coagulation. In this paper we suggest a mathematical model to investigate how shear stress-induced permeability influences the thrombogenic potential of atherosclerotic plaques. Numerical analysis of the model reveals the existence of two hydrodynamic thresholds for activation of blood coagulation in the system and unveils typical scenarios of thrombus formation. The dependence of blood coagulation development on the intensity of blood flow, as well as on geometrical parameters of atherosclerotic plaque is described. Relevant parametric diagrams are drawn. The results suggest a previously unrecognized role of relatively small plaques (resulting in less than 50% of the lumen area reduction) in atherothrombosis and have important implications for the existing stenting guidelines. PMID:26222505

AHA classification of coronary and carotid atherosclerotic plaques by grating-based phase-contrast computed tomography.

PubMed

Hetterich, Holger; Webber, Nicole; Willner, Marian; Herzen, Julia; Birnbacher, Lorenz; Hipp, Alexander; Marschner, Mathias; Auweter, Sigrid D; Habbel, Christopher; Schüller, Ulrich; Bamberg, Fabian; Ertl-Wagner, Birgit; Pfeiffer, Franz; Saam, Tobias

2016-09-01

To evaluate the potential of grating-based phase-contrast computed-tomography (gb-PCCT) to classify human carotid and coronary atherosclerotic plaques according to modified American Heart Association (AHA) criteria. Experiments were carried out at a laboratory-based set-up consisting of X-ray tube (40 kVp), grating-interferometer and detector. Eighteen human carotid and coronary artery specimens were examined. Histopathology served as the standard of reference. Vessel cross-sections were classified as AHA lesion type I/II, III, IV/V, VI, VII or VIII plaques by two independent reviewers blinded to histopathology. Conservative measurements of diagnostic accuracies for the detection and differentiation of plaque types were evaluated. A total of 127 corresponding gb-PCCT/histopathology sections were analyzed. Based on histopathology, lesion type I/II was present in 12 (9.5 %), III in 18 (14.2 %), IV/V in 38 (29.9 %), VI in 16 (12.6 %), VII in 34 (26.8 %) and VIII in 9 (7.0 %) cross-sections. Sensitivity, specificity and positive and negative predictive value were ≥0.88 for most analyzed plaque types with a good level of agreement (Cohen's kappa = 0.90). Overall, results were better in carotid (kappa = 0.97) than in coronary arteries (kappa = 0.85). Inter-observer agreement was high with kappa = 0.85, p < 0.0001. These results indicate that gb-PCCT can reliably classify atherosclerotic plaques according to modified AHA criteria with excellent agreement to histopathology. • Different atherosclerotic plaque types display distinct morphological features in phase-contrast CT. • Phase-contrast CT can detect and differentiate AHA plaque types. • Calcifications caused streak artefacts and reduced sensitivity in type VI lesions. • Overall agreement was higher in carotid than in coronary arteries.

Characterization of the europium tetracycline complex as a biomarker for atherosclerosis

NASA Astrophysics Data System (ADS)

Courrol, Lilia C.; da Silva, Mônica N.; Sicchieri, Leticia B.

2016-04-01

Atherosclerosis is a narrowing of the arteries caused by an increase of atheromatous plaque: material formed by macrophage cells containing cholesterol and fatty acids, calcium and a variable amount of fibrous connective tissue. The elation between vulnerable plaques and cardiovascular events can be determined using plaque biomarkers. In this work, atherosclerotic plaques stained with different molar ratios of europium, in a potential plaque biomarker, europium tetracycline complex, were studied by fluorescence microscopy. The tetracycline antibiotic used was chlortetracycline. The growth of atherosclerotic plaque was followed during 60 days in New Zealand rabbits divided in two groups: an experimental group (EG), with nine animals and a control group (CG) with three animals. The animals in the EG received a diet with 1% of cholesterol and the animals of GC received a normal diet. The aortic arch of the animals with 60 days were cut in the vertical plane in 6 μm thick slices, which were mounted on glass slides and stained with hematoxylin an eosin and europium chlortetracycline complex (EuCTc). The fluorescence images were obtained exciting the EuCTc absorption band with a filter cube D (BP 355 - 425) and the emission was collected with a LP 470 suppression filter. Light intensity, detector gain and acquisition time were fixed for comparisons. The 20× magnified images were collected with 12 bit (or 4096 gray tones) resolution. The mean value of gray scale for each molar ratio of EuCTc was different, indicating that the complex interacts with the components of atherosclerotic plaque and the best molar ratio was 1.5 EuCTc. These results indicate the potential use of the EuCTc biomarker for atherosclerotic plaque characterization.

Gadolinium Enhancement in Intracranial Atherosclerotic Plaque and Ischemic Stroke: A Systematic Review and Meta-Analysis.

PubMed

Gupta, Ajay; Baradaran, Hediyeh; Al-Dasuqi, Khalid; Knight-Greenfield, Ashley; Giambrone, Ashley E; Delgado, Diana; Wright, Drew; Teng, Zhongzhao; Min, James K; Navi, Babak B; Iadecola, Costantino; Kamel, Hooman

2016-08-15

Gadolinium enhancement on high-resolution magnetic resonance imaging (MRI) has been proposed as a marker of inflammation and instability in intracranial atherosclerotic plaque. We performed a systematic review and meta-analysis to summarize the association between intracranial atherosclerotic plaque enhancement and acute ischemic stroke. We searched the medical literature to identify studies of patients undergoing intracranial vessel wall MRI for evaluation of intracranial atherosclerotic plaque. We recorded study data and assessed study quality, with disagreements in data extraction resolved by a third reader. A random-effects odds ratio was used to assess whether, in any given patient, cerebral infarction was more likely in the vascular territory supplied by an artery with MRI-detected plaque enhancement as compared to territory supplied by an artery without enhancement. We calculated between-study heterogeneity using the Cochrane Q test and publication bias using the Begg-Mazumdar test. Eight articles published between 2011 and 2015 met inclusion criteria. These studies provided information about plaque enhancement characteristics from 295 arteries in 330 patients. We found a significant positive relationship between MRI enhancement and cerebral infarction in the same vascular territory, with a random effects odds ratio of 10.8 (95% CI 4.1-28.1, P<0.001). No significant heterogeneity (Q=11.08, P=0.14) or publication bias (P=0.80) was present. Intracranial plaque enhancement on high-resolution vessel wall MRI is strongly associated with ischemic stroke. Evaluation for plaque enhancement on MRI may be a useful test to improve diagnostic yield in patients with ischemic strokes of undetermined etiology. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Effect of intraplaque angiogenesis to atherosclerotic rupture-prone plaque induced by high shear stress in rabbit model

PubMed Central

Qiu, Juhui; Lei, Daoxi; Hu, Jianjun; Yin, Tieying; Zhang, Kang; Yu, Donghong

2017-01-01

Abstract Atherosclerotic prone-rupture plaque is mainly localized in the region of the entrance to the stenosis with high shear stress and the reasons are largely unknown. Our hypothesis is that such a distribution of cells in atherosclerotic plaque may depend on the angiogenesis. Silastic collars induced regions of high shear stress (20.68 ± 5.27 dynes/cm2) in the upstream flow and low shear stress (12.25 ± 1.28 dynes/cm2) in the downstream flow in carotid arteries. Compared with the low shear stress region, plaques in the high shear stress region showed more intraplaque haemorrhaging, less collagen and higher apoptotic rates of vascular smooth muscle cells; endothelial cells (ECs) in the high shear stress region were characterized with integrity and high endothelial nitric oxide synthase (eNOS) expression (1570.3 ± 345.5% vs 172.9 ± 49.9%). The number of intraplaque microvessels is very high in the high shear stress region (15 ± 1.8 n/mm2 vs 3.5 ± 0.4 n/mm2), and the microvessels in the plaque show ECs were abnormal, with membrane blebs, intracytoplasmic vacuoles and leukocyte infiltration. Our current study reveals that the integrity of the endothelium and the vulnerability of atherosclerotic plaques are simultaneously localized in high shear stress regions, and we provide evidence for the first time that microvessels in the intraplaque maybe responsible for rupture-prone plaque formation in the high shear stress region. PMID:28798867

HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages.

PubMed

Sanchez-Gaytan, Brenda L; Fay, Francois; Lobatto, Mark E; Tang, Jun; Ouimet, Mireille; Kim, YongTae; van der Staay, Susanne E M; van Rijs, Sarian M; Priem, Bram; Zhang, Liangfang; Fisher, Edward A; Moore, Kathryn J; Langer, Robert; Fayad, Zahi A; Mulder, Willem J M

2015-03-18

High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle composed of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA-HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA-HDL nanoparticles in atherosclerotic plaques, which colocalized with plaque macrophages. This biomimetic platform integrates the targeting capacity of HDL biomimetic nanoparticles with the characteristic versatility of PLGA-based nanocarriers.

HDL-Mimetic PLGA Nanoparticle To Target Atherosclerosis Plaque Macrophages

PubMed Central

Sanchez-Gaytan, Brenda L.; Fay, Francois; Lobatto, Mark E.; Tang, Jun; Ouimet, Mireille; Kim, YongTae; van der Staay, Susanne E. M.; van Rijs, Sarian M.; Priem, Bram; Zhang, Liangfang; Fisher, Edward A; Moore, Kathryn J.; Langer, Robert; Fayad, Zahi A.; Mulder, Willem J M

2015-01-01

High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle composed of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA–HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA–HDL nanoparticles in atherosclerotic plaques, which colocalized with plaque macrophages. This biomimetic platform integrates the targeting capacity of HDL biomimetic nanoparticles with the characteristic versatility of PLGA-based nanocarriers. PMID:25650634

In vivo Raman spectral pathology of human atherosclerosis and vulnerable plaque

NASA Astrophysics Data System (ADS)

Motz, Jason T.; Fitzmaurice, Maryann; Miller, Arnold; Gandhi, Saumil J.; Haka, Abigail S.; Galindo, Luis; Dasari, Ramachandra R.; Kramer, John R., Jr.; Feld, Michael S.

2006-03-01

The rupture of vulnerable atherosclerotic plaque accounts for the majority of clinically significant acute cardiovascular events. Because stability of these culprit lesions is directly related to chemical and morphological composition, Raman spectroscopy may be a useful technique for their study. Recent developments in optical fiber probe technology have allowed for the real-time in vivo Raman spectroscopic characterization of human atherosclerotic plaque demonstrated in this work. We spectroscopically examine 74 sites during carotid endarterectomy and femoral artery bypass surgeries. Of these, 34 are surgically biopsied and examined histologically. Excellent signal-to-noise ratio spectra are obtained in only 1 s and fit with an established model, demonstrating accurate tissue characterization. We also report the first evidence that Raman spectroscopy has the potential to identify vulnerable plaque, achieving a sensitivity and specificity of 79 and 85%, respectively. These initial findings indicate that Raman spectroscopy has the potential to be a clinically relevant diagnostic tool for studying cardiovascular disease.

Incremental value of live/real time three-dimensional transesophageal echocardiography over the two-dimensional technique in the assessment of aortic atherosclerotic thrombi and ulcers.

PubMed

Elsayed, Mahmoud; Bulur, Serkan; Kalla, Aditi; Ahmed, Mustafa I; Hsiung, Ming C; Uygur, Begum; Alagic, Nermina; Sungur, Aylin; Singh, Satinder; Nanda, Navin C

2016-08-01

We present two cases in whom live/real time three-dimensional transesophageal echocardiography (3DTEE) provided incremental value in the assessment of atherosclerotic disease in the aorta. In one patient, it identified additional atherosclerotic ulcers as well as thrombi within them which were missed by two-dimensional (2D) TEE. In both cases, the size of the large mobile atherosclerotic plaque was underestimated by 2DTEE as compared with 3DTEE. Furthermore, 3DTEE provided volume quantification of the thrombi and ulcers which is not possible by 2DTEE. The echocardiographic findings of atherosclerotic plaques were confirmed by computed tomography in one patient and by surgery in the other. © 2016, Wiley Periodicals, Inc.

Molecular Imaging of Atherothrombotic Diseases: Seeing Is Believing.

PubMed

Wang, Xiaowei; Peter, Karlheinz

2017-06-01

Molecular imaging, with major advances in the development of both innovative targeted contrast agents/particles and radiotracers, as well as various imaging technologies, is a fascinating, rapidly growing field with many preclinical and clinical applications, particularly for personalized medicine. Thrombosis in either the venous or the arterial system, the latter typically caused by rupture of unstable atherosclerotic plaques, is a major determinant of mortality and morbidity in patients. However, imaging of the various thrombotic complications and the identification of plaques that are prone to rupture are at best indirect, mostly unreliable, or not available at all. The development of molecular imaging toward diagnosis and prevention of thrombotic disease holds promise for major advance in this clinically important field. Here, we review the medical need and clinical importance of direct molecular imaging of thrombi and unstable atherosclerotic plaques that are prone to rupture, thereby causing thrombotic complications such as myocardial infarction and ischemic stroke. We systematically compare the advantages/disadvantages of the various molecular imaging modalities, including X-ray computed tomography, magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, fluorescence imaging, and ultrasound. We further systematically discuss molecular targets specific for thrombi and those characterizing unstable, potentially thrombogenic atherosclerotic plaques. Finally, we provide examples for first theranostic approaches in thrombosis, combining diagnosis, targeted therapy, and monitoring of therapeutic success or failure. Overall, molecular imaging is a rapidly advancing field that holds promise of major benefits to many patients with atherothrombotic diseases. © 2017 American Heart Association, Inc.

Mathematical modeling of atherosclerotic plaque destabilization: Role of neovascularization and intraplaque hemorrhage.

PubMed

Guo, Muyi; Cai, Yan; Yao, Xinke; Li, Zhiyong

2018-08-07

Observational studies have identified angiogenesis from the adventitial vasa vasorum and intraplaque hemorrhage (IPH) as critical factors in atherosclerotic plaque progression and destabilization. Here we propose a mathematical model incorporating intraplaque neovascularization and hemodynamic calculation with plaque destabilization for the quantitative evaluation of the role of neoangiogenesis and IPH in the vulnerable atherosclerotic plaque formation. An angiogenic microvasculature is generated by two-dimensional nine-point discretization of endothelial cell proliferation and migration from the vasa vasorum. Three key cells (endothelial cells, smooth muscle cells and macrophages) and three key chemicals (vascular endothelial growth factors, extracellular matrix and matrix metalloproteinase) are involved in the plaque progression model, and described by the reaction-diffusion partial differential equations. The hemodynamic calculation of the microcirculation on the generated microvessel network is carried out by coupling the intravascular, interstitial and transvascular flow. The plasma concentration in the interstitial domain is defined as the description of IPH area according to the diffusion and convection with the interstitial fluid flow, as well as the extravascular movement across the leaky vessel wall. The simulation results demonstrate a series of pathophysiological phenomena during the vulnerable progression of an atherosclerotic plaque, including the expanding necrotic core, the exacerbated inflammation, the high microvessel density (MVD) region at the shoulder areas, the transvascular flow through the capillary wall and the IPH. The important role of IPH in the plaque destabilization is evidenced by simulations with varied model parameters. It is found that the IPH can significantly speed up the plaque vulnerability by increasing necrotic core and thinning fibrous cap. In addition, the decreased MVD and vessel permeability may slow down the process of plaque destabilization by reducing the IPH dramatically. We envision that the present model and its future advances can serve as a valuable theoretical platform for studying the dynamic changes in the microenvironment during the plaque destabilization. Copyright © 2018 Elsevier Ltd. All rights reserved.

Polymeric nanoparticle PET/MR imaging allows macrophage detection in atherosclerotic plaques

PubMed Central

Majmudar, Maulik D.; Yoo, Jeongsoo; Keliher, Edmund J.; Truelove, Jessica; Iwamoto, Yoshiko; Sena, Brena; Dutta, Partha; Borodovsky, Anna; Fitzgerald, Kevin; Di Carli, Marcelo; Libby, Peter; Anderson, Daniel G.; Swirski, Filip K.; Weissleder, Ralph; Nahrendorf, Matthias

2013-01-01

Rationale Myeloid cell content in atherosclerotic plaques associates with rupture and thrombosis. Thus, imaging of lesional monocyte and macrophages (Mo/Mϕ) could serve as a biomarker of disease progression and therapeutic intervention. Objective To noninvasively assess plaque inflammation with dextran nanoparticle-facilitated hybrid PET/MR imaging. Methods and Results Using clinically approved building blocks, we systematically developed 13nm polymeric nanoparticles consisting of crosslinked short chain dextrans which were modified with desferoxamine for zirconium-89 radiolabeling (89Zr-DNP) and a near infrared fluorochrome (VT680) for microscopic and cellular validation. Flow cytometry of cells isolated from excised aortas showed DNP uptake predominantly in Mo/Mϕ (76.7%) and lower signal originating from other leukocytes such as neutrophils and lymphocytes (11.8% and 0.7%, p<0.05 versus Mo/Mϕ). DNP colocalized with the myeloid cell marker CD11b on immunohistochemistry. PET/MRI revealed high uptake of 89Zr-DNP in the aortic root of ApoE−/− mice (standard uptake value, ApoE−/− mice versus wild type controls, 1.9±0.28 versus 1.3±0.03, p<0.05), corroborated by ex vivo scintillation counting and autoradiography. Therapeutic silencing of the monocyte-recruiting receptor CCR2 with siRNA decreased 89Zr-DNP plaque signal (p<0.05) and inflammatory gene expression (p<0.05). Conclusions Hybrid PET/MR imaging with a 13nm DNP enables noninvasive assessment of inflammation in experimental atherosclerotic plaques and reports on therapeutic efficacy of anti-inflammatory therapy. PMID:23300273

Selective removal of cholesterol ester in atherosclerotic plaque using nanosecond pulsed laser at 5.75 μm

NASA Astrophysics Data System (ADS)

Ishii, K.; Tsukimoto, H.; Hazama, H.; Awazu, K.

2008-02-01

Laser angioplasty, for example XeCl excimer laser angioplasty, has gained more attention in addition to conventional methods of surgical and interventional treatment of atherosclerotic diseases such as bypass operation and balloon dilatation. Low degrees of thermal damage after ablation of atherosclerotic lesions have been achieved by XeCl excimer laser at 308 nm. However, in most cases, laser ablation is not selective and normal arterial wall is also damaged. To avoid complications such as severe dissections or perforation of the arterial wall in an angioplasty, a laser light source with high ablation efficiency but low arterial wall injury is desirable. At atherosclerotic lesions, cholesterol accumulates on the tunica intima by establishing an ester bond with fatty acids such as oleic acid, and thus cholesterol ester is the main component of atherosclerotic plaques. Mid-infrared pulsed laser at 5.75 μm is selectively well absorbed in C=O stretching vibration mode of ester bonds. The purpose of this study is to determine the effectiveness of nanosecond pulsed laser at 5.75 μm irradiation of cholesterol ester in atherosclerotic plaques. In this study, we used a mid-infrared tunable solid-state laser which is operated by difference frequency generation method, with a wavelength of 5.75 μm, a pulse width of 5 nsec and a pulse duration of 10 Hz. It was confirmed that non-invasive interaction to normal thoracic aortas could be induce by the parameters, the wavelength of 5.75 μm, the average power densities of 35 W/cm2 and the irradiation time under 10 sec. This study shows that nanosecond pulsed laser irradiations at 5.75 μm provide an alternative laser light source as an effectively cutting, less traumatic tool for removal of atherosclerotic plaque.

Selective ablation of rabbit atherosclerotic plaque with less thermal effect by the control of pulse structure of a quantum cascade laser in the 5.7 μm wavelength range

NASA Astrophysics Data System (ADS)

Hashimura, Keisuke; Ishii, Katsunori; Awazu, Kunio

2016-03-01

Cholesteryl esters are main components of atherosclerotic plaques and have an absorption peak at the wavelength of 5.75 μm originated from C=O stretching vibration mode of ester bond. Our group achieved the selective ablation of atherosclerotic lesions using a quantum cascade laser (QCL) in the 5.7 μm wavelength range. QCLs are relatively new types of semiconductor lasers that can emit mid-infrared range. They are sufficiently compact and considered to be useful for clinical application. However, large thermal effects were observed because the QCL worked as quasicontinuous wave (CW) lasers due to its short pulse interval. Then we tried macro pulse irradiation (irradiation of pulses at intervals) of the QCL and achieved effective ablation with less-thermal effects than conventional quasi-CW irradiation. However, lesion selectivity might be changed by changing pulse structure. Therefore, in this study, irradiation effects of the macro pulse irradiation to rabbit atherosclerotic plaque and normal vessel were compared. The macro pulse width and the macro pulse interval were set to 0.5 and 12 ms, respectively, because the thermal relaxation time of rabbit normal and atherosclerotic aortas in the oscillation wavelength of the QCL was 0.5-12 ms. As a result, cutting difference was achieved between rabbit atherosclerotic and normal aortas by the macro pulse irradiation. Therefore, macro pulse irradiation of a QCL in the 5.7 μm wavelength range is effective for reducing thermal effects and selective ablation of the atherosclerotic plaque. QCLs have the potential of realizing less-invasive laser angioplasty.

Detection and characterization of atherosclerotic plaques by Raman probe spectroscopy and optical coherence tomography (Conference Presentation)

NASA Astrophysics Data System (ADS)

Matthäus, Christian; Dochow, Sebastian; Egodage, Kokila D.; Schie, Iwan; Romeike, Bernd F.; Brehm, Bernhard R.; Popp, Jürgen

2017-02-01

Visualization and characterization of inner arterial plaque depositions is of vital diagnostic interest. Established intravascular imaging techniques provide valuable morphological information, but cannot deliver information about the chemical composition of individual plaques. Probe based Raman spectroscopy offers the possibility for a biochemical characterization of atherosclerotic plaque formations during an intravascular intervention. From post mortem studies it is well known that the severity of a plaque and its stability are strongly correlated with its biochemical composition. Especially the identification of vulnerable plaques remains one of the most important and challenging aspects in cardiology. Thus, specific information about the composition of a plaque would greatly improve the risk assessment and management. Furthermore, knowledge about the composition can offer new therapeutic and medication strategies. Plaque calcifications as well as major lipid components such as cholesterol, cholesterol esters and triglycerides can be spectroscopically easily differentiated. Intravascular optical coherence tomography (OCT) is currently a prominent catheter based imaging technique for the localization and visualization of atherosclerotic plaque depositions. The high resolution of OCT with 10 to 15 µm allows for very detailed characterization of morphological features such as different plaque formations, thin fibrous caps and accurate measurements of lesion lengths. In combination with OCT imaging the obtained spectral information can provide substantial information supporting on on-site diagnosis of various plaque types and therefor an improved risk assessment. The potential and feasibility of combining OCT with Raman spectroscopy is demonstrated on excised plaque samples, as well as under in vivo conditions. Acknowledgements: Financial support from the Carl Zeiss Foundation is greatly acknowledged.

Three-dimensional modeling of oxidized-LDL accumulation and HDL mass transport in a coronary artery: a proof-of-concept study for predicting the region of atherosclerotic plaque development.

PubMed

Sakellarios, Antonis I; Siogkas, Panagiotis K; Athanasiou, Lambros S; Exarchos, Themis P; Papafaklis, Michail I; Bourantas, Christos V; Naka, Katerina K; Michalis, Lampros K; Filipovic, Nenad; Parodi, Oberdan; Fotiadis, Dimitrios I

2013-01-01

Low density lipoprotein (LDL) has a significant role on the atherosclerotic plaque development, while the concentration of high density lipoproteins (HDL) is considered to play an atheroprotective role according to several biochemical mechanisms. In this work, it is the first time that both LDL and HDL concentrations are taken into account in order to predict the regions prone for plaque development. Our modeling approach is based on the use of a realistic three-dimensional reconstructed pig coronary artery in two time points. Biochemical data measured in the pig were also included in order to develop a more customized model. We modeled coronary blood flow by solving the Navier-Stokes equations in the arterial lumen and plasma filtration in the arterial wall using Darcy's Law. HDL transport was modeled only in the arterial lumen using the convection-diffusion equation, while LDL transport was modeled both in the lumen and the arterial wall. An additional novelty of this work is that we model the oxidation of LDL taking into account the atheroprotective role of HDL. The results of our model were in good agreement with histological findings demonstrating that increased oxidized LDL is found near regions of advanced plaques, while non-oxidized LDL is found in regions of early plaque types.

[Study on the effect of rhizoma Chuanxiong, radix paeoniae rubra and the compound of their active ingredients, Xiongshao Capsule, on stability of atherosclerotic plaque in ApoE(-/-) mice].

PubMed

Xu, Hao; Wen, Chuan; Chen, Ke-Ji

2007-06-01

To observe the effect of Rhizoma chuanxiong (RC), Radix Paeoniae rubra (RP) and Xiongshao Capsule (XC, a compound of their active ingredients, Chuanxingols and Paeoniflorins) on stability of atherosclerotic plaque in ApoE-/- mice and to explore the probable mechanisms. The effect of RC, RP and XC in stabilizing atherosclerotic plaque, in terms of pathologic morphology, cell composition and inflammatory reaction, in the atherosclerosis model established on ApoE-/- mice was studied by using optical microscope, immunohistochemical method and computerized imaging analysis respectively. After the ApoE-/- mice being fed with high fat diet for 26 weeks, obvious atherosclerotic lesion with typical unstable characteristics was found in their aortic root. Both RC and RP had certain effects in lowering total cholesterol and increasing the thickness of fibre cap. RC could also lower the serum triglyceride (TC) level and the lipid-core/plaque area ratio as well as reduce the macrocytic infiltration. In addition to the same effects as above mentioned, XS could also raise the levels of high density lipoprotein-cholesterol (HDL-C), lower TC/HDL-C ratio, reduce inflammatory reaction and enlarge the collagen area in plaque. The acting links of RC and RP on atherosclerosis are different, the compound of their active ingredients, XS, shows a more evident effect in intervening unstable plaque. It demonstrates the effect-enhancing power of TCM compound and is worth further studying.

Morphological differences in coronary arteries following rotational atherectomy versus balloon angioplasty: ultrasound and angioscopic observations

NASA Astrophysics Data System (ADS)

Bass, Theodore A.; Gilmore, Paul S.; White, Christopher J.; Chami, Youssef G.; Kircher, Barbara J.; Conetta, Donald A.

1993-09-01

Percutaneous transluminal coronary rotational atherectomy (PTCRA) is an exciting new device to recannulate obstructed coronary arteries. This device works as a high speed `drill,' selectively cutting hard atherosclerotic plaque while preferentially sparing the softer, less diseased vascular luminal surface. At speeds as high as 200,000 rpm the plaque is pulverized into small particles easily handled by the circulatory system with no untoward clinical sequela. Balloon angioplasty does not remove atherosclerotic plaque. It dilates the vessel by mechanically stretching, compressing and splitting the plaque and vessel lining. We compare morphological and surface luminal characteristics of vessels post PTCRA to vessels post PTCA.

Temporal shifts in clinical presentation and underlying mechanisms of atherosclerotic disease.

PubMed

Pasterkamp, Gerard; den Ruijter, Hester M; Libby, Peter

2017-01-01

The concept of the 'vulnerable plaque' originated from pathological observations in patients who died from acute coronary syndrome. This recognition spawned a generation of research that led to greater understanding of how complicated atherosclerotic plaques form and precipitate thrombotic events. In current practice, an increasing number of patients who survive their first event present with non-ST-segment elevation myocardial infarction (NSTEMI) rather than myocardial infarction (MI) with ST-segment elevation (STEMI). The culprit lesions that provide the pathological substrate for NSTEMI can vary considerably from the so-called 'vulnerable plaque'. The shift in clinical presentation of MI and stroke corresponds temporally to a progressive change in the characteristics of human plaques away from the supposed characteristics of vulnerability. These alterations in the structure and function of human atherosclerotic lesions might mirror the modifications that are produced in experimental plaques by lipid lowering, inspired by the vulnerable plaque construct. The shift in the clinical presentations of the acute coronary syndromes mandates a critical reassessment of the underlying mechanisms, proposed risk scores, the results and interpretation of preclinical experiments, as well as recognition of the limitations of the use of population data and samples collected before the application of current preventive interventions.

Tracking Monocyte Recruitment and Macrophage Accumulation in Atherosclerotic Plaque Progression Using a Novel hCD68GFP/ApoE−/− Reporter Mouse—Brief Report

PubMed Central

Iqbal, Asif J.; Jones, Daniel; Patel, Jyoti; Coutinho, Patricia; Taylor, Lewis; Greaves, David R.; Channon, Keith M.

2017-01-01

Objective— To create a model of atherosclerosis using green fluorescent protein (GFP)–targeted monocytes/macrophages, allowing analysis of both endogenous GFP+ and adoptively transferred GFP+ myeloid cells in arterial inflammation. Approach and Results— hCD68GFP reporter mice were crossed with ApoE−/− mice. Expression of GFP was localized to macrophages in atherosclerotic plaques and in angiotensin II–induced aortic aneurysms and correlated with galectin 3 and mCD68 expression. Flow cytometry confirmed GFP+ expression in CD11b+/CD64+, CD11c+/MHC-IIHI, and CD11b+/F4/80+ myeloid cells. Adoptive transfer of GFP+ monocytes demonstrated monocyte recruitment to both adventitia and atherosclerotic plaque, throughout the aortic root, within 72 hours. We demonstrated the biological utility of hCD68GFP monocytes by comparing the recruitment of wild-type and CCR2−/− monocytes to sites of inflammation. Conclusions— hCD68GFP/ApoE−/− mice provide a new approach to study macrophage accumulation in atherosclerotic plaque progression and to identify cells recruited from adoptively transferred monocytes. PMID:27908893

High speed intravascular photoacoustic imaging of atherosclerotic arteries (Conference Presentation)

NASA Astrophysics Data System (ADS)

Piao, Zhonglie; Ma, Teng; Qu, Yueqiao; Li, Jiawen; Yu, Mingyue; He, Youmin; Shung, K. Kirk; Zhou, Qifa; Kim, Chang-Seok; Chen, Zhongping

2016-02-01

Cardiovascular disease is the leading cause of death in the industrialized nations. Accurate quantification of both the morphology and composition of lipid-rich vulnerable atherosclerotic plaque are essential for early detection and optimal treatment in clinics. In previous works, intravascular photoacoustic (IVPA) imaging for detection of lipid-rich plaque within coronary artery walls has been demonstrated in ex vivo, but the imaging speed is still limited. In order to increase the imaging speed, a high repetition rate laser is needed. In this work, we present a high speed integrated IVPA/US imaging system with a 500 Hz optical parametric oscillator laser at 1725 nm. A miniature catheter with 1.0 mm outer diameter was designed with a 200 μm multimode fiber and an ultrasound transducer with 45 MHz center frequency. The fiber was polished at 38 degree and enclosed in a glass capillary for total internal reflection. An optical/electrical rotary junction and pull-back mechanism was applied for rotating and linearly scanning the catheter to obtain three-dimensional imaging. Atherosclerotic rabbit abdominal aorta was imaged as two frame/second at 1725 nm. Furthermore, by wide tuning range of the laser wavelength from 1680 nm to 1770 nm, spectroscopic photoacoustic analysis of lipid-mimicking phantom and an human atherosclerotic artery was performed ex vivo. The results demonstrated that the developed IVPA/US imaging system is capable for high speed intravascular imaging for plaque detection.

Bioinformatics approach to evaluate differential gene expression of M1/M2 macrophage phenotypes and antioxidant genes in atherosclerosis.

PubMed

da Rocha, Ricardo Fagundes; De Bastiani, Marco Antônio; Klamt, Fábio

2014-11-01

Atherosclerosis is a pro-inflammatory process intrinsically related to systemic redox impairments. Macrophages play a major role on disease development. The specific involvement of classically activated, M1 (pro-inflammatory), or the alternatively activated, M2 (anti-inflammatory), on plaque formation and disease progression are still not established. Thus, based on meta-data analysis of public micro-array datasets, we compared differential gene expression levels of the human antioxidant genes (HAG) and M1/M2 genes between early and advanced human atherosclerotic plaques, and among peripheric macrophages (with or without foam cells induction by oxidized low density lipoprotein, oxLDL) from healthy and atherosclerotic subjects. Two independent datasets, GSE28829 and GSE9874, were selected from gene expression omnibus (http://www.ncbi.nlm.nih.gov/geo/) repository. Functional interactions were obtained with STRING (http://string-db.org/) and Medusa (http://coot.embl.de/medusa/). Statistical analysis was performed with ViaComplex(®) (http://lief.if.ufrgs.br/pub/biosoftwares/viacomplex/) and gene score enrichment analysis (http://www.broadinstitute.org/gsea/index.jsp). Bootstrap analysis demonstrated that the activity (expression) of HAG and M1 gene sets were significantly increased in advance compared to early atherosclerotic plaque. Increased expressions of HAG, M1, and M2 gene sets were found in peripheric macrophages from atherosclerotic subjects compared to peripheric macrophages from healthy subjects, while only M1 gene set was increased in foam cells from atherosclerotic subjects compared to foam cells from healthy subjects. However, M1 gene set was decreased in foam cells from healthy subjects compared to peripheric macrophages from healthy subjects, while no differences were found in foam cells from atherosclerotic subjects compared to peripheric macrophages from atherosclerotic subjects. Our data suggest that, different to cancer, in atherosclerosis there is no M1 or M2 polarization of macrophages. Actually, M1 and M2 phenotype are equally induced, what is an important aspect to better understand the disease progression, and can help to develop new therapeutic approaches.

Molecular imaging of inflammation and intraplaque vasa vasorum: A step forward to identification of vulnerable plaques?

PubMed Central

ten Kate, Gerrit L.; Sijbrands, Eric J. G.; Valkema, Roelf; ten Cate, Folkert J.; Feinstein, Steven B.; van der Steen, Antonius F. W.; Daemen, Mat J. A. P.

2010-01-01

Current developments in cardiovascular biology and imaging enable the noninvasive molecular evaluation of atherosclerotic vascular disease. Intraplaque neovascularization sprouting from the adventitial vasa vasorum has been identified as an independent predictor of intraplaque hemorrhage and plaque rupture. These intraplaque vasa vasorum result from angiogenesis, most likely under influence of hypoxic and inflammatory stimuli. Several molecular imaging techniques are currently available. Most experience has been obtained with molecular imaging using positron emission tomography and single photon emission computed tomography. Recently, the development of targeted contrast agents has allowed molecular imaging with magnetic resonance imaging, ultrasound and computed tomography. The present review discusses the use of these molecular imaging techniques to identify inflammation and intraplaque vasa vasorum to identify vulnerable atherosclerotic plaques at risk of rupture and thrombosis. The available literature on molecular imaging techniques and molecular targets associated with inflammation and angiogenesis is discussed, and the clinical applications of molecular cardiovascular imaging and the use of molecular techniques for local drug delivery are addressed. PMID:20552308

Molecular Imaging of Inflammation in Atherosclerosis

PubMed Central

Wildgruber, Moritz; Swirski, Filip K.; Zernecke, Alma

2013-01-01

Acute rupture of vulnerable plaques frequently leads to myocardial infarction and stroke. Within the last decades, several cellular and molecular players have been identified that promote atherosclerotic lesion formation, maturation and plaque rupture. It is now widely recognized that inflammation of the vessel wall and distinct leukocyte subsets are involved throughout all phases of atherosclerotic lesion development. The mechanisms that render a stable plaque unstable and prone to rupture, however, remain unknown and the identification of the vulnerable plaque remains a major challenge in cardiovascular medicine. Imaging technologies used in the clinic offer minimal information about the underlying biology and potential risk for rupture. New imaging technologies are therefore being developed, and in the preclinical setting have enabled new and dynamic insights into the vessel wall for a better understanding of this complex disease. Molecular imaging has the potential to track biological processes, such as the activity of cellular and molecular biomarkers in vivo and over time. Similarly, novel imaging technologies specifically detect effects of therapies that aim to stabilize vulnerable plaques and silence vascular inflammation. Here we will review the potential of established and new molecular imaging technologies in the setting of atherosclerosis, and discuss the cumbersome steps required for translating molecular imaging approaches into the clinic. PMID:24312156

[Pathophysiological role of tissue renin-angiotensin-aldosterone system (RAAS) in human atherosclerosis].

PubMed

Fukui, Kensuke; Yamada, Hiroyuki; Matsubara, Hiroaki

2012-09-01

Renin-angiotensin-aldosterone system (RAAS) has been demonstrated to play an important role in the pathogenesis of atherosclerosis development both in animal experiments and in clinical studies. Numerous clinical studies have shown that blockade of RAAS exerts beneficial effects to restore the impaired endothelial function and to reduce the mortality and morbidity of cardiovascular diseases beyond their blood pressure lowering effect. However, the underlying mechanisms of stabilizing vulnerable plaque and inhibiting plaque rupture associated with acute coronary syndrome have not yet been fully elucidated. Here, we summarized the characteristics of tissue RAAS expressions in human atherosclerotic lesions and assessed their therapeutic relevance in the prevention of atherosclerotic cardiovascular diseases.

HDL mimetic CER-001 targets atherosclerotic plaques in patients.

PubMed

Zheng, Kang He; van der Valk, Fleur M; Smits, Loek P; Sandberg, Mara; Dasseux, Jean-Louis; Baron, Rudi; Barbaras, Ronald; Keyserling, Constance; Coolen, Bram F; Nederveen, Aart J; Verberne, Hein J; Nell, Thijs E; Vugts, Danielle J; Duivenvoorden, Raphaël; Fayad, Zahi A; Mulder, Willem J M; van Dongen, Guus A M S; Stroes, Erik S G

2016-08-01

Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients. CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 ((89)Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of (89)Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001. One hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p < 0.001). Using serial PET/CT imaging, we showed that arterial uptake of CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p < 0.001). Plaque TBRmax correlated with local plaque contrast enhancement (r = 0.56; p = 0.019) as assessed by CE-MRI. Infusion of HDL mimetic CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis. Netherlands Trial Registry - NTR5178. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Racial differences in thoracic aorta atherosclerosis among ischemic stroke patients.

PubMed

Gupta, Vishal; Nanda, Navin C; Yesilbursa, Dilek; Huang, Wen Ying; Gupta, Vijaya; Li, Qing; Gomez, Camilo R

2003-02-01

Atherosclerosis of the thoracic aorta is an independent risk factor for stroke. There is little information on the impact of race in the prevalence of thoracic aorta atherosclerotic plaques among ischemic stroke patients. This study was an attempt to objectively assess the prevalence, thickness, and burden of thoracic aorta atherosclerotic plaques in a large population of ischemic stroke patients and to compare the differences between American blacks and whites. This is a retrospective study of clinical data and transesophageal echocardiography (TEE) of 1553 ischemic stroke patients (664 blacks, 889 whites) over a period of 4.5 years. Atherosclerotic plaque prevalence, thickness, morphology, and burden (sum of maximum thickness in ascending aorta [AA], aortic arch [AO], and descending aorta [DA]) were assessed with TEE. Charts were reviewed for clinical information. Age and sex were similar among blacks and whites. Analyses of clinical data found that blacks had significantly higher hypertension (odds ratio [OR], 2.61; P<0.0001) and diabetes mellitus (OR, 1.99; P<0.0001) and significantly lower coronary artery disease (OR, 0.75; P=0.017) and carotid artery disease (OR, 0.62; P=0.0008) compared with whites. TEE showed that whites had significantly greater plaque prevalence (AA: OR, 1.37; P=0.04; AO: OR, 1.26; P=0.03; DA: OR, 1.39; P=0.002) and plaque burden (blacks, 4.28 mm; whites, 4.97 mm; P=0.007). Whites also had a trend of increased complex plaques and plaques >4 mm thick in all regions of the thoracic aorta. Among ischemic stroke patients, blacks had a lower prevalence of extra cranial atherosclerotic disease even though they had significantly higher hypertension and diabetes mellitus compared with whites. This difference cannot be explained by the existing risk factors in ischemic stroke patients.

Endothelial glycocalyx, apoptosis and inflammation in an atherosclerotic mouse model

PubMed Central

Mensah, Solomon; Hirshberg, Carly; Tarbell, John M.

2016-01-01

Background and aims Previous experiments suggest that both increased endothelial cell apoptosis and endothelial surface glycocalyx shedding could play a role in the endothelial dysfunction and inflammation of athero-prone regions of the vasculature. We sought to elucidate the possibly synergistic mechanisms by which endothelial cell apoptosis and glycocalyx shedding promote atherogenesis. Methods 4- to 6-week old male C57Bl/6 apolipoprotein E knockout (ApoE−/−) mice were fed a Western diet for 10 weeks and developed plaques in their brachiocephalic arteries. Results Glycocalyx coverage and thickness were significantly reduced over the plaque region compared to the non-plaque region (coverage plaque: 71±23%, non-plaque: 97±3%, p= 0.02; thickness plaque: 0.85±0.15 μm, non-plaque: 1.2±0.21 μm, p= 0.006). Values in the non-plaque region were not different from those found in wild type mice fed a normal diet (coverage WT: 92±3%, p= 0.7 vs. non-plaque ApoE−/−, thickness WT: 1.1±0.06 μm, p= 0.2 vs. non-plaque ApoE−/−). Endothelial cell apoptosis was significantly increased in ApoE−/− mice compared to wild type mice (ApoE−/− :64.3±33.0, WT: 1.1±0.5 TUNEL-pos/cm, p= 2×10−7). The number of apoptotic endothelial cells per unit length was 2 times higher in the plaque region than in the non-plaque region of the same vessel (p= 3×10−5). Increased expression of matrix metalloproteinase 9 co-localized with glycocalyx shedding and plaque buildup. Conclusions Our results suggest that, in concert with endothelial apoptosis that increases lipid permeability, glycocalyx shedding initiated by inflammation facilitates monocyte adhesion and macrophage infiltration that promote lipid retention and the development of atherosclerotic plaques. PMID:27529818

Mesenchymal Stem Cells Stabilize Atherosclerotic Vulnerable Plaque by Anti-Inflammatory Properties.

PubMed

Wang, Shuang-shuang; Hu, Si-wang; Zhang, Qing-hua; Xia, Ai-xiang; Jiang, Zhi-xin; Chen, Xiao-min

2015-01-01

Formation and progression of atherosclerotic vulnerable plaque (VP) is the primary cause of many cardio-cerebrovascular diseases such as acute coronary syndrome and stroke. It has been reported that bone marrow mesenchymal stem cells (MSC) exhibit protective effects against many kinds of diseases including myocardial infarction. Here, we examined the effects of intravenous MSC infusion on a VP model and provide novel evidence of its influence as a therapy in this animal disease model. Thirty healthy male New Zealand white rabbits were randomly divided into a MSC, VP or stable plaque (SP) group (n = 10/group) and received high fat diet and cold-induced common carotid artery intimal injury with liquid nitrogen to form atherosclerotic plaques. Serum hs-CRP, TNF-α, IL-6 and IL-10 levels were measured by ELISA at 1, 2, 3, 7, 14, 21 and 28 days after MSC transplantation. The animals were sacrificed at 4 weeks after MSC transplantation. Lesions in the right common carotid were observed using H&E and Masson staining, and the fibrous cap/lipid core ratio of atherosclerotic plaques were calculated. The expression of nuclear factor κB (NF-κB) and matrix metalloproteinase 1, 2, 9 (MMP-1,2,9) in the plaque were detected using immunohistochemistry, and apoptotic cells in the plaques were detected by TUNEL. In addition, the level of TNF-α stimulated gene/protein 6 (TSG-6) mRNA and protein were measured by quantitative Real-Time PCR and Western blotting, respectively. Two rabbits in the VP group died of lung infection and cerebral infarction respectively at 1 week after plaque injury by liquid nitrogen. Both H&E and Masson staining revealed that the plaques from the SP and MSC groups had more stable morphological structure and a larger fibrous cap/lipid core ratio than the VP group. Serum hs-CRP, TNF-α and IL-6 were significantly down-regulated, whereas IL-10 was significantly up-regulated in the MSC group compared with the VP group. .Immunohistochemistry analysis revealed that NF-κB and MMP expression was reduced in the MSC and SP groups compared to the VP group. Cell apoptosis decreased significantly in both the MSC and SP groups in comparison to the VP group. TSG-6 mRNA and protein expression were higher in the plaques of the MSC group compared to the VP and SP groups. Our study results suggest that MSC transplantation can effectively stabilize vulnerable plaques in atherosclerotic rabbits. This may potentially offer a new clinical application of MSC in atherosclerosis.

MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin

PubMed Central

Di Gregoli, Karina; Mohamad Anuar, Nur Najmi; Bianco, Rosaria; White, Stephen J.; Newby, Andrew C.; George, Sarah J.

2017-01-01

Rationale: Atherosclerosis and aneurysms are leading causes of mortality worldwide. MicroRNAs (miRs) are key determinants of gene and protein expression, and atypical miR expression has been associated with many cardiovascular diseases; although their contributory role to atherosclerotic plaque and abdominal aortic aneurysm stability are poorly understood. Objective: To investigate whether miR-181b regulates tissue inhibitor of metalloproteinase-3 expression and affects atherosclerosis and aneurysms. Methods and Results: Here, we demonstrate that miR-181b was overexpressed in symptomatic human atherosclerotic plaques and abdominal aortic aneurysms and correlated with decreased expression of predicted miR-181b targets, tissue inhibitor of metalloproteinase-3, and elastin. Using the well-characterized mouse atherosclerosis models of Apoe−/− and Ldlr−/−, we observed that in vivo administration of locked nucleic acid anti-miR-181b retarded both the development and the progression of atherosclerotic plaques. Systemic delivery of anti-miR-181b in angiotensin II–infused Apoe−/− and Ldlr−/− mice attenuated aneurysm formation and progression within the ascending, thoracic, and abdominal aorta. Moreover, miR-181b inhibition greatly increased elastin and collagen expression, promoting a fibrotic response and subsequent stabilization of existing plaques and aneurysms. We determined that miR-181b negatively regulates macrophage tissue inhibitor of metalloproteinase-3 expression and vascular smooth muscle cell elastin production, both important factors in maintaining atherosclerotic plaque and aneurysm stability. Validation studies in Timp3−/− mice confirmed that the beneficial effects afforded by miR-181b inhibition are largely tissue inhibitor of metalloproteinase-3 dependent, while also revealing an additional protective effect through elevating elastin synthesis. Conclusions: Our findings suggest that the management of miR-181b and its target genes provides therapeutic potential for limiting the progression of atherosclerosis and aneurysms and protecting them from rupture. PMID:27756793

MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin.

PubMed

Di Gregoli, Karina; Mohamad Anuar, Nur Najmi; Bianco, Rosaria; White, Stephen J; Newby, Andrew C; George, Sarah J; Johnson, Jason L

2017-01-06

Atherosclerosis and aneurysms are leading causes of mortality worldwide. MicroRNAs (miRs) are key determinants of gene and protein expression, and atypical miR expression has been associated with many cardiovascular diseases; although their contributory role to atherosclerotic plaque and abdominal aortic aneurysm stability are poorly understood. To investigate whether miR-181b regulates tissue inhibitor of metalloproteinase-3 expression and affects atherosclerosis and aneurysms. Here, we demonstrate that miR-181b was overexpressed in symptomatic human atherosclerotic plaques and abdominal aortic aneurysms and correlated with decreased expression of predicted miR-181b targets, tissue inhibitor of metalloproteinase-3, and elastin. Using the well-characterized mouse atherosclerosis models of Apoe - /- and Ldlr -/- , we observed that in vivo administration of locked nucleic acid anti-miR-181b retarded both the development and the progression of atherosclerotic plaques. Systemic delivery of anti-miR-181b in angiotensin II-infused Apoe -/- and Ldlr -/- mice attenuated aneurysm formation and progression within the ascending, thoracic, and abdominal aorta. Moreover, miR-181b inhibition greatly increased elastin and collagen expression, promoting a fibrotic response and subsequent stabilization of existing plaques and aneurysms. We determined that miR-181b negatively regulates macrophage tissue inhibitor of metalloproteinase-3 expression and vascular smooth muscle cell elastin production, both important factors in maintaining atherosclerotic plaque and aneurysm stability. Validation studies in Timp3 -/- mice confirmed that the beneficial effects afforded by miR-181b inhibition are largely tissue inhibitor of metalloproteinase-3 dependent, while also revealing an additional protective effect through elevating elastin synthesis. Our findings suggest that the management of miR-181b and its target genes provides therapeutic potential for limiting the progression of atherosclerosis and aneurysms and protecting them from rupture. © 2016 The Authors.

Piperlongumine inhibits atherosclerotic plaque formation and vascular smooth muscle cell proliferation by suppressing PDGF receptor signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Son, Dong Ju; Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA; Kim, Soo Yeon

2012-10-19

Highlights: Black-Right-Pointing-Pointer Anti-atherogenic effect of PL was examined using partial carotid ligation model in ApoE KO mice. Black-Right-Pointing-Pointer PL prevented atherosclerotic plaque development, VSMCs proliferation, and NF-{kappa}B activation. Black-Right-Pointing-Pointer Piperlongumine reduced vascular smooth muscle cell activation through PDGF-R{beta} and NF-{kappa}B-signaling. Black-Right-Pointing-Pointer PL may serve as a new therapeutic molecule for atherosclerosis treatment. -- Abstract: Piperlongumine (piplartine, PL) is an alkaloid found in the long pepper (Piper longum L.) and has well-documented anti-platelet aggregation, anti-inflammatory, and anti-cancer properties; however, the role of PL in prevention of atherosclerosis is unknown. We evaluated the anti-atherosclerotic potential of PL in an in vivo murinemore » model of accelerated atherosclerosis and defined its mechanism of action in aortic vascular smooth muscle cells (VSMCs) in vitro. Local treatment with PL significantly reduced atherosclerotic plaque formation as well as proliferation and nuclear factor-kappa B (NF-{kappa}B) activation in an in vivo setting. PL treatment in VSMCs in vitro showed inhibition of migration and platelet-derived growth factor BB (PDGF-BB)-induced proliferation to the in vivo findings. We further identified that PL inhibited PDGF-BB-induced PDGF receptor beta activation and suppressed downstream signaling molecules such as phospholipase C{gamma}1, extracellular signal-regulated kinases 1 and 2 and Akt. Lastly, PL significantly attenuated activation of NF-{kappa}B-a downstream transcriptional regulator in PDGF receptor signaling, in response to PDGF-BB stimulation. In conclusion, our findings demonstrate a novel, therapeutic mechanism by which PL suppresses atherosclerosis plaque formation in vivo.« less

Correlation of inflammation assessed by 18F-FDG PET, active mineral deposition assessed by 18F-fluoride PET, and vascular calcification in atherosclerotic plaque: a dual-tracer PET/CT study.

PubMed

Derlin, Thorsten; Tóth, Zoltán; Papp, László; Wisotzki, Christian; Apostolova, Ivayla; Habermann, Christian R; Mester, Janos; Klutmann, Susanne

2011-07-01

Formation and progression of atherosclerotic plaque is a dynamic and complex process involving various pathophysiologic steps including inflammation and calcification. The purpose of this study was to compare macrophage activity as determined by (18)F-FDG PET and ongoing mineral deposition as measured by (18)F-sodium fluoride PET in atherosclerotic plaque and to correlate these findings with calcified plaque burden as assessed by CT. Forty-five patients were examined by whole-body (18)F-FDG PET, (18)F-sodium fluoride PET, and CT. Tracer uptake in various arterial segments was analyzed both qualitatively and semiquantitatively by measuring the blood-pool-corrected standardized uptake value (target-to-background ratio [TBR]). The pattern of tracer uptake in atherosclerotic lesions was compared after color-coded multistudy image fusion of PET and CT studies. The Fisher exact test and the Spearman correlation coefficient r(s) were used for statistical analysis of image-based results and cardiovascular risk factors. Intra- and interrater reproducibility were evaluated using the Cohen κ. (18)F-sodium fluoride uptake was observed at 105 sites in 27 (60%) of the 45 study patients, and mean TBR was 2.3 ± 0.7. (18)F-FDG uptake was seen at 124 sites in 34 (75.6%) patients, and mean TBR was 1.5 ± 0.3. Calcified atherosclerotic lesions were observed at 503 sites in 34 (75.6%) patients. Eighty-one (77.1%) of the 105 lesions with marked (18)F-sodium fluoride uptake and only 18 (14.5%) of the 124 lesions with (18)F-FDG accumulation were colocalized with arterial calcification. Coincident uptake of both (18)F-sodium fluoride and (18)F-FDG was observed in only 14 (6.5%) of the 215 arterial lesions with radiotracer accumulation. PET/CT with (18)F-FDG and (18)F-sodium fluoride may allow evaluation of distinct pathophysiologic processes in atherosclerotic lesions and might provide information on the complex interactions involved in formation and progression of atherosclerotic plaque.

Vertebral artery ostium atherosclerotic plaque as a potential source of posterior circulation ischemic stroke: result from borgess medical center vertebral artery ostium stenting registry.

PubMed

Al-Ali, Firas; Barrow, Tom; Duan, Li; Jefferson, Anne; Louis, Susan; Luke, Kim; Major, Kevin; Smoker, Sandy; Walker, Sarah; Yacobozzi, Margaret

2011-09-01

Although atherosclerotic plaque in the carotid and coronary arteries is accepted as a cause of ischemia, vertebral artery ostium (VAO) atherosclerotic plaque is not widely recognized as a source of ischemic stroke. We seek to demonstrate its implication in some posterior circulation ischemia. This is a nonrandomized, prospective, single-center registry on consecutive patients presenting with posterior circulation ischemia who underwent VAO stenting for significant atherosclerotic stenosis. Diagnostic evaluation and imaging studies determined the likelihood of this lesion as the symptom source (highly likely, probable, or highly unlikely). Patients were divided into 4 groups in decreasing order of severity of clinical presentation (ischemic stroke, TIA then stroke, TIA, asymptomatic), which were compared with the morphological and hemodynamic characteristics of the VAO plaque. Clinical follow-up 1 year after stenting assessed symptom recurrence. One hundred fourteen patients underwent stenting of 127 lesions; 35% of the lesions were highly likely the source of symptoms, 53% were probable, and 12% were highly unlikely. Clinical presentation correlated directly with plaque irregularity and presence of clot at the VAO, as did bilateral lesions and presence of tandem lesions. Symptom recurrence at 1 year was 2%. Thirty-five percent of the lesions were highly likely the source of the symptoms. A direct relationship between some morphological/hemodynamic characteristics and the severity of clinical presentation was also found. Finally, patients had a very low rate of symptom recurrence after treatment. These 3 observations point strongly to VAO plaque as a potential source of some posterior circulation stroke.

Detection of rupture-prone atherosclerotic plaques by time-resolved laser-induced fluorescence spectroscopy.

PubMed

Marcu, Laura; Jo, Javier A; Fang, Qiyin; Papaioannou, Thanassis; Reil, Todd; Qiao, Jian-Hua; Baker, J Dennis; Freischlag, Julie A; Fishbein, Michael C

2009-05-01

Plaque with dense inflammatory cells, including macrophages, thin fibrous cap and superficial necrotic/lipid core is thought to be prone-to-rupture. We report a time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) technique for detection of such markers of plaque vulnerability in human plaques. The autofluorescence of carotid plaques (65 endarterectomy patients) induced by a pulsed laser (337 nm, 0.7 ns) was measured from 831 distinct areas. The emission was resolved spectrally (360-550 nm range) and temporally (0.3 ns resolution) using a prototype fiber-optic TR-LIFS apparatus. Lesions were evaluated microscopically and quantified as to the % of different components (fibrous cap, necrotic core, inflammatory cells, foam cells, mature and degraded collagen, elastic fibers, calcification, and smooth muscle cell of the vessel wall). We determined that the spectral intensities and time-dependent parameters at discrete emission wavelengths (1) allow for discrimination (sensitivity >81%, specificity >94%) of various compositional and pathological features associated with plaque vulnerability including infiltration of macrophages into intima and necrotic/lipid core under a thin fibrous cap, and (2) show a linear correlation with plaque biochemical content: elastin (P<0.008), collagen (P<0.02), inflammatory cells (P<0.003), necrosis (P<0.004). Our results demonstrate the feasibility of TR-LIFS as a method for the identification of markers of plaque vulnerability. Current findings enable future development of TR-LIFS-based clinical devices for rapid investigation of atherosclerotic plaques and detection of those at high-risk.

Bone marrow endothelial progenitors in atherosclerotic plaque resolution

PubMed Central

Yao, Longbiao; Heuser-Baker, Janet; Herlea-Pana, Oana; Barlic-Dicen, Jana

2013-01-01

Atherosclerosis is a major cause of morbidity and mortality in the United States. Persistently elevated circulating low-density lipoprotein, or hypercholesterolemia, and deposition of low-density lipoprotein in the vascular wall are the main inducers of atherosclerosis, which manifests itself as arterial lesions or plaques. Some plaques become thrombosis-prone and rupture, causing acute myocardial infarction or stroke. Lowering plasma cholesterol through the use of statins is the primary intervention against atherosclerosis. Treatment with statins slows progression of atherosclerosis but can only support limited plaque regression. Partially regressed plaques continue to pose a serious threat due to their remaining potential to rupture. Thus, new interventions inducing complete reversal of atherosclerosis are being sought. Implementation of new therapies will require clear understanding of the mechanisms driving plaque resolution. In this Commentary, we highlight the role of bone marrow endothelial progenitors in atherosclerotic plaque regression and discuss how regenerative cell-based interventions could be used in combination with plasma lipid-lowering to induce plaque reversal in order to prevent and/or reduce adverse cardiovascular events. PMID:23538778

A novel workflow combining plaque imaging, plaque and plasma proteomics identifies biomarkers of human coronary atherosclerotic plaque disruption.

PubMed

Lee, Regent; Fischer, Roman; Charles, Philip D; Adlam, David; Valli, Alessandro; Di Gleria, Katalin; Kharbanda, Rajesh K; Choudhury, Robin P; Antoniades, Charalambos; Kessler, Benedikt M; Channon, Keith M

2017-01-01

Atherosclerotic plaque rupture is the culprit event which underpins most acute vascular syndromes such as acute myocardial infarction. Novel biomarkers of plaque rupture could improve biological understanding and clinical management of patients presenting with possible acute vascular syndromes but such biomarker(s) remain elusive. Investigation of biomarkers in the context of de novo plaque rupture in humans is confounded by the inability to attribute the plaque rupture as the source of biomarker release, as plaque ruptures are typically associated with prompt down-stream events of myocardial necrosis and systemic inflammation. We developed a novel approach to identify potential biomarkers of plaque rupture by integrating plaque imaging, using optical coherence tomography, with both plaque and plasma proteomic analysis in a human model of angioplasty-induced plaque disruption. We compared two pairs of coronary plaque debris, captured by a FilterWire Device, and their corresponding control samples and found matrix metalloproteinase 9 (MMP9) to be significantly enriched in plaque. Plaque contents, as defined by optical coherence tomography, affect the systemic changes of MMP9. Disruption of lipid-rich plaque led to prompt elevation of plasma MMP9, whereas disruption of non-lipid-rich plaque resulted in delayed elevation of plasma MMP9. Systemic MMP9 elevation is independent of the associated myocardial necrosis and systemic inflammation (measured by Troponin I and C-reactive protein, respectively). This information guided the selection of a subset of subjects of for further label free proteomics analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS). We discovered five novel, plaque-enriched proteins (lipopolysaccharide binding protein, Annexin A5, eukaryotic translocation initiation factor, syntaxin 11, cytochrome B5 reductase 3) to be significantly elevated in systemic circulation at 5 min after plaque disruption. This novel approach for biomarker discovery in human coronary artery plaque disruption can identify new biomarkers related to human coronary artery plaque composition and disruption.

Single-Dose and Fractionated Irradiation Promote Initiation and Progression of Atherosclerosis and Induce an Inflammatory Plaque Phenotype in ApoE{sup -/-} Mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoving, Saske; Heeneman, Sylvia; Gijbels, Marion J.J.

2008-07-01

Purpose: Increased risk of atherosclerosis and stroke has been demonstrated in patients receiving radiotherapy for Hodgkin's lymphoma and head-and-neck cancer. We previously showed that 14 Gy to the carotid arteries of hypercholesterolemic ApoE{sup -/-} mice resulted in accelerated development of macrophage-rich, inflammatory atherosclerotic lesions. Here we investigate whether clinically relevant fractionated irradiation schedules and lower single doses also predispose to an inflammatory plaque phenotype. Methods and Materials: ApoE{sup -/-} mice were given 8 or 14 Gy, or 20 x 2.0 Gy in 4 weeks to the neck, and the carotid arteries were subsequently examinated for presence of atherosclerotic lesions, plaquemore » size, and phenotype. Results: At 4 weeks, early atherosclerotic lesions were found in 44% of the mice after single doses of 14 Gy but not in age-matched controls. At 22 to 30 weeks after irradiation there was a twofold increase in the mean number of carotid lesions (8-14 Gy and 20 x 2.0 Gy) and total plaque burden (single doses only), compared with age-matched controls. The majority of lesions seen at 30 to 34 weeks after fractionated irradiation or 14-Gy single doses were granulocyte rich (100% and 63%, respectively), with thrombotic features (90% and 88%), whereas these phenotypes were much less common in age-matched controls or after a single dose of 8 Gy. Conclusions: We showed that fractionated irradiation accelerated the development of atherosclerosis in ApoE{sup -/-} mice and predisposed to the formation of an inflammatory, thrombotic plaque phenotype.« less

CANCER BIOMARKERS IN HUMAN ATHEROSCLEROTIC LESIONS: DETECTION OF DNA ADDUCTS

EPA Science Inventory

Since somatic mutations are suspected to contribute to the pathogenesis not only of cancer but also of atherosclerotic plaques, we measured DNA adducts in the smooth muscle layer of atherosclerotic lesions in abnormal aorta specimens taken at surgery from seven patients. NA adduc...

Pharmacogenomic interaction between the Haptoglobin genotype and vitamin E on atherosclerotic plaque progression and stability.

PubMed

Veiner, Hilla-Lee; Gorbatov, Rostic; Vardi, Moshe; Doros, Gheorghe; Miller-Lotan, Rachel; Zohar, Yaniv; Sabo, Edmond; Asleh, Rabea; Levy, Nina S; Goldfarb, Levi J; Berk, Thomas A; Haas, Tali; Shalom, Hadar; Suss-Toby, Edith; Kam, Adi; Kaplan, Marielle; Tamir, Ronit; Ziskind, Anna; Levy, Andrew P

2015-03-01

Homozygosity for a 1.7 kb intragenic duplication of the Haptoglobin (Hp) gene (Hp 2-2 genotype), present in 36% of the population, has been associated with a 2-3 fold increased incidence of atherothrombosis in individuals with Diabetes (DM) in 10 longitudinal studies compared to DM individuals not homozygous for this duplication (Hp 1-1/2-1). The increased CVD risk associated with the Hp 2-2 genotype has been shown to be prevented with vitamin E supplementation in man. We sought to determine if there was an interaction between the Hp genotype and vitamin E on atherosclerotic plaque growth and stability in a transgenic model of the Hp polymorphism. Brachiocephalic artery atherosclerotic plaque volume was serially assessed by high resolution ultrasound in 28 Hp 1-1 and 26 Hp 2-2 mice in a C57Bl/6 ApoE(-/-) background. Hp 2-2 mice had more rapid plaque growth and an increased incidence of plaque hemorrhage and rupture. Vitamin E significantly reduced plaque growth in Hp 2-2 but not in Hp 1-1 mice with a significant pharmacogenomic interaction between the Hp genotype and vitamin E on plaque growth. These results may help explain why vitamin E supplementation in man can prevent CVD in Hp 2-2 DM but not in non Hp 2-2 DM individuals. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Dickkopf1 destabilizes atherosclerotic plaques and promotes plaque formation by inducing apoptosis of endothelial cells through activation of ER stress

PubMed Central

Di, Mingxue; Wang, Lin; Li, Mengmeng; Zhang, Yu; Liu, Xinxin; Zeng, Renya; Wang, Han; Chen, Yifei; Chen, Weijia; Zhang, Yun; Zhang, Mei

2017-01-01

Several clinical studies reported that Dickkopf1 (DKK1) plasma levels are correlated with atherosclerosis. However, the impact of DKK1 on the formation and vulnerability of atherosclerotic plaques remains elusive. This study investigated DKK1’s effects on enlargement and destabilization of plaques by targeting endothelial cells and assessing the possible cellular mechanisms involved. The effects of DKK1 on atherogenesis and plaque stability were evaluated in ApoE−/− mice using lentivirus injections to knockdown and knock-in the DKK1 gene. The presence of DKK1 resulted in enlarged and destabilized atherosclerotic lesions and increased apoptosis, while silencing of DKK1 alleviated plaque formation and vulnerability in the whole progression of atherosclerosis. DKK1 expression was upregulated in response to ox-LDL treatment in a time- and concentration-dependent manner on human umbilical vein endothelial cell (HUVEC). The interference of DKK1 reversed ox-LDL-induced apoptosis in HUVECs. The mechanism underlying this effect was DKK1’s activation of the JNK signal transduction pathway and inhibition of canonical Wnt signaling, following by activation of the IRE1α and eif2α/CHOP pathways. In conclusion, DKK1 promotes plaque formation and vulnerability partly by inducing apoptosis in endothelial cells, which partly through inducing the JNK-endoplasmic reticulum stress pathway and inhibiting canonical Wnt signaling. PMID:28703797

Potential benefits of eicosapentaenoic acid on atherosclerotic plaques.

PubMed

Nelson, J R; Wani, O; May, H T; Budoff, M

2017-04-01

Residual cardiovascular (CV) risk remains in some patients despite optimized statin therapy and may necessitate add-on therapy to reduce this risk. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, lowers plasma triglyceride levels without raising low-density lipoprotein cholesterol levels and has potential beneficial effects on atherosclerotic plaques. Animal studies have shown that EPA reduces levels of pro-inflammatory cytokines and chemokines. In clinical trials utilizing a wide spectrum of plaque imaging modalities, EPA has shown beneficial effects on plaque characteristics. Studies of patients with coronary artery disease receiving statin therapy suggest that EPA may decrease plaque vulnerability and prevent plaque progression. EPA also decreased pentraxin-3 and macrophage accumulation. A large, randomized, Japanese study reported that EPA plus a statin resulted in a 19% relative reduction in major coronary events at 5years versus a statin alone in patients with hypercholesterolemia (P=0.011). Icosapent ethyl, a high-purity prescription form of EPA ethyl ester, has been shown to reduce triglyceride levels and markers of atherosclerotic inflammation. Results of an ongoing CV outcomes study will further define the potential clinical benefits of icosapent ethyl in reducing CV risk in high-risk patients receiving statin therapy. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Italian Chapter of the International Society of Cardiovascular Ultrasound expert consensus document on coronary computed tomography angiography: overview and new insights.

PubMed

Sozzi, Fabiola B; Maiello, Maria; Pelliccia, Francesco; Parato, Vito Maurizio; Canetta, Ciro; Savino, Ketty; Lombardi, Federico; Palmiero, Pasquale

2016-09-01

Coronary computed tomography angiography is a noninvasive heart imaging test currently undergoing rapid development and advancement. The high resolution of the three-dimensional pictures of the moving heart and great vessels is performed during a coronary computed tomography to identify coronary artery disease and classify patient risk for atherosclerotic cardiovascular disease. The technique provides useful information about the coronary tree and atherosclerotic plaques beyond simple luminal narrowing and plaque type defined by calcium content. This application will improve image-guided prevention, medical therapy, and coronary interventions. The ability to interpret coronary computed tomography images is of utmost importance as we develop personalized medical care to enable therapeutic interventions stratified on the bases of plaque characteristics. This overview provides available data and expert's recommendations in the utilization of coronary computed tomography findings. We focus on the use of coronary computed tomography to detect coronary artery disease and stratify patients at risk, illustrating the implications of this test on patient management. We describe its diagnostic power in identifying patients at higher risk to develop acute coronary syndrome and its prognostic significance. Finally, we highlight the features of the vulnerable plaques imaged by coronary computed tomography angiography. © 2016, Wiley Periodicals, Inc.

Protease-Activated Receptor-2 Deficiency Attenuates Atherosclerotic Lesion Progression and Instability in Apolipoprotein E-Deficient Mice

PubMed Central

Zuo, Pengfei; Zuo, Zhi; Zheng, Yueyue; Wang, Xin; Zhou, Qianxing; Chen, Long; Ma, Genshan

2017-01-01

Inflammatory mechanisms are involved in the process of atherosclerotic plaque formation and rupture. Accumulating evidence suggests that protease-activated receptor (PAR)-2 contributes to the pathophysiology of chronic inflammation on the vasculature. To directly examine the role of PAR-2 in atherosclerosis, we generated apolipoprotein E/PAR-2 double-deficient mice. Mice were fed with high-fat diet for 12 weeks starting at ages of 6 weeks. PAR-2 deficiency attenuated atherosclerotic lesion progression with reduced total lesion area, reduced percentage of stenosis and reduced total necrotic core area. PAR-2 deficiency increased fibrous cap thickness and collagen content of plaque. Moreover, PAR-2 deficiency decreased smooth muscle cell content, macrophage accumulation, matrix metallopeptidase-9 expression and neovascularization in plaque. Relative quantitative PCR assay using thoracic aorta revealed that PAR-2 deficiency reduced mRNA expression of inflammatory molecules, such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1. In vitro experiment, we found that PAR-2 deficiency reduced mRNA expression of interferon-γ, interleukin-6, TNF-α and MCP-1 in macrophage under unstimulated and lipopolysaccharide-stimulated conditions. These results suggest that PAR-2 deficiency attenuates the progression and instability of atherosclerotic plaque. PMID:28959204

Engineering adeno-associated virus 2 vectors for targeted gene delivery to atherosclerotic lesions.

PubMed

White, K; Büning, H; Kritz, A; Janicki, H; McVey, J; Perabo, L; Murphy, G; Odenthal, M; Work, L M; Hallek, M; Nicklin, S A; Baker, A H

2008-03-01

Targeted delivery of biological agents to atherosclerotic plaques may provide a novel treatment and/or useful tool for imaging of atherosclerosis in vivo. However, there are no known viral vectors that possess the desired tropism. Two plaque-targeting peptides, CAPGPSKSC (CAP) and CNHRYMQMC (CNH) were inserted into the capsid of adeno-associated virus 2 (AAV2) to assess vector retargeting. AAV2-CNH produced significantly higher levels of transduction than unmodified AAV2 in human, murine and rat endothelial cells, whereas transduction of nontarget HeLa cells was unaltered. Transduction studies and surface plasmon resonance suggest that AAV2-CNH uses membrane type 1 matrix metalloproteinase as a surface receptor. AAV2-CAP only produced higher levels of transduction in rat endothelial cells, possibly because the virus was found to be affected by proteasomal degradation. In vivo substantially higher levels of both peptide-modified AAV2 vectors was detected in the brachiocephalic artery (site of advanced atherosclerotic plaques) and aorta, whereas reduced levels were detected in all other organs examined. These results suggest that in the AAV2 platform the peptides are exposed on the capsid surface in a way that enables efficient receptor binding and so creates effective atherosclerotic plaque targeted vectors.

IGF-1 Has Plaque-Stabilizing Effects in Atherosclerosis by Altering Vascular Smooth Muscle Cell Phenotype

PubMed Central

von der Thüsen, Jan H.; Borensztajn, Keren S.; Moimas, Silvia; van Heiningen, Sandra; Teeling, Peter; van Berkel, Theo J.C.; Biessen, Erik A.L.

2011-01-01

Insulin-like growth factor-1 (IGF-1) signaling is important for the maintenance of plaque stability in atherosclerosis due to its effects on vascular smooth muscle cell (vSMC) phenotype. To investigate this hypothesis, we studied the effects of the highly inflammatory milieu of the atherosclerotic plaque on IGF-1 signaling and stability-related phenotypic parameters of murine vSMCs in vitro, and the effects of IGF-1 supplementation on plaque phenotype in an atherosclerotic mouse model. M1-polarized, macrophage-conditioned medium inhibited IGF-1 signaling by ablating IGF-1 and increasing IGF-binding protein 3, increased vSMC apoptosis, and decreased proliferation. Expression of α-actin and col3a1 genes was strongly attenuated by macrophage-conditioned medium, whereas expression of matrix-degrading enzymes was increased. Importantly, all of these effects could be corrected by supplementation with IGF-1. In vivo, treatment with the stable IGF-1 analog Long R3 IGF-1 in apolipoprotein E knockout mice reduced stenosis and core size, and doubled cap/core ratio in early atherosclerosis. In advanced plaques, Long R3 IGF-1 increased the vSMC content of the plaque by more than twofold and significantly reduced the rate of intraplaque hemorrhage. We believe that IGF-1 in atherosclerotic plaques may have a role in preventing plaque instability, not only by modulating smooth muscle cell turnover, but also by altering smooth muscle cell phenotype. PMID:21281823

Vulnerable Atherosclerotic Plaque Elasticity Reconstruction Based on a Segmentation-Driven Optimization Procedure Using Strain Measurements: Theoretical Framework

PubMed Central

Le Floc’h, Simon; Tracqui, Philippe; Finet, Gérard; Gharib, Ahmed M.; Maurice, Roch L.; Cloutier, Guy; Pettigrew, Roderic I.

2016-01-01

It is now recognized that prediction of the vulnerable coronary plaque rupture requires not only an accurate quantification of fibrous cap thickness and necrotic core morphology but also a precise knowledge of the mechanical properties of plaque components. Indeed, such knowledge would allow a precise evaluation of the peak cap-stress amplitude, which is known to be a good biomechanical predictor of plaque rupture. Several studies have been performed to reconstruct a Young’s modulus map from strain elastograms. It seems that the main issue for improving such methods does not rely on the optimization algorithm itself, but rather on preconditioning requiring the best estimation of the plaque components’ contours. The present theoretical study was therefore designed to develop: 1) a preconditioning model to extract the plaque morphology in order to initiate the optimization process, and 2) an approach combining a dynamic segmentation method with an optimization procedure to highlight the modulogram of the atherosclerotic plaque. This methodology, based on the continuum mechanics theory prescribing the strain field, was successfully applied to seven intravascular ultrasound coronary lesion morphologies. The reconstructed cap thickness, necrotic core area, calcium area, and the Young’s moduli of the calcium, necrotic core, and fibrosis were obtained with mean relative errors of 12%, 4% and 1%, 43%, 32%, and 2%, respectively. PMID:19164080

Compartment-resolved Proteomic Analysis of Mouse Aorta during Atherosclerotic Plaque Formation Reveals Osteoclast-specific Protein Expression.

PubMed

Wierer, Michael; Prestel, Matthias; Schiller, Herbert B; Yan, Guangyao; Schaab, Christoph; Azghandi, Sepiede; Werner, Julia; Kessler, Thorsten; Malik, Rainer; Murgia, Marta; Aherrahrou, Zouhair; Schunkert, Heribert; Dichgans, Martin; Mann, Matthias

2018-02-01

Atherosclerosis leads to vascular lesions that involve major rearrangements of the vascular proteome, especially of the extracellular matrix (ECM). Using single aortas from ApoE knock out mice, we quantified formation of plaques by single-run, high-resolution mass spectrometry (MS)-based proteomics. To probe localization on a proteome-wide scale we employed quantitative detergent solubility profiling. This compartment- and time-resolved resource of atherogenesis comprised 5117 proteins, 182 of which changed their expression status in response to vessel maturation and atherosclerotic plaque development. In the insoluble ECM proteome, 65 proteins significantly changed, including relevant collagens, matrix metalloproteinases and macrophage derived proteins. Among novel factors in atherosclerosis, we identified matrilin-2, the collagen IV crosslinking enzyme peroxidasin as well as the poorly characterized MAM-domain containing 2 (Mamdc2) protein as being up-regulated in the ECM during atherogenesis. Intriguingly, three subunits of the osteoclast specific V-ATPase complex were strongly increased in mature plaques with an enrichment in macrophages thus implying an active de-mineralization function. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Compartment-resolved Proteomic Analysis of Mouse Aorta during Atherosclerotic Plaque Formation Reveals Osteoclast-specific Protein Expression*

PubMed Central

Wierer, Michael; Prestel, Matthias; Schiller, Herbert B.; Yan, Guangyao; Schaab, Christoph; Azghandi, Sepiede; Werner, Julia; Kessler, Thorsten; Malik, Rainer; Murgia, Marta; Aherrahrou, Zouhair; Schunkert, Heribert; Dichgans, Martin; Mann, Matthias

2018-01-01

Atherosclerosis leads to vascular lesions that involve major rearrangements of the vascular proteome, especially of the extracellular matrix (ECM). Using single aortas from ApoE knock out mice, we quantified formation of plaques by single-run, high-resolution mass spectrometry (MS)-based proteomics. To probe localization on a proteome-wide scale we employed quantitative detergent solubility profiling. This compartment- and time-resolved resource of atherogenesis comprised 5117 proteins, 182 of which changed their expression status in response to vessel maturation and atherosclerotic plaque development. In the insoluble ECM proteome, 65 proteins significantly changed, including relevant collagens, matrix metalloproteinases and macrophage derived proteins. Among novel factors in atherosclerosis, we identified matrilin-2, the collagen IV crosslinking enzyme peroxidasin as well as the poorly characterized MAM-domain containing 2 (Mamdc2) protein as being up-regulated in the ECM during atherogenesis. Intriguingly, three subunits of the osteoclast specific V-ATPase complex were strongly increased in mature plaques with an enrichment in macrophages thus implying an active de-mineralization function. PMID:29208753

Atherosclerotic plaque in the left carotid artery is more vulnerable than in the right.

PubMed

Selwaness, Mariana; van den Bouwhuijsen, Quirijn; van Onkelen, Robbert S; Hofman, Albert; Franco, Oscar H; van der Lugt, Aad; Wentzel, Jolanda J; Vernooij, Meike

2014-11-01

Ischemic stroke is more often diagnosed in the left hemisphere than in the right. It is unknown whether this asymmetrical prevalence relates to differences in carotid atherosclerosis. We compared atherosclerotic plaque prevalence, severity, and composition between left and right carotid arteries. In a population-based cohort, carotid MRI scanning was performed in 1414 stroke-free participants (≥45 years). Using a multisequence MRI protocol, we assessed the prevalence, stenosis, and thickness of the plaque and its predominant component (ie, lipid core, intraplaque hemorrhage, calcification, or fibrous tissue in each carotid artery). Differences between left and right side were tested using paired t tests, McNemar test and Generalized Estimating Equation analyses. The majority (85%) of the participants had bilateral carotid plaques. Unilateral plaques were twice more prevalent on the left than on the right side (67% versus 33%; P<0.001). Plaque thickness was also greater on the left (3.1±1.2 versus 2.9±1.3 mm; P<0.001); degree of stenosis did not differ. Intraplaque hemorrhage and fibrous tissue were more prevalent on the left (9.1 versus 5.9%; P<0.001 and 45.0 versus 38.5%; P<0.001), whereas calcification occurred more often on the right (37.4 versus 31.6% at the left; P<0.001). Lipid was equally distributed. Carotid atherosclerotic plaque size and composition are not symmetrically distributed. Predominance of intraplaque hemorrhage in left-sided carotid plaques suggests a greater vulnerability as opposed to right-sided plaques, which are more calcified and therefore considered more stable. © 2014 American Heart Association, Inc.

Prevalence of Subclinical Coronary Artery Disease in Masters Endurance Athletes With a Low Atherosclerotic Risk Profile.

PubMed

Merghani, Ahmed; Maestrini, Viviana; Rosmini, Stefania; Cox, Andrew T; Dhutia, Harshil; Bastiaenan, Rachel; David, Sarojini; Yeo, Tee Joo; Narain, Rajay; Malhotra, Aneil; Papadakis, Michael; Wilson, Mathew G; Tome, Maite; AlFakih, Khaled; Moon, James C; Sharma, Sanjay

2017-07-11

Studies in middle-age and older (masters) athletes with atherosclerotic risk factors for coronary artery disease report higher coronary artery calcium (CAC) scores compared with sedentary individuals. Few studies have assessed the prevalence of coronary artery disease in masters athletes with a low atherosclerotic risk profile. We assessed 152 masters athletes 54.4±8.5 years of age (70% male) and 92 controls of similar age, sex, and low Framingham 10-year coronary artery disease risk scores with an echocardiogram, exercise stress test, computerized tomographic coronary angiogram, and cardiovascular magnetic resonance imaging with late gadolinium enhancement and a 24-hour Holter. Athletes had participated in endurance exercise for an average of 31±12.6 years. The majority (77%) were runners, with a median of 13 marathon runs per athlete. Most athletes (60%) and controls (63%) had a normal CAC score. Male athletes had a higher prevalence of atherosclerotic plaques of any luminal irregularity (44.3% versus 22.2%; P =0.009) compared with sedentary males, and only male athletes showed a CAC ≥300 Agatston units (11.3%) and a luminal stenosis ≥50% (7.5%). Male athletes demonstrated predominantly calcific plaques (72.7%), whereas sedentary males showed predominantly mixed morphology plaques (61.5%). The number of years of training was the only independent variable associated with increased risk of CAC >70th percentile for age or luminal stenosis ≥50% in male athletes (odds ratio, 1.08; 95% confidence interval, 1.01-1.15; P =0.016); 15 (14%) male athletes but none of the controls revealed late gadolinium enhancement on cardiovascular magnetic resonance imaging. Of these athletes, 7 had a pattern consistent with previous myocardial infarction, including 3(42%) with a luminal stenosis ≥50% in the corresponding artery. Most lifelong masters endurance athletes with a low atherosclerotic risk profile have normal CAC scores. Male athletes are more likely to have a CAC score >300 Agatston units or coronary plaques compared with sedentary males with a similar risk profile. The significance of these observations is uncertain, but the predominantly calcific morphology of the plaques in athletes indicates potentially different pathophysiological mechanisms for plaque formation in athletic versus sedentary men. Coronary plaques are more abundant in athletes, whereas their stable nature could mitigate the risk of plaque rupture and acute myocardial infarction. © 2017 American Heart Association, Inc.

Effect of chronic treatment with acetylsalicylic acid and clopidogrel on atheroprogression and atherothrombosis in ApoE-deficient mice in vivo.

PubMed

Schulz, Christian; Konrad, Ildiko; Sauer, Susanne; Orschiedt, Lena; Koellnberger, Maria; Lorenz, Reinhard; Walter, Ulrich; Massberg, Steffen

2008-01-01

Acetylsalicylic acid (ASA) and the thienopyridine clopidogrel are established anti-platelet drugs that significantly reduce secondary cardiovascular events in patients with manifest atherosclerosis. However, their impact on atherosclerotic lesion development remains controversial. Four-week-old ApoE-deficient mice were randomly assigned to four groups receiving a cholesterol diet together with either ASA (5 mg/kg), or clopidogrel (25 mg/kg), or a combination of both ASA and clopidogrel, or vehicle for 8-12 weeks. Using intravital microscopy we found that daily administration of ASA in combination with clopidogrel reduces platelet thrombus formation following rupture of atherosclerotic plaque in vivo by approximately 50%. However, therapy with ASA or clopidogrel alone, or in combination for a period of 8-12 weeks had no significant effect on adhesion of platelets to dysfunctional endothelial cells or on atherosclerotic lesion formation in the aortic root or the carotid artery. In conclusion, anti-platelet therapy is effective in reducing platelet adhesion and subsequent thrombus formation following rupture of atherosclerotic plaque in vivo. However, our data do not support a role of either drug in the primary prevention of atherosclerosis in ApoE-deficient mice.

Mesenchymal Stem Cells Stabilize Atherosclerotic Vulnerable Plaque by Anti-Inflammatory Properties

PubMed Central

Wang, Shuang-shuang; Hu, Si-wang; Zhang, Qing-hua; Xia, Ai-xiang

2015-01-01

Background and objectives Formation and progression of atherosclerotic vulnerable plaque (VP) is the primary cause of many cardio-cerebrovascular diseases such as acute coronary syndrome and stroke. It has been reported that bone marrow mesenchymal stem cells (MSC) exhibit protective effects against many kinds of diseases including myocardial infarction. Here, we examined the effects of intravenous MSC infusion on a VP model and provide novel evidence of its influence as a therapy in this animal disease model. Subjects and methods Thirty healthy male New Zealand white rabbits were randomly divided into a MSC, VP or stable plaque (SP) group (n = 10/group) and received high fat diet and cold-induced common carotid artery intimal injury with liquid nitrogen to form atherosclerotic plaques. Serum hs-CRP, TNF-α, IL-6 and IL-10 levels were measured by ELISA at 1, 2, 3, 7, 14, 21 and 28 days after MSC transplantation. The animals were sacrificed at 4 weeks after MSC transplantation. Lesions in the right common carotid were observed using H&E and Masson staining, and the fibrous cap/lipid core ratio of atherosclerotic plaques were calculated. The expression of nuclear factor κB (NF-κB) and matrix metalloproteinase 1, 2, 9 (MMP-1,2,9) in the plaque were detected using immunohistochemistry, and apoptotic cells in the plaques were detected by TUNEL. In addition, the level of TNF-α stimulated gene/protein 6 (TSG-6) mRNA and protein were measured by quantitative Real-Time PCR and Western blotting, respectively. Results Two rabbits in the VP group died of lung infection and cerebral infarction respectively at 1 week after plaque injury by liquid nitrogen. Both H&E and Masson staining revealed that the plaques from the SP and MSC groups had more stable morphological structure and a larger fibrous cap/lipid core ratio than the VP group. Serum hs-CRP, TNF-α and IL-6 were significantly down-regulated, whereas IL-10 was significantly up-regulated in the MSC group compared with the VP group. .Immunohistochemistry analysis revealed that NF-κB and MMP expression was reduced in the MSC and SP groups compared to the VP group. Cell apoptosis decreased significantly in both the MSC and SP groups in comparison to the VP group. TSG-6 mRNA and protein expression were higher in the plaques of the MSC group compared to the VP and SP groups. Conclusions Our study results suggest that MSC transplantation can effectively stabilize vulnerable plaques in atherosclerotic rabbits. This may potentially offer a new clinical application of MSC in atherosclerosis. PMID:26288013

Raman spectroscopy imaging reveals interplay between atherosclerosis and medial calcification in the human aorta

PubMed Central

You, Amanda Y. F.; Bergholt, Mads S.; St-Pierre, Jean-Philippe; Kit-Anan, Worrapong; Pence, Isaac J.; Chester, Adrian H.; Yacoub, Magdi H.; Bertazzo, Sergio; Stevens, Molly M.

2017-01-01

Medial calcification in the human aorta accumulates during aging and is known to be aggravated in several diseases. Atherosclerosis, another major cause of cardiovascular calcification, shares some common aggravators. However, the mechanisms of cardiovascular calcification remain poorly understood. To elucidate the relationship between medial aortic calcification and atherosclerosis, we characterized the cross-sectional distributions of the predominant minerals in aortic tissue, apatite and whitlockite, and the associated extracellular matrix. We also compared the cellular changes between atherosclerotic and nonatherosclerotic human aortic tissues. This was achieved through the development of Raman spectroscopy imaging methods that adapted algorithms to distinguish between the major biomolecules present within these tissues. We present a relationship between apatite, cholesterol, and triglyceride in atherosclerosis, with the relative amount of all molecules concurrently increased in the atherosclerotic plaque. Further, the increase in apatite was disproportionately large in relation to whitlockite in the aortic media directly underlying a plaque, indicating that apatite is more pathologically significant in atherosclerosis-aggravated medial calcification. We also discovered a reduction of β-carotene in the whole aortic intima, including a plaque in atherosclerotic aortic tissues compared to nonatherosclerotic tissues. This unprecedented biomolecular characterization of the aortic tissue furthers our understanding of pathological and physiological cardiovascular calcification events in humans. PMID:29226241

Novel drug discovery strategies for atherosclerosis that target necrosis and necroptosis.

PubMed

Coornaert, Isabelle; Hofmans, Sam; Devisscher, Lars; Augustyns, Koen; Van Der Veken, Pieter; De Meyer, Guido R Y; Martinet, Wim

2018-06-01

Formation and enlargement of a necrotic core play a pivotal role in atherogenesis. Since the discovery of necroptosis, which is a regulated form of necrosis, prevention of necrotic cell death has become an attractive therapeutic goal to reduce plaque formation. Areas covered: This review highlights the triggers and consequences of (unregulated) necrosis and necroptosis in atherosclerosis. The authors discuss different pharmacological strategies to inhibit necrotic cell death in advanced atherosclerotic plaques. Expert opinion: Addition of a necrosis or necroptosis inhibitor to standard statin therapy could be a promising strategy for primary prevention of cardiovascular disease. However, a necrosis inhibitor cannot block all necrosis stimuli in atherosclerotic plaques. A necroptosis inhibitor could be more effective, because necroptosis is mediated by specific proteins, termed receptor-interacting serine/threonine-protein kinases (RIPK) and mixed lineage kinase domain-like pseudokinase (MLKL). Currently, only RIPK1 inhibitors have been successfully used in atherosclerotic mouse models to inhibit necroptosis. However, because RIPK1 is involved in both necroptosis and apoptosis, and also RIPK1-independent necroptosis can occur, we feel that targeting RIPK3 and MLKL could be a more attractive therapeutic approach to inhibit necroptosis. Therefore, future challenges will consist of developing RIPK3 and MLKL inhibitors applicable in both preclinical and clinical settings.

Detection of Rupture-Prone Atherosclerotic Plaques by Time-Resolved Laser Induced Fluorescence Spectroscopy

PubMed Central

Marcu, Laura; Jo, Javier A.; Fang, Qiyin; Papaioannou, Thanassis; Reil, Todd; Qiao, Jian-Hua; Baker, J. Dennis; Freischlag, Julie A.; Fishbein, Michael C.

2009-01-01

Objective Plaque with dense inflammatory cells, including macrophages, thin fibrous cap and superficial necrotic/lipid core is thought to be prone-to-rupture. We report a time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) technique for detection of such markers of plaque vulnerability in human plaques. Methods The autofluorescence of carotid plaques (65 endarterectomy patients) induced by a pulsed laser (337 nm, 0.7 ns) was measured from 831 distinct areas. The emission was resolved spectrally- (360–550 nm range) and temporally- (0.3 ns resolution) using a prototype fiber-optic TR-LIFS apparatus. Lesions were evaluated microscopically and quantified as to the % of different components (fibrous cap, necrotic core, inflammatory cells, foam cells, mature and degraded collagen, elastic fibers, calcification, and smooth muscle cell of the vessel wall). Results We determined that the spectral intensities and time-dependent parameters at discrete emission wavelengths 1) allow for discrimination (sensitivity >81%, specificity >94%) of various compositional and pathological features associated with plaque vulnerability including infiltration of macrophages into intima and necrotic/lipid core under a thin fibrous cap, and 2) show a linear correlation with plaque biochemical content: elastin (P<0.008), collagen (P<0.02), inflammatory cells (P<0.003), necrosis (P<0.004). Conclusion Our results demonstrate the feasibility of TR-LIFS as a method for the identification of markers of plaque vulnerability. Current findings enable future development of TR-LIFS based clinical devices for rapid investigation of atherosclerotic plaques and detection of those at high-risk. PMID:18926540

An ultrasound-based comparative study on carotid plaques in HIV-positive patients vs. atherosclerotic and arteritis patients: atherosclerotic or inflammatory lesions?

PubMed

Maggi, Paolo; Perilli, Francesco; Lillo, Antonio; Carito, Valentina; Epifani, Giuseppe; Bellacosa, Chiara; Pastore, Giuseppe; Regina, Guido

2007-02-01

We have previously described two cases of HIV-1-positive patients undergoing surgery for stenosis of the internal carotid arteries. Histology revealed an extensive inflammatory infiltration of the vascular wall and no evidence of atheromasic plaque. This unexpected pattern of carotid damage prompted us to perform a more accurate investigation of the characteristics of carotid plaques in a group of HIV-positive patients. The results were compared with those obtained from young patients affected by atherosclerosis of the epi-aortic vessels and patients with arteritis. The patients underwent ultrasonography of the epi-aortic vessels using one of the latest generation power color-Doppler with 7.5 MHz probes. The study population included 61 HIV-positive patients and 47 HIV-negative patients (37 atherosclerotic and 10 with arteritis). Compared with HIV-negative atherosclerotic patients, there were significantly higher proportions of HIV-positive patients with iso-hypoechogenic lesions (81.8 vs. 29%) that were homogeneous both in their parietal and endoluminal portions (96.7 vs. 21.6% and 88.5 vs. 54.0%, respectively), with a smooth or slightly irregular surface (99.0 vs. 56.7%) (P=0.001 for all differences). No statistically significant differences were seen between HIV-positive and arteritis patients. Our study evidenced that the ultrasonographic structure of the epi-aortic lesions in HIV-positive patients substantially differ from those of the plaques in atherosclerotic patients, although they share similar characteristics with patients affected by arteritis. Further investigations are warranted to better define the structure and the mechanism of onset of these lesions.

Green tea polyphenol epigallocatechin-3-gallate increases atherosclerotic plaque stability in apolipoprotein E-deficient mice fed a high-fat diet.

PubMed

Wang, Qiming; Zhang, Jian; Li, Yafei; Shi, Haojie; Wang, Hao; Chen, Bingrui; Wang, Fang; Wang, Zemu; Yang, Zhijian; Wang, Liansheng

2018-06-04

Epigallocatechin-3-gallate (EGCG), which is the principal component of green tea, has been shown to prevent the formation of atherosclerosis. However, the effect of EGCG on atherosclerotic plaque stability remains unknown. This study aimed to assess whether EGCG can enhance atherosclerotic plaque stability and to investigate the underlying mechanisms. Apolipoprotein E-deficient mice fed a high-fat diet were injected intraperitoneally with EGCG (10 mg/kg ) for 16 weeks. Cross sections of the brachiocephalic arteries were stained with hematoxylin and eosin (HE) for morphometric analyses or Masson's trichrome for collagen content analyses. Immunohistochemistry was performed to evaluate the percentage of macrophages and smooth muscle cells (SMCs). Protein expression and matrix metalloproteinase (MMP) activity were assayed by Western blot and gelatin zymography, respectively. Serum inflammatory cytokine levels were quantified by enzyme-linked immunosorbent assay. After 16 weeks of feeding the high-fat diet, there was clear atherosclerosis formation in the proximal brachiocephalic artery segments according to HE staining. EGCG treatment significantly increased the thickness of the fibrous cap. In the atherosclerotic plaques of the EGCG group, the relative macrophage content was decreased, whereas the relative SMC and collagen contents were increased. The expression levels of MMP-2, MMP-9 and extracellular matrix metalloproteinase inducer (EMMPRIN) were significantly decreased by EGCG treatment. In addition, EGCG treatment decreased the circulating TNF-a, IL-6, MCP-1 and IFN-γ levels in apolipoprotein E-deficient mice. EGCG promotes atherosclerotic lesion stability in apolipoprotein E-deficient mice. Potentially, these effects are mediated through the inhibition of inflammatory cytokine, MMPs and EMMPRIN expression.

Quantification of atherosclerotic plaque activity and vascular inflammation using [18-F] fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT).

PubMed

Mehta, Nehal N; Torigian, Drew A; Gelfand, Joel M; Saboury, Babak; Alavi, Abass

2012-05-02

Conventional non-invasive imaging modalities of atherosclerosis such as coronary artery calcium (CAC) and carotid intimal medial thickness (C-IMT) provide information about the burden of disease. However, despite multiple validation studies of CAC, and C-IMT, these modalities do not accurately assess plaque characteristics, and the composition and inflammatory state of the plaque determine its stability and, therefore, the risk of clinical events. [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) imaging using positron-emission tomography (PET)/computed tomography (CT) has been extensively studied in oncologic metabolism. Studies using animal models and immunohistochemistry in humans show that FDG-PET/CT is exquisitely sensitive for detecting macrophage activity, an important source of cellular inflammation in vessel walls. More recently, we and others have shown that FDG-PET/CT enables highly precise, novel measurements of inflammatory activity of activity of atherosclerotic plaques in large and medium-sized arteries. FDG-PET/CT studies have many advantages over other imaging modalities: 1) high contrast resolution; 2) quantification of plaque volume and metabolic activity allowing for multi-modal atherosclerotic plaque quantification; 3) dynamic, real-time, in vivo imaging; 4) minimal operator dependence. Finally, vascular inflammation detected by FDG-PET/CT has been shown to predict cardiovascular (CV) events independent of traditional risk factors and is also highly associated with overall burden of atherosclerosis. Plaque activity by FDG-PET/CT is modulated by known beneficial CV interventions such as short term (12 week) statin therapy as well as longer term therapeutic lifestyle changes (16 months). The current methodology for quantification of FDG uptake in atherosclerotic plaque involves measurement of the standardized uptake value (SUV) of an artery of interest and of the venous blood pool in order to calculate a target to background ratio (TBR), which is calculated by dividing the arterial SUV by the venous blood pool SUV. This method has shown to represent a stable, reproducible phenotype over time, has a high sensitivity for detection of vascular inflammation, and also has high inter-and intra-reader reliability. Here we present our methodology for patient preparation, image acquisition, and quantification of atherosclerotic plaque activity and vascular inflammation using SUV, TBR, and a global parameter called the metabolic volumetric product (MVP). These approaches may be applied to assess vascular inflammation in various study samples of interest in a consistent fashion as we have shown in several prior publications.

Quantitative colorimetry of atherosclerotic plaque using the L*a*b* color space during angioscopy for the detection of lipid cores underneath thin fibrous caps.

PubMed

Ishibashi, Fumiyuki; Yokoyama, Shinya; Miyahara, Kengo; Dabreo, Alexandra; Weiss, Eric R; Iafrati, Mark; Takano, Masamichi; Okamatsu, Kentaro; Mizuno, Kyoichi; Waxman, Sergio

2007-12-01

Yellow plaques seen during angioscopy are thought to represent lipid cores underneath thin fibrous caps (LCTCs) and may be indicative of vulnerable sites. However, plaque color assessment during angioscopy has been criticized because of its qualitative nature. The purpose of the present study was to test the ability of a quantitative colorimetric system to measure yellow color intensity of atherosclerotic plaques during angioscopy and to characterize the color of LCTCs. Using angioscopy and a quantitative colorimetry system based on the L*a*b* color space [L* describes brightness (-100 to +100), b* describes blue to yellow (-100 to +100)], the optimal conditions for measuring plaque color were determined in three flat standard color samples and five artificial plaque models in cylinder porcine carotid arteries. In 88 human tissue samples, the colorimetric characteristics of LCTCs were then evaluated. In in-vitro samples and ex-vivo plaque models, brightness L* between 40 and 80 was determined to be optimal for acquiring b* values, and the variables unique to angioscopy in color perception did not impact b* values after adjusting for brightness L* by manipulating light or distance. In ex-vivo human tissue samples, b* value >/=23 (35.91 +/- 8.13) with L* between 40 and 80 was associated with LCTCs (fibrous caps <100 mum). Atherosclerotic plaque color can be consistently measured during angioscopy with quantitative colorimetry. High yellow color intensity, determined by this system, was associated with LCTCs. Quantitative colorimetry during angioscopy may be used for detection of LCTCs, which may be markers of vulnerability.

Absence of Akt1 reduces vascular smooth muscle cell migration and survival and induces features of plaque vulnerability and cardiac dysfunction during atherosclerosis

PubMed Central

Fernández-Hernando, Carlos; József, Levente; Jenkins, Deborah; Lorenzo, Annarita Di; Sessa, William C.

2009-01-01

Objective Deletion of Akt1 leads to severe atherosclerosis and occlusive coronary artery disease. VSMC are an important component of atherosclerotic plaques, responsible for promoting plaque stability in advanced lesions. Fibrous caps of unstable plaques contain less collagen and ECM components and fewer VSMCs than caps from stable lesions. Here, we investigated the role of Akt1 in VSMC proliferation, migration and oxidative stress-induce apoptosis. In addition, we also characterized the atherosclerotic plaque morphology and cardiac function in an atherosclerosis-prone mouse model deficient in Akt1. Methods and Results Absence of Akt1 reduces VSMC proliferation and migration. Mechanistically, the proliferation and migratory phenotype found in Akt1 null VSMCs was linked to reduced Rac-1 activity and MMP-2 secretion. Serum starvation and stress-induced apoptosis was enhanced in Akt1 null VSMCs as determined by flow cytometry using Annexin V/PI staining. Immunohistochemical analysis of atherosclerotic plaques from Akt1−/−ApoE−/− mice showed a dramatic increase in plaque vulnerability characteristics such as enlarged necrotic core and reduced fibrous cap and collagen content. Finally, we show evidences of myocardial infarcts and cardiac dysfunction in Akt1−/−ApoE−/− mice analyzed by immunohistochemistry and echocardiography respectively. Conclusion Akt1 is essential for VSMC proliferation, migration and protection against oxidative stress-induce apoptosis. Absence of Akt1 induces features of plaque vulnerability and cardiac dysfunction in a mouse model of atherosclerosis. PMID:19762778

Increased popliteal circumferential wall tension induced by orthostatic body posture is associated with local atherosclerotic plaques.

PubMed

Gemignani, Tiago; Azevedo, Renata C; Higa, Celina M; Coelho, Otávio R; Matos-Souza, José R; Nadruz, Wilson

2012-09-01

Lower limb arteries are exposed to higher hemodynamic burden in erectile posture. This study evaluated the effects of body posture on popliteal, carotid and brachial circumferential wall tension (CWT) and investigated the relationship between local CWT and atherosclerotic plaques in subjects with cardiovascular risk factors. Two hundred and three subjects (118 women and 85 men) with cardiovascular risk factors (smoking, hypertension or diabetes mellitus) underwent clinical and laboratory analysis and had their blood pressure measured in the arm and calf in supine and orthostatic positions. Arteries were evaluated by ultrasound analysis, while CWT was calculated according to Laplace's law. Among the enrolled participants, 47%, 29% and none presented popliteal, carotid and brachial plaques, respectively. Carotid CWT measurements were not associated with local plaques after adjustment for potential confounders. Conversely, general linear model and logistic regression analyses adjusted for potential confounders demonstrated that peak orthostatic CWT was the only local hemodynamic parameter showing significant relationship with popliteal plaques in the whole sample. In gender-specific analyses, although positively correlated with popliteal plaques in both genders, local peak orthostatic CWT exhibited an independent association with popliteal plaques after adjustment for potential confounders only in women. Popliteal CWT measured in orthostatic posture, rather than in supine position, is associated with popliteal atherosclerotic plaques, particularly in women. These findings suggest that erectile posture might play a role in the atherogenesis of leg arteries by modifying local hemodynamic forces and that there may be gender differences in this regard. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Validating Intravascular Imaging with Serial Optical Coherence Tomography and Confocal Fluorescence Microscopy.

PubMed

Tardif, Pier-Luc; Bertrand, Marie-Jeanne; Abran, Maxime; Castonguay, Alexandre; Lefebvre, Joël; Stähli, Barbara E; Merlet, Nolwenn; Mihalache-Avram, Teodora; Geoffroy, Pascale; Mecteau, Mélanie; Busseuil, David; Ni, Feng; Abulrob, Abedelnasser; Rhéaume, Éric; L'Allier, Philippe; Tardif, Jean-Claude; Lesage, Frédéric

2016-12-15

Atherosclerotic cardiovascular diseases are characterized by the formation of a plaque in the arterial wall. Intravascular ultrasound (IVUS) provides high-resolution images allowing delineation of atherosclerotic plaques. When combined with near infrared fluorescence (NIRF), the plaque can also be studied at a molecular level with a large variety of biomarkers. In this work, we present a system enabling automated volumetric histology imaging of excised aortas that can spatially correlate results with combined IVUS/NIRF imaging of lipid-rich atheroma in cholesterol-fed rabbits. Pullbacks in the rabbit aortas were performed with a dual modality IVUS/NIRF catheter developed by our group. Ex vivo three-dimensional (3D) histology was performed combining optical coherence tomography (OCT) and confocal fluorescence microscopy, providing high-resolution anatomical and molecular information, respectively, to validate in vivo findings. The microscope was combined with a serial slicer allowing for the imaging of the whole vessel automatically. Colocalization of in vivo and ex vivo results is demonstrated. Slices can then be recovered to be tested in conventional histology.

Blood Flow in Stenotic Carotid Bifurcation

NASA Astrophysics Data System (ADS)

Rayz, Vitaliy L.; Williamson, Shobha Devi; Berger, Stanley A.; Saloner, David

2004-11-01

Mechanical forces induced by blood flow on an arterial wall play an important role in the development and growth of atherosclerotic plaque. To assess vulnerability of a plaque it is important to model the flow in a realistic, patient-specific geometry. Three-dimensional models of stenotic carotid bifurcations were obtained from MR images and grids were generated for the flow domains. The unsteady, incompressible Navier-Stokes equations were solved numerically using physiological boundary conditions. The results obtained by computations were compared with in-vivo ultrasound measurements and flow visualization experiments carried out for the same geometry. The simulations show a high velocity jet forming at the stenotic throat and a strong recirculation zone downstream of the stenosis. The jet grows rapidly during the systolic part of the pulse. During diastole the flow is more stagnant. The flow is highly three-dimensional and unsteady which is clearly demonstrated by the flow streamlines. These unsteady flows cause rapid temporal and spatial changes of the forces acting on the atherosclerotic plaque, which has important effects on its growth and stability.

Nanomedicine for the molecular diagnosis of cardiovascular pathologies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Juenet, Maya; Varna, Mariana; Aid-Launais, Rachida

Predicting acute clinical events caused by atherosclerotic plaque rupture remains a clinical challenge. Anatomic mapping of the vascular tree provided by standard imaging technologies is not always sufficient for a robust diagnosis. Yet biological mechanisms leading to unstable plaques have been identified and corresponding biomarkers have been described. Nanosystems charged with contrast agents and targeted towards these specific biomarkers have been developed for several types of imaging modalities. The first systems that have reached the clinic are ultrasmall superparamagnetic iron oxides for Magnetic Resonance Imaging. Their potential relies on their passive accumulation by predominant physiological mechanisms in rupture-prone plaques. Activemore » targeting strategies are under development to improve their specificity and set up other types of nanoplatforms. Preclinical results show a huge potential of nanomedicine for cardiovascular diagnosis, as long as the safety of these nanosystems in the body is studied in depth. - Highlights: • Ischemic stroke and myocardial infarction are the main causes of death in the world. • Their prevalence is related to late detection of high-risk atherosclerotic plaques. • Biomarkers of atherosclerosis evolution and potential ligands have been identified. • Nanosystems based on these ligands appear promising for early molecular diagnosis. • Preclinical and clinical nanosystems for common imaging modalities are described.« less

A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation.

PubMed

Massberg, Steffen; Brand, Korbinian; Grüner, Sabine; Page, Sharon; Müller, Elke; Müller, Iris; Bergmeier, Wolfgang; Richter, Thomas; Lorenz, Michael; Konrad, Ildiko; Nieswandt, Bernhard; Gawaz, Meinrad

2002-10-07

The contribution of platelets to the process of atherosclerosis remains unclear. Here, we show in vivo that platelets adhere to the vascular endothelium of the carotid artery in ApoE(-)(/)(-) mice before the development of manifest atherosclerotic lesions. Platelet-endothelial cell interaction involved both platelet glycoprotein (GP)Ibalpha and GPIIb-IIIa. Platelet adhesion to the endothelium coincides with inflammatory gene expression and preceded atherosclerotic plaque invasion by leukocytes. Prolonged blockade of platelet adhesion in ApoE(-)(/)(-) mice profoundly reduced leukocyte accumulation in the arterial intima and attenuated atherosclerotic lesion formation in the carotid artery bifurcation, the aortic sinus, and the coronary arteries. These findings establish the platelet as a major player in initiation of the atherogenetic process.

Characterization of human arterial tissue affected by atherosclerosis using multimodal nonlinear optical microscopy

NASA Astrophysics Data System (ADS)

Baria, Enrico; Cicchi, Riccardo; Rotellini, Matteo; Nesi, Gabriella; Massi, Daniela; Pavone, Francesco S.

2016-03-01

Atherosclerosis is a widespread cardiovascular disease caused by the deposition of lipids (such as cholesterol and triglycerides) on the inner arterial wall. The rupture of an atherosclerotic plaque, resulting in a thrombus, is one of the leading causes of death in the Western World. Preventive assessment of plaque vulnerability is therefore extremely important and can be performed by studying collagen organization and lipid composition in atherosclerotic arterial tissues. Routinely used diagnostic methods, such as histopathological examination, are limited to morphological analysis of the examined tissues, whereas an exhaustive characterization requires immune-histochemical examination and a morpho-functional approach. Instead, a label-free and non-invasive alternative is provided by nonlinear microscopy. In this study, we combined SHG and FLIM microscopy in order to characterize collagen organization and lipids in human carotid ex vivo tissues affected by atherosclerosis. SHG and TPF images, acquired from different regions within atherosclerotic plaques, were processed through image pattern analysis methods (FFT, GLCM). The resulting information on collagen and cholesterol distribution and anisotropy, combined with collagen and lipids fluorescence lifetime measured from FLIM images, allowed characterization of carotid samples and discrimination of different tissue regions. The presented method can be applied for automated classification of atherosclerotic lesions and plaque vulnerability. Moreover, it lays the foundation for a potential in vivo diagnostic tool to be used in clinical setting.

The use of plaque score measurements to assess changes in atherosclerotic plaque burden induced by lipid-lowering therapy over time: the METEOR study.

PubMed

Peters, Sanne A E; Dogan, Soner; Meijer, Rudy; Palmer, Mike K; Grobbee, Diederick E; Crouse, John R; O'Leary, Daniel H; Evans, Gregory W; Raichlen, Joel S; Bots, Michiel L

2011-01-01

To evaluate whether plaque scoring measurements are able to track changes in atherosclerotic plaque burden over time and to study whether this is affected by lipid-lowering therapy. Data used were from METEOR (Measuring Effects on Intima-Media Thickness: an Evaluation Of Rosuvastatin), a randomized controlled trial of rosuvastatin 40 mg among 984 low-risk patients with modest carotid intima-media thickening (CIMT). In this analysis, duplicate ultrasound images from 12 carotid sites were collected at the baseline and end of the study from 495 European patients and were evaluated for plaque presence and severity. Plaques were scored from near and far walls of the 12 sites (0= none; 1= minimal; 2= moderate; 3= severe) and plaque scores (PS) were combined into two summary measures for each examination. The MeanMaxPS is the mean over the 12 carotid sites of the maximum score at each site and the MaxMaxPS reflects the most severe lesion at any site. Baseline MeanMaxPS and MaxMaxPS were 0.31 (SD: 0.20) and 1.15 (SD: 0.51), respectively. Changes in MeanMaxPS and MaxMaxPS significantly differed between rosuvastatin and placebo (mean difference: -0.03 [SE: 0.01; p =0.016] and -0.09 [SE: 0.04; p =0.027], respectively). In contrast to rosuvastatin, which demonstrated no change from the baseline, placebo showed significant progression in MeanMaxPS and MaxMaxPS (p =0.002; both). The plaque-scoring method proved capable of assessing the change in atherosclerotic plaque burden over time and proved useful to evaluate lipid-lowering in asymptomatic individuals with a low risk of cardiovascular disease and subclinical atherosclerosis.

p62-enriched inclusion bodies in macrophages protect against atherosclerosis

PubMed Central

Sergin, Ismail; Bhattacharya, Somashubhra; Emanuel, Roy; Esen, Emel; Stokes, Carl J.; Evans, Trent D.; Arif, Batool; Curci, John A.; Razani, Babak

2016-01-01

Autophagy is a catabolic cellular mechanism that degrades dysfunctional proteins and organelles. Atherosclerotic plaque formation is enhanced in mice with macrophages that cannot undergo autophagy because of a deficiency of an autophagy component such as ATG5. We showed that exposure of macrophages to atherogenic lipids led to an increase in the abundance of the autophagy chaperone p62, which colocalized with polyubiquitinated proteins in cytoplasmic inclusions. p62 accumulation was increased in ATG5-null macrophages, which had large cytoplasmic ubiquitin-positive p62 inclusions. Aortas from atherosclerotic mice and plaques from human endarterectomy samples showed increased abundance of p62 and polyubiquitinated proteins that co-localized with plaque macrophages, suggesting that p62-enriched protein aggregates were characteristic of atherosclerosis. The formation of the cytoplasmic inclusions depended on p62 because lipid-loaded p62-null macrophages accumulated polyubiquitinated proteins in a diffuse cytoplasmic pattern. The failure of these aggregates to form was associated with increased secretion of IL-1β and enhanced macrophage apoptosis, which depended on the p62 ubiquitin-binding domain and at least partly involved p62-mediated clearance of NLRP3 inflammasomes. Consistent with our in vitro observations, p62-deficient mice formed greater numbers of more complex atherosclerotic plaques, and p62 deficiency further increased atherosclerotic plaque burden in mice with a macrophage-specific ablation of ATG5. Together, these data suggested that sequestration of cytotoxic ubiquitinated proteins by p62 protects against atherogenesis, a condition in which the clearance of protein aggregates is disrupted. PMID:26732762

αVβ3 integrin-targeted microSPECT/CT imaging of inflamed atherosclerotic plaques in mice.

PubMed

Vancraeynest, David; Roelants, Véronique; Bouzin, Caroline; Hanin, François-Xavier; Walrand, Stephan; Bol, Vanesa; Bol, Anne; Pouleur, Anne-Catherine; Pasquet, Agnès; Gerber, Bernhard; Lesnik, Philippe; Huby, Thierry; Jamar, François; Vanoverschelde, Jean-Louis

2016-12-01

αVβ3-integrin is expressed by activated endothelial cells and macrophages in atherosclerotic plaques and may represent a valuable marker of high-risk plaques. We evaluated (99m)Tc-maraciclatide, an integrin-specific tracer, for imaging vascular inflammation in atherosclerotic lesions in mice. Apolipoprotein E-negative (ApoE(-/-)) mice on a Western diet (n = 10) and normally fed adult C57BL/6 control mice (n = 4) were injected with (99m)Tc-maraciclatide (51.8 ± 3.7 MBq). A blocking peptide was infused in three ApoE(-/-) mice; this condition served as another control. After 90 min, the animals were imaged via single-photon emission computed tomography (SPECT). While maintained in the same position, the mice were transferred to computed tomography (CT) to obtain contrast-enhanced images of the aortic arch. Images from both modalities were fused, and signal was quantified in the aortic arch and in the vena cava for subtraction of blood-pool activity. The aorta was carefully dissected after imaging for gamma counting, autoradiography, and histology. Tracer uptake was significantly higher in ApoE(-/-) mice than in both groups of control mice (1.56 ± 0.33 vs. 0.82 ± 0.24 vs. 0.98 ± 0.11, respectively; P = 0.006). Furthermore, higher tracer activity was detected via gamma counting in the aorta of hypercholesterolemic mice than in both groups of control mice (1.52 ± 0.43 vs. 0.78 ± 0.19 vs. 0.47 ± 0.31 (99m)Tc-maraciclatide %ID/g, respectively; P = 0.018). Autoradiography showed significantly higher tracer uptake in the atherosclerotic aorta than in the control aorta (P = 0.026). Finally, in the atherosclerotic aorta, immunostaining indicated that the integrin signal came predominantly from macrophages and was correlated with the macrophage CD68 immunomarker (r = 0.73). (99m)Tc-maraciclatide allows in vivo detection of inflamed atherosclerotic plaques in mice and may represent a non-invasive approach for identifying high-risk plaques in patients.

Indocyanine Green Enables Near-Infrared Fluorescence Imaging of Lipid-Rich, Inflamed Atherosclerotic Plaques

PubMed Central

Vinegoni, Claudio; Botnaru, Ion; Aikawa, Elena; Calfon, Marcella A.; Iwamoto, Yoshiko; Folco, Eduardo J.; Ntziachristos, Vasilis; Weissleder, Ralph; Libby, Peter; Jaffer, Farouc A.

2011-01-01

New high-resolution molecular and structural imaging strategies are needed to visualize high-risk plaques that are likely to cause acute myocardial infarction, because current diagnostic methods do not reliably identify at-risk subjects. While molecular imaging agents are available for lower-resolution detection of atherosclerosis in large arteries, a lack of imaging agents coupled to high-resolution modalities has limited molecular imaging of atherosclerosis in the smaller coronary arteries [AU: ok? YES]. Here, we have demonstrated that indocyanine green (ICG), an FDA-approved near-infrared fluorescence (NIRF) emitting compound, targets atheromas within 20 minutes of injection and provides sufficient signal enhancement for in vivo detection of lipid-rich, inflamed, coronary-sized plaques in atherosclerotic rabbits. In vivo NIRF sensing was achieved with an intravascular wire in the aortae, a vessel of comparable caliber to human coronary arteries. Ex vivo fluorescence reflectance imaging studies showed high plaque target-to-background ratios in atheroma-bearing rabbits injected with ICG, compared to atheroma-bearing rabbits injected with saline. In vitro studies using human macrophages established that ICG preferentially targets lipid-loaded macrophages. In an early clinical study of human atheroma specimens from four patients, we found that ICG colocalized with plaque macrophages and lipids. The atheroma-targeting capability of ICG has the potential to accelerate the clinical development of NIRF molecular imaging of high-risk plaques in humans. PMID:21613624

Tumor Necrosis Factor-α Regulates Triggering Receptor Expressed on Myeloid Cells-1-dependent Matrix Metalloproteinases in the Carotid Plaques of Symptomatic Patients with Carotid Stenosis

PubMed Central

Rao, Velidi H.; Rai, Vikrant; Stoupa, Samantha; Subramanian, Saravanan; Agrawal, Devendra K

2016-01-01

Objective To determine the relationship between increased triggering receptor expressed on myeloid cells (TREM)-1 and plaque stability in atherosclerotic carotid stenosis. Methods The mRNA transcripts and protein for TREM-1, MMP-1, MMP-9, collagen type I (COL1A1) and collagen type III (COL3A1) were analyzed by qPCR and immunofluorescence in both tissues and VSMCs isolated from atherosclerotic carotid plaques of symptomatic and asymptomatic patients with carotid stenosis. Results The TREM-1, MMP-1 and MMP-9 mRNA transcripts were significantly increased (TREM-1, p<0.01; MMP-1, p<0.01 and MMP-9, p<0.001) while COL1A1 and COL3A1 mRNA transcripts were decreased (p<0.001) in VSMCs isolated from carotid plaques of symptomatic (S) than asymptomatic (AS) patients. Stimulation of cells with TNF-α further increased the mRNA transcripts of TREM-1, MMPs, COL1A1 and COL3A1. Modulation of TREM-1 by treatment with TREM-1 decoy receptor rTREM-1/Fc, and either TREM-1 antibodies or TREM-1 siRNA attenuated the TNF-α induced expression of MMP-1 and MMP-9 (p<0.01) and COL1A1 and COL3A1 (p<0.01) in S compared to AS VSMCs isolated from carotid plaques. Inhibition of NF-kB (BAY 11-7085), JNK (SP600125) and PI3K (LY294002) signaling pathways decreased the expression of TREM-1 (p<0.01), MMP-1 (p<0.001) and MMP-9 (p<0.01) in TNF-α treated VSMCs isolated from S carotid plaques compared to AS patients. Conclusion Increased expression of TREM-1 in S compared to AS patients involving MMP-1 and MMP-9 suggest a potential role of TREM-1 in plaque destabilization. Selective blockade of TREM-1 may contribute to the development of new therapies and promising targets for stabilizing vulnerable atherosclerotic plaques. PMID:27017522

Endothelial glycocalyx, apoptosis and inflammation in an atherosclerotic mouse model.

PubMed

Cancel, Limary M; Ebong, Eno E; Mensah, Solomon; Hirschberg, Carly; Tarbell, John M

2016-09-01

Previous experiments suggest that both increased endothelial cell apoptosis and endothelial surface glycocalyx shedding could play a role in the endothelial dysfunction and inflammation of athero-prone regions of the vasculature. We sought to elucidate the possibly synergistic mechanisms by which endothelial cell apoptosis and glycocalyx shedding promote atherogenesis. 4- to 6-week old male C57Bl/6 apolipoprotein E knockout (ApoE(-/-)) mice were fed a Western diet for 10 weeks and developed plaques in their brachiocephalic arteries. Glycocalyx coverage and thickness were significantly reduced over the plaque region compared to the non-plaque region (coverage plaque: 71 ± 23%, non-plaque: 97 ± 3%, p = 0.02; thickness plaque: 0.85 ± 0.15 μm, non-plaque: 1.2 ± 0.21 μm, p = 0.006). Values in the non-plaque region were not different from those found in wild type mice fed a normal diet (coverage WT: 92 ± 3%, p = 0.7 vs. non-plaque ApoE(-/-), thickness WT: 1.1 ± 0.06 μm, p = 0.2 vs. non-plaque ApoE(-/-)). Endothelial cell apoptosis was significantly increased in ApoE(-/-) mice compared to wild type mice (ApoE(-/-):64.3 ± 33.0, WT: 1.1 ± 0.5 TUNEL-pos/cm, p = 2 × 10(-7)). The number of apoptotic endothelial cells per unit length was 2 times higher in the plaque region than in the non-plaque region of the same vessel (p = 3 × 10(-5)). Increased expression of matrix metalloproteinase 9 co-localized with glycocalyx shedding and plaque buildup. Our results suggest that, in concert with endothelial apoptosis that increases lipid permeability, glycocalyx shedding initiated by inflammation facilitates monocyte adhesion and macrophage infiltration that promote lipid retention and the development of atherosclerotic plaques. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Porphyromonas gingivalis Accelerates Inflammatory Atherosclerosis in the Innominate Artery of ApoE Deficient Mice

PubMed Central

Hayashi, Chie; Viereck, Jason; Hua, Ning; Phinikaridou, Alkystis; Madrigal, Andres G.; Gibson, Frank C.; Hamilton, James A.; Genco, Caroline A.

2011-01-01

Objective Studies in humans support a role for the oral pathogen Porphyromonas gingivalis in the development of inflammatory atherosclerosis. The goal of this study was to determine if P. gingivalis infection accelerates inflammation and atherosclerosis in the innominate artery of mice, an artery which has been reported to exhibit many features of human atherosclerotic disease, including plaque rupture. Methods and Results Apolipoprotein E-deficient (ApoE−/−) mice were orally infected with P. gingivalis, and Magnetic Resonance Imaging (MRI) was used to monitor the progression of atherosclerosis in live mice. P. gingivalis infected mice exhibited a statistically significant increase in atherosclerotic plaque in the innominate artery as compared to uninfected mice. Polarized light microscopy and immunohistochemistry revealed that the innominate arteries of infected mice had increased lipids, macrophages and T cells as compared to uninfected mice. Increases in plaque, total cholesterol esters and cholesterol monohydrate crystals, macrophages, and T cells were prevented by immunization with heat-killed P. gingivalis prior to pathogen exposure. Conclusions These are the first studies to demonstrate progression of inflammatory plaque accumulation in the innominate arteries by in-vivo MRI analysis following pathogen exposure, and to document protection from plaque progression in the innominate artery via immunization. PMID:21251656

Joint learning of ultrasonic backscattering statistical physics and signal confidence primal for characterizing atherosclerotic plaques using intravascular ultrasound.

PubMed

Sheet, Debdoot; Karamalis, Athanasios; Eslami, Abouzar; Noël, Peter; Chatterjee, Jyotirmoy; Ray, Ajoy K; Laine, Andrew F; Carlier, Stephane G; Navab, Nassir; Katouzian, Amin

2014-01-01

Intravascular Ultrasound (IVUS) is a predominant imaging modality in interventional cardiology. It provides real-time cross-sectional images of arteries and assists clinicians to infer about atherosclerotic plaques composition. These plaques are heterogeneous in nature and constitute fibrous tissue, lipid deposits and calcifications. Each of these tissues backscatter ultrasonic pulses and are associated with a characteristic intensity in B-mode IVUS image. However, clinicians are challenged when colocated heterogeneous tissue backscatter mixed signals appearing as non-unique intensity patterns in B-mode IVUS image. Tissue characterization algorithms have been developed to assist clinicians to identify such heterogeneous tissues and assess plaque vulnerability. In this paper, we propose a novel technique coined as Stochastic Driven Histology (SDH) that is able to provide information about co-located heterogeneous tissues. It employs learning of tissue specific ultrasonic backscattering statistical physics and signal confidence primal from labeled data for predicting heterogeneous tissue composition in plaques. We employ a random forest for the purpose of learning such a primal using sparsely labeled and noisy samples. In clinical deployment, the posterior prediction of different lesions constituting the plaque is estimated. Folded cross-validation experiments have been performed with 53 plaques indicating high concurrence with traditional tissue histology. On the wider horizon, this framework enables learning of tissue-energy interaction statistical physics and can be leveraged for promising clinical applications requiring tissue characterization beyond the application demonstrated in this paper. Copyright © 2013 Elsevier B.V. All rights reserved.

Painting blood vessels and atherosclerotic plaques with an adhesive drug depot

PubMed Central

Kastrup, Christian J.; Nahrendorf, Matthias; Figueiredo, Jose Luiz; Lee, Haeshin; Kambhampati, Swetha; Lee, Timothy; Cho, Seung-Woo; Gorbatov, Rostic; Iwamoto, Yoshiko; Dang, Tram T.; Dutta, Partha; Yeon, Ju Hun; Cheng, Hao; Pritchard, Christopher D.; Vegas, Arturo J.; Siegel, Cory D.; MacDougall, Samantha; Okonkwo, Michael; Thai, Anh; Stone, James R.; Coury, Arthur J.; Weissleder, Ralph; Langer, Robert; Anderson, Daniel G.

2012-01-01

The treatment of diseased vasculature remains challenging, in part because of the difficulty in implanting drug-eluting devices without subjecting vessels to damaging mechanical forces. Implanting materials using adhesive forces could overcome this challenge, but materials have previously not been shown to durably adhere to intact endothelium under blood flow. Marine mussels secrete strong underwater adhesives that have been mimicked in synthetic systems. Here we develop a drug-eluting bioadhesive gel that can be locally and durably glued onto the inside surface of blood vessels. In a mouse model of atherosclerosis, inflamed plaques treated with steroid-eluting adhesive gels had reduced macrophage content and developed protective fibrous caps covering the plaque core. Treatment also lowered plasma cytokine levels and biomarkers of inflammation in the plaque. The drug-eluting devices developed here provide a general strategy for implanting therapeutics in the vasculature using adhesive forces and could potentially be used to stabilize rupture-prone plaques. PMID:23236189

Detection of atherosclerotic plaques in ApoE-deficient mice using (99m)Tc-duramycin.

PubMed

Liu, Zhonglin; Larsen, Brandon T; Lerman, Lilach O; Gray, Brian D; Barber, Christy; Hedayat, Ahmad F; Zhao, Ming; Furenlid, Lars R; Pak, Koon Y; Woolfenden, James M

2016-08-01

Apoptosis of macrophages and smooth muscle cells is linked to atherosclerotic plaque destabilization. The apoptotic cascade leads to exposure of phosphatidylethanolamine (PE) on the outer leaflet of the cell membrane, thereby making apoptosis detectable using probes targeting PE. The objective of this study was to exploit capabilities of a PE-specific imaging probe, (99m)Tc-duramycin, in localizing atherosclerotic plaque and assessing plaque evolution in apolipoprotein-E knockout (ApoE(-/-)) mice. Atherosclerosis was induced in ApoE(-/-) mice by feeding an atherogenic diet. (99m)Tc-duramycin images were acquired using a small-animal SPECT imager. Six ApoE(-/-) mice at 20weeks of age (Group I) were imaged and then sacrificed for ex vivo analyses. Six additional ApoE(-/-) mice (Group II) were imaged at 20 and 40weeks of age before sacrifice. Six ApoE wild-type (ApoE(+/+)) mice (Group III) were imaged at 40weeks as controls. Five additional ApoE(-/-) mice (40weeks of age) (Group IV) were imaged with a (99m)Tc-labeled inactive peptide, (99m)Tc-LinDUR, to assess (99m)Tc-duramycin targeting specificity. Focal (99m)Tc-duramycin uptake in the ascending aorta and aortic arch was detected at 20 and 40weeks in the ApoE(-/-) mice but not in ApoE(+/+) mice. (99m)Tc-duramycin uptake in the aortic lesions increased 2.2-fold on quantitative imaging in the ApoE(-/-) mice between 20 and 40weeks. Autoradiographic and histological data indicated significantly increased (99m)Tc-duramycin uptake in the ascending aorta and aortic arch associated with advanced plaques. Quantitative autoradiography showed that the ratio of activity in the aortic arch to descending thoracic aorta, which had no plaques or radioactive uptake, was 2.1 times higher at 40weeks than at 20weeks (6.62±0.89 vs. 3.18±0.29, P<0.01). There was barely detectable focal uptake of (99m)Tc-duramycin in the aortic arch of ApoE(+/+) mice. No detectable (99m)Tc-LinDUR uptake was observed in the aortas of ApoE(-/-) mice. PE-targeting properties of (99m)Tc-duramycin in the atherosclerotic mouse aortas were noninvasively characterized. (99m)Tc-duramycin is promising in localizing advanced atherosclerotic plaques. Copyright © 2016 Elsevier Inc. All rights reserved.

H19, a marker of developmental transition, is reexpressed in human atherosclerotic plaques and is regulated by the insulin family of growth factors in cultured rabbit smooth muscle cells.

PubMed

Han, D K; Khaing, Z Z; Pollock, R A; Haudenschild, C C; Liau, G

1996-03-01

H19 is a developmentally regulated gene with putative tumor suppressor activity, and loss of H19 expression may be involved in Wilms' tumorigenesis. In this report, we have performed in situ hybridization analysis of H19 expression during normal rabbit development and in human atherosclerotic plaques. We have also used cultured smooth muscle cells to identify H19 regulatory factors. Our data indicate that H19 expression in the developing skeletal and smooth muscles correlated with specific differentiation events in these tissues. Expression of H19 in the skeletal muscle correlated with nonproliferative, actin-positive muscle cells. In the prenatal blood vessel, H19 expression was both temporally and spatially regulated with initial loss of expression in the inner smooth muscle layers adjacent to the lumen. We also identified H19-positive cells within the adult atherosclerotic lesion and we suggest that these cells may recapitulate earlier developmental events. These results, along with the identification of the insulin family of growth factors as potent regulatory molecules for H19 expression, provide additional clues toward understanding the physiological regulation and function of H19.

H19, a marker of developmental transition, is reexpressed in human atherosclerotic plaques and is regulated by the insulin family of growth factors in cultured rabbit smooth muscle cells.

PubMed Central

Han, D K; Khaing, Z Z; Pollock, R A; Haudenschild, C C; Liau, G

1996-01-01

H19 is a developmentally regulated gene with putative tumor suppressor activity, and loss of H19 expression may be involved in Wilms' tumorigenesis. In this report, we have performed in situ hybridization analysis of H19 expression during normal rabbit development and in human atherosclerotic plaques. We have also used cultured smooth muscle cells to identify H19 regulatory factors. Our data indicate that H19 expression in the developing skeletal and smooth muscles correlated with specific differentiation events in these tissues. Expression of H19 in the skeletal muscle correlated with nonproliferative, actin-positive muscle cells. In the prenatal blood vessel, H19 expression was both temporally and spatially regulated with initial loss of expression in the inner smooth muscle layers adjacent to the lumen. We also identified H19-positive cells within the adult atherosclerotic lesion and we suggest that these cells may recapitulate earlier developmental events. These results, along with the identification of the insulin family of growth factors as potent regulatory molecules for H19 expression, provide additional clues toward understanding the physiological regulation and function of H19. PMID:8636440

Anti-atherosclerotic effects of pravastatin in brachiocephalic artery in comparison with en face aorta and aortic roots in ApoE/LDLR-/- mice.

PubMed

Kostogrys, Renata B; Franczyk-Zarow, Magdalena; Gasior-Glogowska, Marlena; Kus, Edyta; Jasztal, Agnieszka; Wrobel, Tomasz P; Baranska, Malgorzata; Czyzynska-Cichon, Izabela; Drahun, Anna; Manterys, Angelika; Chlopicki, Stefan

2017-02-01

Cholesterol-dependent and independent mechanisms were proposed to explain anti-atherosclerotic action of statins in humans. However, their effects in murine models of atherosclerosis have not been consistently demonstrated. Here, we studied the effects of pravastatin on atherosclerosis in ApoE/LDLR -/- mice fed a control and atherogenic diet. ApoE/LDLR -/- mice were fed a control (CHOW) or an atherogenic (Low Carbohydrate High Protein, LCHP) diet. Two doses of pravastatin (40mg/kg and 100mg/kg) were used. The anti-atherosclerotic effects of pravastatin in en face aorta, cross-sections of aortic roots and brachiocephalic artery (BCA) were analysed. The lipid profile was determined. Fourier Transform Infrared Spectroscopy followed by Fuzzy C-Means (FCM) clustering was used for the quantitative assessment of plaque composition. Treatment with pravastatin (100mg/kg) decreased total and LDL cholesterol only in the LCHP group, but displayed a pronounced anti-atherosclerotic effect in BCA and abdominal aorta. The anti-atherosclerotic effect of pravastatin (100mg/kg) in BCA was associated with significant alterations of the chemical plaque composition, including a fall in cholesterol and cholesterol esters contents independently on total cholesterol and LDL concentration in plasma. Pravastatin at high (100mg/kg), but not low dose displayed a pronounced anti-atherosclerotic effect in ApoE/LDLR -/- mice fed a CHOW or LCHP diet that was remarkable in BCA, visible in en face aorta, whereas it was not observed in aortic roots, suggesting that previous inconsistencies might have been due to the various sites of atherosclerotic plaque analysis. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Assessing carotid atherosclerosis by fiber-optic multispectral photoacoustic tomography

NASA Astrophysics Data System (ADS)

Hui, Jie; Li, Rui; Wang, Pu; Phillips, Evan; Bruning, Rebecca; Liao, Chien-Sheng; Sturek, Michael; Goergen, Craig J.; Cheng, Ji-Xin

2015-03-01

Atherosclerotic plaque at the carotid bifurcation is the underlying cause of the majority of ischemic strokes. Noninvasive imaging and quantification of the compositional changes preceding gross anatomic changes within the arterial wall is essential for diagnosis of disease. Current imaging modalities such as duplex ultrasound, computed tomography, positron emission tomography are limited by the lack of compositional contrast and the detection of flow-limiting lesions. Although high-resolution magnetic resonance imaging has been developed to characterize atherosclerotic plaque composition, its accessibility for wide clinical use is limited. Here, we demonstrate a fiber-based multispectral photoacoustic tomography system for excitation of lipids and external acoustic detection of the generated ultrasound. Using sequential ultrasound imaging of ex vivo preparations we achieved ~2 cm imaging depth and chemical selectivity for assessment of human arterial plaques. A multivariate curve resolution alternating least squares analysis method was applied to resolve the major chemical components, including intravascular lipid, intramuscular fat, and blood. These results show the promise of detecting carotid plaque in vivo through esophageal fiber-optic excitation of lipids and external acoustic detection of the generated ultrasound. This imaging system has great potential for serving as a point-ofcare device for early diagnosis of carotid artery disease in the clinic.

Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype

PubMed Central

Cardilo-Reis, Larissa; Gruber, Sabrina; Schreier, Sabine M; Drechsler, Maik; Papac-Milicevic, Nikolina; Weber, Christian; Wagner, Oswald; Stangl, Herbert; Soehnlein, Oliver; Binder, Christoph J

2012-01-01

Atherosclerotic lesions are characterized by the accumulation of oxidized LDL (OxLDL) and the infiltration of macrophages and T cells. Cytokine expression in the microenvironment of evolving lesions can profoundly contribute to plaque development. While the pro-atherogenic effect of T helper (Th) 1 cytokines, such as IFN-γ, is well established, the role of Th2 cytokines is less clear. Therefore, we characterized the role of the Th2 cytokine interleukin (IL)-13 in murine atherosclerosis. Here, we report that IL-13 administration favourably modulated the morphology of already established atherosclerotic lesions by increasing lesional collagen content and reducing vascular cell adhesion molecule-1 (VCAM-1)-dependent monocyte recruitment, resulting in decreased plaque macrophage content. This was accompanied by the induction of alternatively activated (M2) macrophages, which exhibited increased clearance of OxLDL compared to IFN-γ-activated (M1) macrophages in vitro. Importantly, deficiency of IL-13 results in accelerated atherosclerosis in LDLR−/− mice without affecting plasma cholesterol levels. Thus, IL-13 protects from atherosclerosis and promotes a favourable plaque morphology, in part through the induction of alternatively activated macrophages. PMID:23027612

Utility of 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines in HIV-Infected Adults With Carotid Atherosclerosis.

PubMed

Phan, Binh An P; Weigel, Bernard; Ma, Yifei; Scherzer, Rebecca; Li, Danny; Hur, Sophia; Kalapus, S C; Deeks, Steven; Hsue, Priscilla

2017-07-01

Although HIV is associated with increased atherosclerotic cardiovascular disease (CVD) risk, it is unknown whether guidelines can identify HIV-infected adults who may benefit from statins. We compared the 2013 American College of Cardiology/American Heart Association and 2004 Adult Treatment Panel III recommendations in HIV-infected adults and evaluated associations with carotid artery intima-media thickness and plaque. Carotid artery intima-media thickness was measured at baseline and 3 years later in 352 HIV-infected adults without clinical atherosclerotic CVD and not on statins. Plaque was defined as IMT >1.5 mm in any segment. At baseline, the median age was 43 (interquartile range, 39-49), 85% were men, 74% were on antiretroviral medication, and 50% had plaque. The American College of Cardiology/American Heart Association guidelines were more likely to recommend statins compared with the Adult Treatment Panel III guidelines, both overall (26% versus 14%; P <0.001), in those with plaque (32% versus 17%; P =0.0002), and in those without plaque (16% versus 7%; P =0.025). In multivariable analysis, older age, higher low-density lipoprotein cholesterol, pack per year of smoking, and history of opportunistic infection were associated with baseline plaque. Baseline IMT (hazard ratio, 1.18 per 10% increment; 95% confidence interval, 1.05-1.33; P =0.005) and plaque (hazard ratio, 2.06; 95% confidence interval, 1.02-4.08; P =0.037) were each associated with all-cause mortality, independent of traditional CVD risk factors. Although the American College of Cardiology/American Heart Association guidelines recommended statins to a greater number of HIV-infected adults compared with the Adult Treatment Panel III guidelines, both failed to recommend therapy in the majority of HIV-affected adults with carotid plaque. Baseline carotid atherosclerosis but not atherosclerotic CVD risk scores was an independent predictor of mortality. HIV-specific guidelines that include detection of subclinical atherosclerosis may help to identify HIV-infected adults who are at increased atherosclerotic CVD risk and may be considered for statins. © 2017 The Authors.

Design and Synthesis of Gold Nanoparticle Contrast Agents for Atherosclerosis Imaging with Computed tomography

NASA Astrophysics Data System (ADS)

Chhour, Peter

Cell tracking offers the opportunity to study migration and localization of cells in vivo, allowing investigations of disease mechanisms and drug efficacy. Monocytes play a key role in the progression of atherosclerotic plaques in the coronary arteries. While x-ray computed tomography (CT) is commonly used to clinically assess coronary plaque burden, cell tracking with CT is mostly unexplored. The establishment of monocyte cell tracking tools would allow for the direct investigation of gene and drug therapies aimed at monocyte recruitment in atherosclerosis. In this thesis, we present the design and optimization of gold nanoparticles as CT contrast agents for cell tracking of monocyte recruitment to atherosclerotic plaques. Gold nanoparticle polymer constructs with controlled localization are evaluated as potential monocyte labels. However, cytotoxic effects were observed at concentrations necessary for cell labeling. Therefore, variations in physical and chemical properties of gold nanoparticles were explored as cell labels for monocyte tracking. Each formulation was screened for effects on cell viability, cell function and uptake in monocytes. The uptake in monocytes revealed a complex relationship with nanoparticle size behavior dependent on the surface ligand used. This led to the selection of an optimal size and coating for monocyte labeling, 11-mercaptoundecanoic acid coated 15 nm gold nanoparticles. This formulation was further investigated for cell viability, function, and uptake with isolated primary monocytes. Moreover, primary monocytes labeled with this formulation were used to observe monocyte recruitment in atherosclerotic mice. Mice with early atherosclerotic plaques received intravenously injections of gold labeled monocytes and their recruitment to plaques were observed over 5 days with CT. Increases in CT attenuation in the plaque and transmission electron microscopy of plaque sections indicated the presence of gold labeled monocytes in the plaque. These results demonstrate the feasibility of using CT to track ex-vivo labeled cells non-invasively with CT and could further be used to investigate drugs aimed at modulating monocyte recruitment in the treatment of atherosclerosis. This work expands the applications of cell tracking and may lead to additional uses in other diseases.

Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE-/- mouse model of atherosclerosis with alterations in IL10/AMPKα pathway.

PubMed

Thompson, D; Morrice, N; Grant, L; Le Sommer, S; Ziegler, K; Whitfield, P; Mody, N; Wilson, H M; Delibegović, M

2017-08-01

Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD. We generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE -/- /LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed. Myeloid-PTP1B knockout mice on atherogenic background (ApoE -/- /LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKα and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE 2 ), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting. Here we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE -/- mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk.

Emerging applications of nanotechnology for the diagnosis and management of vulnerable atherosclerotic plaques

PubMed Central

Yu, Shann S.; Ortega, Ryan A.; Reagan, Brendan W.; McPherson, John A.; Sung, Hak-Joon; Giorgio, Todd D.

2017-01-01

An estimated 16 million people in the United States have coronary artery disease (CAD), and approximately 325,000 people die annually from cardiac arrest. About two-thirds of unexpected cardiac deaths occur without prior recognition of cardiac disease. A vast majority of these deaths are attributable to the rupture of ‘Vulnerable atherosclerotic plaques’. Clinically, plaque vulnerability is typically assessed through imaging techniques, and ruptured plaques leading to acute myocardial infarction are treated through angioplasty or stenting. Despite significant advances, it is clear that current imaging methods are insufficiently capable for elucidating plaque composition—which is a key determinant of vulnerability. Further, the exciting improvement in the treatment of CAD afforded by stenting procedures has been buffered by significant undesirable host-implant effects, including restenosis and late thrombosis. Nanotechnology has led to some potential solutions to these problems by yielding constructs that interface with plaque cellular components at an unprecedented size scale. By leveraging the innate ability of macrophages to phagocytose nanoparticles, contrast agents can now be targeted to plaque inflammatory activity. Improvements in nano-patterning procedures have now led to increased ability to regenerate tissue isotropy directly on stents, enabling gradual regeneration of normal, physiologic vascular structures. Advancements in immunoassay technologies promise lower costs for biomarker measurements, and in the near future, may enable the addition of routine blood testing to the clinician’s toolbox—decreasing the costs of atherosclerosis-related medical care. These are merely three examples among many stories of how nanotechnology continues to promise advances in the diagnosis and treatment of vulnerable atherosclerotic plaques. PMID:21834059

Short Telomeres, but Not Telomere Attrition Rates, Are Associated With Carotid Atherosclerosis.

PubMed

Toupance, Simon; Labat, Carlos; Temmar, Mohamed; Rossignol, Patrick; Kimura, Masayuki; Aviv, Abraham; Benetos, Athanase

2017-08-01

Short telomeres are associated with atherosclerosis. However, the temporal relationship between atherosclerosis and telomere length is unclear. The objective of this work was to examine the temporal formation and progression of carotid atherosclerotic plaques in relation to telomere dynamics. In a longitudinal study, comprising 154 French men and women (aged 31-76 years at baseline), carotid plaques were quantified by echography, and telomere length on leucocytes was measured by Southern blots at baseline and follow-up examinations. Telomere attrition rates during the 9.5-year follow-up period were not different in individuals with plaques at both baseline and follow-up examinations (23.3±2.0 base pairs/y) than in individuals who developed plaques during the follow-up period (26.5±2.0 base pairs/y) and those without plaques at either baseline or follow-up examination (22.5±2.3 base pairs/y; P =0.79). At baseline, telomere length was associated with presence of carotid plaques ( P =0.02) and with the number of regions with plaques ( P =0.005). An interaction ( P =0.03) between age and the presence of plaques was observed, such that the association between plaques and telomere length was more pronounced at a younger age. In conclusion, carotid atherosclerosis is not associated with increased telomere attrition during a 9.5-year follow-up period. Short telomere length is more strongly associated with early-onset than late-onset carotid atherosclerosis. Our results support the thesis that heightened telomere attrition during adult life might not explain the short telomeres observed in subjects with atherosclerotic disease. Rather, short telomeres antecedes the clinical manifestation of the disease. © 2017 American Heart Association, Inc.

Optical pathology study of human abdominal aorta tissues using confocal micro resonance Raman spectroscopy

NASA Astrophysics Data System (ADS)

Liu, Cheng-hui; Boydston-White, Susie; Wang, Wubao; Sordillo, Laura A.; Shi, Lingyan; Weisberg, Arel; Tomaselli, Vincent P.; Sordillo, Peter P.; Alfano, Robert R.

2016-03-01

Resonance Raman (RR) spectroscopic technique has a high potential for label-free and in-situ detection of biomedical lesions in vivo. This study evaluates the ability of RR spectroscopy method as an optical histopathology tool to detect the atherosclerotic plaque states of abdominal aorta in vitro. This part demonstrates the RR spectral molecular fingerprint features from different sites of the atherosclerotic abdominal aortic wall tissues. Total 57 sites of five pieces aortic samples in intimal and adventitial wall from an autopsy specimen were examined using confocal micro Raman system of WITec 300R with excitation wavelength of 532nm. The preliminary RR spectral biomarkers of molecular fingerprints indicated that typical calcified atherosclerotic plaque (RR peak at 964cm-1) tissue; fibrolipid plaque (RR peaks at 1007, 1161, 1517 and 2888cm-1) tissue, lipid pool with the fatty precipitation cholesterol) with collagen type I (RR peaks at 864, 1452, 1658, 2888 and 2948cm-1) in the soft tissue were observed and investigated.

Combination of fluvastatin and losartan relieves atherosclerosis and macrophage infiltration in atherosclerotic plaques in rabbits

PubMed Central

Yang, Ya-pei; Dong, Qiu-li; Zhang, Xu-hong; Zhang, Yue-hui; Zhu, Li; Li, Shu-ying; Liu, Zhong-zhi; Xu, Hui; Wang, Nan; Jiang, Hong; Liu, Chun-xi; Liu, Xian-xi; Dong, Bo

2011-01-01

Aim: To investigate whether the combination of fluvastatin and losartan synergistically relieve atherosclerosis and plaque inflammation induced by a high-cholesterol diet in rabbits. Methods: Atherosclerosis was induced with a high-cholesterol diet for 3 months in 36 New Zealand white rabbits. The animals were randomly divided into model group, fluvastatin (10 mg·kg-1·d-1) group, losartan (25 mg·kg-1·d-1) group, and fluvastatin plus losartan group. After the 16-week treatments, the blood samples the animals were collected, and the thoracic aortas were examined immunohistochemically. The mRNA and protein expression levels of monocyte chemotactic protein-1 (MCP-1) were measured using RT-PCR and Western blot. Results: Compared to the treatment with losartan or fluvastatin alone, the combined treatment did not produce higher efficacy in reduction of blood cholesterol level. However, the combination did synergistically decrease the intimal and media thickness of thoracic aortas with significantly reduced macrophage infiltration and MCP-1 expression in the plaques. Conclusion: The combined treatment with losartan and fluvastatin significantly inhibited atherosclerotic progress and reduced inflammation associated with atherosclerotic plaques. PMID:21909126

A Critical Role of Platelet Adhesion in the Initiation of Atherosclerotic Lesion Formation

PubMed Central

Massberg, Steffen; Brand, Korbinian; Grüner, Sabine; Page, Sharon; Müller, Elke; Müller, Iris; Bergmeier, Wolfgang; Richter, Thomas; Lorenz, Michael; Konrad, Ildiko; Nieswandt, Bernhard; Gawaz, Meinrad

2002-01-01

The contribution of platelets to the process of atherosclerosis remains unclear. Here, we show in vivo that platelets adhere to the vascular endothelium of the carotid artery in ApoE − / − mice before the development of manifest atherosclerotic lesions. Platelet–endothelial cell interaction involved both platelet glycoprotein (GP)Ibα and GPIIb-IIIa. Platelet adhesion to the endothelium coincides with inflammatory gene expression and preceded atherosclerotic plaque invasion by leukocytes. Prolonged blockade of platelet adhesion in ApoE − / − mice profoundly reduced leukocyte accumulation in the arterial intima and attenuated atherosclerotic lesion formation in the carotid artery bifurcation, the aortic sinus, and the coronary arteries. These findings establish the platelet as a major player in initiation of the atherogenetic process. PMID:12370251

Atorvastatin Upregulates the Expression of miR-126 in Apolipoprotein E-knockout Mice with Carotid Atherosclerotic Plaque.

PubMed

Pan, Xudong; Hou, Rongyao; Ma, Aijun; Wang, Ting; Wu, Mei; Zhu, Xiaoyan; Yang, Shaonan; Xiao, Xing

2017-01-01

Carotid atherosclerosis (AS) is a chronic inflammatory disease of the carotid arterial wall, which is very important in terms of the occurrence of cerebral vascular accidents. Studies have demonstrated that microRNAs (miRNAs) and their target genes are involved in the formation of atherosclerosis and that atorvastatin might reduce atherosclerotic plaques by regulating the expression of miRNAs. However, the related mechanism is not yet known. In this study, we first investigated the effects of atorvastatin on miR-126 and its target gene, i.e., vascular cell adhesion molecule-1 (VCAM-1) in apolipoprotein E-knockout (ApoE-/-) mice with carotid atherosclerotic plaque in vivo. We compared the expressions of miR-126 and VCAM-1 between the control, atherosclerotic model and atorvastatin treatment groups of ApoE-/- mice using RT-PCR and Western blot. We found the miR-126 expression was significantly down-regulated, and the VCAM-1 expression was significantly up-regulated in the atherosclerotic model group, which accelerated the progression of atherosclerosis in the ApoE-/- mice. These results following atorvastatin treatment indicated that miR-126 expression was significantly up-regulated, VCAM-1 expression was significantly down-regulated and atherosclerotic lesions were reduced. The present results might explain the mechanism by which miR-126 is involved in the formation of atherosclerosis in vivo. Our study first indicated that atorvastatin might exert its anti-inflammatory effects in atherosclerosis by regulating the expressions of miR-126 and VCAM-1 in vivo.

Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis

PubMed Central

Roth Flach, Rachel J.; Skoura, Athanasia; Matevossian, Anouch; Danai, Laura V.; Zheng, Wei; Cortes, Christian; Bhattacharya, Samit K.; Aouadi, Myriam; Hagan, Nana; Yawe, Joseph C.; Vangala, Pranitha; Menendez, Lorena Garcia; Cooper, Marcus P.; Fitzgibbons, Timothy P.; Buckbinder, Leonard; Czech, Michael P.

2015-01-01

Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe−/− mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe−/− and Ldlr−/− mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic lesion area. MAP4K4 silencing in cultured ECs attenuates cell surface adhesion molecule expression while reducing nuclear localization and activity of NFκB, which is critical for promoting EC activation and atherosclerosis. Taken together, these results reveal that MAP4K4 is a key signalling node that promotes immune cell recruitment in atherosclerosis. PMID:26688060

Effect of ascorbic acid on prevention of hypercholesterolemia induced atherosclerosis.

PubMed

Das, S; Ray, R; Snehlata; Das, N; Srivastava, L M

2006-04-01

The notion that oxidation of lipids and propagation of free radicals may contribute to the pathogenesis of atherosclerosis is supported by a large body of evidence. To circumvent the damage caused by oxygen free radicals, antioxidants are needed which provide the much needed neutralization of free radical by allowing the pairing of electrons. In this study we have investigated the effect of ascorbic acid, a water soluble antioxidant on the development of hypercholesterolemia induced atherosclerosis in rabbits. Rabbits were made hypercholesterolemic and atherosclerotic by feeding 100 mg cholesterol/day. Different doses of ascorbic acid were administered to these rabbits. Low dose of ascorbic acid (0.5 mg/100 g body weight/day) did not have any significant effect on the percent of total area covered by atherosclerotic plaque. However, ascorbic acid when fed at a higher dose (15 mg/100 g body weight/day) was highly effective in reducing the atherogenecity. With this dose the percent of total surface area covered by atherosclerotic plaque was significantly less (p < 0.001). This suggests that use of ascorbic acid may have great promise in the prevention of hypercholesterolemia induced atherosclerosis.

Enzyme-Sensitive MR Imaging Targeting Myeloperoxidase Identifies Active Inflammation in Experimental Rabbit Atherosclerotic Plaques

PubMed Central

Ronald, John A.; Chen, John W.; Chen, Yuanxin; Hamilton, Amanda M.; Rodriguez, Elisenda; Reynolds, Fred; Hegele, Robert A.; Rogers, Kem A.; Querol, Manel; Bogdanov, Alexei; Weissleder, Ralph; Rutt, Brian K.

2009-01-01

Background Inflammation undermines the stability of atherosclerotic plaques, rendering them susceptible to acute rupture, the cataclysmic event that underlies clinical expression of this disease. Myeloperoxidase (MPO) is a central inflammatory enzyme secreted by activated macrophages, and is involved in multiple stages of plaque destabilization and patient outcome. We report here that a unique functional in vivo magnetic resonance (MR) agent can visualize MPO activity in atherosclerotic plaques in a rabbit model. Methods and Results We performed MR imaging of the thoracic aorta of New Zealand white (NZW) rabbits fed a cholesterol (n=11) or normal (n=4) diet up to 2 hours after injection of the MPO sensor bis-5HT-DTPA(Gd) (MPO(Gd)), the conventional agent, DTPA(Gd), or an MPO (Gd) analog, bis-tyr-DTPA(Gd), as controls. Delayed MPO(Gd) images (2 hour post injection) showed focal areas of increased contrast (>2-fold) in diseased wall, but not in normal wall (p=0.84), compared to both DTPA(Gd) (n=11; p<0.001) and bis-tyr-DTPA(Gd) (n=3; p<0.05). Biochemical assays confirmed that diseased wall possessed three-fold elevated MPO activity compared to normal wall (p<0.01). Areas detected by MPO(Gd) imaging co-localized and correlated with MPO-rich areas infiltrated by macrophages on histopathological evaluations (r=0.91, p<0.0001). While macrophages were the main source of MPO, not all macrophages secreted MPO, suggesting that distinct subpopulations contribute differently to atherogenesis and supporting our functional approach. Conclusions Our study represents a unique approach in the detection of inflammation in atherosclerotic plaques by examining macrophage function and the activity of an effector enzyme, to noninvasively provide both anatomic and functional information in vivo. PMID:19652086

Mast cells mediate neutrophil recruitment during atherosclerotic plaque progression.

PubMed

Wezel, Anouk; Lagraauw, H Maxime; van der Velden, Daniël; de Jager, Saskia C A; Quax, Paul H A; Kuiper, Johan; Bot, Ilze

2015-08-01

Activated mast cells have been identified in the intima and perivascular tissue of human atherosclerotic plaques. As mast cells have been described to release a number of chemokines that mediate leukocyte fluxes, we propose that activated mast cells may play a pivotal role in leukocyte recruitment during atherosclerotic plaque progression. Systemic IgE-mediated mast cell activation in apoE(-/-)μMT mice resulted in an increase in atherosclerotic lesion size as compared to control mice, and interestingly, the number of neutrophils was highly increased in these lesions. In addition, peritoneal mast cell activation led to a massive neutrophil influx into the peritoneal cavity in C57Bl6 mice, whereas neutrophil numbers in mast cell deficient Kit(W(-sh)/W(-sh)) mice were not affected. Within the newly recruited neutrophil population, increased levels of CXCR2(+) and CXCR4(+) neutrophils were observed after mast cell activation. Indeed, mast cells were seen to contain and release CXCL1 and CXCL12, the ligands for CXCR2 and CXCR4. Intriguingly, peritoneal mast cell activation in combination with anti-CXCR2 receptor antagonist resulted in decreased neutrophil recruitment, thus establishing a prominent role for the CXCL1/CXCR2 axis in mast cell-mediated neutrophil recruitment. Our data suggest that chemokines, and in particular CXCL1, released from activated mast cells induce neutrophil recruitment to the site of inflammation, thereby aggravating the ongoing inflammatory response and thus affecting plaque progression and destabilization. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Identifying Vulnerable Atherosclerotic Plaque in Rabbits Using DMSA-USPIO Enhanced Magnetic Resonance Imaging to Investigate the Effect of Atorvastatin

PubMed Central

Li, Dongye; Wu, Weiheng; Gong, Lei; Li, Yong; Zhang, Qingdui; Zhang, Tao; Zhang, Chao; Zhang, Yu

2015-01-01

Background Rupture of an atherosclerotic plaque is the primary cause of acute cardiovascular and cerebrovascular syndromes. Early and non-invasive detection of vulnerable atherosclerotic plaques (VP) would be significant in preventing some aspects of these syndromes. As a new contrast agent, dimercaptosuccinic acid (DMSA) modified ultra-small super paramagnetic iron oxide (USPIO) was synthesized and used to identify VP and rupture plaque by magnetic resonance imaging (MRI). Methods Atherosclerosis was induced in male New Zealand White rabbits by feeding a high cholesterol diet (n = 30). Group A with atherosclerosis plaque (n = 10) were controls. VP was established in groups B (n = 10) and C (n = 10) using balloon-induced endothelial injury of the abdominal aorta. Adenovirus-carrying p53 genes were injected into the aortic segments rich in plaques after 8 weeks. Group C was treated with atorvastatin for 8 weeks. Sixteen weeks later, all rabbits underwent pharmacological triggering, and imaging were taken daily for 5 d after DMSA-USPIO infusion. At the first day and before being killed, serum MMP-9, sCD40L, and other lipid indicators were measured. Results DMSA-USPIO particles accumulated in VP and rupture plaques. Rupture plaques appeared as areas of hyper-intensity on DMSA-USPIO enhanced MRI, especially T2*-weighted sequences, with a signal strength peaking at 96 h. The group given atorvastatin showed few DMSA-USPIO particles and had lower levels of serum indicators. MMP-9 and sCD40L levels in group B were significantly higher than in the other 2 groups (P <0.05). Conclusion After successfully establishing a VP model in rabbits, DMSA-USPIO was used to enhance MRI for clear identification of plaque inflammation and rupture. Rupture plaques were detectable in this way probably due to an activating inflammatory process. Atorvastatin reduced the inflammatory response and stabilizing VP possibly by decreasing MMP-9 and sCD40L levels. PMID:25973795

CD98 regulates vascular smooth muscle cell proliferation in atherosclerosis.

PubMed

Baumer, Yvonne; McCurdy, Sara; Alcala, Martin; Mehta, Nehal; Lee, Bog-Hieu; Ginsberg, Mark H; Boisvert, William A

2017-01-01

Vascular smooth muscle cells (VSMC) migrate and proliferate to form a stabilizing fibrous cap that encapsulates atherosclerotic plaques. CD98 is a transmembrane protein made of two subunits, CD98 heavy chain (CD98hc) and one of six light chains, and is known to be involved in cell proliferation and survival. Because the influence of CD98hc on atherosclerosis development is unknown, our aim was to determine if CD98hc expressed on VSMC plays a role in shaping the morphology of atherosclerotic plaques by regulating VSMC function. In addition to determining the role of CD98hc in VSMC proliferation and apoptosis, we utilized mice with SMC-specific deletion of CD98hc (CD98hc fl/fl SM22αCre + ) to determine the effects of CD98hc deficiency on VSMC function in atherosclerotic plaque. After culturing for 5 days in vitro, CD98hc -/- VSMC displayed dramatically reduced cell counts, reduced proliferation, as well as reduced migration compared to control VSMC. Analysis of aortic VSCM after 8 weeks of HFD showed a reduction in CD98hc -/- VSMC proliferation as well as increased apoptosis compared to controls. A long-term atherosclerosis study using SMC-CD98hc -/- /ldlr -/- mice was performed. Although total plaque area was unchanged, CD98hc -/- mice showed reduced presence of VSMC within the plaque (2.1 ± 0.4% vs. 4.3 ± 0.4% SM22α-positive area per plaque area, p < 0.05), decreased collagen content, as well as increased necrotic core area (25.8 ± 1.9% vs. 10.9 ± 1.6%, p < 0.05) compared to control ldlr -/- mice. We conclude that CD98hc is required for VSMC proliferation, and that its deficiency leads to significantly reduced presence of VSMC in the neointima. Thus, CD98hc expression in VSMC contributes to the formation of plaques that are morphologically more stable, and thereby protects against atherothrombosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation

PubMed Central

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F.; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

Objective CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). Methods and Results CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse “flow cessation model,” in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. Conclusions These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression. PMID:26335690

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation.

PubMed

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse "flow cessation model," in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression.

Correlation Between Arterial FDG Uptake and Biomarkers in Peripheral Artery Disease

PubMed Central

Myers, Kelly S.; Rudd, James H. F.; Hailman, Eric P.; Bolognese, James A.; Burke, Joanne; Pinto, Cathy Anne; Klimas, Michael; Hargreaves, Richard; Dansky, Hayes M.; Fayad, Zahi A.

2014-01-01

OBJECTIVES A prospective, multicenter 18fluorine-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) imaging study was performed to estimate the correlations among arterial FDG uptake and atherosclerotic plaque biomarkers in patients with peripheral artery disease. BACKGROUND Inflammation within atherosclerotic plaques is associated with instability of the plaque and future cardiovascular events. Previous studies have shown that 18F-FDG-PET/CT is able to quantify inflammation within carotid artery atherosclerotic plaques, but no studies to date have investigated this correlation in peripheral arteries with immunohistochemical confirmation. METHODS Thirty patients across 5 study sites underwent 18F-FDG-PET/CT imaging before Silver-Hawk atherectomy (FoxHollow Technologies, Redwood City, California) for symptomatic common or superficial femoral arterial disease. Vascular FDG uptake (expressed as target-to-background ratio) was measured in the carotid arteries and aorta and femoral arteries, including the region of atherectomy. Immunohistochemistry was performed on the excised atherosclerotic plaque extracts, and cluster of differentiation 68 (CD68) level as a measure of macrophage content was determined. Correlations between target-to-background ratio of excised lesions, as well as entire arterial regions, and CD68 levels were determined. Imaging was performed during the 2 weeks before surgery in all cases. RESULTS Twenty-one patients had adequate-quality 18F-FDG-PET/CT peripheral artery images, and 34 plaque specimens were obtained. No significant correlation between lesion target-to-background ratio and CD68 level was observed. CONCLUSIONS There were no significant correlations between CD68 level (as a measure of macrophage content) and FDG uptake in the peripheral arteries in this multicenter study. Differences in lesion extraction technique, lesion size, the degree of inflammation, and imaging coregistration techniques may have been responsible for the failure to observe the strong correlations with vascular FDG uptake observed in previous studies of the carotid artery and in several animal models of atherosclerosis. PMID:22239891

Improvement of endothelial function in a murine model of mild cholesterol-induced atherosclerosis by mineralocorticoid antagonism.

PubMed

Kratz, Mario T; Schirmer, Stephan H; Baumhäkel, Magnus; Böhm, Michael

2016-08-01

The renin-angiotensin-aldosterone-system (RAAS) plays a role in endothelial dysfunction and atherosclerosis. During treatment with RAAS-inhibitors, elevated aldosterone may sustain "aldosterone escape". We investigated the effects of treatment with the mineralocorticoid antagonist eplerenone (Ep) compared with ramipril (Rami) or the combination of both on oxidative stress, plaque formation and endothelial function, in atherosclerotic apolipoprotein E deficient mice (ApoE(-/-)-mice). ApoE(-/-)-mice were fed a cholesterol rich diet (21% fat, 19.5% casein, 1.25% cholesterol) for 8 weeks to produce mild atherosclerosis (i.e. plaque load 20-30%). ApoE(-/-)-mice (control), ApoE(-/-)-mice treated with Ep (25 mg/kg/day), Rami (2.5 mg/kg/day) and their combination were compared. Heart rate (HR) and blood pressure (BP) were measured using the tail-cuff-method. Endothelial function was measured in aortic rings and corpora cavernosal strips (CCs). Atherosclerotic plaque burden, collagen content, oxidative stress (Dihydroethidium (DHE) staining) and macrophages were determined. Treatments had no effects on HR and slightly reduced BP in ApoE(-/-)-mice treated with the combination of eplerenone and ramipril. Endothelium-dependent relaxation of aortic rings and CCs with carbachol was significantly improved in animals treated with Ep, Rami or their combination (p = 0.05 - p = 0.001). DHE-stained penile and aortic sections revealed a significant reduction in superoxide production in all treated groups (p = 0.035 - p = 0.001). In parallel, aortic and penile collagen content in ApoE(-/-)-mice was significantly decreased (p = 0.035 - p < 0.001) in animals treated with Ep, Rami or their combination. In agreement, there was a trend towards a reduction of aortic plaque area by treatment with Ep (-9.0 ± 3.2%) and Rami (-11.9 ± 4%). Only the treatment with the combination induced a significant reduction of the atherosclerotic plaque burden (p = 0.045). Moreover, the treatment of ApoE(-/-)-mice with Ep, Rami and their combination significantly reduced the count macrophage count in atherosclerotic plaque lesions. Ep restored endothelial function by reduction of oxidative stress, atherosclerotic macrophage content, atherosclerotic lesion size and fibrosis to the same extent as treatment with Rami or the combination. Mineralocorticoid antagonism provides vasculoprotective effects and should be clinically evaluated for vascular disease such as erectile dysfunction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Labeling monocytes with gold nanoparticles to track their recruitment in atherosclerosis with computed tomography

PubMed Central

Chhour, Peter; Naha, Pratap C.; O’Neill, Sean M.; Litt, Harold I.; Reilly, Muredach P.; Ferrari, Victor A.; Cormode, David P.

2016-01-01

Monocytes are actively recruited from the circulation into developing atherosclerotic plaques. In the plaque, monocytes differentiate into macrophages and eventually form foam cells. Continued accumulation of foam cells can lead to plaque rupture and subsequent myocardial infarction. X-ray computed tomography (CT) is the best modality to image the coronary arteries non-invasively, therefore we have sought to track the accumulation of monocytes into atherosclerotic plaques using CT. Gold nanoparticles were synthesized and stabilized with a variety of ligands. Select formulations were incubated with an immortalized monocyte cell line in vitro and evaluated for cytotoxicity, effects on cytokine release, and cell uptake. These data identified a lead formulation, 11-MUDA capped gold nanoparticles, to test for labeling primary monocytes. The formulation did not the affect the viability or cytokine release of primary monocytes and was highly taken up by these cells. Gold labeled primary monocytes were injected into apolipoprotein E deficient mice kept on Western diet for 10 weeks. Imaging was done with a microCT scanner. A significant increase in attenuation was measured in the aorta of mice receiving the gold labeled cells as compared to control animals. Following the experiment, the biodistribution of gold was evaluated in major organs. Additionally, plaques were sectioned and examined with electron microscopy. The results showed that gold nanoparticles were present inside monocytes located within plaques. This study demonstrates the feasibility of using gold nanoparticles as effective cell labeling contrast agents for non-invasive imaging of monocyte accumulation within plaques with CT. PMID:26914700

Labeling monocytes with gold nanoparticles to track their recruitment in atherosclerosis with computed tomography.

PubMed

Chhour, Peter; Naha, Pratap C; O'Neill, Sean M; Litt, Harold I; Reilly, Muredach P; Ferrari, Victor A; Cormode, David P

2016-05-01

Monocytes are actively recruited from the circulation into developing atherosclerotic plaques. In the plaque, monocytes differentiate into macrophages and eventually form foam cells. Continued accumulation of foam cells can lead to plaque rupture and subsequent myocardial infarction. X-ray computed tomography (CT) is the best modality to image the coronary arteries non-invasively, therefore we have sought to track the accumulation of monocytes into atherosclerotic plaques using CT. Gold nanoparticles were synthesized and stabilized with a variety of ligands. Select formulations were incubated with an immortalized monocyte cell line in vitro and evaluated for cytotoxicity, effects on cytokine release, and cell uptake. These data identified a lead formulation, 11-MUDA capped gold nanoparticles, to test for labeling primary monocytes. The formulation did not the affect the viability or cytokine release of primary monocytes and was highly taken up by these cells. Gold labeled primary monocytes were injected into apolipoprotein E deficient mice kept on Western diet for 10 weeks. Imaging was done with a microCT scanner. A significant increase in attenuation was measured in the aorta of mice receiving the gold labeled cells as compared to control animals. Following the experiment, the biodistribution of gold was evaluated in major organs. Additionally, plaques were sectioned and examined with electron microscopy. The results showed that gold nanoparticles were present inside monocytes located within plaques. This study demonstrates the feasibility of using gold nanoparticles as effective cell labeling contrast agents for non-invasive imaging of monocyte accumulation within plaques with CT. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multiple yellow plaques assessed by angioscopy with quantitative colorimetry in patients with myocardial infarction.

PubMed

Inami, Shigenobu; Ishibashi, Fumiyuki; Waxman, Sergio; Okamatsu, Kentaro; Seimiya, Koji; Takano, Masamichi; Uemura, Ryota; Sano, Junko; Mizuno, Kyoichi

2008-03-01

Multiple angioscopic yellow plaques are associated with diffuse atherosclerotic plaque, and may be prevalent in patients with myocardial infarction (MI), so in the present study the yellow plaques in the coronary arteries of patients with MI was evaluated using quantitative colorimetry, and compared with those of patients with stable angina (SA). In the recorded angioscopic images of 3 coronary vessels in 29 patients (15 patients with MI, 14 with SA), yellow plaques were determined as visually yellow regions with b* value >0 (yellow color intensity) measured by the quantitative colorimetric method. A total of 90 yellow plaques were identified (b* =19.35+/-8.3, 3.05-45.35). Yellow plaques were significantly more prevalent in 14 (93%) of 15 culprit lesions of MI as compared with 8 (57%) of 14 of SA (p=0.03). In non-culprit segments, yellow plaques were similarly prevalent in 13 (87%) patients with MI and 11 (79%) with SA (p=0.65). Overall, multiple (> or =2) yellow plaques were prevalent in 13 (87%) patients with MI, similar to the 10 (71%) with SA (p=0.38). The number of yellow plaques was significantly higher in patients with MI (3.8+/-1.9) than in those with SA (2.4+/-1.6, p=0.03). The present study suggests that patients with MI tend to have diffuse atherosclerotic plaque in their coronary arteries.

MRI-based biomechanical parameters for carotid artery plaque vulnerability assessment.

PubMed

Speelman, Lambert; Teng, Zhongzhao; Nederveen, Aart J; van der Lugt, Aad; Gillard, Jonathan H

2016-03-01

Carotid atherosclerotic plaques are a major cause of ischaemic stroke. The biomechanical environment to which the arterial wall and plaque is subjected to plays an important role in the initiation, progression and rupture of carotid plaques. MRI is frequently used to characterize the morphology of a carotid plaque, but new developments in MRI enable more functional assessment of carotid plaques. In this review, MRI based biomechanical parameters are evaluated on their current status, clinical applicability, and future developments. Blood flow related biomechanical parameters, including endothelial wall shear stress and oscillatory shear index, have been shown to be related to plaque formation. Deriving these parameters directly from MRI flow measurements is feasible and has great potential for future carotid plaque development prediction. Blood pressure induced stresses in a plaque may exceed the tissue strength, potentially leading to plaque rupture. Multi-contrast MRI based stress calculations in combination with tissue strength assessment based on MRI inflammation imaging may provide a plaque stress-strength balance that can be used to assess the plaque rupture risk potential. Direct plaque strain analysis based on dynamic MRI is already able to identify local plaque displacement during the cardiac cycle. However, clinical evidence linking MRI strain to plaque vulnerability is still lacking. MRI based biomechanical parameters may lead to improved assessment of carotid plaque development and rupture risk. However, better MRI systems and faster sequences are required to improve the spatial and temporal resolution, as well as increase the image contrast and signal-to-noise ratio.

Material properties of components in human carotid atherosclerotic plaques: a uniaxial extension study.

PubMed

Teng, Zhongzhao; Zhang, Yongxue; Huang, Yuan; Feng, Jiaxuan; Yuan, Jianmin; Lu, Qingsheng; Sutcliffe, Michael P F; Brown, Adam J; Jing, Zaiping; Gillard, Jonathan H

2014-12-01

Computational modelling to calculate the mechanical loading within atherosclerotic plaques has been shown to be complementary to defining anatomical plaque features in determining plaque vulnerability. However, its application has been partially impeded by the lack of comprehensive knowledge about the mechanical properties of various tissues within the plaque. Twenty-one human carotid plaques were collected from endarterectomy. The plaque was cut into rings, and different type of atherosclerotic tissues, including media, fibrous cap (FC), lipid and intraplaque haemorrhage/thrombus (IPH/T) was dissected for uniaxial extension testing. In total, 65 media strips from 17 samples, 59 FC strips from 14 samples, 38 lipid strips from 11 samples, and 21 IPH/T strips from 11 samples were tested successfully. A modified Mooney-Rivlin strain energy density function was used to characterize the stretch-stress relationship. The stiffnesses of media and FC are comparable, as are lipid and IPH/T. However, both media and FC are stiffer than either lipid or IPH/T. The median values of incremental Young's modulus of media, FC, lipid and IPH/T at λ=1 are 290.1, 244.5, 104.4, 52.9, respectively; they increase to 1019.5, 817.4, 220.7 and 176.9 at λ=1.1; and 4302.7, 3335.0, 533.4 and 268.8 at λ=1.15 (unit, kPa; λ, stretch ratio). The material constants of each tissue type are suggested to be: media, c1=0.138kPa, D1=3.833kPa and D2=18.803; FC, c1=0.186kPa, D1=5.769kPa and D2=18.219; lipid, c1=0.046kPa, D1=4.885kPa and D2=5.426; and IPH/T, c1=0.212kPa, D1=4.260kPa and D2=5.312. It is concluded that all soft atherosclerotic tissues are non-linear, and both media and FC are stiffer than either lipid or IPH/T. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Fish consumption, fish oil supplements and risk of atherosclerosis in the Tromsø study.

PubMed

Johnsen, Stein Harald; Jacobsen, Bjarne K; Brækkan, Sigrid K; Hansen, John-Bjarne; Mathiesen, Ellisiv B

2018-05-25

Whether long-chain n-3 PUFAs of marine origin have an anti-atherogenic effect in the general population has hardly been studied. In this population-based study, we hypothesized that fatty fish and fish oil intake protect against development of novel atherosclerotic plaques and is associated with reduced plaque size. We obtained questionnaire-based information on fish consumption and carotid ultrasonography from 3900 persons aged 45-74 years. The questionnaires were validated by measuring serum concentrations of PUFAs and triglycerides in a subgroup. At follow-up seven years later, 2983 (76%) went through a second ultrasound scanning. Logistic regression and general linear models were used to analyze the outcome (plaque presence and plaque area) as a function of fish consumption, including analyses stratified on fish oil supplements. At baseline, lean fish intake < 1 time/week vs. 1-1.9 times/week was associated with risk of plaque (OR 1.34, 95% CI 1.03-1.76). Fatty fish intake and use of fish oil supplements were not statistically significantly associated with atherosclerosis at baseline. In persons without plaque at baseline, total fish consumption ≥3 times/week vs. 1-1.9 times/week was associated with risk of novel plaque (OR 1.32, 95% CI 1.01-1.73) and larger plaque area (1.76 mm 2 vs. 1.46 mm 2 , p = 0.02) at follow-up. Adjustments for use of fish oil supplements had no impact on the associations, and no interactions were seen between total, fatty or lean fish consumption and fish oil intake. We found no protective effect of fatty fish eating or fish oil supplements on atherosclerotic plaque formation or plaque area in a general population. Lean fish consumption was associated with a reduced risk for plaque in cross-sectional analysis, suggesting that the beneficial effects of fish consumption on atherosclerosis may be mediated through other mechanisms than n-3 PUFAs.

Characterization of lipid-rich plaques using spectroscopic optical coherence tomography

NASA Astrophysics Data System (ADS)

Nam, Hyeong Soo; Song, Joon Woo; Jang, Sun-Joo; Lee, Jae Joong; Oh, Wang-Yuhl; Kim, Jin Won; Yoo, Hongki

2016-07-01

Intravascular optical coherence tomography (IV-OCT) is a high-resolution imaging method used to visualize the internal structures of walls of coronary arteries in vivo. However, accurate characterization of atherosclerotic plaques with gray-scale IV-OCT images is often limited by various intrinsic artifacts. In this study, we present an algorithm for characterizing lipid-rich plaques with a spectroscopic OCT technique based on a Gaussian center of mass (GCOM) metric. The GCOM metric, which reflects the absorbance properties of lipids, was validated using a lipid phantom. In addition, the proposed characterization method was successfully demonstrated in vivo using an atherosclerotic rabbit model and was found to have a sensitivity and specificity of 94.3% and 76.7% for lipid classification, respectively.

Activation of cannabinoid CB2 receptor ameliorates atherosclerosis associated with suppression of adhesion molecules.

PubMed

Zhao, Yan; Yuan, Zuyi; Liu, Yan; Xue, Jiahong; Tian, Yuling; Liu, Weimin; Zhang, Weiping; Shen, Yan; Xu, Wei; Liang, Xiao; Chen, Tao

2010-03-01

Adhesion molecules have been implicated in the development and progression of atherosclerosis. Cannabinoids have been reported to modulate the migration and adhesion molecules expression of various cell types. Here we examined the effects of WIN55212-2, a cannabinoid receptor 1 (CB1-R)/cannabinoid receptor 2 (CB2-R) agonist on the development of atherosclerotic lesions in apolipoprotein E-deficient (ApoE-/-) mice, which are vulnerable because of their high plasma cholesterol and triacylglycerol levels, focusing on the expression of endothelial adhesion molecules. In the aorta of ApoE-/- mice, WIN55212-2 significantly reduced aortic root plaque area. The mechanism for this seemed to be reduced infiltration of macrophages into the atherosclerotic plaque which was also associated with reduced expression of vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and P-selectin in the aorta. In vitro studies revealed reduced cell adhesion of a monocytic cell line (U937) to human umbilical vein endothelial cells after incubation with WIN55212-2. The reduction in macrophage adhesion also correlated with significant reductions in the expression of VCAM-1, ICAM-1, and P-selectin, indicating that reduced infiltration of macrophages in atherosclerotic plaques may occur as a result of the direct effect of WIN55212-2 on adhesion molecules in macrophages and endothelial cells. In conclusion, WIN55212-2 seems to have direct anti-atherosclerotic effects in an animal model of atherosclerosis. These effects were at least partly due to effects on the expression of VCAM-1, ICAM-1, and P-selectin, which led to reduced macrophage adhesion and infiltration. Furthermore, the protective effects completely blocked by the highly selective CB2 receptor antagonist AM630 suggest that these beneficial effects of WIN55212-2 may be mediated through the CB2 receptor.

Circulating Immunoglobulins Are Not Associated with Intraplaque Mast Cell Number and Other Vulnerable Plaque Characteristics in Patients with Carotid Artery Stenosis

PubMed Central

Quax, Paul H. A.; de Borst, Gert Jan; de Vries, Jean-Paul P. M.; Moll, Frans L.; Kuiper, Johan; Toes, René E. M.; de Jager, Saskia C. A.; de Kleijn, Dominique P. V.; Hoefer, Imo E.; Pasterkamp, Gerard; Bot, Ilze

2014-01-01

Background Recently, we have shown that intraplaque mast cell numbers are associated with atherosclerotic plaque vulnerability and with future cardiovascular events, which renders inhibition of mast cell activation of interest for future therapeutic interventions. However, the endogenous triggers that activate mast cells during the progression and destabilization of atherosclerotic lesions remain unidentified. Mast cells can be activated by immunoglobulins and in the present study, we aimed to establish whether specific immunoglobulins in plasma of patients scheduled for carotid endarterectomy were related to (activated) intraplaque mast cell numbers and plasma tryptase levels. In addition, the levels were related to other vulnerable plaque characteristics and baseline clinical data. Methods and Results OxLDL-IgG, total IgG and total IgE levels were measured in 135 patients who underwent carotid endarterectomy. No associations were observed between the tested plasma immunoglobulin levels and total mast cell numbers in atherosclerotic plaques. Furthermore, no associations were found between IgG levels and the following plaque characteristics: lipid core size, degree of calcification, number of macrophages or smooth muscle cells, amount of collagen and number of microvessels. Interestingly, statin use was negatively associated with plasma IgE and oxLDL-IgG levels. Conclusions In patients suffering from carotid artery disease, total IgE, total IgG and oxLDL-IgG levels do not associate with plaque mast cell numbers or other vulnerable plaque histopathological characteristics. This study thus does not provide evidence that the immunoglobulins tested in our cohort play a role in intraplaque mast cell activation or grade of atherosclerosis. PMID:24586471

Effects of Combination of Ezetimibe and Rosuvastatin on Coronary Artery Plaque in Patients with Coronary Heart Disease.

PubMed

Wang, Xiaofang; Zhao, Xiaoyan; Li, Ling; Yao, Haimu; Jiang, Yan; Zhang, Jinying

2016-05-01

In approximately 80% of cardiovascular disease-related deaths, patients suffer from coronary atherosclerotic heart disease. Ezetimibe is the first intestinal cholesterol absorption inhibitor. Its combination with statins for treating coronary atherosclerotic heart disease has attracted attention worldwide. The study group comprised 106 patients with coronary atherosclerotic heart disease and hyperlipidaemia. Each was randomly assigned to one of two groups: (1) Ezetimibe (10mg, once a night) plus rosuvastatin (10mg, once a night) (n=55) or (2) Rosuvastatin alone (10mg, once a night) (n=51). The primary endpoint was new or recurrent myocardial infarction, unstable angina pectoris, cardiac death, and stroke. Blood lipid, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9) levels were measured before treatment and at one, six and 12 months after treatment. Coronary plaque size and compositional changes were determined using intravascular ultrasonography. The combination of ezetimibe plus rosuvastatin decreased total cholesterol, low-density lipoprotein cholesterol, hsCRP, IL-6, and MMP-9 levels at six and 12 months after treatment. Statistical significance was detected between two groups. At 12 months, the plaque burden, plaque cross-sectional area, and percentage of necrotic plaque composition were significantly lower in the combination group than in rosuvastatin alone group (P<0.05). And compared with rosuvastatin alone group, the primary endpoint decreased more effectively in combination group. The combination of ezetimibe and rosuvastatin apparently diminishes lipid levels and plaque burden and improves plaque stability, which may be associated with the potent inhibitory effects of ezetimibe and rosuvastatin on inflammatory cytokines. Copyright © 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

64Cu-DOTATATE PET/MRI for Detection of Activated Macrophages in Carotid Atherosclerotic Plaques: Studies in Patients Undergoing Endarterectomy.

PubMed

Pedersen, Sune Folke; Sandholt, Benjamin Vikjær; Keller, Sune Høgild; Hansen, Adam Espe; Clemmensen, Andreas Ettrup; Sillesen, Henrik; Højgaard, Liselotte; Ripa, Rasmus Sejersten; Kjær, Andreas

2015-07-01

A feature of vulnerable atherosclerotic plaques of the carotid artery is high activity and abundance of lesion macrophages. There is consensus that this is of importance for plaque vulnerability, which may lead to clinical events, such as stroke and transient ischemic attack. We used positron emission tomography (PET) and the novel PET ligand [(64)Cu] [1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid]-d-Phe1,Tyr3-octreotate ((64)Cu-DOTATATE) to specifically target macrophages via the somatostatin receptor subtype-2 in vivo. Ten patients underwent simultaneous PET/MRI to measure (64)Cu-DOTATATE uptake in carotid artery plaques before carotid endarterectomy. (64)Cu-DOTATATE uptake was significantly higher in symptomatic plaque versus the contralateral carotid artery (P<0.001). Subsequently, a total of 62 plaque segments were assessed for gene expression of selected markers of plaque vulnerability using real-time quantitative polymerase chain reaction. These results were compared with in vivo (64)Cu-DOTATATE uptake calculated as the mean standardized uptake value. Univariate analysis of real-time quantitative polymerase chain reaction and PET showed that cluster of differentiation 163 (CD163) and CD68 gene expression correlated significantly but weakly with mean standardized uptake value in scans performed 85 minutes post injection (P<0.001 and P=0.015, respectively). Subsequent multivariate analysis showed that CD163 correlated independently with (64)Cu-DOTATATE uptake (P=0.031) whereas CD68 did not contribute significantly to the final model. The novel PET tracer (64)Cu-DOTATATE accumulates in atherosclerotic plaques of the carotid artery. CD163 gene expression correlated independently with (64)Cu-DOTATATE uptake measured by real-time quantitative polymerase chain reaction in the final multivariate model, indicating that (64)Cu-DOTATATE PET is detecting alternatively activated macrophages. This association could potentially improve noninvasive identification and characterization of vulnerable plaques. © 2015 The Authors.

Aortic atherosclerotic plaque detection using a multiwavelength handheld photoacoustic imaging system

NASA Astrophysics Data System (ADS)

Hirano, Susumu; Namita, Takeshi; Kondo, Kengo; Yamakawa, Makoto; Shiina, Tsuyoshi

2016-03-01

Patients affected by diseases caused by arteriosclerosis are increasing. Atherosclerosis, which is becoming an especially difficult health problem, forms plaques from lipids such as cholesterol located in walls of the aorta, cerebral artery, and coronary artery. Because lipid-rich plaques are vulnerable and because arterial rupture causes acute vascular occlusion, early detection is crucially important to prevent plaque growth and rupture. Ultrasound systems can detect plaques but cannot discriminate between vulnerable and equable plaques. To evaluate plaques non-invasively and easily, we developed a handheld photoacoustic imaging device. Its usefulness was verified in phantom experiments with a bovine aorta in which mimic plaque had been embedded. Photoacoustic images taken at wavelengths that produce high light absorbance by lipids show strong photoacoustic signals from the boundary of the mimic plaque. Results confirmed that our system can evaluate plaque properties by analysis with the photoacoustic spectrum. The effects of surrounding tissues and tissue components on plaque evaluation were investigated using a layered phantom. The mimic plaque located under a 6 mm blood layer was also evaluated. Results of these analyses demonstrate the system's usefulness.

A Salmon Protein Hydrolysate Exerts Lipid-Independent Anti-Atherosclerotic Activity in ApoE-Deficient Mice

PubMed Central

Busnelli, Marco; Bjørndal, Bodil; Holm, Sverre; Brattelid, Trond; Manzini, Stefano; Ganzetti, Giulia S.; Dellera, Federica; Halvorsen, Bente; Aukrust, Pål; Sirtori, Cesare R.; Nordrehaug, Jan E.; Skorve, Jon; Berge, Rolf K.; Chiesa, Giulia

2014-01-01

Fish consumption is considered health beneficial as it decreases cardiovascular disease (CVD)-risk through effects on plasma lipids and inflammation. We investigated a salmon protein hydrolysate (SPH) that is hypothesized to influence lipid metabolism and to have anti-atherosclerotic and anti-inflammatory properties. 24 female apolipoprotein (apo) E−/− mice were divided into two groups and fed a high-fat diet with or without 5% (w/w) SPH for 12 weeks. The atherosclerotic plaque area in aortic sinus and arch, plasma lipid profile, fatty acid composition, hepatic enzyme activities and gene expression were determined. A significantly reduced atherosclerotic plaque area in the aortic arch and aortic sinus was found in the 12 apoE−/− mice fed 5% SPH for 12 weeks compared to the 12 casein-fed control mice. Immunohistochemical characterization of atherosclerotic lesions in aortic sinus displayed no differences in plaque composition between mice fed SPH compared to controls. However, reduced mRNA level of Icam1 in the aortic arch was found. The plasma content of arachidonic acid (C20∶4n-6) and oleic acid (C18∶1n-9) were increased and decreased, respectively. SPH-feeding decreased the plasma concentration of IL-1β, IL-6, TNF-α and GM-CSF, whereas plasma cholesterol and triacylglycerols (TAG) were unchanged, accompanied by unchanged mitochondrial fatty acid oxidation and acyl-CoA:cholesterol acyltransferase (ACAT)-activity. These data show that a 5% (w/w) SPH diet reduces atherosclerosis in apoE−/− mice and attenuate risk factors related to atherosclerotic disorders by acting both at vascular and systemic levels, and not directly related to changes in plasma lipids or fatty acids. PMID:24840793

Detection and characterization of early plaque formations by Raman probe spectroscopy and optical coherence tomography: an in vivo study on a rabbit model

NASA Astrophysics Data System (ADS)

Matthäus, Christian; Dochow, Sebastian; Egodage, Kokila D.; Romeike, Bernd F.; Brehm, Bernhard R.; Popp, Jürgen

2018-01-01

Intravascular imaging techniques provide detailed specification about plaque appearance and morphology, but cannot deliver information about the biochemical composition of atherosclerotic plaques. As the biochemical composition is related to the plaque type, important aspects such as the risk of a plaque rupture and treatment are still difficult to assess. Currently, various spectroscopic techniques are tested for potential applications for the chemical analysis of plaque depositions. Here, we employ Raman spectroscopy in combination with optical coherence tomography (OCT) for the characterization of plaques on rabbits in vivo. Experiments were carried out on New Zealand white rabbits treated with a fat- and cholesterol-enriched diet, using a Raman probe setup with a 785-nm multimode laser as an excitation source. Subsequently, OCT images were acquired with a swept source at 1305±55 nm at 22.6 mW. Raman spectra were recorded from normal regions and regions with early plaque formations. The probe positioning was monitored by x-ray angiography. The spectral information identified plaque depositions consisting of lipids, with triglycerides as the major component. Afterward, OCT images of the spectroscopically investigated areas were obtained. The spectral information correlates well with the observed intravascular morphology and is in good agreement with histology. Raman spectroscopy can provide detailed biochemical specification of atherosclerotic plaques.

Role of KCa3.1 Channels in Macrophage Polarization and Its Relevance in Atherosclerotic Plaque Instability.

PubMed

Xu, Rende; Li, Chenguang; Wu, Yizhe; Shen, Li; Ma, Jianying; Qian, Juying; Ge, Junbo

2017-02-01

Emerging evidence indicates that proinflammatory macrophage polarization imbalance plays a key role in atherosclerotic plaque progression and instability. The calcium-activated potassium channel KCa3.1 is critically involved in macrophage activation and function. However, the role of KCa3.1 in macrophage polarization is unknown. This study investigates the potential role of KCa3.1 in transcriptional regulation in macrophage polarization and its relationship to plaque instability. Human monocytes were differentiated into macrophages using macrophage colony-stimulating factor. Macrophages were then polarized into proinflammatory M1 cells by interferon-γ and lipopolysaccharide and into alternative M2 macrophages by interleukin-4. A model for plaque instability was induced by combined partial ligation of the left renal artery and left common carotid artery in apolipoprotein E knockout mice. Significant upregulation of KCa3.1 expression was observed during the differentiation of human monocytes into macrophages. Blocking KCa3.1 significantly reduced the expression of proinflammatory genes during macrophages polarization. Further mechanistic studies indicated that blocking KCa3.1 inhibited macrophage differentiation toward the M1 phenotype by downregulating signal transducer and activator of transcription-1 phosphorylation. In animal models, KCa3.1 blockade therapy strikingly reduced the incidence of plaque rupture and luminal thrombus in carotid arteries, decreased the expression of markers associated with M1 macrophage polarization, and enhanced the expression of M2 markers within atherosclerotic lesions. These results suggest that blocking KCa3.1 suppresses plaque instability in advanced stages of atherosclerosis by inhibiting macrophage polarization toward an M1 phenotype. © 2016 American Heart Association, Inc.

Comparison between MDCT and Grayscale IVUS in a Quantitative Analysis of Coronary Lumen in Segments with or without Atherosclerotic Plaques

PubMed Central

Falcão, João L. A. A.; Falcão, Breno A. A.; Gurudevan, Swaminatha V.; Campos, Carlos M.; Silva, Expedito R.; Kalil-Filho, Roberto; Rochitte, Carlos E.; Shiozaki, Afonso A.; Coelho-Filho, Otavio R.; Lemos, Pedro A.

2015-01-01

Background The diagnostic accuracy of 64-slice MDCT in comparison with IVUS has been poorly described and is mainly restricted to reports analyzing segments with documented atherosclerotic plaques. Objectives We compared 64-slice multidetector computed tomography (MDCT) with gray scale intravascular ultrasound (IVUS) for the evaluation of coronary lumen dimensions in the context of a comprehensive analysis, including segments with absent or mild disease. Methods The 64-slice MDCT was performed within 72 h before the IVUS imaging, which was obtained for at least one coronary, regardless of the presence of luminal stenosis at angiography. A total of 21 patients were included, with 70 imaged vessels (total length 114.6 ± 38.3 mm per patient). A coronary plaque was diagnosed in segments with plaque burden > 40%. Results At patient, vessel, and segment levels, average lumen area, minimal lumen area, and minimal lumen diameter were highly correlated between IVUS and 64-slice MDCT (p < 0.01). However, 64-slice MDCT tended to underestimate the lumen size with a relatively wide dispersion of the differences. The comparison between 64-slice MDCT and IVUS lumen measurements was not substantially affected by the presence or absence of an underlying plaque. In addition, 64-slice MDCT showed good global accuracy for the detection of IVUS parameters associated with flow-limiting lesions. Conclusions In a comprehensive, multi-territory, and whole-artery analysis, the assessment of coronary lumen by 64-slice MDCT compared with coronary IVUS showed a good overall diagnostic ability, regardless of the presence or absence of underlying atherosclerotic plaques. PMID:25993595

Dietary rose hip exerts antiatherosclerotic effects and increases nitric oxide-mediated dilation in ApoE-null mice.

PubMed

Cavalera, Michele; Axling, Ulrika; Rippe, Catarina; Swärd, Karl; Holm, Cecilia

2017-06-01

Atherosclerosis is a disease in which atheromatous plaques develop inside arteries, leading to reduced or obstructed blood flow that in turn may cause stroke and heart attack. Rose hip is the fruit of plants of the genus Rosa, belonging to the Rosaceae family, and it is rich in antioxidants with high amounts of ascorbic acid and phenolic compounds. Several studies have shown that fruits, seeds and roots of these plants exert antidiabetic, antiobesity and cholesterol-lowering effects in rodents as well as humans. The aim of this study was to elucidate the mechanisms by which rose hip lowers plasma cholesterol and to evaluate its effects on atherosclerotic plaque formation. ApoE-null mice were fed either an HFD (CTR) or HFD with rose hip supplementation (RH) for 24 weeks. At the end of the study, we found that blood pressure and atherosclerotic plaques, together with oxidized LDL, total cholesterol and fibrinogen levels were markedly reduced in the RH group. Fecal cholesterol content, liver expression of Ldlr and selected reverse cholesterol transport (RCT) genes such as Abca1, Abcg1 and Scarb1 were significantly increased upon RH feeding. In the aorta, the scavenger receptor Cd36 and the proinflammatory Il1β genes were markedly down-regulated compared to the CTR mice. Finally, we found that RH increased nitric oxide-mediated dilation of the caudal artery. Taken together, these results suggest that rose hip is a suitable dietary supplement for preventing atherosclerotic plaques formation by modulating systemic blood pressure and the expression of RCT and inflammatory genes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Metoprolol Reduces Proinflammatory Cytokines and Atherosclerosis in ApoE−/− Mice

PubMed Central

Ulleryd, Marcus A.; Bernberg, Evelina; Yang, Li Jin; Bergström, Göran M. L.; Johansson, Maria E.

2014-01-01

A few studies in animals and humans suggest that metoprolol (β1-selective adrenoceptor antagonist) may have a direct antiatherosclerotic effect. However, the mechanism behind this protective effect has not been established. The aim of the present study was to evaluate the effect of metoprolol on development of atherosclerosis in ApoE−/− mice and investigate its effect on the release of proinflammatory cytokines. Male ApoE−/− mice were treated with metoprolol (2.5 mg/kg/h) or saline for 11 weeks via osmotic minipumps. Atherosclerosis was assessed in thoracic aorta and aortic root. Total cholesterol levels and Th1/Th2 cytokines were analyzed in serum and macrophage content in lesions by immunohistochemistry. Metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta (P < 0.05 versus Control). Further, metoprolol reduced serum TNFα and the chemokine CXCL1 (P < 0.01 versus Control for both) as well as decreasing the macrophage content in the plaques (P < 0.01 versus Control). Total cholesterol levels were not affected. In this study we found that a moderate dose of metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta of ApoE−/− mice. Metoprolol also decreased serum levels of proinflammatory cytokines TNFα and CXCL1 and macrophage content in the plaques, showing that metoprolol has an anti-inflammatory effect. PMID:25105129

Biomechanics of Atherosclerotic Coronary Plaque: Site, Stability and In Vivo Elasticity Modeling

PubMed Central

Ohayon, Jacques; Finet, Gérard; Le Floc’h, Simon; Cloutier, Guy; Gharib, Ahmed M.; Heroux, Julie; Pettigrew, Roderic I.

2016-01-01

Coronary atheroma develop in local sites that are widely variable among patients and are considerably variable in their vulnerability for rupture. This article summarizes studies conducted by our collaborative laboratories on predictive biomechanical modeling of coronary plaques. It aims to give insights into the role of biomechanics in the development and localization of atherosclerosis, the morphologic features that determine vulnerable plaque stability, and emerging in vivo imaging techniques that may detect and characterize vulnerable plaque. Composite biomechanical and hemodynamic factors that influence the actual site of development of plaques have been studied. Plaque vulnerability, in vivo, is more challenging to assess. Important steps have been made in defining the biomechanical factors that are predictive of plaque rupture and the likelihood of this occurring if characteristic features are known. A critical key in defining plaque vulnerability is the accurate quantification of both the morphology and the mechanical properties of the diseased arteries. Recently, an early IVUS based palpography technique developed to assess local strain, elasticity and mechanical instabilities has been successfully revisited and improved to account for complex plaque geometries. This is based on an initial best estimation of the plaque components’ contours, allowing subsequent iteration for elastic modulus assessment as a basis for plaque stability determination. The improved method has also been preliminarily evaluated in patients with successful histologic correlation. Further clinical evaluation and refinement are on the horizon. PMID:24043605

The nature of iron deposits differs between symptomatic and asymptomatic carotid atherosclerotic plaques

DOE PAGES

Kopriva, David; Kisheev, Anastasye; Meena, Deiter; ...

2015-11-25

Iron within atherosclerotic plaque has been implicated as a catalyst of oxidative stress that causes progression of plaque, and plaque rupture. Iron is believed to accumulate within plaque by incorporation of erythrocytes following plaque rupture and hemorrhage. There is only indirect evidence to support this hypothesis. Plaque specimens were obtained from ten symptomatic and fifteen asymptomatic patients undergoing carotid endarterectomy at a single institution. Plaques were sectioned for study using synchrotron radiation induced X-ray fluorescence the study the distribution of zinc, calcium and iron. Histologic staining was carried out with Prussian Blue, and immunohistochemical staining was done to localize macrophagesmore » with CD68. Data were compared against patient clinical variables. Ten symptomatic (15 ± 10 days between index symptoms and surgery) and fifteen asymptomatic carotid plaques were studied. Zinc and calcium co-localized in mineralized areas of symptomatic and asymptomatic plaque. Iron was identified away from zinc and calcium in both symptomatic and asymptomatic plaques. Within the symptomatic plaques, iron was found within the thrombus associated with plaque rupture and hemorrhage. It did not stain with Prussian Blue, but was found in association with CD68 positive macrophages. In symptomatic plaques, the abundance of iron showed an association with the source patient’s LDL cholesterol (R 2 = 0.39, Significance F = 0.05). Iron in asymptomatic plaque was present as hemosiderin/ferritin that stained positive with Prussian Blue, and was observed in association with CD68 positive macrophages. Iron in acutely symptomatic plaques is found within thrombus, in the presence of macrophages. Moreover, the abundance of iron in symptomatic plaques is associated with the source patient’s LDL cholesterol. Within asymptomatic plaques, iron is found in association with macrophages, as hemosiderin/ferritin.« less

The Nature of Iron Deposits Differs between Symptomatic and Asymptomatic Carotid Atherosclerotic Plaques

PubMed Central

Kopriva, David; Kisheev, Anastasye; Meena, Deiter; Pelle, Shaneen; Karnitsky, Max; Lavoie, Andrea; Buttigieg, Josef

2015-01-01

Iron within atherosclerotic plaque has been implicated as a catalyst of oxidative stress that causes progression of plaque, and plaque rupture. Iron is believed to accumulate within plaque by incorporation of erythrocytes following plaque rupture and hemorrhage. There is only indirect evidence to support this hypothesis. Plaque specimens were obtained from ten symptomatic and fifteen asymptomatic patients undergoing carotid endarterectomy at a single institution. Plaques were sectioned for study using synchrotron radiation induced X-ray fluorescence the study the distribution of zinc, calcium and iron. Histologic staining was carried out with Prussian Blue, and immunohistochemical staining was done to localize macrophages with CD68. Data were compared against patient clinical variables. Ten symptomatic (15 ± 10 days between index symptoms and surgery) and fifteen asymptomatic carotid plaques were studied. Zinc and calcium co-localized in mineralized areas of symptomatic and asymptomatic plaque. Iron was identified away from zinc and calcium in both symptomatic and asymptomatic plaques. Within the symptomatic plaques, iron was found within the thrombus associated with plaque rupture and hemorrhage. It did not stain with Prussian Blue, but was found in association with CD68 positive macrophages. In symptomatic plaques, the abundance of iron showed an association with the source patient’s LDL cholesterol (R2 = 0.39, Significance F = 0.05). Iron in asymptomatic plaque was present as hemosiderin/ferritin that stained positive with Prussian Blue, and was observed in association with CD68 positive macrophages. Iron in acutely symptomatic plaques is found within thrombus, in the presence of macrophages. The abundance of iron in symptomatic plaques is associated with the source patient’s LDL cholesterol. Within asymptomatic plaques, iron is found in association with macrophages, as hemosiderin/ferritin. PMID:26606178

The nature of iron deposits differs between symptomatic and asymptomatic carotid atherosclerotic plaques

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kopriva, David; Kisheev, Anastasye; Meena, Deiter

Iron within atherosclerotic plaque has been implicated as a catalyst of oxidative stress that causes progression of plaque, and plaque rupture. Iron is believed to accumulate within plaque by incorporation of erythrocytes following plaque rupture and hemorrhage. There is only indirect evidence to support this hypothesis. Plaque specimens were obtained from ten symptomatic and fifteen asymptomatic patients undergoing carotid endarterectomy at a single institution. Plaques were sectioned for study using synchrotron radiation induced X-ray fluorescence the study the distribution of zinc, calcium and iron. Histologic staining was carried out with Prussian Blue, and immunohistochemical staining was done to localize macrophagesmore » with CD68. Data were compared against patient clinical variables. Ten symptomatic (15 ± 10 days between index symptoms and surgery) and fifteen asymptomatic carotid plaques were studied. Zinc and calcium co-localized in mineralized areas of symptomatic and asymptomatic plaque. Iron was identified away from zinc and calcium in both symptomatic and asymptomatic plaques. Within the symptomatic plaques, iron was found within the thrombus associated with plaque rupture and hemorrhage. It did not stain with Prussian Blue, but was found in association with CD68 positive macrophages. In symptomatic plaques, the abundance of iron showed an association with the source patient’s LDL cholesterol (R 2 = 0.39, Significance F = 0.05). Iron in asymptomatic plaque was present as hemosiderin/ferritin that stained positive with Prussian Blue, and was observed in association with CD68 positive macrophages. Iron in acutely symptomatic plaques is found within thrombus, in the presence of macrophages. Moreover, the abundance of iron in symptomatic plaques is associated with the source patient’s LDL cholesterol. Within asymptomatic plaques, iron is found in association with macrophages, as hemosiderin/ferritin.« less

Use of high-resolution 3.0-T magnetic resonance imaging to characterize atherosclerotic plaques in patients with cerebral infarction

PubMed Central

XU, PENG; LV, LULU; LI, SHAODONG; GE, HAITAO; RONG, YUTAO; HU, CHUNFENG; XU, KAI

2015-01-01

The present study aimed to evaluate the utility of high-resolution magnetic resonance imaging (MRI) in the characterization of atherosclerotic plaques in patients with acute and non-acute cerebral infarction. High-resolution MRI of unilateral stenotic middle cerebral arteries was performed to evaluate the degree of stenosis, the wall and plaque areas, plaque enhancement patterns and lumen remodeling features in 15 and 17 patients with acute and non-acute cerebral infarction, respectively. No significant difference was identified in the vascular stenosis rate between acute and non-acute patients. Overall, plaque eccentricity was observed in 29 patients, including 13 acute and 16 non-acute cases, with no significant difference identified between these groups. The wall area of stenotic arteries and the number of cases with plaque enhancement were significantly greater in the acute patients, but no significant difference in plaque or lumen area was identified between the 2 patient groups. Lumen remodeling patterns of stenotic arteries significantly differed between the acute and non-acute patients; the former predominantly demonstrated positive remodeling, and the latter group demonstrated evidence of negative remodeling. In conclusion, patients with acute and non-acute cerebral infarction exhibit specific characteristics in stenotic arteries and plaques, which can be effectively evaluated by high-resolution MRI. PMID:26668651

A vascular biology network model focused on inflammatory processes to investigate atherogenesis and plaque instability

PubMed Central

2014-01-01

Background Numerous inflammation-related pathways have been shown to play important roles in atherogenesis. Rapid and efficient assessment of the relative influence of each of those pathways is a challenge in the era of “omics” data generation. The aim of the present work was to develop a network model of inflammation-related molecular pathways underlying vascular disease to assess the degree of translatability of preclinical molecular data to the human clinical setting. Methods We constructed and evaluated the Vascular Inflammatory Processes Network (V-IPN), a model representing a collection of vascular processes modulated by inflammatory stimuli that lead to the development of atherosclerosis. Results Utilizing the V-IPN as a platform for biological discovery, we have identified key vascular processes and mechanisms captured by gene expression profiling data from four independent datasets from human endothelial cells (ECs) and human and murine intact vessels. Primary ECs in culture from multiple donors revealed a richer mapping of mechanisms identified by the V-IPN compared to an immortalized EC line. Furthermore, an evaluation of gene expression datasets from aortas of old ApoE-/- mice (78 weeks) and human coronary arteries with advanced atherosclerotic lesions identified significant commonalities in the two species, as well as several mechanisms specific to human arteries that are consistent with the development of unstable atherosclerotic plaques. Conclusions We have generated a new biological network model of atherogenic processes that demonstrates the power of network analysis to advance integrative, systems biology-based knowledge of cross-species translatability, plaque development and potential mechanisms leading to plaque instability. PMID:24965703

Genetic and Pharmacological Inhibition of TREM-1 Limits the Development of Experimental Atherosclerosis.

PubMed

Joffre, Jeremie; Potteaux, Stephane; Zeboudj, Lynda; Loyer, Xavier; Boufenzer, Amir; Laurans, Ludivine; Esposito, Bruno; Vandestienne, Marie; de Jager, Saskia C A; Hénique, Carole; Zlatanova, Ivana; Taleb, Soraya; Bruneval, Patrick; Tedgui, Alain; Mallat, Ziad; Gibot, Sebastien; Ait-Oufella, Hafid

2016-12-27

Innate immune responses activated through myeloid cells contribute to the initiation, progression, and complications of atherosclerosis in experimental models. However, the critical upstream pathways that link innate immune activation to foam cell formation are still poorly identified. This study sought to investigate the hypothesis that activation of the triggering receptor expressed on myeloid cells (TREM-1) plays a determinant role in macrophage atherogenic responses. After genetically invalidating Trem-1 in chimeric Ldlr -/- Trem-1 -/- mice and double knockout ApoE -/- Trem-1 -/- mice, we pharmacologically inhibited Trem-1 using LR12 peptide. Ldlr -/- mice reconstituted with bone marrow deficient for Trem-1 (Trem-1 -/- ) showed a strong reduction of atherosclerotic plaque size in both the aortic sinus and the thoracoabdominal aorta, and were less inflammatory compared to plaques of Trem-1 +/+ chimeric mice. Genetic invalidation of Trem-1 led to alteration of monocyte recruitment into atherosclerotic lesions and inhibited toll-like receptor 4 (TLR 4)-initiated proinflammatory macrophage responses. We identified a critical role for Trem-1 in the upregulation of cluster of differentiation 36 (CD36), thereby promoting the formation of inflammatory foam cells. Genetic invalidation of Trem-1 in ApoE -/- /Trem-1 -/- mice or pharmacological blockade of Trem-1 in ApoE -/- mice using LR-12 peptide also significantly reduced the development of atherosclerosis throughout the vascular tree, and lessened plaque inflammation. TREM-1 was expressed in human atherosclerotic lesions, mainly in lipid-rich areas with significantly higher levels of expression in atheromatous than in fibrous plaques. We identified TREM-1 as a major upstream proatherogenic receptor. We propose that TREM-1 activation orchestrates monocyte/macrophage proinflammatory responses and foam cell formation through coordinated and combined activation of CD36 and TLR4. Blockade of TREM-1 signaling may constitute an attractive novel and double-hit approach for the treatment of atherosclerosis. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Fiber optic label-free biophotonic diagnostic tool for cardiovascular disease

NASA Astrophysics Data System (ADS)

Rius, Cristina; Ackermann, Tobias N.; Dorado, Beatriz; Muñoz-Berbel, Xavier; Andrés, Vicente; Llobera, Andreu

2015-06-01

A label-free compact method for performing photonic characterization of "healthy" versus "diseased" arteries has been developed. It permits the detection of atherosclerotic lesion in living mouse arteries. Using this prototype, we observed that the spectral response (photonic fingerprint, PIN) obtained from aortas of wild-type mice differs from the response of ApoE-KO mice fed with high-fat diet (an atheroprone mouse model). Benchmark of the results against gold standard was performed by staining the aortas with Oil-Red-O to visualize atherosclerotic plaques.

Experience With Intravascular Ultrasound Imaging Of Human Atherosclerotic Arteries

NASA Astrophysics Data System (ADS)

Mallery, John A.; Gessert, James M.; Maciel, Mario; Tobis, John M.; Griffith, James M.; Berns, Michael W.; Henry, Walter L.

1989-08-01

Normal human arteries have a well-defined structure on intravascular images. The intima appears very thin and is most likely represented by a bright reflection arising from the internal elastic lamina. The smooth muscle tunica media is echo-lucent on the ultrasound image and appears as a dark band separating the intima from the adventitia. The adventitia is a brightly reflective layer of variable thickness. The thickness of the intima, and therefore of the atherosclerotic plaque can be accurately measured from the ultrasound images and correlates well with histology. Calcification within the wall of arteries is seen as bright echo reflection with shadowing of the peripheral wall. Fibrotic regions are highly reflective but do not shadow. Necrotic liquid regions within advanced atherosclerotic plaques are seen on ultrasound images as large lucent zones surrounded by echogenic tissue. Imaging can be performed before and after interventional procedures, such as laser angioplasty, balloon angioplasty and atherectomy. Intravascular ultrasound appears to provide an imaging modality for identifying the histologic characteristics of diseased arteries and for quantifying plaque thickness. It might be possible to perform such quantification to evaluate the results of interventional procedures.

Induction of endothelial cell proliferation by angiogenic factors released by activated monocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pakala, Rajbabu; Watanabe, Takuya; Benedict, Claude R

2002-06-01

Introduction: Cell-cell interaction is an essential component of atherosclerotic plaque development. Activated monocytes appear to play a central role in the development of atherosclerosis, not only through foam cell formation but also via the production of various growth factors that induce proliferation of different cell types that are involved in the plaque development. Using serum free co-culture method, we determined the effect of monocytes on endothelial cell proliferation. Methods: Endothelial cell proliferation is determined by the amount of [{sup 3}H]thymidine incorporated in to the DNA. Basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) levels inmore » the conditioned medium were determined by ELISA. Results: Conditioned medium from unactivated monocytes partially inhibited endothelial cell proliferation, whereas conditioned medium from activated monocytes promoted endothelial cell proliferation. The mitogenic effect of conditioned medium derived from activated monocytes is due to the presence of b-FGF, VEGF and IL-8. Neutralizing antibodies against b-FGF, VEGF and IL-8 partially reversed the mitogenic effect of conditioned medium derived from activated monocytes. When b-FGF, VEGF and IL-8 were immunoprecipitated from conditioned medium derived from activated monocytes, it is less mitogenic to endothelial cells. Conclusion: Activated monocytes may play an important role in the development of atherosclerotic plaque by producing endothelial cell growth factors.« less

Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis.

PubMed

Jones, Gareth W; McLeod, Louise; Kennedy, Catherine L; Bozinovski, Steven; Najdovska, Meri; Jenkins, Brendan J

2015-02-01

Interleukin (IL)-6 is a key modulator of the acute phase response (APR), and while both are implicated in atherosclerosis, the pathological role of specific IL-6 signalling cascades is ill-defined. Since IL-6 employs the cytokine receptor gp130 to primarily activate the STAT3 pathway, here we evaluate whether gp130-dependent STAT3 activation modulates atherosclerosis. High-fat diet-induced atherosclerosis was established in ApoE(-/-) mice crossed with gp130(F/F) knock-in mice displaying elevated gp130-dependent STAT3 activation and production of the APR protein, serum amyloid A (SAA). Also generated were gp130(F/F):Stat3(-/+):ApoE(-/-) mice displaying genetically-normalised STAT3 activation and SAA levels, and bone marrow chimeras involving ApoE(-/-) and gp130(F/F):ApoE(-/-) mice. At 10 weeks post high-fat diet, aortic atherosclerotic lesions, including the presence of CD68(+) macrophages, and plasma lipid and SAA profiles, were assessed. Aortic plaque development and plasma triglyceride levels in gp130(F/F):ApoE(-/-) mice were significantly reduced (3-fold, P < 0.001) compared to ApoE(-/-) littermates. By contrast, in gp130(F/F):ApoE(-/-) mice, atherosclerotic plaques contained augmented CD68(+) macrophage infiltrates, and plasma SAA levels were elevated, compared to ApoE(-/-) mice. Atherosclerotic lesion development and plasma triglyceride levels in gp130(F/F):ApoE(-/-) and gp130(F/F):Stat3(-/+):ApoE(-/-) mice were comparable, despite a significant (P < 0.05) reduction in macrophage numbers in lesions, and also plasma SAA levels, in gp130(F/F):Stat3(-/+):ApoE(-/-) mice. Aortic plaque development and plasma triglyceride levels were comparable in ApoE(-/-) mice reconstituted with gp130(F/F):ApoE(-/-) (ApoE(F/F:ApoE)) or ApoE(-/-) (ApoE(ApoE)) bone marrow cells. Deregulation of gp130/STAT3 signalling augments the APR and macrophage infiltration during atherosclerosis without impacting on the development of aortic plaques. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Directional spatial frequency analysis of lipid distribution in atherosclerotic plaque

NASA Astrophysics Data System (ADS)

Korn, Clyde; Reese, Eric; Shi, Lingyan; Alfano, Robert; Russell, Stewart

2016-04-01

Atherosclerosis is characterized by the growth of fibrous plaques due to the retention of cholesterol and lipids within the artery wall, which can lead to vessel occlusion and cardiac events. One way to evaluate arterial disease is to quantify the amount of lipid present in these plaques, since a higher disease burden is characterized by a higher concentration of lipid. Although therapeutic stimulation of reverse cholesterol transport to reduce cholesterol deposits in plaque has not produced significant results, this may be due to current image analysis methods which use averaging techniques to calculate the total amount of lipid in the plaque without regard to spatial distribution, thereby discarding information that may have significance in marking response to therapy. Here we use Directional Fourier Spatial Frequency (DFSF) analysis to generate a characteristic spatial frequency spectrum for atherosclerotic plaques from C57 Black 6 mice both treated and untreated with a cholesterol scavenging nanoparticle. We then use the Cauchy product of these spectra to classify the images with a support vector machine (SVM). Our results indicate that treated plaque can be distinguished from untreated plaque using this method, where no difference is seen using the spatial averaging method. This work has the potential to increase the effectiveness of current in-vivo methods of plaque detection that also use averaging methods, such as laser speckle imaging and Raman spectroscopy.

A uni-extension study on the ultimate material strength and extreme extensibility of atherosclerotic tissue in human carotid plaques.

PubMed

Teng, Zhongzhao; Feng, Jiaxuan; Zhang, Yongxue; Sutcliffe, Michael P F; Huang, Yuan; Brown, Adam J; Jing, Zaiping; Lu, Qingsheng; Gillard, Jonathan H

2015-11-05

Atherosclerotic plaque rupture occurs when mechanical loading exceeds its material strength. Mechanical analysis has been shown to be complementary to the morphology and composition for assessing vulnerability. However, strength and stretch thresholds for mechanics-based assessment are currently lacking. This study aims to quantify the ultimate material strength and extreme extensibility of atherosclerotic components from human carotid plaques. Tissue strips of fibrous cap, media, lipid core and intraplaque hemorrhage/thrombus were obtained from 21 carotid endarterectomy samples of symptomatic patients. Uni-extension test with tissue strips was performed until they broke or slid. The Cauchy stress and stretch ratio at the peak loading of strips broken about 2mm away from the clamp were used to characterize their ultimate strength and extensibility. Results obtained indicated that ultimate strength of fibrous cap and media were 158.3 [72.1, 259.3] kPa (Median [Inter quartile range]) and 247.6 [169.0, 419.9] kPa, respectively; those of lipid and intraplaque hemorrhage/thrombus were 68.8 [48.5, 86.6] kPa and 83.0 [52.1, 124.9] kPa, respectively. The extensibility of each tissue type were: fibrous cap - 1.18 [1.10, 1.27]; media - 1.21 [1.17, 1.32]; lipid - 1.25 [1.11, 1.30] and intraplaque hemorrhage/thrombus - 1.20 [1.17, 1.44]. Overall, the strength of fibrous cap and media were comparable and so were lipid and intraplaque hemorrhage/thrombus. Both fibrous cap and media were significantly stronger than either lipid or intraplaque hemorrhage/thrombus. All atherosclerotic components had similar extensibility. Moreover, fibrous cap strength in the proximal region (closer to the heart) was lower than that of the distal. These results are helpful in understanding the material behavior of atherosclerotic plaques. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Fractal analysis of plaque border, a novel method for the quantification of atherosclerotic plaque contour irregularity, is associated with pro-atherogenic plasma lipid profile in subjects with non-obstructive carotid stenoses.

PubMed

Moroni, Francesco; Magnoni, Marco; Vergani, Vittoria; Ammirati, Enrico; Camici, Paolo G

2018-01-01

Plaque border irregularity is a known imaging characteristic of vulnerable plaques, but its evaluation heavily relies on subjective evaluation and operator expertise. Aim of the present work is to propose a novel fractal-analysis based method for the quantification of atherosclerotic plaque border irregularity and assess its relation with cardiovascular risk factors. Forty-two asymptomatic subjects with carotid stenosis underwent ultrasound evaluation and assessment of cardiovascular risk factors. Total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) plasma cholesterol and triglycerides concentrations were measured for each subject. Fractal analysis was performed in all the carotid segments affected by atherosclerosis, i.e. 147 segments. The resulting fractal dimension (FD) is a measure of irregularity of plaque profile on long axis view of the plaque. FD in the severest stenosis (main plaque FD,mFD) was 1.136±0.039. Average FD per patient (global FD,gFD) was 1.145±0.039. FD was independent of other plaque characteristics. mFD significantly correlated with plasma HDL (r = -0.367,p = 0.02) and triglycerides-to-HDL ratio (r = 0.480,p = 0.002). Fractal analysis is a novel, readily available, reproducible and inexpensive technique for the quantitative measurement of plaque irregularity. The correlation between low HDL levels and plaque FD suggests a role for HDL in the acquisition of morphologic features of plaque instability. Further studies are needed to validate the prognostic value of fractal analysis in carotid plaques evaluation.

Automatic plaque characterization and vessel wall segmentation in magnetic resonance images of atherosclerotic carotid arteries

NASA Astrophysics Data System (ADS)

Adame, Isabel M.; van der Geest, Rob J.; Wasserman, Bruce A.; Mohamed, Mona; Reiber, Johan H. C.; Lelieveldt, Boudewijn P. F.

2004-05-01

Composition and structure of atherosclerotic plaque is a primary focus of cardiovascular research. In vivo MRI provides a meanse to non-invasively image and assess the morphological features of athersclerotic and normal human carotid arteries. To quantitatively assess the vulnerability and the type of plaque, the contours of the lumen, outer boundary of the vessel wall and plaque components, need to be traced. To achieve this goal, we have developed an automated contou detection technique, which consists of three consecutive steps: firstly, the outer boundary of the vessel wall is detected by means of an ellipse-fitting procedure in order to obtain smoothed shapes; secondly, the lumen is segnented using fuzzy clustering. Thre region to be classified is that within the outer vessel wall boundary obtained from the previous step; finally, for plaque detection we follow the same approach as for lumen segmentation: fuzzy clustering. However, plaque is more difficult to segment, as the pixel gray value can differ considerably from one region to another, even when it corresponds to the same type of tissue. That makes further processing necessary. All these three steps might be carried out combining information from different sequences (PD-, T2-, T1-weighted images, pre- and post-contrast), to improve the contour detection. The algorithm has been validated in vivo on 58 high-resolution PD and T1 weighted MR images (19 patients). The results demonstrate excellent correspondence between automatic and manual area measurements: lumen (r=0.94), outer (r=0.92), and acceptable for fibrous cap thickness (r=0.76).

Effect of rosuvastatin on atherosclerotic plaque stability: An intravascular ultrasound elastography study.

PubMed

Li, Zhaohuan; Wang, Lin; Hu, Xiaobo; Zhang, Pengfei; Chen, Yifei; Liu, Xinxin; Xu, Mingjun; Zhang, Yun; Zhang, Mei

2016-05-01

The present study aimed to investigate the effect of potent rosuvastatin therapy on plaque mechanical stabilization as seen on IVUSE. 14 purebred New Zealand rabbits were fed a high-cholesterol diet; the abdominal aorta endothelium was balloon-injured after 2 weeks; at week 13, 7 rabbits received rosuvastatin (1.5 mg/kg/day), and the other 7 received an equal volume of saline. IVUS images of abdominal aortas were acquired, and 2 consecutive frames near the end-diastole images in situ were used to construct an IVUS elastogram. Control rabbits showed a significant increase in shear strain (SS) and area strain (AS) in total plaques. The rosuvastatin group showed no change in SS and AS, but serum TG and LDL-C levels were reduced, with less lipid deposition, macrophage infiltration, production of proinflammatory cytokines and apoptosis in plaques. The changes in SS and AS from baseline between groups significantly differed (SS: 1.15 (1.96) % vs. -0.99 ± 2.83%, p = 0.013; AS: 1.25 (2.29) % vs. -1.67 ± 5.05%, p = 0.022). At follow-up, for controls, strain values were increased in the shoulder of eccentric plaques (SS: 2.66 ± 1.31% vs. 4.86 ± 1.93%, p = 0.016; AS: 4.45 ± 2.33% vs. 7.91 ± 2.74%, p = 0.009) but not the plaque body. Changes in SS and AS in the plaque shoulder differed between the control and rosuvastatin groups (SS: 2.20 ± 2.17% vs. -0.87 ± 3.31%, p = 0.028; AS: 2.10 (4.61) % vs. -2.75 ± 5.97%, p = 0.009). Rosuvastatin therapy in rabbits with atherosclerotic plaques led to less vulnerable plaque features. IVUSE is a very sensitive technique for detecting pharmacologically-induced mechanical changes in rabbit atherosclerotic plaques. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Near-infrared hyperspectral imaging of atherosclerotic tissue phantom

NASA Astrophysics Data System (ADS)

Ishii, K.; Nagao, R.; Kitayabu, A.; Awazu, K.

2013-06-01

A method to identify vulnerable plaques that are likely to cause acute coronary events has been required. The object of this study is identifying vulnerable plaques by hyperspectral imaging in near-infrared range (NIR-HSI) for an angioscopic application. In this study, NIR-HSI of atherosclerotic tissue phantoms was demonstrated under simulated angioscopic conditions. NIR-HSI system was constructed by a NIR super continuum light and a mercury-cadmium-telluride camera. Spectral absorbance values were obtained in the wavelength range from 1150 to 2400 nm at 10 nm intervals. The hyperspectral images were constructed with spectral angle mapper algorithm. As a result, detections of the lipid area in the atherosclerotic tissue phantom under angioscopic observation conditions were achieved especially in the wavelength around 1200 nm, which corresponds to the second overtone of CH stretching vibration mode.

Prevalence and clinical characteristics of lower limb atherosclerotic lesions in newly diagnosed patients with ketosis-onset diabetes: a cross-sectional study

PubMed Central

2014-01-01

Background The clinical features of atherosclerotic lesions in ketosis-onset diabetes are largely absent. We aimed to compare the characteristics of lower limb atherosclerotic lesions among type 1, ketosis-onset and non-ketotic type 2 diabetes. Methods A cross-sectional study was performed in newly diagnosed Chinese patients with diabetes, including 53 type 1 diabetics with positive islet-associated autoantibodies, 208 ketosis-onset diabetics without islet-associated autoantibodies, and 215 non-ketotic type 2 diabetics. Sixty-two subjects without diabetes were used as control. Femoral intima-media thickness (FIMT), lower limb atherosclerotic plaque and stenosis were evaluated and compared among the four groups based on ultrasonography. The risk factors associated with lower limb atherosclerotic plaque were evaluated via binary logistic regression in patients with diabetes. Results After adjusting for age and sex, the prevalence of lower limb plaque in the patients with ketosis-onset diabetes (47.6%) was significantly higher than in the control subjects (25.8%, p = 0.013), and showed a higher trend compared with the patients with type 1 diabetes (39.6%, p = 0.072), but no difference was observed in comparison to the patients with non-ketotic type 2 diabetes (62.3%, p = 0.859). The mean FIMT in the ketosis-onset diabetics (0.73 ± 0.17 mm) was markedly greater than that in the control subjects (0.69 ± 0.13 mm, p = 0.045) after controlling for age and sex, but no significant differences were found between the ketosis-onset diabetics and the type 1 diabetics (0.71 ± 0.16 mm, p = 0.373), and the non-ketotic type 2 diabetics (0.80 ± 0.22 mm, p = 0.280), respectively. Age and FIMT were independent risk factors for the presence of lower limb plaque in both the ketosis-onset and non-ketotic type 2 diabetic patients, while sex and age in the type 1 diabetic patients. Conclusions The prevalence and risk of lower limb atherosclerotic plaque in the ketosis-onset diabetes were remarkably higher than in the control subjects without diabetes. The features and risk factors of lower limb atherosclerotic lesions in the ketosis-onset diabetes resembled those in the non-ketotic type 2 diabetes, but different from those in the type 1 diabetes. Our findings provide further evidences to support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes rather than idiopathic type 1 diabetes. PMID:24926320

Detection of high-risk atherosclerotic lesions by time-resolved fluorescence spectroscopy based on the Laguerre deconvolution technique

NASA Astrophysics Data System (ADS)

Jo, J. A.; Fang, Q.; Papaioannou, T.; Qiao, J. H.; Fishbein, M. C.; Beseth, B.; Dorafshar, A. H.; Reil, T.; Baker, D.; Freischlag, J.; Marcu, L.

2006-02-01

This study introduces new methods of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) data analysis for tissue characterization. These analytical methods were applied for the detection of atherosclerotic vulnerable plaques. Upon pulsed nitrogen laser (337 nm, 1 ns) excitation, TR-LIFS measurements were obtained from carotid atherosclerotic plaque specimens (57 endarteroctomy patients) at 492 distinct areas. The emission was both spectrally- (360-600 nm range at 5 nm interval) and temporally- (0.3 ns resolution) resolved using a prototype clinically compatible fiber-optic catheter TR-LIFS apparatus. The TR-LIFS measurements were subsequently analyzed using a standard multiexponential deconvolution and a recently introduced Laguerre deconvolution technique. Based on their histopathology, the lesions were classified as early (thin intima), fibrotic (collagen-rich intima), and high-risk (thin cap over necrotic core and/or inflamed intima). Stepwise linear discriminant analysis (SLDA) was applied for lesion classification. Normalized spectral intensity values and Laguerre expansion coefficients (LEC) at discrete emission wavelengths (390, 450, 500 and 550 nm) were used as features for classification. The Laguerre based SLDA classifier provided discrimination of high-risk lesions with high sensitivity (SE>81%) and specificity (SP>95%). Based on these findings, we believe that TR-LIFS information derived from the Laguerre expansion coefficients can provide a valuable additional dimension for the diagnosis of high-risk vulnerable atherosclerotic plaques.

RP105 deficiency attenuates early atherosclerosis via decreased monocyte influx in a CCR2 dependent manner.

PubMed

Wezel, Anouk; van der Velden, Daniël; Maassen, Johanna M; Lagraauw, H Maxime; de Vries, Margreet R; Karper, Jacco C; Kuiper, Johan; Bot, Ilze; Quax, Paul H A

2015-01-01

Toll like receptor 4 (TLR4) plays a key role in inflammation and previously it was established that TLR4 deficiency attenuates atherosclerosis. RadioProtective 105 (RP105) is a structural homolog of TLR4 and an important regulator of TLR4 signaling, suggesting that RP105 may also be an important effector in atherosclerosis. We thus aimed to determine the role of RP105 in atherosclerotic lesion development using RP105 deficient mice on an atherosclerotic background. Atherosclerosis was induced in Western-type diet fed low density lipoprotein receptor deficient (LDLr(-/-)) and LDLr/RP105 double knockout (LDLr(-/-)/RP105(-/-)) mice by means of perivascular carotid artery collar placement. Lesion size was significantly reduced by 58% in LDLr(-/-)/RP105(-/-) mice, and moreover, plaque macrophage content was markedly reduced by 40%. In a model of acute peritonitis, monocyte influx was almost 3-fold reduced in LDLr(-/-)/RP105(-/-) mice (P = 0.001), while neutrophil influx remained unaltered, suggestive of an altered migratory capacity of monocytes upon deletion of RP105. Interestingly, in vitro stimulation of monocytes with LPS induced a downregulation of CCR2, a chemokine receptor crucially involved in monocyte influx to atherosclerotic lesions, which was more pronounced in LDLr(-/-)/RP105(-/-) monocytes as compared to LDLr(-/-) monocytes. We here show that RP105 deficiency results in reduced early atherosclerotic plaque development with a marked decrease in lesional macrophage content, which may be due to disturbed migration of RP105 deficient monocytes resulting from CCR2 downregulation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Arterial ageing: from endothelial dysfunction to vascular calcification.

PubMed

Tesauro, M; Mauriello, A; Rovella, V; Annicchiarico-Petruzzelli, M; Cardillo, C; Melino, G; Di Daniele, N

2017-05-01

Complex structural and functional changes occur in the arterial system with advancing age. The aged artery is characterized by changes in microRNA expression patterns, autophagy, smooth muscle cell migration and proliferation, and arterial calcification with progressively increased mechanical vessel rigidity and stiffness. With age the vascular smooth muscle cells modify their phenotype from contractile to 'synthetic' determining the development of intimal thickening as early as the second decade of life as an adaptive response to forces acting on the arterial wall. The increased permeability observed in intimal thickening could represent the substrate on which low-level atherosclerotic stimuli can promote the development of advanced atherosclerotic lesions. In elderly patients the atherosclerotic plaques tend to be larger with increased vascular stenosis. In these plaques there is a progressive accumulation of both lipids and collagen and a decrease of inflammation. Similarly the plaques from elderly patients show more calcification as compared with those from younger patients. The coronary artery calcium score is a well-established marker of adverse cardiovascular outcomes. The presence of diffuse calcification in a severely stenotic segment probably induces changes in mechanical properties and shear stress of the arterial wall favouring the rupture of a vulnerable lesion in a less stenotic adjacent segment. Oxidative stress and inflammation appear to be the two primary pathological mechanisms of ageing-related endothelial dysfunction even in the absence of clinical disease. Arterial ageing is no longer considered an inexorable process. Only a better understanding of the link between ageing and vascular dysfunction can lead to significant advances in both preventative and therapeutic treatments with the aim that in the future vascular ageing may be halted or even reversed. © 2017 The Association for the Publication of the Journal of Internal Medicine.

Basilar artery atherosclerotic plaques in paramedian and lacunar pontine infarctions: a high-resolution MRI study.

PubMed

Klein, Isabelle F; Lavallée, Philippa C; Mazighi, Mikael; Schouman-Claeys, Elisabeth; Labreuche, Julien; Amarenco, Pierre

2010-07-01

Pontine infarction is most often related to basilar artery atherosclerosis when the lesion abuts on the basal surface (paramedian pontine infarction), whereas small medial pontine lesion is usually attributed to small vessel lipohyalinosis. A previous study has found that high-resolution MRI can detect basilar atherosclerotic plaques in up to 70% of patient with paramedian pontine infarction, even in patients with normal angiograms, but none has evaluated the presence of basilar artery plaque by high-resolution MRI in patients with small medial pontine lesion in the medial part of the pons. Consecutive patients with pontine infarction underwent basilar angiography using time-of-flight and contrast-enhanced 3-dimensional MR angiography to assess the presence of basilar artery stenosis and high-resolution MRI to assess the presence of atherosclerotic plaque. Basilar artery angiogram was scored as "normal," "irregular," or "stenosed" >or=30%" and basilar artery by high-resolution MRI was scored as "normal" or "presence of plaque." Medial pontine infarcts were divided into paramedian pontine infarction and small medial pontine lesion groups. Forty-one patients with pontine infarction were included, 26 with paramedian pontine infarction and 15 with small medial pontine lesion. High-resolution MRI detected basilar artery atherosclerosis in 42% of patients with a pontine infarction and normal basilar angiograms. Among patients with paramedian pontine infarction, 65% had normal basilar angiograms but 77% had basilar artery atherosclerosis detected on high-resolution MRI. Among patients with small medial pontine lesion, 46% had normal basilar angiograms but 73% had basilar artery plaques detected on by high-resolution MRI. This study suggests that medial pontine lacunes may be due to a penetrating artery disease secondary to basilar artery atherosclerosis. High-resolution MRI could help precise stroke subtyping.

Mathematical modeling of coupled drug and drug-encapsulated nanoparticle transport in patient-specific coronary artery walls

NASA Astrophysics Data System (ADS)

Hossain, Shaolie S.; Hossainy, Syed F. A.; Bazilevs, Yuri; Calo, Victor M.; Hughes, Thomas J. R.

2012-02-01

The majority of heart attacks occur when there is a sudden rupture of atherosclerotic plaque, exposing prothrombotic emboli to coronary blood flow, forming clots that can cause blockages of the arterial lumen. Diseased arteries can be treated with drugs delivered locally to vulnerable plaques. The objective of this work was to develop a computational tool-set to support the design and analysis of a catheter-based nanoparticulate drug delivery system to treat vulnerable plaques and diffuse atherosclerosis. A three-dimensional mathematical model of coupled mass transport of drug and drug-encapsulated nanoparticles was developed and solved numerically utilizing isogeometric finite element analysis. Simulations were run on a patient-specific multilayered coronary artery wall segment with a vulnerable plaque and the effect of artery and plaque inhomogeneity was analyzed. The method captured trends observed in local drug delivery and demonstrated potential for optimizing drug design parameters, including delivery location, nanoparticle surface properties, and drug release rate.

High fat diet induced atherosclerosis is accompanied with low colonic bacterial diversity and altered abundances that correlates with plaque size, plasma A-FABP and cholesterol: a pilot study of high fat diet and its intervention with Lactobacillus rhamnosus GG (LGG) or telmisartan in ApoE-/- mice.

PubMed

Chan, Yee Kwan; Brar, Manreetpal Singh; Kirjavainen, Pirkka V; Chen, Yan; Peng, Jiao; Li, Daxu; Leung, Frederick Chi-Ching; El-Nezami, Hani

2016-11-08

Atherosclerosis appears to have multifactorial causes - microbial component like lipopolysaccharides (LPS) and other pathogen associated molecular patterns may be plausible factors. The gut microbiota is an ample source of such stimulants, and its dependent metabolites and altered gut metagenome has been an established link to atherosclerosis. In this exploratory pilot study, we aimed to elucidate whether microbial intervention with probiotics L. rhamnosus GG (LGG) or pharmaceuticals telmisartan (TLM) could improve atherosclerosis in a gut microbiota associated manner. Atherosclerotic phenotype was established by 12 weeks feeding of high fat (HF) diet as opposed to normal chow diet (ND) in apolipoprotein E knockout (ApoE -/- ) mice. LGG or TLM supplementation to HF diet was studied. Both LGG and TLM significantly reduced atherosclerotic plaque size and improved various biomarkers including endotoxin to different extents. Colonial microbiota analysis revealed that TLM restored HF diet induced increase in Firmicutes/Bacteroidetes ratio and decrease in alpha diversity; and led to a more distinct microbial clustering closer to ND in PCoA plot. Eubacteria, Anaeroplasma, Roseburia, Oscillospira and Dehalobacteria appeared to be protective against atherosclerosis and showed significant negative correlation with atherosclerotic plaque size and plasma adipocyte - fatty acid binding protein (A-FABP) and cholesterol. LGG and TLM improved atherosclerosis with TLM having a more distinct alteration in the colonic gut microbiota. Altered bacteria genera and reduced alpha diversity had significant correlations to atherosclerotic plaque size, plasma A-FABP and cholesterol. Future studies on such bacterial functional influence in lipid metabolism will be warranted.

64Cu-Labeled LyP-1-Dendrimer for PET-CT Imaging of Atherosclerotic Plaque

PubMed Central

2015-01-01

The ability to detect and quantify macrophage accumulation can provide important diagnostic and prognostic information for atherosclerotic plaque. We have previously shown that LyP-1, a cyclic 9-amino acid peptide, binds to p32 proteins on activated macrophages, facilitating the visualization of atherosclerotic plaque with PET. Yet, the in vivo plaque accumulation of monomeric [18F]FBA-LyP-1 was low (0.31 ± 0.05%ID/g). To increase the avidity of LyP-1 constructs to p32, we synthesized a dendritic form of LyP-1 on solid phase using lysine as the core structural element. Imaging probes (FAM or 6-BAT) were conjugated to a lysine or cysteine on the dendrimer for optical and PET studies. The N-terminus of the dendrimer was further modified with an aminooxy group in order to conjugate LyP-1 and ARAL peptides bearing a ketone. Oxime ligation of peptides to both dendrimers resulted in (LyP-1)4- and (ARAL)4-dendrimers with optical (FAM) and PET probes (6-BAT). For PET-CT studies, (LyP-1)4- and (ARAL)4-dendrimer-6-BAT were labeled with 64Cu (t1/2 = 12.7 h) and intravenously injected into the atherosclerotic (ApoE–/–) mice. After two hours of circulation, PET-CT coregistered images demonstrated greater uptake of the (LyP-1)4-dendrimer-64Cu than the (ARAL)4-dendrimer-64Cu in the aortic root and descending aorta. Ex vivo images and the biodistribution acquired at three hours after injection also demonstrated a significantly higher uptake of the (LyP-1)4-dendrimer-64Cu (1.1 ± 0.26%ID/g) than the (ARAL)4-dendrimer-64Cu (0.22 ± 0.05%ID/g) in the aorta. Similarly, subcutaneous injection of the LyP-1-dendrimeric carriers resulted in preferential accumulation in plaque-containing regions over 24 h. In the same model system, ex vivo fluorescence images within aortic plaque depict an increased accumulation and penetration of the (LyP-1)4-dendrimer-FAM as compared to the (ARAL)4-dendrimer-FAM. Taken together, the results suggest that the (LyP-1)4-dendrimer can be applied for in vivo PET imaging of plaque and that LyP-1 could be further exploited for the delivery of therapeutics with multivalent carriers or nanoparticles. PMID:24433095

[Effects of berberine on serum inflammatory factors and carotid atherosclerotic plaques in patients with acute cerebral ischemic stroke].

PubMed

Li, Ying; Wang, Pei; Chai, Mei-Jing; Yang, Fan; Li, Hong-Shan; Zhao, Jing; Wang, Huan; Lu, Dan-Dan

2016-11-01

This study aims to analyze the effect of berberine on serum inflammatory factors and carotid atherosclerotic plaques in ppatients with acute cerebral ischemic stroke(AIS). In the study, 120 patients with AIS were randomly divided into berberine group(n=60) and general group (n=60). The 60 cases in the general group were provided with general therapy according to the latest guidelines of diagnosis and treatment of AIS. The berberine group received berberine 300 mg(tid) in addition to the therapy of the general group. The levels of serum inflammatory factors, the nerve function defect grades and the indexes of carotid atherosclerosis plaques [including the total plaque area(TPA), intima-media thickness(IMT) and the number of unstable carotid atherosclerotic plaques] were measured and compared. The results indicated that the levels of serum inflammatory factors, the NIHSS(national institute of health stroke scales) cores and the indexes of carotid atherosclerosis plaques were not significantly different between the berberine groups of general group, with positive correlation between serum inflammatory factors and NIHSS scores(P<0.05). The levels of serum inflammatory factors and NIHSS scores of the berberine groups on 14 d were significantly lower than those on 1 d(P<0.05). The levels of serum inflammatory factors and NIHSS scores of the berberine group on 14 d were significantly lower than those of the general group(P<0.05). The TPA and the number of unstable carotid atherosclerotic plaques of the berberine groups on 90 d were significantly lower than those of general group, with significant differences(P<0.05). The IMT showed a downward trend, but with significant difference.The mRS(modified rankin scale) scores of the berberine group on 90 d were significantly lower, with a higher rate of short-term favorable prognosis (P<0.05). There was no significant difference in the incidence of adverse reactions between the two groups. This study showed that berberine in addition to the general therapy can significantly lower the levels of serum MIF and IL-6, reduce the degree of carotid atherosclerosis to some extent and improve neurological impairment and the prognosis of patients with AIS. Copyright© by the Chinese Pharmaceutical Association.

Effects of Low Carbohydrate High Protein (LCHP) diet on atherosclerotic plaque phenotype in ApoE/LDLR-/- mice: FT-IR and Raman imaging.

PubMed

Wrobel, T P; Marzec, K M; Chlopicki, S; Maślak, E; Jasztal, A; Franczyk-Żarów, M; Czyżyńska-Cichoń, I; Moszkowski, T; Kostogrys, R B; Baranska, M

2015-09-22

Low Carbohydrate High Protein (LCHP) diet displays pro-atherogenic effects, however, the exact mechanisms involved are still unclear. Here, with the use of vibrational imaging, such as Fourier transform infrared (FT-IR) and Raman (RS) spectroscopies, we characterize biochemical content of plaques in Brachiocephalic Arteries (BCA) from ApoE/LDLR(-/-) mice fed LCHP diet as compared to control, recomended by American Institute of Nutrition, AIN diet. FT-IR images were taken from 6-10 sections of BCA from each mice and were complemented with RS measurements with higher spatial resolution of chosen areas of plaque sections. In aortic plaques from LCHP fed ApoE/LDLR(-/-) mice, the content of cholesterol and cholesterol esters was increased, while that of proteins was decreased as evidenced by global FT-IR analysis. High resolution imaging by RS identified necrotic core/foam cells, lipids (including cholesterol crystals), calcium mineralization and fibrous cap. The decreased relative thickness of the outer fibrous cap and the presence of buried caps were prominent features of the plaques in ApoE/LDLR(-/-) mice fed LCHP diet. In conclusion, FT-IR and Raman-based imaging provided a complementary insight into the biochemical composition of the plaque suggesting that LCHP diet increased plaque cholesterol and cholesterol esters contents of atherosclerotic plaque, supporting the cholesterol-driven pathogenesis of LCHP-induced atherogenesis.

Intravascular photoacoustic imaging: a new tool for vulnerable plaque identification.

PubMed

Jansen, Krista; van Soest, Gijs; van der Steen, Antonius F W

2014-06-01

The vulnerable atherosclerotic plaque is believed to be at the root of the majority of acute coronary events. Even though the exact origins of plaque vulnerability remain elusive, the thin-cap fibroatheroma, characterized by a lipid-rich necrotic core covered by a thin fibrous cap, is considered to be the most prominent type of vulnerable plaque. No clinically available imaging technique can characterize atherosclerotic lesions to the extent needed to determine plaque vulnerability prognostically. Intravascular photoacoustic imaging (IVPA) has the potential to take a significant step in that direction by imaging both plaque structure and composition. IVPA is a natural extension of intravascular ultrasound that adds tissue type specificity to the images. IVPA utilizes the optical contrast provided by the differences in the absorption spectra of plaque components to image composition. Its capability to image lipids in human coronary atherosclerosis has been shown extensively ex vivo and has recently been translated to an in vivo animal model. Other disease markers that have been successfully targeted are calcium and inflammatory markers, such as macrophages and matrix metalloproteinase; the latter two through application of exogenous contrast agents. By simultaneously displaying plaque morphology and composition, IVPA can provide a powerful prognostic marker for disease progression, and as such has the potential to transform the current practice in percutaneous coronary intervention. Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Porphyromonas gingivalis-dendritic cell interactions: consequences for coronary artery disease.

PubMed

Zeituni, Amir E; Carrion, Julio; Cutler, Christopher W

2010-12-21

An estimated 80 million US adults have one or more types of cardiovascular diseases. Atherosclerosis is the single most important contributor to cardiovascular diseases; however, only 50% of atherosclerosis patients have currently identified risk factors. Chronic periodontitis, a common inflammatory disease, is linked to an increased cardiovascular risk. Dendritic cells (DCs) are potent antigen presenting cells that infiltrate arterial walls and may destabilize atherosclerotic plaques in cardiovascular disease. While the source of these DCs in atherosclerotic plaques is presently unclear, we propose that dermal DCs from peripheral inflamed sites such as CP tissues are a potential source. This review will examine the role of the opportunistic oral pathogen Porphyromonas gingivalis in invading DCs and stimulating their mobilization and misdirection through the bloodstream. Based on our published observations, combined with some new data, as well as a focused review of the literature we will propose a model for how P. gingivalis may exploit DCs to gain access to systemic circulation and contribute to coronary artery disease. Our published evidence supports a significant role for P. gingivalis in subverting normal DC function, promoting a semimature, highly migratory, and immunosuppressive DC phenotype that contributes to the inflammatory development of atherosclerosis and, eventually, plaque rupture.

The association of lesion eccentricity with plaque morphology and components in the superficial femoral artery: a high-spatial-resolution, multi-contrast weighted CMR study.

PubMed

Li, Feiyu; McDermott, Mary McGrae; Li, Debiao; Carroll, Timothy J; Hippe, Daniel S; Kramer, Christopher M; Fan, Zhaoyang; Zhao, Xihai; Hatsukami, Thomas S; Chu, Baocheng; Wang, Jinnan; Yuan, Chun

2010-07-01

Atherosclerotic plaque morphology and components are predictors of subsequent cardiovascular events. However, associations of plaque eccentricity with plaque morphology and plaque composition are unclear. This study investigated associations of plaque eccentricity with plaque components and morphology in the proximal superficial femoral artery using cardiovascular magnetic resonance (CMR). Twenty-eight subjects with an ankle-brachial index less than 1.00 were examined with 1.5 T high-spatial-resolution, multi-contrast weighted CMR. One hundred and eighty diseased locations of the proximal superficial femoral artery (about 40 mm) were analyzed. The eccentric lesion was defined as [(Maximum wall thickness- Minimum wall thickness)/Maximum wall thickness] >or= 0.5. The arterial morphology and plaque components were measured using semi-automatic image analysis software. One hundred and fifteen locations were identified as eccentric lesions and sixty-five as concentric lesions. The eccentric lesions had larger wall but similar lumen areas, larger mean and maximum wall thicknesses, and more calcification and lipid rich necrotic core, compared to concentric lesions. For lesions with the same lumen area, the degree of eccentricity was associated with an increased wall area. Eccentricity (dichotomous as eccentric or concentric) was independently correlated with the prevalence of calcification (odds ratio 3.78, 95% CI 1.47-9.70) after adjustment for atherosclerotic risk factors and wall area. Plaque eccentricity is associated with preserved lumen size and advanced plaque features such as larger plaque burden, more lipid content, and increased calcification in the superficial femoral artery.

Atherosclerotic plaque rupture and thrombosis. Evolving concepts.

PubMed

Fuster, V; Stein, B; Ambrose, J A; Badimon, L; Badimon, J J; Chesebro, J H

1990-09-01

Rupture of an atherosclerotic plaque associated with partial or complete thrombotic vessel occlusion is fundamental to the development of ischemic coronary syndromes. Plaques that produce only mild-to-moderate angiographic luminal stenosis are frequently those that undergo abrupt disruption, leading to unstable angina or acute myocardial infarction. Plaques with increased lipid content appear more prone to rupture, particularly when the lipid pool is localized eccentrically within the intima. Macrophages appear to play an important role in atherogenesis, perhaps by participating in the uptake and metabolism of lipoproteins, secretion of growth factors, and production of enzymes and toxic metabolites that may facilitate plaque rupture. In addition, the particular composition or configuration of a plaque and the hemodynamic forces to which it is exposed may determine its susceptibility to disruption. Exposure of collagen, lipids, and smooth muscle cells after plaque rupture leads to the activation of platelets and the coagulation cascade system. The resulting thrombus may lead to marked reduction in myocardial perfusion and the development of an unstable coronary syndrome, or it may become organized and incorporated into the diseased vessel, thus contributing to the progression of atherosclerosis. In unstable angina, plaque disruption leads to thrombosis, which is usually labile and results in only a transient reduction in myocardial perfusion. Release of vasoactive substances, arterial spasm, or increases in myocardial oxygen demand may contribute to ischemia. In acute myocardial infarction, plaque disruption results in a more persistent thrombotic vessel occlusion; the extent of necrosis depends on the size of the artery, the duration of occlusion, the presence of collateral flow, and the integrity of the fibrinolytic system. Thrombi that undergo lysis expose a highly thrombogenic surface to the circulating blood, which has the capacity of activating platelets and the coagulation cascade system and may lead to thrombotic reocclusion. Measurements aimed at reversing the process of atherosclerosis via cholesterol reduction and enhanced high density lipoprotein activity are encouraging. Active research is being focused on the development of new antithrombotic tools, such as inhibitors of thrombin, thromboxane, and serotonin receptor antagonists, and monoclonal antibodies aimed at blocking platelet membrane receptors or adhesive proteins. These compounds may prove useful when immediate and potent inhibition of the hemostatic system is desired. Intensive research is still needed in the areas of pathogenesis and therapeutic intervention in atherosclerosis.

An integrated method for atherosclerotic carotid plaque segmentation in ultrasound image.

PubMed

Qian, Chunjun; Yang, Xiaoping

2018-01-01

Carotid artery atherosclerosis is an important cause of stroke. Ultrasound imaging has been widely used in the diagnosis of atherosclerosis. Therefore, segmenting atherosclerotic carotid plaque in ultrasound image is an important task. Accurate plaque segmentation is helpful for the measurement of carotid plaque burden. In this paper, we propose and evaluate a novel learning-based integrated framework for plaque segmentation. In our study, four different classification algorithms, along with the auto-context iterative algorithm, were employed to effectively integrate features from ultrasound images and later also the iteratively estimated and refined probability maps together for pixel-wise classification. The four classification algorithms were support vector machine with linear kernel, support vector machine with radial basis function kernel, AdaBoost and random forest. The plaque segmentation was implemented in the generated probability map. The performance of the four different learning-based plaque segmentation methods was tested on 29 B-mode ultrasound images. The evaluation indices for our proposed methods were consisted of sensitivity, specificity, Dice similarity coefficient, overlap index, error of area, absolute error of area, point-to-point distance, and Hausdorff point-to-point distance, along with the area under the ROC curve. The segmentation method integrated the random forest and an auto-context model obtained the best results (sensitivity 80.4 ± 8.4%, specificity 96.5 ± 2.0%, Dice similarity coefficient 81.0 ± 4.1%, overlap index 68.3 ± 5.8%, error of area -1.02 ± 18.3%, absolute error of area 14.7 ± 10.9%, point-to-point distance 0.34 ± 0.10 mm, Hausdorff point-to-point distance 1.75 ± 1.02 mm, and area under the ROC curve 0.897), which were almost the best, compared with that from the existed methods. Our proposed learning-based integrated framework investigated in this study could be useful for atherosclerotic carotid plaque segmentation, which will be helpful for the measurement of carotid plaque burden. Copyright © 2017 Elsevier B.V. All rights reserved.

Atherosclerosis of the carotid artery: evaluation by magnetic resonance angiography.

PubMed

Wildy, K S; Yuan, C; Tsuruda, J S; Ferguson, M S; Wen, N; Subramaniam, D S; Strandness, D E

1996-01-01

Carotid artery atherosclerotic plaques (APs) can lead to brain ischemia, an event shown to correlate with both the degree of stenosis and the composition of the AP. Currently, accurate estimates of stenosis can be obtained by either x-ray angiography or three-dimensional time-of-flight (TOF) magnetic resonance angiography (MRA). Our purpose was to determine whether three-dimensional TOF MRA images could also provide information on plaque location, morphology, and composition. Seven pre-endarterectomy patients underwent three-dimensional TOF MRA. After endarterectomy, plaque histology was evaluated. Three-dimensional TOF MRA images contained sufficient soft tissue contrast to differentiate the plaques from the surrounding tissues in all cases. Estimation of plaque morphology had 80% correlation with histology. Finally, intraplaque hemorrhage and calcification were deplicted as regions of moderately high and very low intensity, respectively. These preliminary results suggest that three-dimensional TOF MRA may be useful in studying the development and progression of carotid atherosclerosis.

Development of an intravascular ultrasound elastography based on a dual-element transducer

NASA Astrophysics Data System (ADS)

Shih, Cho-Chiang; Chen, Pei-Yu; Ma, Teng; Zhou, Qifa; Shung, K. Kirk; Huang, Chih-Chung

2018-04-01

The ability to measure the elastic properties of plaques and vessels would be useful in clinical diagnoses, particularly for detecting a vulnerable plaque. This study demonstrates the feasibility of the combination of intravascular ultrasound (IVUS) and acoustic radiation force elasticity imaging for detecting the distribution of stiffness within atherosclerotic arteries ex vivo. A dual-frequency IVUS transducer with two elements was used to induce the propagation of the shear wave (by the 8.5 MHz pushing element) which could be simultaneously monitored by the 31 MHz imaging element. The wave-amplitude image and the wave-velocity image were reconstructed by measuring the peak displacement and wave velocity of shear wave propagation, respectively. System performance was verified using gelatin phantoms. The phantom results demonstrate that the stiffness differences of shear modulus of 1.6 kPa can be distinguished through the wave-amplitude and wave-velocity images. The stiffness distributions of the atherosclerotic aorta from a rabbit were obtained, for which the values of peak displacement and the shear wave velocity were 3.7 ± 1.2 µm and 0.38 ± 0.19 m s-1 for the lipid-rich plaques, and 1.0 ± 0.2 µm and 3.45 ± 0.45 m s-1 for the arterial walls, respectively. These results indicate that IVUS elasticity imaging can be used to distinguish the elastic properties of plaques and vessels.

Atherosclerotic plaque delamination: Experiments and 2D finite element model to simulate plaque peeling in two strains of transgenic mice.

PubMed

Merei, Bilal; Badel, Pierre; Davis, Lindsey; Sutton, Michael A; Avril, Stéphane; Lessner, Susan M

2017-03-01

Finite element analyses using cohesive zone models (CZM) can be used to predict the fracture of atherosclerotic plaques but this requires setting appropriate values of the model parameters. In this study, material parameters of a CZM were identified for the first time on two groups of mice (ApoE -/- and ApoE -/- Col8 -/- ) using the measured force-displacement curves acquired during delamination tests. To this end, a 2D finite-element model of each plaque was solved using an explicit integration scheme. Each constituent of the plaque was modeled with a neo-Hookean strain energy density function and a CZM was used for the interface. The model parameters were calibrated by minimizing the quadratic deviation between the experimental force displacement curves and the model predictions. The elastic parameter of the plaque and the CZM interfacial parameter were successfully identified for a cohort of 11 mice. The results revealed that only the elastic parameter was significantly different between the two groups, ApoE -/- Col8 -/- plaques being less stiff than ApoE -/- plaques. Finally, this study demonstrated that a simple 2D finite element model with cohesive elements can reproduce fairly well the plaque peeling global response. Future work will focus on understanding the main biological determinants of regional and inter-individual variations of the material parameters used in the model. Copyright © 2016 Elsevier Ltd. All rights reserved.

Vaspin attenuates the progression of atherosclerosis by inhibiting ER stress-induced macrophage apoptosis in apoE−/− mice

PubMed Central

LIN, YING; ZHUANG, JIANHUI; LI, HAILING; ZHU, GUOFU; ZHOU, SHUNPING; LI, WEIMING; PENG, WENHUI; XU, YAWEI

2016-01-01

Visceral adipose tissue-derived serine protease inhibitor (vaspin) is a novel adipokine with potential insulin-sensitizing properties, which was initially detected in the visceral adipose tissue of genetically obese rats. Previous studies have demonstrated that vaspin exerts a protective effect on arteries undergoing atherosclerosis in vitro, and it has been shown to exert anti-inflammatory and antimigratory effects on vascular smooth muscle cells. Vaspin promotes proliferation and inhibits apoptosis in endothelial cells, and decreases proliferation of the arterial intima under diabetic conditions. In addition, macrophage apoptosis is an important characteristic of atherosclerotic plaque development. In vivo experiments were performed by histological analysis, including Oil Red O, hematoxylin and eosin and Masson's trichrome staining. Mice were injected with lentivirus via the tail vein and tissues were obtained for histological analysis. Cell apoptosis was determined by flow cytometry of Annexin-V/propidium iodide dual staining and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay. Total proteins were extracted and protein expression levels were detected by western blot analysis. The present study aimed to investigate whether vaspin was able to protect against atherosclerotic development in vivo, and to explore the underlying mechanisms of the potential antiatherogenic effects. The results of the current study indicated that vaspin inhibited the progression of atherosclerotic plaques in apoE−/− mice by inhibiting endoplasmic reticulum stress-induced macrophage apoptosis. PMID:26708512

Carotid Plaque Lipid Content and Fibrous Cap Status Predict Systemic CV Outcomes: The MRI Substudy in AIM-HIGH.

PubMed

Sun, Jie; Zhao, Xue-Qiao; Balu, Niranjan; Neradilek, Moni B; Isquith, Daniel A; Yamada, Kiyofumi; Cantón, Gádor; Crouse, John R; Anderson, Todd J; Huston, John; O'Brien, Kevin; Hippe, Daniel S; Polissar, Nayak L; Yuan, Chun; Hatsukami, Thomas S

2017-03-01

The aim of this study was to investigate whether and what carotid plaque characteristics predict systemic cardiovascular outcomes in patients with clinically established atherosclerotic disease. Advancements in atherosclerosis imaging have allowed assessment of various plaque characteristics, some of which are more directly linked to the pathogenesis of acute cardiovascular events compared to plaque burden. As part of the event-driven clinical trial AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes), subjects with clinically established atherosclerotic disease underwent multicontrast carotid magnetic resonance imaging (MRI) to detect plaque tissue composition and high-risk features. Prospective associations between MRI measurements and the AIM-HIGH primary endpoint (fatal and nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, and symptom-driven revascularization) were analyzed using Cox proportional hazards survival models. Of the 232 subjects recruited, 214 (92.2%) with diagnostic image quality constituted the study population (82% male, mean age 61 ± 9 years, 94% statin use). During median follow-up of 35.1 months, 18 subjects (8.4%) reached the AIM-HIGH endpoint. High lipid content (hazard ratio [HR] per 1 SD increase in percent lipid core volume: 1.57; p = 0.002) and thin/ruptured fibrous cap (HR: 4.31; p = 0.003) in carotid plaques were strongly associated with the AIM-HIGH endpoint. Intraplaque hemorrhage had a low prevalence (8%) and was marginally associated with the AIM-HIGH endpoint (HR: 3.00; p = 0.053). High calcification content (HR per 1 SD increase in percent calcification volume: 0.66; p = 0.20), plaque burden metrics, and clinical risk factors were not significantly associated with the AIM-HIGH endpoint. The associations between carotid plaque characteristics and the AIM-HIGH endpoint changed little after adjusting for clinical risk factors, plaque burden, or AIM-HIGH randomized treatment assignment. Among patients with clinically established atherosclerotic disease, carotid plaque lipid content and fibrous cap status were strongly associated with systemic cardiovascular outcomes. Markers of carotid plaque vulnerability may serve as novel surrogate markers for systemic atherothrombotic risk. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Haploinsufficiency of E-selectin ligand-1 is Associated with Reduced Atherosclerotic Plaque Macrophage Content while Complete Deficiency Leads to Early Embryonic Lethality in Mice

PubMed Central

Luo, Wei; Wang, Hui; Guo, Chiao; Wang, Jintao; Kwak, Jeffrey; Bahrou, Kristina L; Eitzman, Daniel T.

2012-01-01

E-selectin-1 (ESL-1), also known as golgi complex-localized glycoprotein-1 (GLG1), homocysteine-rich fibroblast growth factor receptor (CGR-1), and latent transforming growth factor-β complex protein 1 (LTCP-1), is a multifunctional protein with widespread tissue distribution. To determine the functional consequences of ESL-1 deficiency, mice were generated carrying an ESL-1 gene trap. After backcrossing to C57BL6/J for 6 generations, mice heterozygous for the gene trap (ESL-1+/-) were intercrossed to produce ESL-1-/- mice, however ESL-1-/- mice were not viable, even at embryonic day E10.5. To determine the effect of heterozygous ESL-1 deficiency on atherosclerosis, apolipoprotein E deficient (ApoE-/-), ESL-1+/- mice were generated and fed western diet. Compared to ApoE-/-, ESL-1++ mice, atherosclerotic lesions from ApoE-/-, ESL-1+/- contained more collagen and fewer macrophages, suggesting increased plaque stability. In conclusion, heterozygous deficiency of ESL-1 is associated with features of increased atherosclerotic plaque stability while complete deficiency of ESL-1 leads to embryonic lethality. PMID:22939356

Quantifying progression and regression of thrombotic risk in experimental atherosclerosis.

PubMed

Palekar, Rohun U; Jallouk, Andrew P; Goette, Matthew J; Chen, Junjie; Myerson, Jacob W; Allen, John S; Akk, Antonina; Yang, Lihua; Tu, Yizheng; Miller, Mark J; Pham, Christine T N; Wickline, Samuel A; Pan, Hua

2015-07-01

Currently, there are no generally applicable noninvasive methods for defining the relationship between atherosclerotic vascular damage and risk of focal thrombosis. Herein, we demonstrate methods to delineate the progression and regression of vascular damage in response to an atherogenic diet by quantifying the in vivo accumulation of semipermeable 200-300 nm perfluorocarbon core nanoparticles (PFC-NP) in ApoE null mouse plaques with [(19)F] magnetic resonance spectroscopy (MRS). Permeability to PFC-NP remained minimal until 12 weeks on diet, then increased rapidly following 12 weeks, but regressed to baseline within 8 weeks after diet normalization. Markedly accelerated clotting (53.3% decrease in clotting time) was observed in carotid artery preparations of fat-fed mice subjected to photochemical injury as defined by the time to flow cessation. For all mice on and off diet, an inverse linear relationship was observed between the permeability to PFC-NP and accelerated thrombosis (P = 0.02). Translational feasibility for quantifying plaque permeability and vascular damage in vivo was demonstrated with clinical 3 T MRI of PFC-NP accumulating in plaques of atherosclerotic rabbits. These observations suggest that excessive permeability to PFC-NP may indicate prothrombotic risk in damaged atherosclerotic vasculature, which resolves within weeks after dietary therapy. © FASEB.

Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming

PubMed Central

Zimmer, Sebastian; Grebe, Alena; Bakke, Siril S.; Bode, Niklas; Halvorsen, Bente; Ulas, Thomas; Skjelland, Mona; De Nardo, Dominic; Labzin, Larisa I.; Kerksiek, Anja; Hempel, Chris; Heneka, Michael T.; Hawxhurst, Victoria; Fitzgerald, Michael L; Trebicka, Jonel; Gustafsson, Jan-Åke; Westerterp, Marit; Tall, Alan R.; Wright, Samuel D.; Espevik, Terje; Schultze, Joachim L.; Nickenig, Georg; Lütjohann, Dieter; Latz, Eicke

2016-01-01

Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Since cholesterol accumulation and deposition of cholesterol crystals (CCs) triggers a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility, in preventing and reversing atherosclerosis. Here we show that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load, and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques, and promoted liver X receptor (LXR)-mediated transcriptional reprogramming to improve cholesterol efflux and exert anti-inflammatory effects. In vivo, this CD-mediated LXR agonism was required for the anti-atherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Since CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis. PMID:27053774

Rosuvastatin reduces atherosclerotic lesions and promotes progenitor cell mobilisation and recruitment in apolipoprotein E knockout mice.

PubMed

Schroeter, Marco R; Humboldt, Tim; Schäfer, Katrin; Konstantinides, Stavros

2009-07-01

Statins enhance incorporation of bone marrow-derived cells into experimental neointimal lesions. However, the contribution of progenitor cells to progression of spontaneous atherosclerotic plaques, and the possible modulatory role of statins in this process, remain poorly understood. We compared the effects of rosuvastatin (1 and 10mg/kg BW) and pravastatin (10mg/kg) on progenitor cell mobilisation, recruitment into atherosclerotic plaques, and lesion growth. Statins were administered over 8 weeks to apolipoprotein E knockout mice on atherogenic diet. In addition, mice were lethally irradiated, followed by transplantation of bone marrow from LacZ transgenic mice. Rosuvastatin reduced lesion area and intima-to-media ratio at the brachiocephalic artery compared to vehicle, while both parameters were not significantly altered by pravastatin. Rosuvastatin also augmented endothelialisation (P<0.05) and reduced the smooth muscle cells (SMC) content (P=0.042) of lesions. Numbers of c-kit, sca-1 and flk-1, sca-1 double-positive progenitor cells were significantly increased in rosuvastatin compared to control-treated mice, both in the bone marrow and the peripheral blood. Similarly, the number of spleen-derived acLDL, lectin double-positive progenitor cells (P=0.001) and colony-forming units (P=0.0104) was significantly increased in mice treated with rosuvastatin compared to vehicle alone. In the bone marrow, increased Akt and p42/44 MAP kinase phosphorylation and upregulated SDF1alpha mRNA expression were observed. Importantly, rosuvastatin treatment also increased the plasma levels of c-kit ligand (P=0.003), and the number of c-kit-positive cells within atherosclerotic lesions (P=0.041). Our findings suggest that rosuvastatin reduces the size of atherosclerotic plaques, and this effect appears to involve progenitor cell mobilisation and recruitment into vascular lesions.

Coronary atherosclerosis evaluation among Iranian patients with zero coronary calcium score in computed tomography coronary angiography.

PubMed

Moradi, Maryam; Varasteh, Elham

2016-01-01

Coronary artery calcification (CAC) is a specific indicator of and a sensitive marker for the atherosclerotic disease process. However, calcium scoring may miss noncalcified plaques with clinical importance. The present study aimed to identify the presence and extent of coronary plaques in computed tomography coronary angiography (CTCA) in patients with a zero CAC score and the secondary endpoint was to evaluate the association between coronary risk factors and the presence of noncalcified plaques. In a retrospective descriptive-analytic study, a total of 2000 consecutive patients who undergone CTCA between September 2012 and September 2014 at Alzahra Hospital in Isfahan, Iran were analyzed. Three hundred and eighty-five patients with a zero calcium score were included in the study. The demographic information and coronary artery disease (CAD), risk factors including diabetes mellitus (DM), hypertension, hyperlipidemia, smoking, and family history of CAD, were obtained from the questionnaire. Furthermore, the presence of plaques and extent of stenosis were evaluated in patients with zero CAC score. Of the 385 patients with a zero calcium score, 16 (4.2%) had atherosclerotic plaques. Among them, 6 (1.6%) had significant (>50%) coronary stenosis, and 10 (2.6%) had no significant (<50%) coronary stenosis. Hyperlipidemia, DM, and smoking were significantly associated with obstructive CAD. Furthermore, in patients with zero calcium score, DM, hyperlipidemia, and smoking had odds ratios of 5.9, 14, and 32.5 for the development of coronary artery plaques, respectively. Although, CAC scoring is a noninvasive and valuable method to evaluate CAD; but zero CAC score does not absolutely exclude the CAD, especially in the presence of risk factors such as diabetes, hyperlipidemia, and smoking.

Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice.

PubMed

Kritikou, Eva; van Puijvelde, Gijs H M; van der Heijden, Thomas; van Santbrink, Peter J; Swart, Maarten; Schaftenaar, Frank H; Kröner, Mara J; Kuiper, Johan; Bot, Ilze

2016-11-24

Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA 1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA 1/3 antagonism using the small molecule Ki16425. We show that LPA 1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA 1/3 blockade enhanced the percentage of non-inflammatory, Ly6C low monocytes and CD4 + CD25 + FoxP3 + T-regulatory cells. Finally, we demonstrate that LPA 1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA 1/3 receptors may prove a promising approach to diminish atherosclerosis development.

[Plaque segmentation of intracoronary optical coherence tomography images based on K-means and improved random walk algorithm].

PubMed

Wang, Guanglei; Wang, Pengyu; Han, Yechen; Liu, Xiuling; Li, Yan; Lu, Qian

2017-06-01

In recent years, optical coherence tomography (OCT) has developed into a popular coronary imaging technology at home and abroad. The segmentation of plaque regions in coronary OCT images has great significance for vulnerable plaque recognition and research. In this paper, a new algorithm based on K -means clustering and improved random walk is proposed and Semi-automated segmentation of calcified plaque, fibrotic plaque and lipid pool was achieved. And the weight function of random walk is improved. The distance between the edges of pixels in the image and the seed points is added to the definition of the weight function. It increases the weak edge weights and prevent over-segmentation. Based on the above methods, the OCT images of 9 coronary atherosclerotic patients were selected for plaque segmentation. By contrasting the doctor's manual segmentation results with this method, it was proved that this method had good robustness and accuracy. It is hoped that this method can be helpful for the clinical diagnosis of coronary heart disease.

CML/CD36 accelerates atherosclerotic progression via inhibiting foam cell migration.

PubMed

Xu, Suining; Li, Lihua; Yan, Jinchuan; Ye, Fei; Shao, Chen; Sun, Zhen; Bao, Zhengyang; Dai, Zhiyin; Zhu, Jie; Jing, Lele; Wang, Zhongqun

2018-01-01

Among the various complications of type 2 diabetes mellitus, atherosclerosis causes the highest disability and morbidity. A multitude of macrophage-derived foam cells are retained in atherosclerotic plaques resulting not only from recruitment of monocytes into lesions but also from a reduced rate of macrophage migration from lesions. Nε-carboxymethyl-Lysine (CML), an advanced glycation end product, is responsible for most complications of diabetes. This study was designed to investigate the mechanism of CML/CD36 accelerating atherosclerotic progression via inhibiting foam cell migration. In vivo study and in vitro study were performed. For the in vivo investigation, CML/CD36 accelerated atherosclerotic progression via promoting the accumulation of macrophage-derived foam cells in aorta and inhibited macrophage-derived foam cells in aorta migrating to the para-aorta lymph node of diabetic apoE -/- mice. For the in vitro investigation, CML/CD36 inhibited RAW264.7-derived foam cell migration through NOX-derived ROS, FAK phosphorylation, Arp2/3 complex activation and F-actin polymerization. Thus, we concluded that CML/CD36 inhibited foam cells of plaque migrating to para-aorta lymph nodes, accelerating atherosclerotic progression. The corresponding mechanism may be via free cholesterol, ROS generation, p-FAK, Arp2/3, F-actin polymerization. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Characterization and morphology of atherosclerotic plaque of coronary arteries: utility of electron-beam tomography to detect non-calcified plaque: a comparison with conventional coronary angiography and intravascular ultrasound.

PubMed

Funabashi, Nobusada; Misumi, Kazuo; Ohnishi, Hiroyuki; Asano, Miki; Komuro, Issei

2007-01-31

Electron-beam tomography (EBT) may provide useful information about characterization and morphology of atherosclerotic plaque of coronary arteries. Twenty-six subjects (20 male, 6 female) with suspected coronary heart disease had two routine (r) and one enhanced (e) EBT scans to detect non-calcified plaque (NCP) in the coronary arterial lumen, and were compared with conventional coronary angiograms (CAG) and intravascular ultrasound (IVUS). Three had the sites, which did not have high CT values suggesting calcification in rEBT, nor which was not enhanced by contrast material in eEBT. One had the site with positive CT values that were supposed to be the proliferation intima or organized thrombus and at the corresponding site mixed plaque was observed in the IVUS image. The other two had the site with negative CT values that were supposed to be fat tissue with significant stenosis in CAG. We also made the cross-sectional images of the vessel and the morphology of the NCP, which projected into the lumen, could be evaluated. We could detect the NCP, differentiate fat tissue from soft tissue and evaluate the morphology of the plaque in EBT.

Autophagy is required for endothelial cell alignment and atheroprotection under physiological blood flow

PubMed Central

Vion, Anne-Clemence; Hammoutene, Adel; Poisson, Johanne; Lasselin, Juliette; Devue, Cecile; Pic, Isabelle; Dupont, Nicolas; Busse, Johanna; Stark, Konstantin; Lafaurie-Janvore, Julie; Barakat, Abdul I.; Loyer, Xavier; Souyri, Michele; Viollet, Benoit; Julia, Pierre; Tedgui, Alain; Codogno, Patrice; Rautou, Pierre-Emmanuel

2017-01-01

It has been known for some time that atherosclerotic lesions preferentially develop in areas exposed to low SS and are characterized by a proinflammatory, apoptotic, and senescent endothelial phenotype. Conversely, areas exposed to high SS are protected from plaque development, but the mechanisms have remained elusive. Autophagy is a protective mechanism that allows recycling of defective organelles and proteins to maintain cellular homeostasis. We aimed to understand the role of endothelial autophagy in the atheroprotective effect of high SS. Atheroprotective high SS stimulated endothelial autophagic flux in human and murine arteries. On the contrary, endothelial cells exposed to atheroprone low SS were characterized by inefficient autophagy as a result of mammalian target of rapamycin (mTOR) activation, AMPKα inhibition, and blockade of the autophagic flux. In hypercholesterolemic mice, deficiency in endothelial autophagy increased plaque burden only in the atheroresistant areas exposed to high SS; plaque size was unchanged in atheroprone areas, in which endothelial autophagy flux is already blocked. In cultured cells and in transgenic mice, deficiency in endothelial autophagy was characterized by defects in endothelial alignment with flow direction, a hallmark of endothelial cell health. This effect was associated with an increase in endothelial apoptosis and senescence in high-SS regions. Deficiency in endothelial autophagy also increased TNF-α–induced inflammation under high-SS conditions and decreased expression of the antiinflammatory factor KLF-2. Altogether, these results show that adequate endothelial autophagic flux under high SS limits atherosclerotic plaque formation by preventing endothelial apoptosis, senescence, and inflammation. PMID:28973855

Modeling plaque fissuring and dissection during balloon angioplasty intervention.

PubMed

Gasser, T Christian; Holzapfel, Gerhard A

2007-05-01

Balloon angioplasty intervention is traumatic to arterial tissue. Fracture mechanisms such as plaque fissuring and/or dissection occur and constitute major contributions to the lumen enlargement. However, these types of mechanically-based traumatization of arterial tissue are also contributing factors to both acute procedural complications and chronic restenosis of the treatment site. We propose physical and finite element models, which are generally useable to trace fissuring and/or dissection in atherosclerotic plaques during balloon angioplasty interventions. The arterial wall is described as an anisotropic, heterogeneous, highly deformable, nearly incompressible body, whereas tissue failure is captured by a strong discontinuity kinematics and a novel cohesive zone model. The numerical implementation is based on the partition of unity finite element method and the interface element method. The later is used to link together meshes of the different tissue components. The balloon angioplasty-based failure mechanisms are numerically studied in 3D by means of an atherosclerotic-prone human external iliac artery, with a type V lesion. Image-based 3D geometry is generated and tissue-specific material properties are considered. Numerical results show that in a primary phase the plaque fissures at both shoulders of the fibrous cap and stops at the lamina elastica interna. In a secondary phase, local dissections between the intima and the media develop at the fibrous cap location with the smallest thickness. The predicted results indicate that plaque fissuring and dissection cause localized mechanical trauma, but prevent the main portion of the stenosis from high stress, and hence from continuous tissue damage.

Differentiation of early from advanced coronary atherosclerotic lesions: systematic comparison of CT, intravascular US, and optical frequency domain imaging with histopathologic examination in ex vivo human hearts.

PubMed

Maurovich-Horvat, Pál; Schlett, Christopher L; Alkadhi, Hatem; Nakano, Masataka; Stolzmann, Paul; Vorpahl, Marc; Scheffel, Hans; Tanaka, Atsushi; Warger, William C; Maehara, Akiko; Ma, Shixin; Kriegel, Matthias F; Kaple, Ryan K; Seifarth, Harald; Bamberg, Fabian; Mintz, Gary S; Tearney, Guillermo J; Virmani, Renu; Hoffmann, Udo

2012-11-01

To establish an ex vivo experimental setup for imaging coronary atherosclerosis with coronary computed tomographic (CT) angiography, intravascular ultrasonography (US), and optical frequency domain imaging (OFDI) and to investigate their ability to help differentiate early from advanced coronary plaques. All procedures were performed in accordance with local and federal regulations and the Declaration of Helsinki. Approval of the local Ethics Committee was obtained. Overall, 379 histologic cuts from nine coronary arteries from three donor hearts were acquired, coregistered among modalities, and assessed for the presence and composition of atherosclerotic plaque. To assess the discriminatory capacity of the different modalities in the detection of advanced lesions, c statistic analysis was used. Interobserver agreement was assessed with the Cohen κ statistic. Cross sections without plaque at coronary CT angiography and with fibrous plaque at OFDI almost never showed advanced lesions at histopathologic examination (odds ratio [OR]: 0.02 and 0.06, respectively; both P<.0001), while mixed plaque at coronary CT angiography, calcified plaque at intravascular US, and lipid-rich plaque at OFDI were associated with advanced lesions (OR: 2.49, P=.0003; OR: 2.60, P=.002; and OR: 31.2, P<.0001, respectively). OFDI had higher accuracy for discriminating early from advanced lesions than intravascular US and coronary CT angiography (area under the receiver operating characteristic curve: 0.858 [95% confidence interval {CI}: 0.802, 0.913], 0.631 [95% CI: 0.554, 0.709], and 0.679 [95% CI: 0.618, 0.740]; respectively, P<.0001). Interobserver agreement was excellent for OFDI and coronary CT angiography (κ=0.87 and 0.85, respectively) and was good for intravascular US (κ=0.66). Systematic and standardized comparison between invasive and noninvasive modalities for coronary plaque characterization in ex vivo specimens demonstrated that coronary CT angiography and intravascular US are reasonably associated with plaque composition and lesion grading according to histopathologic findings, while OFDI was strongly associated. These data may help to develop initial concepts of sequential imaging strategies to identify patients with advanced coronary plaques. © RSNA, 2012

Advances in atheroma imaging in the carotid.

PubMed

Gillard, Jonathan H

2007-01-01

Atherosclerosis affects all vascular beds, including the coronary, carotid, intracerebral, peripheral and aortic vascular beds, and is responsible for tremendous morbidity and mortality, with the most serious outcomes being myocardial infarction, stroke and death. Historically the effects of vascular narrowing and associated thrombosis have been key indicators of disease in the coronary and carotid territories, with degrees of vascular stenosis being of profound importance in carotid surgery trials. Our improving understanding of the biology of atheromatous lesions and the development of alternative therapeutic agents which can initiate actual plaque regression have created a need to attempt to image plaque itself, with the carotid artery being an achievable target. This article reviews current strategies for assessing carotid atherosclerotic disease, particularly with reference to identifying plaque components and risk of rupture, the so-called vulnerable plaque. Copyright 2007 S. Karger AG, Basel.

Sildenafil Inhibits the Proliferation of Cultured Human Endothelial Cells

PubMed Central

Erdogan, Ali; Luedders, Doerte Wiebke; Muenz, Benedikt Manuel; Schaefer, Christian Alexander; Tillmanns, Harald; Wiecha, Johannes; Kuhlmann, Christoph Ruediger Wolfram

2007-01-01

The proliferation of endothelial cells plays a crucial role in the development of intraplaque angiogenesis (IPA). IPA is a major source of intraplaque hemorrhage and therefore contributes to the destabilization of atherosclerotic plaques. Therefore, the aim of the present study was to examine, whether sildenafil inhibits endothelial cell growth. The proliferation of human endothelial cells derived from umbilical cord veins (HUVEC) was examined on DNA level by measurements of (3H)-thymidine incorporation. Cell viability was analyzed using trypan blue staining. The proliferation of cultured human endothelial cells was significantly decreased by 1 μmol/l (-48.4%) and 10 μmol/l (-89.6%) sildenafil (n=10, p<0.05). This was not a cytotoxic effect, because cell viability was only reduced at sildenafil concentrations of 50 μmol/l or greater. In addition sildenafil significantly reduced endothelial proliferation induced by bFGF (n=10, p<0.05). The presented results demonstrate an antiangiogenic effect of sildenafil that might be useful in the prevention of atherosclerotic plaque vascularization. PMID:23675029

AIBP reduces atherosclerosis by promoting reverse cholesterol transport and ameliorating inflammation in apoE-/- mice.

PubMed

Zhang, Min; Zhao, Guo-Jun; Yao, Feng; Xia, Xiao-Dan; Gong, Duo; Zhao, Zhen-Wang; Chen, Ling-Yan; Zheng, Xi-Long; Tang, Xiao-Er; Tang, Chao-Ke

2018-06-01

ApoA-1 binding protein (AIBP) is a secreted protein that interacts with apoA-I and accelerates cholesterol efflux from cells. We have recently reported that AIBP promotes apoA-1 binding to ABCA1 in the macrophage cell membrane, partially through 115-123 amino acids. However, the effects of AIBP on the development of atherosclerosis in vivo remain unknown. ApoE -/- mice with established atherosclerotic plaques were infected with rAAV-AIBP or rAAV-AIBP(Δ115-123), respectively. AIBP-treated mice showed reduction of atherosclerotic lesion formation, increase in circulating HDL levels and enhancement of reverse cholesterol transport to the plasma, liver, and feces. AIBP increased ABCA1 protein levels in aorta and peritoneal macrophages. Furthermore, AIBP could diminish atherosclerotic plaque macrophage content and the expression of chemotaxis-related factors. In addition, AIBP prevented macrophage inflammation by inactivating NF-κB and promoted the expression of M2 markers like Mrc-1 and Arg-1. However, lack of 115-123 amino acids of AIBP(Δ115-123) had no such preventive effects on the progression of atherosclerosis. Our observations demonstrate that AIBP inhibits atherosclerosis progression and suggest that it may be an effective target for prevention of atherosclerosis. Copyright © 2018 Elsevier B.V. All rights reserved.

SAP deficiency mitigated atherosclerotic lesions in ApoE(-/-) mice.

PubMed

Zheng, Lingyun; Wu, Teng; Zeng, Cuiling; Li, Xiangli; Li, Xiaoqiang; Wen, Dingwen; Ji, Tianxing; Lan, Tian; Xing, Liying; Li, Jiangchao; He, Xiaodong; Wang, Lijing

2016-01-01

Serum amyloid P conpoent (SAP), a member of the pentraxin family, interact with pathogens and cell debris to promote their removal by macrophages and neutrophils and is co-localized with atherosclerotic plaques in patients. However, the exact mechanism of SAP in atherogenesis is still unclear. We investigated whether SAP influence macrophage recruitment and foam cell formation and ultimately affect atherosclerotic progression. we generated apoE(-/-); SAP(-/-) (DKO) mice and fed them western diet for 4 and 8 weeks to characterize atherosclerosis development. SAP deficiency effectively reduced plaque size both in the aorta (p = 0.0006 for 4 wks; p = 0.0001 for 8 wks) and the aortic root (p = 0.0061 for 4 wks; p = 0.0079 for 8wks) compared with apoE(-/-) mice. Meanwhile, SAP deficiency inhibited oxLDL-induced foam cell formation (p = 0.0004) compared with apoE(-/-) mice and SAP treatment increases oxLDL-induced foam cell formation (p = 0.002) in RAW cells. Besides, SAP deficiency reduced macrophages recruitment (p = 0.035) in vivo and in vitro (p = 0.026). Furthermore, SAP treatment enhanced CD36 (p = 0.007) and FcγRI (p = 0.031) expression induced by oxLDL through upregulating JNK and p38 MAPK phosphorylation whereas specific JNK1/2 inhibitor reduced CD36 (p = 0.0005) and FcγRI (P = 0.0007) expression in RAW cell. SAP deficiency also significantly decreased the expression of M1 and M2 macrophage markers and inflammatory cytokines in oxLDL-induced macrophages. SAP deficiency mitigated foam cell formation and atherosclerotic development in apoE(-/-) mice, due to reduction in macrophages recruitment, polarization and pro-inflammatory cytokines and inhibition the CD36/FcγR-dependent signaling pathway. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Xanthine Oxidase Inhibition by Febuxostat Attenuates Experimental Atherosclerosis in Mice

PubMed Central

Nomura, Johji; Busso, Nathalie; Ives, Annette; Matsui, Chieko; Tsujimoto, Syunsuke; Shirakura, Takashi; Tamura, Mizuho; Kobayashi, Tsunefumi; So, Alexander; Yamanaka, Yoshihiro

2014-01-01

Atherosclerosis is a chronic inflammatory disease due to lipid deposition in the arterial wall. Multiple mechanisms participate in the inflammatory process, including oxidative stress. Xanthine oxidase (XO) is a major source of reactive oxygen species (ROS) and has been linked to the pathogenesis of atherosclerosis, but the underlying mechanisms remain unclear. Here, we show enhanced XO expression in macrophages in the atherosclerotic plaque and in aortic endothelial cells in ApoE−/− mice, and that febuxostat, a highly potent XO inhibitor, suppressed plaque formation, reduced arterial ROS levels and improved endothelial dysfunction in ApoE−/− mice without affecting plasma cholesterol levels. In vitro, febuxostat inhibited cholesterol crystal-induced ROS formation and inflammatory cytokine release in murine macrophages. These results demonstrate that in the atherosclerotic plaque, XO-mediated ROS formation is pro-inflammatory and XO-inhibition by febuxostat is a potential therapy for atherosclerosis. PMID:24686534

Endoplasmic reticulum stress in perivascular adipose tissue promotes destabilization of atherosclerotic plaque by regulating GM-CSF paracrine.

PubMed

Ying, Ru; Li, Sheng-Wei; Chen, Jia-Yuan; Zhang, Hai-Feng; Yang, Ying; Gu, Zhen-Jie; Chen, Yang-Xin; Wang, Jing-Feng

2018-04-18

Perivascular adipose tissue (PVAT) accelerates plaque progression and increases cardiovascular risk. We tested the hypothesis that PVAT contributed to plaque vulnerability and investigated whether endoplasmic reticulum stress (ER stress) in PVAT played an important role in vulnerable plaque. We transplanted thoracic aortic PVAT or subcutaneous adipose tissue as a control, from donor mice to carotid arteries of recipient apolipoprotein E deficient (apoE -/- ) mice after removing carotid artery collar placed for 6 weeks. Two weeks after transplantation, ER stress inhibitor 4-phenyl butyric acid (4-PBA) was locally administrated to the transplanted PVAT and then animals were euthanized after 4 weeks. Immunohistochemistry was performed to quantify plaque composition and neovascularization. Mouse angiogenesis antibody array kit was used to test the angiogenic factors produced by transplanted adipose tissue. In vitro tube formation assay, scratch wound migration assay and mouse aortic ring assay were used to assess the angiogenic capacity of supernatant of transplanted PVAT. Ultrastructural detection by transmission electron microscopy showed transplanted PVAT was a mixed population of white and brown adipocytes with abundant mitochondria. Transplanted PVAT increased the intraplaque macrophage infiltration, lipid core, intimal and vasa vasorum neovascularization and MMP2/9 expression in plaque while decreased smooth muscle cells and collagen in atherosclerotic plaque, which were restored by local 4-PBA-treatment. Antibody array analysis showed that 4-PBA reduced several angiogenic factors [Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), MCP-1, IL-6] secreted by PVAT. Besides, conditioned medium from 4-PBA treated-PVAT inhibited tube formation and migration capacity of endothelial cells and ex vivo mouse aortic ring angiogenesis compared to conditioned medium from transplanted PVAT. mRNA expression and protein levels of GM-CSF were markedly elevated in adipocytes under ER stress which would be suppressed by 4-PBA. In addition, ER stress enhanced NF-κB binding to the promoter of the mouse GM-CSF gene in adipocytes confirmed by Chromatin immunoprecipitation analyses. Our findings demonstrate that ER stress in PVAT destabilizes atherosclerotic plaque, in part through increasing GM-CSF paracrine via transcription factor NF-κB.

RANTES/CCL5 and risk for coronary events: results from the MONICA/KORA Augsburg case-cohort, Athero-Express and CARDIoGRAM studies.

PubMed

Herder, Christian; Peeters, Wouter; Illig, Thomas; Baumert, Jens; de Kleijn, Dominique P V; Moll, Frans L; Poschen, Ulrike; Klopp, Norman; Müller-Nurasyid, Martina; Roden, Michael; Preuss, Michael; Karakas, Mahir; Meisinger, Christa; Thorand, Barbara; Pasterkamp, Gerard; Koenig, Wolfgang; Assimes, Themistocles L; Deloukas, Panos; Erdmann, Jeanette; Holm, Hilma; Kathiresan, Sekar; König, Inke R; McPherson, Ruth; Reilly, Muredach P; Roberts, Robert; Samani, Nilesh J; Schunkert, Heribert; Stewart, Alexandre F R

2011-01-01

The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75-1.42] and 1.11 [0.81-1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (>22,000 cases, >60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years). High RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies.

Freehand three-dimensional ultrasound imaging of carotid artery using motion tracking technology.

PubMed

Chung, Shao-Wen; Shih, Cho-Chiang; Huang, Chih-Chung

2017-02-01

Ultrasound imaging has been extensively used for determining the severity of carotid atherosclerotic stenosis. In particular, the morphological characterization of carotid plaques can be performed for risk stratification of patients. However, using 2D ultrasound imaging for detecting morphological changes in plaques has several limitations. Due to the scan was performed on a single longitudinal cross-section, the selected 2D image is difficult to represent the entire morphology and volume of plaque and vessel lumen. In addition, the precise positions of 2D ultrasound images highly depend on the radiologists' experience, it makes the serial long-term exams of anti-atherosclerotic therapies are difficult to relocate the same corresponding planes by using 2D B-mode images. This has led to the recent development of three-dimensional (3D) ultrasound imaging, which offers improved visualization and quantification of complex morphologies of carotid plaques. In the present study, a freehand 3D ultrasound imaging technique based on optical motion tracking technology is proposed. Unlike other optical tracking systems, the marker is a small rigid body that is attached to the ultrasound probe and is tracked by eight high-performance digital cameras. The probe positions in 3D space coordinates are then calibrated at spatial and temporal resolutions of 10μm and 0.01s, respectively. The image segmentation procedure involves Otsu's and the active contour model algorithms and accurately detects the contours of the carotid arteries. The proposed imaging technique was verified using normal artery and atherosclerotic stenosis phantoms. Human experiments involving freehand scanning of the carotid artery of a volunteer were also performed. The results indicated that compared with manual segmentation, the lowest percentage errors of the proposed segmentation procedure were 7.8% and 9.1% for the external and internal carotid arteries, respectively. Finally, the effect of handshaking was calibrated using the optical tracking system for reconstructing a 3D image. Copyright © 2016 Elsevier B.V. All rights reserved.

Rationale and design of dal-PLAQUE: A study assessing efficacy and safety of dalcetrapib on progression or regression of atherosclerosis using magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography/computed tomography

PubMed Central

Fayad, Zahi A.; Mani, Venkatesh; Woodward, Mark; Kallend, David; Bansilal, Sameer; Pozza, Joseph; Burgess, Tracy; Fuster, Valentin; Rudd, James H. F.; Tawakol, Ahmed; Farkouh, Michael E.

2014-01-01

dal-PLAQUE is a placebo-controlled multicenter study designed to assess the effect of dalcetrapib on imaging measures of plaque inflammation and plaque burden. dal-PLAQUE is a multimodality imaging study in the context of the large dal-HEART Program. Decreased high-density lipoprotein cholesterol is linked to increased risk of coronary heart disease (CHD). Dalcetrapib, a compound that increases high-density lipoprotein cholesterol by modulating cholesteryl ester transfer protein, is being studied to assess if it can reduce the progression of atherosclerotic disease and thereby decrease cardiovascular morbidity and mortality. Patients with CHD or CHD-risk equivalents were randomized to receive 600 mg dalcetrapib or placebo daily for 24 months, in addition to conventional lipid-lowering medication and other medications for cardiovascular risk factors. The primary outcomes are the effect of dalcetrapib on 18F-fluorodeoxyglucose positron emission tomography target-to-background ratio after 6 months and magnetic resonance imaging (MRI) plaque burden (wall area, wall thickness, total vessel area, and wall area/total vessel area ratio) after 12 months. Secondary objectives include positron emission tomography target-to-background ratio at 3 months and MRI plaque burden at 6 and 24 months; plaque composition at 6, 12, and 24 months; and aortic compliance at 6 months. A tertiary objective is to examine the dynamic contrast-enhanced MRI parameters of plaque neovascularization. In total, 189 subjects entered screening, and 130 were randomized. dal-PLAQUE will provide important information on the effects of dalcetrapib on markers of inflammation and atherosclerotic plaque burden and, thereby, on the safety of cholesteryl ester transfer protein modulation with dalcetrapib. Results are expected in 2011. PMID:21835280

Currently available methodologies for the processing of intravascular ultrasound and optical coherence tomography images.

PubMed

Athanasiou, Lambros; Sakellarios, Antonis I; Bourantas, Christos V; Tsirka, Georgia; Siogkas, Panagiotis; Exarchos, Themis P; Naka, Katerina K; Michalis, Lampros K; Fotiadis, Dimitrios I

2014-07-01

Optical coherence tomography and intravascular ultrasound are the most widely used methodologies in clinical practice as they provide high resolution cross-sectional images that allow comprehensive visualization of the lumen and plaque morphology. Several methods have been developed in recent years to process the output of these imaging modalities, which allow fast, reliable and reproducible detection of the luminal borders and characterization of plaque composition. These methods have proven useful in the study of the atherosclerotic process as they have facilitated analysis of a vast amount of data. This review presents currently available intravascular ultrasound and optical coherence tomography processing methodologies for segmenting and characterizing the plaque area, highlighting their advantages and disadvantages, and discusses the future trends in intravascular imaging.

Atherosclerosis in the circle of Willis: Spatial differences in composition and in distribution of plaques.

PubMed

Denswil, Nerissa P; van der Wal, Allard C; Ritz, Katja; de Boer, Onno J; Aronica, Eleonora; Troost, Dirk; Daemen, Mat J A P

2016-08-01

Intracranial atherosclerosis is one of the main causes of ischemic stroke. However, the characteristics of intracranial arteries and atherosclerosis have rarely been studied. Therefore, we systematically investigated atherosclerotic changes in all arteries of the Circle of Willis (CoW). Sixty-seven CoWs obtained at autopsy from randomly chosen hospital patients (mean age, 67.3 ± 12.5 years), of which a total of 1220 segments were collected from 22 sites. Atherosclerotic plaques were classified according to the revised American Heart Association classification and were related to local vessel characteristics, such as the presence of an external and internal elastic lamina and the elastic fibre density of the media. 181 out of the 1220 segments had advanced plaques (15%), which were mainly observed in large arteries such as the internal carotid, middle cerebral, basilar and vertebral artery. Only 11 out of 1220 segments (1%) showed complicated plaques (p < 0.001). Six of these were intraplaque hemorrhages (IPH) and observed only in patients who had cardiovascular-related events (p = 0.015). The frequency of characteristics such as the external elastic lamina and a high elastin fibre density in the media was most often associated with the vertebral artery. Only 3% (n = 33) of the CoW arteries contained calcification (p < 0.001), which were mostly observed in the vertebral artery (n = 13, 12%). Advanced atherosclerotic plaques in the CoW are relatively scarce and mainly located in the 4 large arteries, and mostly characterized by an early and stable phenotype, a low calcific burden, and a low frequency of IPH. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness.

PubMed

Yu, Emma P K; Reinhold, Johannes; Yu, Haixiang; Starks, Lakshi; Uryga, Anna K; Foote, Kirsty; Finigan, Alison; Figg, Nichola; Pung, Yuh-Fen; Logan, Angela; Murphy, Michael P; Bennett, Martin

2017-12-01

Mitochondrial DNA (mtDNA) damage is present in murine and human atherosclerotic plaques. However, whether endogenous levels of mtDNA damage are sufficient to cause mitochondrial dysfunction and whether decreasing mtDNA damage and improving mitochondrial respiration affects plaque burden or composition are unclear. We examined mitochondrial respiration in human atherosclerotic plaques and whether augmenting mitochondrial respiration affects atherogenesis. Human atherosclerotic plaques showed marked mitochondrial dysfunction, manifested as reduced mtDNA copy number and oxygen consumption rate in fibrous cap and core regions. Vascular smooth muscle cells derived from plaques showed impaired mitochondrial respiration, reduced complex I expression, and increased mitophagy, which was induced by oxidized low-density lipoprotein. Apolipoprotein E-deficient (ApoE -/- ) mice showed decreased mtDNA integrity and mitochondrial respiration, associated with increased mitochondrial reactive oxygen species. To determine whether alleviating mtDNA damage and increasing mitochondrial respiration affects atherogenesis, we studied ApoE -/- mice overexpressing the mitochondrial helicase Twinkle (Tw + /ApoE -/- ). Tw + /ApoE -/- mice showed increased mtDNA integrity, copy number, respiratory complex abundance, and respiration. Tw + /ApoE -/- mice had decreased necrotic core and increased fibrous cap areas, and Tw + /ApoE -/- bone marrow transplantation also reduced core areas. Twinkle increased vascular smooth muscle cell mtDNA integrity and respiration. Twinkle also promoted vascular smooth muscle cell proliferation and protected both vascular smooth muscle cells and macrophages from oxidative stress-induced apoptosis. Endogenous mtDNA damage in mouse and human atherosclerosis is associated with significantly reduced mitochondrial respiration. Reducing mtDNA damage and increasing mitochondrial respiration decrease necrotic core and increase fibrous cap areas independently of changes in reactive oxygen species and may be a promising therapeutic strategy in atherosclerosis. © 2017 The Authors.

The influence of computational strategy on prediction of mechanical stress in carotid atherosclerotic plaques: comparison of 2D structure-only, 3D structure-only, one-way and fully coupled fluid-structure interaction analyses.

PubMed

Huang, Yuan; Teng, Zhongzhao; Sadat, Umar; Graves, Martin J; Bennett, Martin R; Gillard, Jonathan H

2014-04-11

Compositional and morphological features of carotid atherosclerotic plaques provide complementary information to luminal stenosis in predicting clinical presentations. However, they alone cannot predict cerebrovascular risk. Mechanical stress within the plaque induced by cyclical changes in blood pressure has potential to assess plaque vulnerability. Various modeling strategies have been employed to predict stress, including 2D and 3D structure-only, 3D one-way and fully coupled fluid-structure interaction (FSI) simulations. However, differences in stress predictions using different strategies have not been assessed. Maximum principal stress (Stress-P1) within 8 human carotid atherosclerotic plaques was calculated based on geometry reconstructed from in vivo computerized tomography and high resolution, multi-sequence magnetic resonance images. Stress-P1 within the diseased region predicted by 2D and 3D structure-only, and 3D one-way FSI simulations were compared to 3D fully coupled FSI analysis. Compared to 3D fully coupled FSI, 2D structure-only simulation significantly overestimated stress level (94.1 kPa [65.2, 117.3] vs. 85.5 kPa [64.4, 113.6]; median [inter-quartile range], p=0.0004). However, when slices around the bifurcation region were excluded, stresses predicted by 2D structure-only simulations showed a good correlation (R(2)=0.69) with values obtained from 3D fully coupled FSI analysis. 3D structure-only model produced a small yet statistically significant stress overestimation compared to 3D fully coupled FSI (86.8 kPa [66.3, 115.8] vs. 85.5 kPa [64.4, 113.6]; p<0.0001). In contrast, one-way FSI underestimated stress compared to 3D fully coupled FSI (78.8 kPa [61.1, 100.4] vs. 85.5 kPa [64.4, 113.7]; p<0.0001). A 3D structure-only model seems to be a computationally inexpensive yet reasonably accurate approximation for stress within carotid atherosclerotic plaques with mild to moderate luminal stenosis as compared to fully coupled FSI analysis. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Myocardial Bridge and Acute Plaque Rupture.

PubMed

Perl, Leor; Daniels, David; Schwartz, Jonathan; Tanaka, Shige; Yeung, Alan; Tremmel, Jennifer A; Schnittger, Ingela

2016-01-01

A myocardial bridge (MB) is a common anatomic variant, most frequently located in the left anterior descending coronary artery, where a portion of the coronary artery is covered by myocardium. Importantly, MBs are known to result in a proximal atherosclerotic lesion. It has recently been postulated that these lesions predispose patients to acute coronary events, even in cases of otherwise low-risk patients. One such mechanism may involve acute plaque rupture. In this article, we report 2 cases of patients with MBs who presented with acute coronary syndromes despite having low cardiovascular risk. Their presentation was life-risking and both were treated urgently and studied with coronary angiographies and intravascular ultrasound. This latter modality confirmed a rupture of an atherosclerotic plaque proximal to the MB as a likely cause of the acute events. These cases, of unexplained acute coronary syndrome in low-risk patients, raise the question of alternative processes leading to the event and the role MB play as an underlying cause of ruptured plaques. In some cases, an active investigation for this entity may be warranted, due to the prognostic implications of the different therapeutic modalities, should an MB be discovered.

Overexpression of hypoxia/inflammatory markers in atherosclerotic carotid plaques.

PubMed

Luque, Ana; Turu, Marta; Juan-Babot, Oriol; Cardona, Pere; Font, Angels; Carvajal, Ana; Slevin, Mark; Iborra, Elena; Rubio, Francisco; Badimon, Lina; Krupinski, Jerzy

2008-05-01

Hypoxia, angiogenesis and inflammation leads to plaque progression and remodelling and may significantly contribute towards plaque rupture and subsequent cerebrovascular events. Our aim was to study, markers of hypoxia and inflammation previously identified by microarray analysis, in atherosclerotic carotid arteries with low to moderate stenosis. We hoped to describe different cellular populations expressing the studied markers. The location of selected inflammatory molecules obtained as vascular transplants from organ donors were analysed by immunohistochemistry with monoclonal and polyclonal antibodies. Paraffin-embedded sections were cut and probed with antibodies recognizing active B and T-lymphocytes (CD30), hypoxia-inducible factor-1alpha, endoglin (CD105), Interleukin-6 and C-reactive protein. We observed a notable overexpression of HIF-1alpha in inflammatory and hypoxic areas of carotid arteries in all types of lesions from type II-V taken from the patients with carotid stenosis less than 50%. This suggests that HIF-1alpha may have a putative role in atherosclerosis progression and angiogenesis. Dynamic changes in the non-occluding plaques may explain some of the clinical events in patients with low to moderate carotid stenosis.

Profilin-1 Is Expressed in Human Atherosclerotic Plaques and Induces Atherogenic Effects on Vascular Smooth Muscle Cells

PubMed Central

Caglayan, Evren; Romeo, Giulio R.; Kappert, Kai; Odenthal, Margarete; Südkamp, Michael; Body, Simon C.; Shernan, Stanton K.; Hackbusch, Daniel; Vantler, Marius; Kazlauskas, Andrius; Rosenkranz, Stephan

2010-01-01

Background Profilin-1 is an ubiquitous actin binding protein. Under pathological conditions such as diabetes, profilin-1 levels are increased in the vascular endothelium. We recently demonstrated that profilin-1 overexpression triggers indicators of endothelial dysfunction downstream of LDL signaling, and that attenuated expression of profilin-1 confers protection from atherosclerosis in vivo. Methodology Here we monitored profilin-1 expression in human atherosclerotic plaques by immunofluorescent staining. The effects of recombinant profilin-1 on atherogenic signaling pathways and cellular responses such as DNA synthesis (BrdU-incorporation) and chemotaxis (modified Boyden-chamber) were evaluated in cultured rat aortic and human coronary vascular smooth muscle cells (VSMCs). Furthermore, the correlation between profilin-1 serum levels and the degree of atherosclerosis was assessed in humans. Principal Findings In coronary arteries from patients with coronary heart disease, we found markedly enhanced profilin expression in atherosclerotic plaques compared to the normal vessel wall. Stimulation of rat aortic and human coronary VSMCs with recombinant profilin-1 (10−6 M) in vitro led to activation of intracellular signaling cascades such as phosphorylation of Erk1/2, p70S6 kinase and PI3K/Akt within 10 minutes. Furthermore, profilin-1 concentration-dependently induced DNA-synthesis and migration of both rat and human VSMCs, respectively. Inhibition of PI3K (Wortmannin, LY294002) or Src-family kinases (SU6656, PP2), but not PLCγ (U73122), completely abolished profilin-induced cell cycle progression, whereas PI3K inhibition partially reduced the chemotactic response. Finally, we found that profilin-1 serum levels were significantly elevated in patients with severe atherosclerosis in humans (p<0.001 vs. no atherosclerosis or control group). Conclusions Profilin-1 expression is significantly enhanced in human atherosclerotic plaques compared to the normal vessel wall, and the serum levels of profilin-1 correlate with the degree of atherosclerosis in humans. The atherogenic effects exerted by profilin-1 on VSMCs suggest an auto-/paracrine role within the plaque. These data indicate that profilin-1 might critically contribute to atherogenesis and may represent a novel therapeutic target. PMID:21049052

TU-F-12A-06: BEST IN PHYSICS (IMAGING) - A Novel Catheter-Based Radionuclide Imaging System to Characterize Atherosclerotic Plaque

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zaman, R; Kosuge, H; Carpenter, C

2014-06-15

Purpose: Atherosclerosis underlies coronary artery diseases, the leading cause of death in the United States and worldwide. In this study, we developed a novel catheter-based radionuclide imaging (CRI) system to image 18F-fluorodeoxyglucose (18F-FDG), a radionuclide, a marker of vascular inflammation, in murine carotid arteries and characterized the system for spatial resolution from multiple scintillating materials. Methods: The catheter system includes 35 mm and 8 mm fixed focal length lenses, which are subsequently connected to a CMOS camera and fiber holder. The distal ferrule of an image bundle is terminated with a wide-angle lens. The novelty of this system is amore » scintillating balloon with a crystal tip in the front of the wide angle lens to image light from the decay of 18F-FDG emission signal. The scintillating balloon is fabricated from 1mL of silicone RTV catalyst mixed with 1 mL base and 50 mg/mL calcium fluoride doped with Europium (CaF2:Eu). To identify the optimal scintillating materials with respect to resolution, we calculated modulation transfer function (MTF) of Yttrium Aluminum Garnet doped with Cerium (YAG:Ce), anthracene, and CaF2:Eu phosphors using a thin line optical phantom (Fig. 1a-1b). Macrophage-rich FVB murine atherosclerotic carotid plaque model (n = 4) was used in ex vivo experiments. Confirmatory imaging was also performed by an external optical imaging system (IVIS-200). Results: Analysis of the different phosphors (Fig 1b) showed that CaF2:Eu enabled the best resolution of 1.2μm. The CRI system visualized 18F-FDG in atherosclerotic plaques (Fig. 1d). The ligated left carotid (LR) artery exhibited 4× higher 18F-FDG signal intensity compared to the non-ligated right carotid (negative control) artery (1.65×10{sup 2} ±4.07×10{sup 1} vs. 4.44×10{sup 1}±2.17×10{sup 0}, A.U., p = 0.005) and confirmed with IVIS-200 (Fig. 1d). Conclusion: This CRI system enables high-resolution and sensitive detection of 18F-FDG uptake by murine atherosclerotic plaques.« less

4-phenylbutyrate and valproate treatment attenuates the progression of atherosclerosis and stabilizes existing plaques.

PubMed

Huang, Aric; Young, Tayler L; Dang, Vi T; Shi, Yuanyuan; McAlpine, Cameron S; Werstuck, Geoff H

2017-11-01

Recent evidence suggests that endoplasmic reticulum (ER) stress signaling through glycogen synthase kinase (GSK)-3α/β is involved in the activation of pro-atherosclerotic processes. In this study, we examined the effects of small molecules that interfere with ER stress-GSK3α/β signaling on the progression and regression of atherosclerosis in a mouse model. To examine atherosclerotic progression, low-density lipoprotein receptor deficient (Ldlr -/- ) mice were placed on a high-fat diet (HFD) and treated with the chemical chaperone, 4-phenylbutyrate (4PBA, 3.8  g/L drinking water), or the GSK3α/β inhibitor, valproate (VPA, 625 mg VPA/kg diet), for 10 weeks. To examine potential effects on atherosclerotic regression, 4 week old Ldlr -/- mice were placed on a HFD for 16 weeks. Subsets of mice were harvested at this time or switched to a chow (low fat) diet, or a chow diet with 4PBA or VPA treatment for 4 weeks. In the progression model, the 4PBA- and VPA-treated mice had significantly reduced lesion and necrotic core size. Treatments had no effect on metabolic parameters, including plasma and hepatic lipid levels, or plaque composition. In the regression model, mice with 4PBA or VPA treatment showed no alterations in lesion size, but the lesions had significantly smaller necrotic cores, increased vascular smooth muscle cell content, and increased collagen content. These features are consistent with more stable plaques. The pharmacological attenuation of ER stress or inhibition of GSK3α/β impedes the development of atherosclerosis in Ldlr -/- mice and appears to promote the stabilization of existing lesions. Copyright © 2017 Elsevier B.V. All rights reserved.

Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy

PubMed Central

Zhang, Mengyuan; He, Jianhua; Jiang, Cuiping; Zhang, Wenli; Yang, Yun; Wang, Zhiyu; Liu, Jianping

2017-01-01

Increasing evidence has highlighted the pivotal role that intimal macrophage (iMΦ) plays in the pathophysiology of atherosclerotic plaques, which represents an attractive target for atherosclerosis treatment. In this work, to address the insufficient specificity of conventional reconstituted high-density lipoprotein (rHDL) for iMΦ and its limited cholesterol efflux ability, we designed a hyaluronan (HA)-anchored core–shell rHDL. This nanoparticle achieved efficient iMΦ-targeted drug delivery via a multistage-targeting approach, and excellent cellular cholesterol removal. It contained a biodegradable poly (lactic-co-glycolic acid) (PLGA) core within a lipid bilayer, and apolipoprotein A-I (apoA-I) absorbing on the lipid bilayer was covalently decorated with HA. The covalent HA coating with superior stability and greater shielding was favorable for not only minimizing the liver uptake but also facilitating the accumulation of nanoparticles at leaky endothelium overexpressing CD44 receptors in atherosclerotic plaques. The ultimate iMΦ homing was achieved via apoA-I after HA coating degraded by hyaluronidase (HAase) (abundant in atherosclerotic plaque). The multistage-targeting mechanism was revealed on the established injured endothelium–macrophage co-culture dynamic system. Upon treatment with HAase in vitro, the nanoparticle HA-(C)-PLGA-rHDL exhibited a greater cholesterol efflux capacity compared with conventional rHDL (2.43-fold). Better targeting efficiency toward iMΦ and attenuated liver accumulation were further proved by results from ex vivo imaging and iMΦ-specific fluorescence localization. Ultimately, HA-(C)-PLGA-rHDL loaded with simvastatin realized the most potent anti-atherogenic efficacies in model animals over other preparations. Thus, the HAase-responsive HDL-mimetic nanoparticle was shown in this study to be a promising nanocarrier for anti-atherogenic therapy, in the light of efficient iMΦ-targeted drug delivery and excellent function of mediating cellular cholesterol efflux. PMID:28144137

The influence of constitutive law choice used to characterise atherosclerotic tissue material properties on computing stress values in human carotid plaques.

PubMed

Teng, Zhongzhao; Yuan, Jianmin; Feng, Jiaxuan; Zhang, Yongxue; Brown, Adam J; Wang, Shuo; Lu, Qingsheng; Gillard, Jonathan H

2015-11-05

Calculating high stress concentration within carotid atherosclerotic plaques has been shown to be complementary to anatomical features in assessing vulnerability. Reliability of stress calculation may depend on the constitutive laws/strain energy density functions (SEDFs) used to characterize tissue material properties. Different SEDFs, including neo-Hookean, one-/two-term Ogden, Yeoh, 5-parameter Mooney-Rivlin, Demiray and modified Mooney-Rivlin, have been used to describe atherosclerotic tissue behavior. However, the capacity of SEDFs to fit experimental data and the difference in the stress calculation remains unexplored. In this study, seven SEDFs were used to fit the stress-stretch data points of media, fibrous cap, lipid and intraplaque hemorrhage/thrombus obtained from 21 human carotid plaques. Semi-analytic solution, 2D structure-only and 3D fully coupled fluid-structure interaction (FSI) analyses were used to quantify stress using different SEDFs and the related material stability examined. Results show that, except for neo-Hookean, all other six SEDFs fitted the experimental points well, with vessel stress distribution in the circumferential and radial directions being similar. 2D structural-only analysis was successful for all seven SEDFs, but 3D FSI were only possible with neo-Hookean, Demiray and modified Mooney-Rivlin models. Stresses calculated using Demiray and modified Mooney-Rivlin models were nearly identical. Further analyses indicated that the energy contours of one-/two-term Ogden and 5-parameter Mooney-Rivlin models were not strictly convex and the material stability indictors under homogeneous deformations were not always positive. In conclusion, considering the capacity in characterizing material properties and stabilities, Demiray and modified Mooney-Rivlin SEDF appear practical choices for mechanical analyses to predict the critical mechanical conditions within carotid atherosclerotic plaques. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

NF-κB inhibitors that prevent foam cell formation and atherosclerotic plaque accumulation.

PubMed

Plotkin, Jesse D; Elias, Michael G; Dellinger, Anthony L; Kepley, Christopher L

2017-08-01

The transformation of monocyte-derived macrophages into lipid-laden foam cells is one inflammatory process underlying atherosclerotic disease. Previous studies have demonstrated that fullerene derivatives (FDs) have inflammation-blunting properties. Thus, it was hypothesized that FD could inhibit the transformation process underlying foam cell formation. Fullerene derivatives inhibited the phorbol myristic acid/oxidized low-density lipoprotein-induced differentiation of macrophages into foam cells as determined by lipid staining and morphology.Lipoprotein-induced generation of TNF-α, C5a-induced MC activation, ICAM-1 driven adhesion, and CD36 expression were significantly inhibited in FD treated cells compared to non-treated cells. Inhibition appeared to be mediated through the NF-κB pathway as FD reduced expression of NF-κB and atherosclerosis-associated genes. Compared to controls, FD dramatically inhibited plaque formation in arteries of apolipoprotein E null mice. Thus, FD may be an unrecognized therapy to prevent atherosclerotic lesions via inhibition of foam cell formation and MC stabilization. Copyright © 2017 Elsevier Inc. All rights reserved.

Detection of inflamed atherosclerotic lesions with diadenosine-5',5'''-P1,P4-tetraphosphate (Ap4A) and positron-emission tomography.

PubMed

Elmaleh, D R; Fischman, A J; Tawakol, A; Zhu, A; Shoup, T M; Hoffmann, U; Brownell, A-L; Zamecnik, P C

2006-10-24

Diadenosine-5',5'''-P(1),P(4)-tetraphosphate (Ap(4)A) and its analog P(2),P(3)-monochloromethylene diadenosine-5',5'''-P(1),P(4)-tetraphosphate (AppCHClppA) are competitive inhibitors of adenosine diphosphate-induced platelet aggregation, which plays a central role in arterial thrombosis and plaque formation. In this study, we evaluate the imaging capabilities of positron-emission tomography (PET) with P(2),P(3)-[(18)F]monofluoromethylene diadenosine-5',5'''-P(1),P(4)-tetraphosphate ([(18)F]AppCHFppA) to detect atherosclerotic lesions in male New Zealand White rabbits. Three to six months after balloon injury to the aorta, the rabbits were injected with [(18)F]AppCHFppA, and microPET imaging showed rapid accumulation of this radiopharmaceutical in the atherosclerotic abdominal aorta, with lesions clearly visible 30 min after injection. Computed tomographic images were coregistered with PET images to improve delineation of aortoiliac tracer activity. Plaque macrophage density, quantified by immunostaining with RAM11 against rabbit macrophages, correlated with PET measurements of [(18)F]AppCHFppA uptake (r = 0.87, P < 0.0001), whereas smooth-muscle cell density, quantified by immunostaining with 1A4 against smooth muscle actin, did not. Biodistribution studies of [(18)F]AppCHFppA in normal rats indicated typical adenosine dinucleotide behavior with insignificant myocardial uptake and fast kidney clearance. The accumulation of [(18)F]AppCHFppA in macrophage-rich atherosclerotic plaques can be quantified noninvasively with PET. Hence, [(18)F]AppCHFppA holds promise for the noninvasive characterization of vascular inflammation.

Identification of Atherosclerotic Plaques in Carotid Artery by Fluorescence Spectroscopy

NASA Astrophysics Data System (ADS)

Rocha, Rick; Villaverde, Antonio Balbin; Silveira, Landulfo; Costa, Maricília Silva; Alves, Leandro Procópio; Pasqualucci, Carlos Augusto; Brugnera, Aldo

2008-04-01

The aim of this work was to identify the presence of atherosclerotic plaques in carotid artery using the Fluorescence Spectroscopy. The most important pathogeny in the cardiovascular disorders is the atherosclerosis, which may affect even younger individuals. With approximately 1.2 million heart attacks and 750,000 strokes afflicting an aging American population each year, cardiovascular disease remains the number one cause of death. Carotid artery samples were obtained from the Autopsy Service at the University of São Paulo (São Paulo, SP, Brazil) taken from cadavers. After a histopathological analysis the 60 carotid artery samples were divided into two groups: normal (26) and atherosclerotic plaques (34). Samples were irradiated with the wavelength of 488 nm from an Argon laser. A 600 μm core optical fiber, coupled to the Argon laser, was used for excitation of the sample, whereas another 600 optical fiber, coupled to the spectrograph entrance slit, was used for collecting the fluorescence from the sample. Measurements were taken at different points on each sample and then averaged. Fluorescence spectra showed a single broad line centered at 549 nm. The fluorescence intensity for each sample was calculated by subtracting the intensity at the peak (550 nm) and at the bottom (510 nm) and then data were statistically analyzed, looking for differences between both groups of samples. ANOVA statistical test showed a significant difference (p<0,05) between both types of tissues, with regard to the fluorescence peak intensities. Our results indicate that this technique could be used to detect the presence of the atherosclerotic in carotid tissue.

Preclinical carotid atherosclerosis in patients with rheumatoid arthritis.

PubMed

Roman, Mary J; Moeller, Elfi; Davis, Adrienne; Paget, Stephen A; Crow, Mary K; Lockshin, Michael D; Sammaritano, Lisa; Devereux, Richard B; Schwartz, Joseph E; Levine, Daniel M; Salmon, Jane E

2006-02-21

Rheumatoid arthritis is associated with increased morbidity and mortality because of cardiovascular disease, independent of traditional risk factors. To determine the prevalence of preclinical atherosclerosis in patients with rheumatoid arthritis and to identify clinical and biological markers for atherosclerotic disease in this patient population. Matched, cross-sectional study. Hospital for Special Surgery in New York City. 98 consecutive outpatients with rheumatoid arthritis who were followed by rheumatologists and 98 controls matched on age, sex, and ethnicity. Cardiovascular risk factor ascertainment and carotid ultrasonography in all participants; disease severity, disease treatment, and inflammatory markers in patients with rheumatoid arthritis. Despite a more favorable risk factor profile, patients with rheumatoid arthritis had a 3-fold increase in carotid atherosclerotic plaque (44% vs. 15%; P < 0.001). The relationship between rheumatoid arthritis and carotid atherosclerotic plaque remained after accounting for age, serum cholesterol levels, smoking history, and hypertensive status; adjusted predicted prevalence was 7.4% (95% CI, 3.4% to 15.2%) for the control group and 38.5% (CI, 25.4% to 53.5%) for patients with rheumatoid arthritis. Age (P < 0.001) and current cigarette use (P < 0.014) were also significantly associated with carotid atherosclerotic plaque. Among patients with rheumatoid arthritis, atherosclerosis was related to age, hypertension status, and use of tumor necrosis factor-alpha inhibitors (a possible marker of disease severity). The study had a cross-sectional design, and inflammatory markers were determined only once. Patients with rheumatoid arthritis have a high prevalence of preclinical atherosclerosis independent of traditional risk factors, suggesting that chronic inflammation and, possibly, disease severity are atherogenic in this population.

Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/- mice.

PubMed

Thorp, Edward; Cui, Dongying; Schrijvers, Dorien M; Kuriakose, George; Tabas, Ira

2008-08-01

Atherosclerotic plaques that are prone to disruption and acute thrombotic vascular events are characterized by large necrotic cores. Necrotic cores result from the combination of macrophage apoptosis and defective phagocytic clearance (efferocytosis) of these apoptotic cells. We previously showed that macrophages with tyrosine kinase-defective Mertk receptor (Mertk(KD)) have a defect in phagocytic clearance of apoptotic macrophages in vitro. Herein we test the hypothesis that the Mertk(KD) mutation would result in increased accumulation of apoptotic cells and promote necrotic core expansion in a mouse model of advanced atherosclerosis. Mertk(KD);Apoe(-/-) mice and control Apoe(-/-) mice were fed a Western-type diet for 10 or 16 weeks, and aortic root lesions were analyzed for apoptosis and plaque necrosis. We found that the plaques of the Mertk(KD);Apoe(-/-) mice had a significant increase in terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive apoptotic cells. Most importantly, there were more non-macrophage-associated apoptotic cells in the Mertk(KD) lesions, consistent with defective efferocytosis. The more advanced (16-week) Mertk(KD);Apoe(-/-) plaques were more necrotic, consistent with a progression from apoptotic cell accumulation to plaque necrosis in the setting of a defective efferocytosis receptor. In a mouse model of advanced atherosclerosis, mutation of the phagocytic Mertk receptor promotes the accumulation of apoptotic cells and the formation of necrotic plaques. These data are consistent with the notion that a defect in an efferocytosis receptor can accelerate the progression of atherosclerosis and suggest a novel therapeutic target to prevent advanced plaque progression and its clinical consequences.

Novel molecular imaging ligands targeting matrix metalloproteinases 2 and 9 for imaging of unstable atherosclerotic plaques

PubMed Central

Molenaar, Ger; de Waard, Vivian; Lutgens, Esther; van Eck-Smit, Berthe L. F.; de Bruin, Kora; Piek, Jan J.; Eersels, Jos L. H.; Booij, Jan; Verberne, Hein J.; Windhorst, Albert D.

2017-01-01

Molecular imaging of matrix metalloproteinases (MMPs) may allow detection of atherosclerotic lesions vulnerable to rupture. In this study, we develop a novel radiolabelled compound that can target gelatinase MMP subtypes (MMP2/9) with high selectivity and inhibitory potency. Inhibitory potencies of several halogenated analogues of MMP subtype-selective inhibitors (N-benzenesulfonyliminodiacetyl monohydroxamates and N-halophenoxy-benzenesulfonyl iminodiacetyl monohydroxamates) were in the nanomolar range for MMP2/9. The analogue with highest inhibitory potency and selectivity was radiolabelled with [123I], resulting in moderate radiochemical yield, and high radiochemical purity. Biodistribution studies in mice, revealed stabilization in blood 1 hour after intravenous bolus injection. Intravenous infusion of the radioligand and subsequent autoradiography of excised aortas showed tracer uptake in atheroprone mice. Distribution of the radioligand showed co-localization with MMP2/9 immunohistochemical staining. In conclusion, we have developed a novel selective radiolabeled MMP2/9 inhibitor, suitable for single photon emission computed tomography (SPECT) imaging that effectively targets atherosclerotic lesions in mice. PMID:29190653

Plaque imaging with CT—a comprehensive review on coronary CT angiography based risk assessment

PubMed Central

Kolossváry, Márton; Szilveszter, Bálint; Merkely, Béla

2017-01-01

CT based technologies have evolved considerably in recent years. Coronary CT angiography (CTA) provides robust assessment of coronary artery disease (CAD). Early coronary CTA imaging—as a gate-keeper of invasive angiography—has focused on the presence of obstructive stenosis. Coronary CTA is currently the only non-invasive imaging modality for the evaluation of non-obstructive CAD, which has been shown to contribute to adverse cardiac events. Importantly, improved spatial resolution of CT scanners and novel image reconstruction algorithms enable the quantification and characterization of atherosclerotic plaques. State-of-the-art CT imaging can therefore reliably assess the extent of CAD and differentiate between various plaque features. Recent studies have demonstrated the incremental prognostic value of adverse plaque features over luminal stenosis. Comprehensive coronary plaque assessment holds potential to significantly improve individual risk assessment incorporating adverse plaque characteristics, the extent and severity of atherosclerotic plaque burden. As a result, several coronary CTA based composite risk scores have been proposed recently to determine patients at high risk for adverse events. Coronary CTA became a promising modality for the evaluation of functional significance of coronary lesions using CT derived fractional flow reserve (FFR-CT) and/or rest/dynamic myocardial CT perfusion. This could lead to substantial reduction in unnecessary invasive catheterization procedures and provide information on ischemic burden of CAD. Discordance between the degree of stenosis and ischemia has been recognized in clinical landmark trials using invasive FFR. Both lesion stenosis and composition are possibly related to myocardial ischemia. The evaluation of lesion-specific ischemia using combined functional and morphological plaque information could ultimately improve the diagnostic performance of CTA and thus patient care. In this review we aimed to summarize current evidence on comprehensive coronary artery plaque assessment using coronary CTA. PMID:29255692

The Association of Pericardial Fat with Coronary Artery Plaque Index at MR Imaging: The Multi-Ethnic Study of Atherosclerosis (MESA)

PubMed Central

Miao, Cuilian; Chen, Shaoguang; Ding, Jingzhong; Liu, Kiang; Li, Debiao; Macedo, Robson; Lai, Shenghan; Vogel-Claussen, Jens; Brown, Elizabeth R.; Lima, João A. C.

2011-01-01

Purpose: To determine the relationship of pericardial fat, which secretes proinflammatory markers that have been implicated in coronary atherosclerosis, with atherosclerotic plaque in an asymptomatic population–based cohort. Materials and Methods: In this institutional review board–approved study, all participants supplied written informed consent. One hundred eighty-three participants (89 women, 94 men; mean age, 61 years ± 9 [standard deviation]) from the community-based Multi-Ethnic Study of Atherosclerosis (MESA) were included. The coronary artery eccentricity (ratio of maximal to minimal coronary artery wall thickness) was determined by using magnetic resonance (MR) imaging and served as an index of plaque burden. The pericardial fat volume was determined by using computed tomography. Linear regression coefficient analysis was used to correlate pericardial fat volume with coronary artery wall thickness and plaque eccentricity. Results: Pericardial fat volume correlated significantly with degree of plaque eccentricity (P < .05) in both men and women. After adjustments for body mass index (BMI) and waist circumference, traditional risk factors, C-reactive protein level, and coronary artery calcium content, the relationship between pericardial fat and plaque eccentricity remained significant in men (P < .01) but not in women. BMI and waist circumference correlated with degree of plaque eccentricity in the univariate model (P < .05) but not after adjustment for pericardial fat volume or traditional risk factors. Conclusion: Pericardial fat volume, rather than BMI and waist circumference, was more strongly related to plaque eccentricity as a measure of coronary atherosclerotic plaque burden. The results support the proposed role of pericardial fat in association with atherosclerosis. © RSNA, 2011 PMID:21846753

Insights into Atherosclerosis Using Nanotechnology

PubMed Central

Linton, MacRae F.; Fazio, Sergio; Haselton, Frederick R.

2010-01-01

A developing forefront in vascular disease research is the application of nanotechnology, the engineering of devices at the molecular scale, for diagnostic and therapeutic applications in atherosclerosis. Promising research in this field over the past decade has resulted in the preclinical validation of nanoscale devices that target cellular and molecular components of the atherosclerotic plaque, including one of its prominent cell types, the macrophage. Nanoscale contrast agents targeting constituents of plaque biology have been adapted for application in multiple imaging modalities, leading toward more detailed diagnostic readouts, whereas nanoscale drug delivery devices can be tailored for site-specific therapeutic activity. This review highlights recent progress in utilizing nanotechnology for the clinical management of atherosclerosis, drawing upon recent preclinical studies relevant to diagnosis and treatment of the plaque and promising future applications. PMID:20425261

Hexim1 heterozygosity stabilizes atherosclerotic plaque and decreased steatosis in ApoE null mice fed atherogenic diet.

PubMed

Dhar-Mascareno, Manya; Rozenberg, Inna; Iqbal, Jahangir; Hussain, M Mahmood; Beckles, Daniel; Mascareno, Eduardo

2017-02-01

Hexim-1 is an inhibitor of RNA polymerase II transcription elongation. Decreased Hexim-1 expression in animal models of chronic diseases such as left ventricular hypertrophy, obesity and cancer triggered significant changes in adaptation and remodeling. The main aim of this study was to evaluate the role of Hexim1 in lipid metabolism focused in the progression of atherosclerosis and steatosis. We used the C57BL6 apolipoprotein E (ApoE null) crossed bred to C57BL6Hexim1 heterozygous mice to obtain ApoE null - Hexim1 heterozygous mice (ApoE-HT). Both ApoE null backgrounds were fed high fat diet for twelve weeks. Then, we evaluated lipid metabolism, atherosclerotic plaque formation and liver steatosis. In order to understand changes in the transcriptome of both backgrounds during the progression of steatosis, we performed Affymetrix mouse 430 2.0 microarray. After 12 weeks of HFD, ApoE null and ApoE-HT showed similar increase of cholesterol and triglycerides in plasma. Plaque composition was altered in ApoE-HT. Additionally, liver triglycerides and steatosis were decreased in ApoE-HT mice. Affymetrix analysis revealed that decreased steatosis might be due to impaired inducible SOCS3 expression in ApoE-HT mice. In conclusion, decreased Hexim-1 expression does not alter cholesterol metabolism in ApoE null background after HFD. However, it promotes stable atherosclerotic plaque and decreased steatosis by promoting the anti-inflammatory TGFβ pathway and blocking the expression of the inducible and pro-inflammatory expression of SOCS3 respectively. Published by Elsevier Ltd.

A Recombinant Human Anti-Platelet scFv Antibody Produced in Pichia pastoris for Atheroma Targeting

PubMed Central

Vallet-Courbin, Amelie; Larivière, Mélusine; Hocquellet, Agnès; Hemadou, Audrey; Parimala, Sarjapura-Nagaraja; Laroche-Traineau, Jeanny; Santarelli, Xavier; Clofent-Sanchez, Gisèle; Jacobin-Valat, Marie-Josée; Noubhani, Abdelmajid

2017-01-01

Cells of the innate and adaptive immune system are key factors in the progression of atherosclerotic plaque, leading to plaque instability and rupture, potentially resulting in acute atherothrombotic events such as coronary artery disease, cerebrovascular disease and peripheral arterial disease. Here, we describe the cloning, expression, purification, and immunoreactivity assessment of a recombinant single-chain variable fragment (scFv) derived from a human anti-αIIbβ3 antibody (HuAb) selected to target atheromatous lesions for the presence of platelets. Indeed, platelets within atheroma plaques have been shown to play a role in inflammation, in platelet-leucocyte aggregates and in thrombi formation and might thus be considered relevant biomarkers of atherosclerotic progression. The DNA sequence that encodes the anti-αIIbβ3 TEG4 scFv previously obtained from a phage-display selection on activated platelets, was inserted into the eukaryote vector (pPICZαA) in fusion with a tag sequence encoding 2 cysteines useable for specific probes grafting experiments. The recombinant protein was expressed at high yields in Pichia pastoris (30 mg/L culture). The advantage of P. pastoris as an expression system is the production and secretion of recombinant proteins in the supernatant, ruling out the difficulties encountered when scFv are produced in the cytoplasm of bacteria (low yield, low solubility and reduced affinity). The improved conditions allowed for the recovery of highly purified and biologically active scFv fragments ready to be grafted in a site-directed way to nanoparticles for the imaging of atherosclerotic plaques involving inflammatory processes and thus at high risk of instability. PMID:28125612

Viral Heart Disease and Acute Coronary Syndromes - Often or Rare Coexistence?

PubMed

Pawlak, Agnieszka; Wiligorska, Natalia; Wiligorska, Diana; Frontczak-Baniewicz, Malgorzata; Przybylski, Maciej; Krzyzewski, Rafal; Ziemba, Andrzej; Gil, Robert J

2018-01-01

Clinical presentation of viral myocarditis can mimic acute coronary syndrome and making diagnosis of viral heart disease (VHD) may be challenging. The presence of coronary artery disease (CAD) does not always exclude VHD and these entities can coexist. However, the incidence of co-occurrence of CAD and VHD is not precisely known. Moreover, inflammatory process caused by viruses may result in atherosclerotic plaque destabilization. The goal of this work is to summarize the current knowledge about co-occurrence of VHD and CAD. This article presents the importance of inflammatory process in both diseases and helps to understand pathophysiological mechanisms underlying their coexistence. It provides information about making differential diagnosis between these entities, including clinical presentation, noninvasive imaging features and findings in endomyocardial biopsy. Although currently there are no standard therapy strategies in coexistence of VHD and CAD, we present some remarkable aspects of treatment of patients, in whom VHD co-occurs with CAD. Viral heart disease may occur both in patients without and with atherosclerotic plaques in coronary arteries. Destabilization of atherosclerotic plaques in coronary arteries can be facilitated by inflammatory process. Increased inflammatory infiltrates in the coronary lesions of patients with VHD can lead to plaques' instability and consequently trigger acute coronary syndrome. In this article we attempted to present that co-occurrence of VHD and CAD may have therapeutic implications and as specific antiviral treatment is currently available, proper diagnosis and treatment can improve patient's condition and prognosis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Periodontal bacteria in human carotid atherothrombosis as a potential trigger for neutrophil activation.

PubMed

Rangé, Hélène; Labreuche, Julien; Louedec, Liliane; Rondeau, Philippe; Planesse, Cynthia; Sebbag, Uriel; Bourdon, Emmanuel; Michel, Jean-Baptiste; Bouchard, Philippe; Meilhac, Olivier

2014-10-01

Epidemiological, biological and clinical links between periodontal and cardiovascular diseases are now well established. Several human studies have detected bacterial DNA corresponding to periodontal pathogens in cardiovascular samples. Intraplaque hemorrhage has been associated with a higher risk of atherosclerotic plaque rupture, potentially mediated by neutrophil activation. In this study, we hypothesized that plaque composition may be related to periodontal pathogens. Carotid culprit plaque samples were collected from 157 patients. Macroscopic characterization was performed at the time of collection: presence of blood, lipid core, calcification and fibrosis. Markers of neutrophil activation released by carotid samples were quantified (myeloperoxidase or MPO, cell-free DNA and DNA-MPO complexes). PCR analysis using specific primers for Porphyromonas gingivalis, Aggregatibacter actinomycetemcommitans, Treponema denticola, Prevotella intermedia and Tannerella forsythia was used to detect DNA from periodontal pathogens in carotid tissues. In addition, bacterial lipopolysaccharide (LPS) and Immunoglobulins G against T. forsythia were quantified in atherosclerotic carotid conditioned medium. Intraplaque hemorrhage was present in 73/157 carotid samples and was associated with neutrophil activation, reflected by the release of MPO, cell-free DNA and MPO-DNA complexes. LPS levels were also linked to intraplaque hemorrhage but not with the neutrophil activation markers. Seventy-three percent of the carotid samples were positive for periodontal bacterial DNA. Furthermore, hemoglobin levels were associated with the detection of T. forsythia and neutrophil activation/inflammation markers. This study suggests a potential role of periodontal microorganisms, especially T. forsythia, in neutrophil activation within hemorrhagic atherosclerotic carotid plaques. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

An algorithm to correct 2D near-infrared fluorescence signals using 3D intravascular ultrasound architectural information

NASA Astrophysics Data System (ADS)

Mallas, Georgios; Brooks, Dana H.; Rosenthal, Amir; Vinegoni, Claudio; Calfon, Marcella A.; Razansky, R. Nika; Jaffer, Farouc A.; Ntziachristos, Vasilis

2011-03-01

Intravascular Near-Infrared Fluorescence (NIRF) imaging is a promising imaging modality to image vessel biology and high-risk plaques in vivo. We have developed a NIRF fiber optic catheter and have presented the ability to image atherosclerotic plaques in vivo, using appropriate NIR fluorescent probes. Our catheter consists of a 100/140 μm core/clad diameter housed in polyethylene tubing, emitting NIR laser light at a 90 degree angle compared to the fiber's axis. The system utilizes a rotational and a translational motor for true 2D imaging and operates in conjunction with a coaxial intravascular ultrasound (IVUS) device. IVUS datasets provide 3D images of the internal structure of arteries and are used in our system for anatomical mapping. Using the IVUS images, we are building an accurate hybrid fluorescence-IVUS data inversion scheme that takes into account photon propagation through the blood filled lumen. This hybrid imaging approach can then correct for the non-linear dependence of light intensity on the distance of the fluorescence region from the fiber tip, leading to quantitative imaging. The experimental and algorithmic developments will be presented and the effectiveness of the algorithm showcased with experimental results in both saline and blood-like preparations. The combined structural and molecular information obtained from these two imaging modalities are positioned to enable the accurate diagnosis of biologically high-risk atherosclerotic plaques in the coronary arteries that are responsible for heart attacks.

The Burden of Hard Atherosclerotic Plaques Does Not Promote Endoleak Development After Endovascular Aortic Aneurysm Repair: A Risk Stratification

DOE Office of Scientific and Technical Information (OSTI.GOV)

Petersen, Johannes, E-mail: johannes.petersen@i-med.ac.at; Glodny, Bernhard, E-mail: bernhard.glodny@i-med.ac.at

Purpose: To objectify the influence of the atherosclerotic burden in the proximal landing zone on the development of endoleaks after endovascular abdominal aortic aneurysm repair (EVAR) or thoracic endovascular aneurysm repair (TEVAR) using objective aortic calcium scoring (ACS). Materials and Methods: This retrospective observation study included 267 patients who received an aortic endograft between 1997 and 2010 and for whom preoperative computed tomography (CT) was available to perform ACS using the CT-based V600 method. The mean follow-up period was 2 {+-} 2.3 years. Results: Type I endoleaks persisted in 45 patients (16.9%), type II in 34 (12.7%), type III inmore » 8 (3%), and type IV or V in 3 patients, respectively (1.1% each). ACS in patients with type I endoleaks was not increased: 0.029 {+-} 0.061 ml compared with 0.075 {+-} 0.1349 ml in the rest of the patients, (p > 0.05; Whitney-Mann U-Test). There were significantly better results for the indication 'traumatic aortic rupture' than for the other indications (p < 0.05). In multivariate logistic regression analyses, age was an independent risk factor for the development of type I endoleaks in the thoracic aorta (Wald 9.5; p = 0.002), whereas ACS score was an independent protective factor (Wald 6.9; p = 0.009). In the abdominal aorta, neither age nor ACS influenced the development of endoleaks. Conclusion: Contrary to previous assumptions, TEVAR and EVAR can be carried out without increasing the risk of an endoleak of any type, even if there is a high atherosclerotic 'hard-plaque' burden of the aorta. The results are significantly better for traumatic aortic.« less

Detecting thermal discrepancies in vessel walls

NASA Technical Reports Server (NTRS)

Casscells, S. Ward (Inventor); Willerson, James T. (Inventor); Eastwood, Michael L. (Inventor); Bearman, Gregory H. (Inventor); Krabach, Timothy N. (Inventor)

1999-01-01

An infrared, heat-sensing catheter particularly useful for identifying potentially fatal arterial plaques in patients with disease of the coronary or other arteries and its use are detailed. In one embodiment, an infrared fiberoptic system (with or without ultrasound) is employed at the tip of the catheter to locate inflamed, heat-producing, atherosclerotic plaque, which is at greater risk for rupture, fissure, or ulceration, and consequent thrombosis and occlusion of the artery. In another embodiment, a catheter with an infrared detector (with or without ultrasound) employed at its tip will likewise locate inflamed heat-producing atherosclerotic plaque. The devices and methods of the invention may be used to detect abscesses, infection, and cancerous regions by the heat such regions differentially display over the ambient temperature of immediately adjacent tissues. The methods and devices of the invention may also be used to detect regions of cooler than ambient tissue in a vessel or organ which indicate cell death, thrombosis, cell death, hemorrhage, calcium or cholesterol accumulations, or foreign materials.

Proteomic Profile of Unstable Atheroma Plaque: Increased Neutrophil Defensin 1, Clusterin, and Apolipoprotein E Levels in Carotid Secretome.

PubMed

Aragonès, Gemma; Auguet, Teresa; Guiu-Jurado, Esther; Berlanga, Alba; Curriu, Marta; Martinez, Salomé; Alibalic, Ajla; Aguilar, Carmen; Hernández, Esteban; Camara, María-Luisa; Canela, Núria; Herrero, Pol; Ruyra, Xavier; Martín-Paredero, Vicente; Richart, Cristóbal

2016-03-04

Because of the clinical significance of carotid atherosclerosis, the search for novel biomarkers has become a priority. The aim of the present study was to compare the protein secretion profile of the carotid atherosclerotic plaque (CAP, n = 12) and nonatherosclerotic mammary artery (MA, n = 10) secretomes. We used a nontargeted proteomic approach that incorporated tandem immunoaffinity depletion, iTRAQ labeling, and nanoflow liquid chromatography coupled to high-resolution mass spectrometry. In total, 162 proteins were quantified, of which 25 showed statistically significant differences in secretome levels between carotid atherosclerotic plaque and nondiseased mammary artery. We found increased levels of neutrophil defensin 1, apolipoprotein E, clusterin, and zinc-alpha-2-glycoprotein in CAP secretomes. Results were validated by ELISA assays. Also, differentially secreted proteins are involved in pathways such as focal adhesion and leukocyte transendothelial migration. In conclusion, this study provides a subset of identified proteins that are differently expressed in secretomes of clinical significance.

Quantitative Evaluation of Atherosclerotic Plaque Using Ultrasound Tissue Characterization.

NASA Astrophysics Data System (ADS)

Yigiter, Ersin

Evaluation of therapeutic methods directed toward interrupting and/or delaying atherogenesis is impeded by the lack of a reliable, non-invasive means for monitoring progression or regression of disease. The ability to characterize the predominant component of plaque may be very valuable in the study of this disease's natural history. The earlier the lesion, the more likely is lipid to be the predominant component. Progression of plaque is usually by way of overgrowth of fibrous tissues around the fatty pool. Calcification is usually a feature of the older or complicated lesion. To explore the feasibility of using ultrasound to characterize plaque we have conducted measurements of the acoustical properties of various atherosclerotic lesions found in freshly excised samples of human abdominal aorta. Our objective has been to determine whether or not the acoustical properties of plaque correlate with the type and/or chemical composition of plaque and, if so, to define a measurement scheme which could be done in-vivo and non-invasively. Our current data base consists of individual tissue samples from some 200 different aortas. Since each aorta yields between 10 to 30 tissue samples for study, we have data on some 4,468 different lesions or samples. Measurements of the acoustical properties of plaque were found to correlate well with the chemical composition of plaque. In short, measurements of impedance and attenuation seem sufficient to classify plaque as to type and to composition. Based on the in-vitro studies, the parameter of attenuation was selected as a means of classifying the plaque. For these measurements, an intravascular ultrasound scanner was modified according to our specifications. Signal processing algorithms were developed which would analyze the complex ultrasound waveforms and estimate tissue properties such as attenuation. Various methods were tried to estimate the attenuation from the pulse-echo backscattered signal. Best results were obtained by comparing averaged power spectra in small time windows at different depths for a series of A-lines. Comparisons between consequent averaged spectra at different depths provided the magnitude and frequency dependence of attenuation. Non-invasive characterization of the physical state of the tissue with quantitative ultrasound holds great promise for the extension of the diagnostic power of conventional B-mode imaging.

Endothelin receptor antagonist macitentan or deletion of mouse mast cell protease 4 delays lesion development in atherosclerotic mice.

PubMed

Houde, Martin; Desbiens, Louisane; Schwertani, Adel; Pejler, Gunnar; Iglarz, Marc; D'Orléans-Juste, Pedro

2016-08-15

To determine the impact of mixed endothelin receptor antagonist and mouse mast cell protease-4 (mMCP-4) in the development of atherosclerosis in the mouse model. Apolipoprotein E (ApoE) KO mice were crossed with mMCP-4 KO mice to generate ApoE/mMCP-4 double KO mice. Atherosclerosis was induced with a normal- or high-fat diet for 12, 27 or 52weeks. Macitentan (30mg/kg/day), a dual ETA/ETB receptor antagonist, was given orally for 6weeks (27week protocol). At sacrifice, aortas and brachiocephalic arteries (BCAs) were collected. En face Sudan IV staining was performed on aortas and BCA sections were subjected to Masson's trichrome stain and α-smooth muscle actin labeling. Under normal diet, both macitentan treatment and the absence of mMCP-4 reduced the development of aortic atherosclerotic lesions in 27-week old ApoE KO mice, but mMCP-4 deletion failed to maintain this effect on 52-week old mice. Under high-fat diet (WD), macitentan, but not the absence of mMCP-4, reduced aortic lesion development in ApoE KO mice. On BCA lesions of 27-week old WD mice, macitentan treatment had a small impact while mMCP-4 deletion showed improved features of plaque stability. These results suggest that the inhibition of mMCP-4 reduces lesion spreading in the earlier phases of atherosclerosis development and can help stabilise the more advanced plaque. Macitentan treatment was more effective to prevent lesion spreading but did not improve plaque features to the same extent. Copyright © 2016 Elsevier Inc. All rights reserved.

IVUS-Based Computational Modeling and Planar Biaxial Artery Material Properties for Human Coronary Plaque Vulnerability Assessment

PubMed Central

Liu, Haofei; Cai, Mingchao; Yang, Chun; Zheng, Jie; Bach, Richard; Kural, Mehmet H.; Billiar, Kristen L.; Muccigrosso, David; Lu, Dongsi; Tang, Dalin

2012-01-01

Image-based computational modeling has been introduced for vulnerable atherosclerotic plaques to identify critical mechanical conditions which may be used for better plaque assessment and rupture predictions. In vivo patient-specific coronary plaque models are lagging due to limitations on non-invasive image resolution, flow data, and vessel material properties. A framework is proposed to combine intravascular ultrasound (IVUS) imaging, biaxial mechanical testing and computational modeling with fluid-structure interactions and anisotropic material properties to acquire better and more complete plaque data and make more accurate plaque vulnerability assessment and predictions. Impact of pre-shrink-stretch process, vessel curvature and high blood pressure on stress, strain, flow velocity and flow maximum principal shear stress was investigated. PMID:22428362

Deficiency of cyclin-dependent kinase inhibitors p21{sup Cip1} and p27{sup Kip1} accelerates atherogenesis in apolipoprotein E-deficient mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akyuerek, Levent M.; Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Goeteborg, SE-405 30; Boehm, Manfred

2010-05-28

Cyclin-dependent kinase inhibitors, p21{sup Cip1} and p27{sup Kip1}, are upregulated during vascular cell proliferation and negatively regulate growth of vascular cells. We hypothesized that absence of either p21{sup Cip1} or p27{sup Kip1} in apolipoprotein E (apoE)-deficiency may increase atherosclerotic plaque formation. Compared to apoE{sup -/-} aortae, both apoE{sup -/-}/p21{sup -/-} and apoE{sup -/-}/p27{sup -/-} aortae exhibited significantly more atherosclerotic plaque following a high-cholesterol regimen. This increase was particularly observed in the abdominal aortic regions. Deficiency of p27{sup Kip1} accelerated plaque formation significantly more than p21{sup -/-} in apoE{sup -/-} mice. This increased plaque formation was in parallel with increased intima/mediamore » area ratios. Deficiency of p21{sup Cip1} and p27{sup Kip1} accelerates atherogenesis in apoE{sup -/-} mice. These findings have significant implications for our understanding of the molecular basis of atherosclerosis associated with excessive proliferation of vascular cells.« less

In vivo detection of macrophages in a rabbit atherosclerotic model by time-resolved laser-induced fluorescence spectroscopy

PubMed Central

Marcu, Laura; Fang, Qiyin; Jo, Javier A.; Papaioannou, Thanassis; Dorafshar, Amir; Reil, Todd; Qiao, Jian-Hua; Baker, J. Dennis; Freischlag, Julie A.; Fishbein, Michael C.

2007-01-01

Accumulation of numerous macrophages in the fibrous cap is a key identifying feature of plaque inflammation and vulnerability. This study investigates the use of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) as a potential tool for detection of macrophage foam cells in the intima of atherosclerotic plaques. Experiments were conducted in vivo on 14 New Zealand rabbits (6 control, 8 hypercholesterolemic) following aortotomy to expose the intimal luminal surface of the aorta. Tissue autofluorescence was induced with a nitrogen pulse laser (337 nm, 1 ns). Lesions were histologically classified by the percent of collagen or macrophage foam cells as well as thickness of the intima. Using parameters derived from the time-resolved fluorescence emission of plaques, we determined that intima rich in macrophage foam cells can be distinguished from intima rich in collagen with high sensitivity (>85%) and specificity (>95%). This study demonstrates, for the first time, that a time-resolved fluorescence-based technique can differentiate and demark macrophage content versus collagen content in vivo. Our results suggest that TR-LIFS technique can be used in clinical applications for identification of inflammatory cells important in plaque formation and rupture. PMID:16039283

In vivo detection of macrophages in a rabbit atherosclerotic model by time-resolved laser-induced fluorescence spectroscopy.

PubMed

Marcu, Laura; Fang, Qiyin; Jo, Javier A; Papaioannou, Thanassis; Dorafshar, Amir; Reil, Todd; Qiao, Jian-Hua; Baker, J Dennis; Freischlag, Julie A; Fishbein, Michael C

2005-08-01

Accumulation of numerous macrophages in the fibrous cap is a key identifying feature of plaque inflammation and vulnerability. This study investigates the use of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) as a potential tool for detection of macrophage foam cells in the intima of atherosclerotic plaques. Experiments were conducted in vivo on 14 New Zealand rabbits (6 control, 8 hypercholesterolemic) following aortotomy to expose the intimal luminal surface of the aorta. Tissue autofluorescence was induced with a nitrogen pulse laser (337 nm, 1 ns). Lesions were histologically classified by the percent of collagen or macrophage foam cells as well as thickness of the intima. Using parameters derived from the time-resolved fluorescence emission of plaques, we determined that intima rich in macrophage foam cells can be distinguished from intima rich in collagen with high sensitivity (>85%) and specificity (>95%). This study demonstrates, for the first time, that a time-resolved fluorescence-based technique can differentiate and demark macrophage content versus collagen content in vivo. Our results suggest that TR-LIFS technique can be used in clinical applications for identification of inflammatory cells important in plaque formation and rupture.

Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis.

PubMed

Clarke, Murray C H; Figg, Nichola; Maguire, Janet J; Davenport, Anthony P; Goddard, Martin; Littlewood, Trevor D; Bennett, Martin R

2006-09-01

Vascular smooth muscle cell (VSMC) apoptosis occurs in many arterial diseases, including aneurysm formation, angioplasty restenosis and atherosclerosis. Although VSMC apoptosis promotes vessel remodeling, coagulation and inflammation, its precise contribution to these diseases is unknown, given that apoptosis frequently accompanies vessel injury or alterations to flow. To study the direct consequences of VSMC apoptosis, we generated transgenic mice expressing the human diphtheria toxin receptor (hDTR, encoded by HBEGF) from a minimal Tagln (also known as SM22alpha) promoter. Despite apoptosis inducing loss of 50-70% of VSMCs, normal arteries showed no inflammation, reactive proliferation, thrombosis, remodeling or aneurysm formation. In contrast, VSMC apoptosis in atherosclerotic plaques of SM22alpha-hDTR Apoe-/- mice induced marked thinning of fibrous cap, loss of collagen and matrix, accumulation of cell debris and intense intimal inflammation. We conclude that VSMC apoptosis is 'silent' in normal arteries, which have a large capacity to withstand cell loss. In contrast, VSMC apoptosis alone is sufficient to induce features of plaque vulnerability in atherosclerosis. SM22alpha-hDTR Apoe-/- mice may represent an important new model to test agents proposed to stabilize atherosclerotic plaques.

Myocardial Bridge and Acute Plaque Rupture

PubMed Central

Perl, Leor; Daniels, David; Schwartz, Jonathan; Tanaka, Shige; Yeung, Alan; Tremmel, Jennifer A.; Schnittger, Ingela

2016-01-01

A myocardial bridge (MB) is a common anatomic variant, most frequently located in the left anterior descending coronary artery, where a portion of the coronary artery is covered by myocardium. Importantly, MBs are known to result in a proximal atherosclerotic lesion. It has recently been postulated that these lesions predispose patients to acute coronary events, even in cases of otherwise low-risk patients. One such mechanism may involve acute plaque rupture. In this article, we report 2 cases of patients with MBs who presented with acute coronary syndromes despite having low cardiovascular risk. Their presentation was life-risking and both were treated urgently and studied with coronary angiographies and intravascular ultrasound. This latter modality confirmed a rupture of an atherosclerotic plaque proximal to the MB as a likely cause of the acute events. These cases, of unexplained acute coronary syndrome in low-risk patients, raise the question of alternative processes leading to the event and the role MB play as an underlying cause of ruptured plaques. In some cases, an active investigation for this entity may be warranted, due to the prognostic implications of the different therapeutic modalities, should an MB be discovered. PMID:28251167

Selective Imaging of Vascular Endothelial Growth Factor Receptor-1 and Receptor-2 in Atherosclerotic Lesions in Diabetic and Non-diabetic ApoE-/- Mice.

PubMed

Tekabe, Yared; Johnson, Lynne L; Rodriquez, Krissy; Li, Qing; Backer, Marina; Backer, Joseph M

2018-02-01

Plaque vulnerability is associated with inflammation and angiogenesis, processes that rely on vascular endothelial growth factor (VEGF) signaling via two receptors, VEGFR-1 and VEGFR-2. We have recently reported that enhanced uptake of scVEGF-PEG-DOTA/Tc-99m (scV/Tc) single photon emission computed tomography (SPECT) tracer that targets both VEGFR-1 and VEGFR-2, identifies accelerated atherosclerosis in diabetic relative to non-diabetic ApoE -/- mice. Since VEGFR-1 and VEGFR-2 may play different roles in atherosclerotic plaques, we reasoned that selective imaging of each receptor can provide more detailed information on plaque biology. Recently described VEGFR-1 and VEGFR-2 selective mutants of scVEGF, named scVR1 and scVR2, were site-specifically derivatized with Tc-99m chelator DOTA via 3.4 kDa PEG linker, and their selectivity to the cognate receptors was confirmed in vitro. scVR1 and scVR2 conjugates were radiolabeled with Tc-99m to specific activity of 110 ± 11 MBq/nmol, yielding tracers named scVR1/Tc and scVR2/Tc. 34-40 week old diabetic and age-matched non-diabetic ApoE -/- mice were injected with tracers, 2-3 h later injected with x-ray computed tomography (CT) contrast agent and underwent hybrid SPECT/CT imaging. Tracer uptake, localized to proximal aorta and brachiocephalic vessels, was quantified as %ID from. Tracer uptake was also quantified as %ID/g from gamma counting of harvested plaques. Harvested atherosclerotic arterial tissue was used for immunofluorescent analyses of VEGFR-1 and VEGFR-2 and various lineage-specific markers. Focal, receptor-mediated uptake in proximal aorta and brachiocephalic vessels was detected for both scVR1/Tc and scVR2/Tc tracers. Uptake of scVR1/Tc and scVR2/Tc was efficiently inhibited only by "cold" proteins of the same receptor selectivity. Tracer uptake in this area, expressed as %ID, was higher in diabetic vs. non- diabetic mice for scVR1/Tc (p = 0.01) but not for scVR2/Tc. Immunofluorescent analysis revealed enhanced VEGFR-1 prevalence in and around plaque area in diabetic mice. Selective VEGFR-1 and VEGFR-2 imaging of atherosclerotic lesions may be useful to explore plaque biology and identify vulnerability.

Dispersive aortic cannulas reduce aortic wall shear stress affecting atherosclerotic plaque embolization.

PubMed

Assmann, Alexander; Gül, Fethi; Benim, Ali Cemal; Joos, Franz; Akhyari, Payam; Lichtenberg, Artur

2015-03-01

Neurologic complications during on-pump cardiovascular surgery are often induced by mobilization of atherosclerotic plaques, which is directly related to enhanced wall shear stress. In the present study, we numerically evaluated the impact of dispersive aortic cannulas on aortic blood flow characteristics, with special regard to the resulting wall shear stress profiles. An idealized numerical model of the human aorta and its branches was created and used to model straight as well as bent dispersive aortic cannulas with meshlike tips inserted in the distal ascending aorta. Standard cannulas with straight beveled or bent tips served as controls. Using a recently optimized computing method, simulations of pulsatile and nonpulsatile extracorporeal circulation were performed. Dispersive aortic cannulas reduced the maximum and average aortic wall shear stress values to approximately 50% of those with control cannulas, while the difference in local values was even larger. Moreover, under pulsatile circulation, dispersive cannulas shortened the time period during which wall shear stress values were increased. The turbulent kinetic energy was also diminished by utilizing dispersive cannulas, reducing the risk of hemolysis. In summary, dispersive aortic cannulas decrease aortic wall shear stress and turbulence during extracorporeal circulation and may therefore reduce the risk of endothelial and blood cell damage as well as that of neurologic complications caused by atherosclerotic plaque mobilization. Copyright © 2014 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Bilirubin Prevents Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice by Inhibiting Endothelial VCAM-1 and ICAM-1 Signaling.

PubMed

Vogel, Megan E; Idelman, Gila; Konaniah, Eddy S; Zucker, Stephen D

2017-04-01

Numerous epidemiological studies support an inverse association between serum bilirubin levels and the incidence of cardiovascular disease; however, the mechanism(s) by which bilirubin may protect against atherosclerosis is undefined. The goals of the present investigations were to assess the ability of bilirubin to prevent atherosclerotic plaque formation in low-density lipoprotein receptor-deficient ( Ldlr -/- ) mice and elucidate the molecular processes underlying this effect. Bilirubin, at physiological concentrations (≤20 μmol/L), dose-dependently inhibits THP-1 monocyte migration across tumor necrosis factor α-activated human umbilical vein endothelial cell monolayers without altering leukocyte binding or cytokine production. A potent antioxidant, bilirubin effectively blocks the generation of cellular reactive oxygen species induced by the cross-linking of endothelial vascular cell adhesion molecule 1 (VCAM-1) or intercellular adhesion molecule 1 (ICAM-1). These findings were validated by treating cells with blocking antibodies or with specific inhibitors of VCAM-1 and ICAM-1 signaling. When administered to Ldlr -/- mice on a Western diet, bilirubin (30 mg/kg intraperitoneally) prevents atherosclerotic plaque formation, but does not alter circulating cholesterol or chemokine levels. Aortic roots from bilirubin-treated animals exhibit reduced lipid and collagen deposition, decreased infiltration of monocytes and lymphocytes, fewer smooth muscle cells, and diminished levels of chlorotyrosine and nitrotyrosine, without changes in VCAM-1 or ICAM-1 expression. Bilirubin suppresses atherosclerotic plaque formation in Ldlr -/- mice by disrupting endothelial VCAM-1- and ICAM-1-mediated leukocyte migration through the scavenging of reactive oxygen species signaling intermediaries. These findings suggest a potential mechanism for the apparent cardioprotective effects of bilirubin. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Myeloperoxidase-mediated Methionine Oxidation Promotes an Amyloidogenic Outcome for Apolipoprotein A-I*

PubMed Central

Chan, Gary K. L.; Witkowski, Andrzej; Gantz, Donald L.; Zhang, Tianqi O.; Zanni, Martin T.; Jayaraman, Shobini; Cavigiolio, Giorgio

2015-01-01

High plasma levels of apolipoprotein A-I (apoA-I) correlate with cardiovascular health, whereas dysfunctional apoA-I is a cause of atherosclerosis. In the atherosclerotic plaques, amyloid deposition increases with aging. Notably, apoA-I is the main component of these amyloids. Recent studies identified high levels of oxidized lipid-free apoA-I in atherosclerotic plaques. Likely, myeloperoxidase (MPO) secreted by activated macrophages in atherosclerotic lesions is the promoter of such apoA-I oxidation. We hypothesized that apoA-I oxidation by MPO levels similar to those present in the artery walls in atherosclerosis can promote apoA-I structural changes and amyloid fibril formation. ApoA-I was exposed to exhaustive chemical (H2O2) oxidation or physiological levels of enzymatic (MPO) oxidation and incubated at 37 °C and pH 6.0 to induce fibril formation. Both chemically and enzymatically oxidized apoA-I produced fibrillar amyloids after a few hours of incubation. The amyloid fibrils were composed of full-length apoA-I with differential oxidation of the three methionines. Met to Leu apoA-I variants were used to establish the predominant role of oxidation of Met-86 and Met-148 in the fibril formation process. Importantly, a small amount of preformed apoA-I fibrils was able to seed amyloid formation in oxidized apoA-I at pH 7.0. In contrast to hereditary amyloidosis, wherein specific mutations of apoA-I cause protein destabilization and amyloid deposition, oxidative conditions similar to those promoted by local inflammation in atherosclerosis are sufficient to transform full-length wild-type apoA-I into an amyloidogenic protein. Thus, MPO-mediated oxidation may be implicated in the mechanism that leads to amyloid deposition in the atherosclerotic plaques in vivo. PMID:25759391

Detection of inflamed atherosclerotic lesions with diadenosine-5′,5‴-P1,P4-tetraphosphate (Ap4A) and positron-emission tomography

PubMed Central

Elmaleh, D. R.; Fischman, A. J.; Tawakol, A.; Zhu, A.; Shoup, T. M.; Hoffmann, U.; Brownell, A.-L.; Zamecnik, P. C.

2006-01-01

Diadenosine-5′,5‴-P1,P4-tetraphosphate (Ap4A) and its analog P2,P3-monochloromethylene diadenosine-5′,5‴-P1,P4-tetraphosphate (AppCHClppA) are competitive inhibitors of adenosine diphosphate-induced platelet aggregation, which plays a central role in arterial thrombosis and plaque formation. In this study, we evaluate the imaging capabilities of positron-emission tomography (PET) with P2,P3-[18F]monofluoromethylene diadenosine-5′,5‴-P1,P4-tetraphosphate ([18F]AppCHFppA) to detect atherosclerotic lesions in male New Zealand White rabbits. Three to six months after balloon injury to the aorta, the rabbits were injected with [18F]AppCHFppA, and microPET imaging showed rapid accumulation of this radiopharmaceutical in the atherosclerotic abdominal aorta, with lesions clearly visible 30 min after injection. Computed tomographic images were coregistered with PET images to improve delineation of aortoiliac tracer activity. Plaque macrophage density, quantified by immunostaining with RAM11 against rabbit macrophages, correlated with PET measurements of [18F]AppCHFppA uptake (r = 0.87, P < 0.0001), whereas smooth-muscle cell density, quantified by immunostaining with 1A4 against smooth muscle actin, did not. Biodistribution studies of [18F]AppCHFppA in normal rats indicated typical adenosine dinucleotide behavior with insignificant myocardial uptake and fast kidney clearance. The accumulation of [18F]AppCHFppA in macrophage-rich atherosclerotic plaques can be quantified noninvasively with PET. Hence, [18F]AppCHFppA holds promise for the noninvasive characterization of vascular inflammation. PMID:17038498

New methods for time-resolved fluorescence spectroscopy data analysis based on the Laguerre expansion technique--applications in tissue diagnosis.

PubMed

Jo, J A; Marcu, L; Fang, Q; Papaioannou, T; Qiao, J H; Fishbein, M C; Beseth, B; Dorafshar, A H; Reil, T; Baker, D; Freischlag, J

2007-01-01

A new deconvolution method for the analysis of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) data is introduced and applied for tissue diagnosis. The intrinsic TR-LIFS decays are expanded on a Laguerre basis, and the computed Laguerre expansion coefficients (LEC) are used to characterize the sample fluorescence emission. The method was applied for the diagnosis of atherosclerotic vulnerable plaques. At a first stage, using a rabbit atherosclerotic model, 73 TR-LIFS in-vivo measurements from the normal and atherosclerotic aorta segments of eight rabbits were taken. The Laguerre deconvolution technique was able to accurately deconvolve the TR-LIFS measurements. More interesting, the LEC reflected the changes in the arterial biochemical composition and provided discrimination of lesions rich in macrophages/foam-cells with high sensitivity (> 85%) and specificity (> 95%). At a second stage, 348 TR-LIFS measurements were obtained from the explanted carotid arteries of 30 patients. Lesions with significant inflammatory cells (macrophages/foam-cells and lymphocytes) were detected with high sensitivity (> 80%) and specificity (> 90%), using LEC-based classifiers. This study has demonstrated the potential of using TR-LIFS information by means of LEC for in vivo tissue diagnosis, and specifically for detecting inflammation in atherosclerotic lesions, a key marker of plaque vulnerability.

Immunohistochemical and ultrastructural detection of advanced glycation end products in atherosclerotic lesions of human aorta with a novel specific monoclonal antibody.

PubMed Central

Kume, S.; Takeya, M.; Mori, T.; Araki, N.; Suzuki, H.; Horiuchi, S.; Kodama, T.; Miyauchi, Y.; Takahashi, K.

1995-01-01

To elucidate the deposition of advanced glycation end products (AGEs) in aortic atherosclerosis, aortic walls were obtained from 25 autopsy cases and examined immunohistochemically and immunoelectron microscopically with a monoclonal antibody specific for AGEs, 6D12. Among the autopsy cases, atherosclerotic lesions were found in the aortas of 22 cases and were composed of diffuse intimal thickening, fatty streaks, atherosclerotic plaques, and/or complicated lesions. In these cases, intracellular AGE accumulation was demonstrated in the intimal lesions of aortic atherosclerosis in 12 cases. Compared with the diffuse intimal thickening, intracellular AGE accumulation was marked in the fatty streaks and atherosclerotic plaques. Immunohistochemical double staining with 6D12 and monoclonal antibodies for macrophages or muscle actin or a polyclonal antibody for scavenger receptors demonstrated that the AGE accumulation in macrophages or their related foam cells was marked in the diffuse intimal thickening and fatty streak lesions and that almost all macrophages and macrophage-derived foam cells possessed scavenger receptors. Immunoelectron microscopic observation revealed the localization of 6D12-positive reaction in lysosomal lipid vacuoles or electron-dense granules of the foam cells. These results indicate that AGE accumulation occurs in macrophages, smooth muscle cells, and their related foam cells. Images Figure 2 Figure 3 Figure 6 PMID:7545874

Ultrasonographic measurements of subclinical carotid atherosclerosis in prediction of ischemic stroke.

PubMed

Mathiesen, E B; Johnsen, S H

2009-01-01

Carotid intima-media thickness (IMT) and plaque measurements are widely used to quantify atherosclerosis and assess the risk of future stroke, and are used as surrogate endpoints for clinical disease. In recent years, it has become clear that carotid IMT and plaque reflect biologically and genetically different aspects of the atherosclerotic process, and are differentially related to risk factors and cardiovascular disease. Plaques are focal manifestations of atherosclerosis while increased IMT represents mainly hypertensive medial hypertrophy. Several prospective studies have showed that IMT and plaque measurements, such as total plaque area and plaque number, are predictive of future stroke. Plaque echogenicity predicts future stroke independent of plaque size. The contribution of IMT and plaque measurements in individual stroke risk prediction in the general population seems to be limited, but may be useful as a tool for individual stratification of high-risk patients.

Macrophage Liver Kinase B1 Inhibits Foam Cell Formation and Atherosclerosis.

PubMed

Liu, Zhaoyu; Zhu, Huaiping; Dai, Xiaoyan; Wang, Cheng; Ding, Ye; Song, Ping; Zou, Ming-Hui

2017-10-13

LKB1 (liver kinase B1) is a serine/threonine kinase and tumor suppressor, which regulates the homeostasis of hematopoietic cells and immune responses. Macrophages transform into foam cells upon taking-in lipids. No role for LKB1 in foam cell formation has previously been reported. We sought to establish the role of LKB1 in atherosclerotic foam cell formation. LKB1 expression was examined in human carotid atherosclerotic plaques and in western diet-fed atherosclerosis-prone Ldlr -/- and ApoE -/- mice. LKB1 expression was markedly reduced in human plaques when compared with nonatherosclerotic vessels. Consistently, time-dependent reduction of LKB1 levels occurred in atherosclerotic lesions in western diet-fed Ldlr -/- and ApoE -/- mice. Exposure of macrophages to oxidized low-density lipoprotein downregulated LKB1 in vitro. Furthermore, LKB1 deficiency in macrophages significantly increased the expression of SRA (scavenger receptor A), modified low-density lipoprotein uptake and foam cell formation, all of which were abolished by blocking SRA. Further, we found LKB1 phosphorylates SRA resulting in its lysosome degradation. To further investigate the role of macrophage LKB1 in vivo, ApoE -/- LKB1 fl/fl LysM cre and ApoE -/- LKB1 fl/fl mice were fed with western diet for 16 weeks. Compared with ApoE -/- LKB1 fl/fl wild-type control, ApoE -/- LKB1 fl/fl LysM cre mice developed more atherosclerotic lesions in whole aorta and aortic root area, with markedly increased SRA expression in aortic root lesions. We conclude that macrophage LKB1 reduction caused by oxidized low-density lipoprotein promotes foam cell formation and the progression of atherosclerosis. © 2017 American Heart Association, Inc.

Doxycycline Stabilizes Vulnerable Plaque via Inhibiting Matrix Metalloproteinases and Attenuating Inflammation in Rabbits

PubMed Central

Dong, Mei; Zhong, Lin; Chen, Wen Qiang; Ji, Xiao Ping; Zhang, Mei; Zhao, Yu Xia; Li, Li; Yao, Gui Hua; Zhang, Peng Fei; Zhang, Cheng; Zhang, Lei; Zhang, Yun

2012-01-01

Enhanced matrix metalloproteinases (MMPs) activity is implicated in the process of atherosclerotic plaque instability. We hypothesized that doxycycline, a broad MMPs inhibitor, was as effective as simvastatin in reducing the incidence of plaque disruption. Thirty rabbits underwent aortic balloon injury and were fed a high-fat diet for 20 weeks. At the end of week 8, the rabbits were divided into three groups for 12-week treatment: a doxycycline-treated group that received oral doxycycline at a dose of 10 mg/kg/d, a simvastatin-treated group that received oral simvastatin at a dose of 5 mg/kg/d, and a control group that received no treatment. At the end of week 20, pharmacological triggering was performed to induce plaque rupture. Biochemical, ultrasonographic, pathologic, immunohistochemical and mRNA expression studies were performed. The results showed that oral administration of doxycycline resulted in a significant increase in the thickness of the fibrous cap of the aortic plaque whereas there was a substantial reduction of MMPs expression, local and systemic inflammation, and aortic plaque vulnerability. The incidence of plaque rupture with either treatment (0% for both) was significantly lower than that for controls (56.0%, P<0.05). There was no significant difference between doxycycline-treated group and simvastatin-treated group in any serological, ultrasonographic, pathologic, immunohistochemical and mRNA expression measurement except for the serum lipid levels that were higher with doxycycline than with simvastatin treatment. In conclusion, doxycycline at a common antimicrobial dose stabilizes atherosclerotic lesions via inhibiting matrix metalloproteinases and attenuating inflammation in a rabbit model of vulnerable plaque. These effects were similar to a large dose of simvastatin and independent of serum lipid levels. PMID:22737253

Non-linear imaging and characterization of atherosclerotic arterial tissue using combined two photon fluorescence, second-harmonic generation and CARS microscopy

NASA Astrophysics Data System (ADS)

Cicchi, Riccardo; Matthäus, Christian; Meyer, Tobias; Lattermann, Annika; Dietzek, Benjamin; Brehm, Bernhard R.; Popp, Jürgen; Pavone, Francesco S.

2014-02-01

Atherosclerosis is among the most widespread cardiovascular diseases and one of the leading cause of death in the Western World. Characterization of arterial tissue in atherosclerotic condition is extremely interesting from the diagnostic point of view. Routinely used diagnostic methods, such as histopathological examination, are limited to morphological analysis of the examined tissues, whereas an exhaustive characterization requires a morpho-functional approach. Multimodal non-linear microscopy has the potential to bridge this gap by providing morpho-functional information on the examined tissues in a label-free way. Here we employed multiple non-linear microscopy techniques, including CARS, TPF, and SHG to provide intrinsic optical contrast from various tissue components in both arterial wall and atherosclerotic plaques. CARS and TPF microscopy were used to respectively image lipid depositions within plaques and elastin in the arterial wall. Cholesterol deposition in the lumen and collagen in the arterial wall were selectively imaged by SHG microscopy and distinguished by forward-backward SHG ratio. Image pattern analysis allowed characterizing collagen organization in different tissue regions. Different values of fiber mean size, distribution and anisotropy are calculated for lumen and media prospectively allowing for automated classification of atherosclerotic lesions. The presented method represents a promising diagnostic tool for evaluating atherosclerotic tissue and has the potential to find a stable place in clinical setting as well as to be applied in vivo in the near future.

Inhaled Diesel Emissions Alter Atherosclerotic Plaque Composition in ApoE−/− Mice

PubMed Central

Campen, Matthew J.; Lund, Amie K.; Knuckles, Travis L.; Conklin, Daniel J.; Bishop, Barbara; Young, David; Seilkop, Steven; Seagrave, JeanClare; Reed, Matthew D.; McDonald, Jacob D.

2009-01-01

Recent epidemiological studies suggest that traffic-related air pollution may have detrimental effects on cardiovascular health. Previous studies reveal that gasoline emissions can induce several enzyme pathways involved in the formation and development of atherosclerotic plaques. As a direct comparison, the present study examined the impact of diesel engine emissions on these pathways, and further examined the effects on vascular lesion pathology. Apolipoprotein E-null mice were simultaneously placed on a high fat chow diet and exposed to four concentrations, plus a high concentration exposure with particulates (PM) removed by filtration, of diesel emissions for 6 h/d for 50 days. Aortas were subsequently assayed for alteration in matrix metalloproteinase-9, endothelin-1, and several other biomarkers. Diesel induced dose-related alterations in gene markers of vascular remodeling and aortic lipid peroxidation; filtration of PM did not significantly alter these vascular responses, indicating that the gaseous portion of the exhaust was a principal driver. Immunohistochemical analysis of aortic leaflet sections revealed no net increase in lesion area, but a significant decrease in lipid-rich regions and increasing trends in macrophage accumulation and collagen content, suggesting that plaques were advanced to a more fragile, potentially more vulnerable state by diesel exhaust exposure. Combined with previous studies, these results indicate that whole emissions from mobile sources may have a significant role in promoting chronic vascular disease. PMID:19891982

Molecular imaging of alpha v beta3 integrin expression in atherosclerotic plaques with a mimetic of RGD peptide grafted to Gd-DTPA.

PubMed

Burtea, Carmen; Laurent, Sophie; Murariu, Oltea; Rattat, Dirk; Toubeau, Gérard; Verbruggen, Alfons; Vansthertem, David; Vander Elst, Luce; Muller, Robert N

2008-04-01

The integrin alpha v beta3 is highly expressed in atherosclerotic plaques by medial and intimal smooth muscle cells and by endothelial cells of angiogenic microvessels. In this study, we have assessed non-invasive molecular magnetic resonance imaging (MRI) of plaque-associated alpha v beta3 integrin expression on transgenic ApoE-/- mice with a low molecular weight peptidomimetic of Arg-Gly-Asp (mimRGD) grafted to gadolinium diethylenetriaminepentaacetate (Gd-DTPA-g-mimRGD). The analogous compound Eu-DTPA-g-mimRGD was employed for an in vivo competition experiment and to confirm the molecular targeting. The specific interaction of mimRGD conjugated to Gd-DTPA or to 99mTc-DTPA with alpha v beta3 integrin was furthermore confirmed on Jurkat T lymphocytes. The mimRGD was synthesized and conjugated to DTPA. DTPA-g-mimRGD was complexed with GdCl3.6H2O, EuCl3.6H2O, or with [99mTc(CO)3(H2O)3]+. MRI evaluation was performed on a 4.7 T Bruker imaging system. Blood pharmacokinetics of Gd-DTPA-g-mimRGD were assessed in Wistar rats and in c57bl/6j mice. The presence of angiogenic blood vessels and the expression of alpha v beta3 integrin were confirmed in aorta specimens by immunohistochemistry. Gd-DTPA-g-mimRGD produced a strong enhancement of the external structures of the aortic wall and of the more profound layers (possibly tunica media and intima). The aortic lumen seemed to be restrained and distorted. Pre-injection of Eu-DTPA-g-mimRGD diminished the Gd-DTPA-g-mimRGD binding to atherosclerotic plaque and confirmed the specific molecular targeting. A slower blood clearance was observed for Gd-DTPA-g-mimRGD, as indicated by a prolonged elimination half-life and a diminished total clearance. The new compound is potentially useful for the diagnosis of vulnerable atherosclerotic plaques and of other pathologies characterized by alpha v beta3 integrin expression, such as cancer and inflammation. The delayed blood clearance, the significant enhancement of the signal-to-noise ratio, and the low immunogenicity of the mimetic molecule highlight its potential for an industrial and clinical implementation.

The influence of composition and location on the toughness of human atherosclerotic femoral plaque tissue.

PubMed

Cunnane, E M; Barrett, H E; Kavanagh, E G; Mongrain, R; Walsh, M T

2016-02-01

The toughness of femoral atherosclerotic tissue is of pivotal importance to understanding the mechanism of luminal expansion during cutting balloon angioplasty (CBA) in the peripheral vessels. Furthermore, the ability to relate this parameter to plaque composition, pathological inclusions and location within the femoral vessels would allow for the improvement of existing CBA technology and for the stratification of patient treatment based on the predicted fracture response of the plaque tissue to CBA. Such information may lead to a reduction in clinically observed complications, an improvement in trial results and an increased adoption of the CBA technique to reduce vessel trauma and further endovascular treatment uptake. This study characterises the toughness of atherosclerotic plaque extracted from the femoral arteries of ten patients using a lubricated guillotine cutting test to determine the critical energy release rate. This information is related to the location that the plaque section was removed from within the femoral vessels and the composition of the plaque tissue, determined using Fourier Transform InfraRed spectroscopy, to establish the influence of location and composition on the toughness of the plaque tissue. Scanning electron microscopy (SEM) is employed to examine the fracture surfaces of the sections to determine the contribution of tissue morphology to toughness. Toughness results exhibit large inter and intra patient and location variance with values ranging far above and below the toughness of healthy porcine arterial tissue (Range: 1330-3035 for location and 140-4560J/m(2) for patients). No significant difference in mean toughness is observed between patients or location. However, the composition parameter representing the calcified tissue content of the plaque correlates significantly with sample toughness (r=0.949, p<0.001). SEM reveals the presence of large calcified regions in the toughest sections that are absent from the least tough sections. Regression analysis highlights the potential of employing the calcified tissue content of the plaque as a preoperative tool for predicting the fracture response of a target lesion to CBA (R(2)=0.885, p<0.001). This study addresses a gap in current knowledge regarding the influence of plaque location, composition and morphology on the toughness of human femoral plaque tissue. Such information is of great importance to the continued improvement of endovascular treatments, particularly cutting balloon angioplasty (CBA), which require experimentally derived data as a framework for assessing clinical cases and advancing medical devices. This study identifies that femoral plaque tissue exhibits large inter and intra patient and location variance regarding tissue toughness. Increasing calcified plaque content is demonstrated to correlate significantly with increasing toughness. This highlights the potential for predicting target lesion toughness which may lead to an increased adoption of the CBA technique and also further the uptake of endovascular treatment. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Blocking Wnt5a signaling decreases CD36 expression and foam cell formation in atherosclerosis.

PubMed

Ackers, Ian; Szymanski, Candice; Duckett, K Jordan; Consitt, Leslie A; Silver, Mitchell J; Malgor, Ramiro

Wnt5a is a highly studied member of the Wnt family and recently has been implicated in the pathogenesis of atherosclerosis, but its precise role is unknown. Foam cell development is a critical process to atherosclerotic plaque formation. In the present study, we investigated the role of noncanonical Wnt5a signaling in the development of foam cells. Human carotid atherosclerotic tissue and THP-1-derived macrophages were used to investigate the contribution of Wnt5a signaling in the formation of foam cells. Immunohistochemistry was used to evaluate protein expression of scavenger receptors and noncanonical Wnt5a receptors [frizzled 5 (Fz5) and receptor tyrosine kinase-like orphan receptor 2 (Ror2)] in human atherosclerotic macrophages/foam cells. Changes in protein expression in response to Wnt5a stimulation/inhibition were determined by Western blot, and lipid accumulation was evaluated by fluorescent lipid droplet staining. Wnt5a (P<.05), Fz5 (P<.01), and Ror2 (P<.01) were significantly expressed in advanced atherosclerotic lesions compared to less advanced lesions (N=10). Wnt5a, Fz5, and Ror2 were expressed in macrophages/foam cells within the plaque. In vitro studies revealed that Wnt5a significantly increased the expression of the lipid uptake receptor CD36 (P<.05) but not the lipid efflux receptor ATP-binding cassette transporter (P>.05). rWnt5a also significantly increased lipid accumulation in THP-1 macrophages (P<.05). Furthermore, inhibition of Wnt5a signaling with Box5 prevented lipid accumulation (P<.01) and prevented CD36 up-regulation (P<.01). These results suggest a direct role for Wnt5a signaling in the pathogenesis of atherosclerosis, specifically the accumulation of lipid in macrophages and the formation of foam cells. Copyright © 2018 Elsevier Inc. All rights reserved.

P2X7R is involved in the progression of atherosclerosis by promoting NLRP3 inflammasome activation

PubMed Central

PENG, KUANG; LIU, LUSHAN; WEI, DANGHENG; LV, YUNCHENG; WANG, GANG; XIONG, WENHAO; WANG, XIAOQING; ALTAF, AFRASYAB; WANG, LILI; HE, DAN; WANG, HONGYAN; QU, PENG

2015-01-01

Purinergic 2X7 receptor (P2X7R) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) are expressed in macrophages in atherosclerotic lesions. However, the mechanisms through which P2X7R participates in the inflammatory response in atherosclerosis remain largely unknown. The aim of the present study was to investigate the role of P2X7R in atherosclerosis and the mechanisms of action of the NLRP3 inflammasome following stimulation with oxidized low-density lipoprotein (oxLDL). We observed the expression and distribution of P2X7R in the atherosclerotic plaque in the coronary arteries from an autopsy specimen and in that of the aortic sinuses of apoE−/− mice by immunohistochemistry and immunofluorescence staining. The specificity of short interfering RNA (siRNA) was used to suppress P2X7R and NLRP3 mRNA expression. RT-qPCR and western blot analysis were used to analyze mRNA and protein expression, respectively. Co-immunoprecipitation was used to examine the interaction between protein kinase R (PKR) phosphorylation and NLRP3. P2X7R and NLRP3 were expressed at high levels in the atherosclerotic plaque in the coronary arteries. Stimulation with oxLDL upregulated P2X7R, NLRP3 and interleukin (IL)-1β expression. P2X7R knockdown by siRNA suppressed NLRP3 inflammasome activation by inhibiting the PKR phosphorylation mediated by oxLDL. In the atherosclerotic lesions in the aortic sinuses of apoE−/− mice, P2X7R expression was found at high levels. Moreover, P2X7R siRNA attenuated the development of atherosclerosis in the apoE−/− mice. In conclusion, our results demonstrate that P2X7R plays a significant role in the development of atherosclerosis and regulates NLRP3 inflammasome activation by promoting PKR phosphorylation. PMID:25761252

17β-estradiol suppresses the macrophage foam cell formation associated with SOCS3.

PubMed

Liang, X; He, M; Chen, T; Wu, Y; Tian, Y; Zhao, Y; Shen, Y; Liu, Y; Yuan, Z

2013-06-01

Evidence from clinical trials and animal experiments has shown that estrogen has anti-atherosclerotic effects when administered to young women or experimental animals. The mechanisms involve the modulation of vascular inflammation, growth factor expression, and oxidative stress injured arteries. However, whether estrogen modulates the foam cell formation in plaque remains unknown. Here, we investigated the effects of 17β-estradiol (E2) on cholesterol efflux in vivo and in vitro. ApoE null mice underwent an ovariectomy at 5(th) week of age and then were treated with E2 or vehicle for the following 8 weeks. Compared with the vehicle-treated mice, the serum total cholesterol level, atherosclerotic plaque size, and lipid deposits were decreased and meanwhile ATP-binding cassette transporter A1 (ABCA1) expression in the plaque was increased in mice with E2 treatment. E2 also increased suppressor of cytokine signaling 3 (SOCS3) expression in the atherosclerotic plaques and in RAW264.7 cells. In vitro, E2 treatment reversed janus kinase/signal transducers and activators of transcription (JAK/STAT)-inhibited ABCA1 expression in RAW264.7 cells but had no effect on ABCA1 expression in SOCS3 knockdown cells. SOCS3 overexpression elevated ABCA1 expression through the inhibition of JAK2/STAT3 phosphorylation. Finally, we also found that E2 enhanced the cholesterol efflux to apoA I in RAW264.7 cells. In summary, E2 reduces atherosclerosis in ApoE null mice associated with upregulating ABCA1 expression and modulating the cholesterol efflux, which are dependent on SOCS3 upregulation. These results provide new insight into the athero-protective effects of estrogen. © Georg Thieme Verlag KG Stuttgart · New York.

Chronic exposure to biomass fuel is associated with increased carotid artery intima-media thickness and a higher prevalence of atherosclerotic plaque

PubMed Central

Painschab, Matthew S; Davila-Roman, Victor G; Gilman, Robert H; Vasquez-Villar, Angel D; Pollard, Suzanne L; Wise, Robert A; Miranda, J Jaime; Checkley, William

2015-01-01

Background Biomass fuels are used for cooking in the majority of rural households worldwide. While their use is associated with an increased risk of lung diseases and all-cause mortality, the effects on cardiovascular disease (CVD) are not well characterised. Exposure to biomass fuel smoke has been associated with lung-mediated inflammation and oxidative stress, which may increase the risk of atherosclerosis as evaluated by carotid intima-media thickness (CIMT), carotid atherosclerotic plaque prevalence and blood pressure. Methods A cross-sectional study was performed in 266 adults aged ≥35 years in Puno, Peru (3825 m above sea level). We stratified participants by their long-term history of exposure to clean fuel (n=112) or biomass fuel (n=154) and measured 24 h indoor particulate matter (PM2.5) in a random subset (n=84). Participants completed questionnaires and underwent a clinical assessment, laboratory analyses and carotid artery ultrasound. The main outcome measures were CIMT, carotid plaque and blood pressure. Results The groups were similar in age and gender. The biomass fuel group had greater unadjusted mean CIMT (0.66 vs 0.60 mm; p<0.001), carotid plaque prevalence (26% vs 14%; p=0.03), systolic blood pressure (118 vs 111 mm Hg; p<0.001) and median household PM2.5 (280 vs 14 μg/m3; p<0.001). In multivariable regression, the biomass fuel group had greater mean CIMT (mean difference=0.03 mm, 95% CI 0.01 to 0.06; p=0.02), a higher prevalence of carotid plaques (OR=2.6, 95% CI 1.1 to 6.0; p=0.03) and higher systolic blood pressure (mean difference=9.2 mm Hg, 95% CI 5.4 to 13.0; p<0.001). Conclusions Chronic exposure to biomass fuel was associated with increased CIMT, increased prevalence of atherosclerotic plaques and higher blood pressure. These findings identify biomass fuel use as a risk factor for CVD, which may have important global health implications. PMID:23619984

Generation and characterization of human smooth muscle cell lines derived from atherosclerotic plaque.

PubMed

Bonin, L R; Madden, K; Shera, K; Ihle, J; Matthews, C; Aziz, S; Perez-Reyes, N; McDougall, J K; Conroy, S C

1999-03-01

The study of atherogenesis in humans has been restricted by the limited availability and brief in vitro life span of plaque smooth muscle cells (SMCs). We describe plaque SMC lines with extended life spans generated by the expression of the human papillomavirus (HPV)-16 E6 and E7 genes, which has been shown to extend the life span of normal adult human aortic SMCs. Resulting cell lines (pdSMC1A and 2) demonstrated at least 10-fold increases in life span; pdSMC1A became immortal. The SMC identity of both pdSMC lines was confirmed by SM22 mRNA expression. pdSMC2 were generally diploid but with various structural and numerical alterations; pdSMC1A demonstrated several chromosomal abnormalities, most commonly -Y, +7, -13, anomalies previously reported in both primary pdSMCs and atherosclerotic tissue. Confluent pdSMC2 appeared grossly similar to HPV-16 E6/E7-expressing normal adult aortic SMCs (AASMCs), exhibiting typical SMC morphology/growth patterns; pdSMC1A displayed irregular cell shape/organization with numerous mitotic figures. Dedifferentiation to a synthetic/proliferative phenotype has been hypothesized as a critical step in atherogenesis, because rat neonatal SMCs and adult intimal SMCs exhibit similar gene expression patterns. To confirm that our pdSMC lines likewise express this apparent plaque phenotype, osteopontin, platelet-derived growth factor B, and elastin mRNA levels were determined in pdSMC1A, pdSMC2, and AASMCs. However, no significant increases in osteopontin or platelet-derived growth factor B expression levels were observed in either pdSMC compared with AASMCs. pdSMC2 alone expressed high levels of elastin mRNA. Lower levels of SM22 mRNA in pdSMC1A suggested greater dedifferentiation and/or additional population doublings in pdSMC1A relative to pdSMC2. Both pdSMC lines (particularly 1A) demonstrated high message levels for matrix Gla protein, previously reported to be highly expressed by human neointimal SMCs in vitro. These results describe 2 novel plaque cell lines exhibiting various features of plaque SMC biology; pdSMC2 may represent an earlier plaque SMC phenotype, whereas pdSMC1A may be representative of cells comprising an advanced atherosclerotic lesion.

Development of a dual-modal tissue diagnostic system combining time-resolved fluorescence spectroscopy and ultrasonic backscatter microscopy.

PubMed

Sun, Yang; Park, Jesung; Stephens, Douglas N; Jo, Javier A; Sun, Lei; Cannata, Jonathan M; Saroufeem, Ramez M G; Shung, K Kirk; Marcu, Laura

2009-06-01

We report a tissue diagnostic system which combines two complementary techniques of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) and ultrasonic backscatter microscopy (UBM). TR-LIFS evaluates the biochemical composition of tissue, while UBM provides tissue microanatomy and enables localization of the region of diagnostic interest. The TR-LIFS component consists of an optical fiber-based time-domain apparatus including a spectrometer, gated multichannel plate photomultiplier, and fast digitizer. It records the fluorescence with high sensitivity (nM concentration range) and time resolution as low as 300 ps. The UBM system consists of a transducer, pulser, receiving circuit, and positioning stage. The transducer used here is 45 MHz, unfocused, with axial and lateral resolutions 38 and 200 microm. Validation of the hybrid system and ultrasonic and spectroscopic data coregistration were conducted both in vitro (tissue phantom) and ex vivo (atherosclerotic tissue specimens of human aorta). Standard histopathological analysis of tissue samples was used to validate the UBM-TRLIFS data. Current results have demonstrated that spatially correlated UBM and TR-LIFS data provide complementary characterization of both morphology (necrotic core and calcium deposits) and biochemistry (collagen, elastin, and lipid features) of the atherosclerotic plaques at the same location. Thus, a combination of fluorescence spectroscopy with ultrasound imaging would allow for better identification of features associated with tissue pathologies. Current design and performance of the hybrid system suggests potential applications in clinical diagnosis of atherosclerotic plaque.

Development of a dual-modal tissue diagnostic system combining time-resolved fluorescence spectroscopy and ultrasonic backscatter microscopy

PubMed Central

Sun, Yang; Park, Jesung; Stephens, Douglas N.; Jo, Javier A.; Sun, Lei; Cannata, Jonathan M.; Saroufeem, Ramez M. G.; Shung, K. Kirk; Marcu, Laura

2009-01-01

We report a tissue diagnostic system which combines two complementary techniques of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) and ultrasonic backscatter microscopy (UBM). TR-LIFS evaluates the biochemical composition of tissue, while UBM provides tissue microanatomy and enables localization of the region of diagnostic interest. The TR-LIFS component consists of an optical fiber-based time-domain apparatus including a spectrometer, gated multichannel plate photomultiplier, and fast digitizer. It records the fluorescence with high sensitivity (nM concentration range) and time resolution as low as 300 ps. The UBM system consists of a transducer, pulser, receiving circuit, and positioning stage. The transducer used here is 45 MHz, unfocused, with axial and lateral resolutions 38 and 200 μm. Validation of the hybrid system and ultrasonic and spectroscopic data coregistration were conducted both in vitro (tissue phantom) and ex vivo (atherosclerotic tissue specimens of human aorta). Standard histopathological analysis of tissue samples was used to validate the UBM-TRLIFS data. Current results have demonstrated that spatially correlated UBM and TR-LIFS data provide complementary characterization of both morphology (necrotic core and calcium deposits) and biochemistry (collagen, elastin, and lipid features) of the atherosclerotic plaques at the same location. Thus, a combination of fluorescence spectroscopy with ultrasound imaging would allow for better identification of features associated with tissue pathologies. Current design and performance of the hybrid system suggests potential applications in clinical diagnosis of atherosclerotic plaque. PMID:19566223

Development of a dual-modal tissue diagnostic system combining time-resolved fluorescence spectroscopy and ultrasonic backscatter microscopy

NASA Astrophysics Data System (ADS)

Sun, Yang; Park, Jesung; Stephens, Douglas N.; Jo, Javier A.; Sun, Lei; Cannata, Jonathan M.; Saroufeem, Ramez M. G.; Shung, K. Kirk; Marcu, Laura

2009-06-01

We report a tissue diagnostic system which combines two complementary techniques of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) and ultrasonic backscatter microscopy (UBM). TR-LIFS evaluates the biochemical composition of tissue, while UBM provides tissue microanatomy and enables localization of the region of diagnostic interest. The TR-LIFS component consists of an optical fiber-based time-domain apparatus including a spectrometer, gated multichannel plate photomultiplier, and fast digitizer. It records the fluorescence with high sensitivity (nM concentration range) and time resolution as low as 300 ps. The UBM system consists of a transducer, pulser, receiving circuit, and positioning stage. The transducer used here is 45 MHz, unfocused, with axial and lateral resolutions 38 and 200 μm. Validation of the hybrid system and ultrasonic and spectroscopic data coregistration were conducted both in vitro (tissue phantom) and ex vivo (atherosclerotic tissue specimens of human aorta). Standard histopathological analysis of tissue samples was used to validate the UBM-TRLIFS data. Current results have demonstrated that spatially correlated UBM and TR-LIFS data provide complementary characterization of both morphology (necrotic core and calcium deposits) and biochemistry (collagen, elastin, and lipid features) of the atherosclerotic plaques at the same location. Thus, a combination of fluorescence spectroscopy with ultrasound imaging would allow for better identification of features associated with tissue pathologies. Current design and performance of the hybrid system suggests potential applications in clinical diagnosis of atherosclerotic plaque.

Effects of atorvastatin on serum lipids, serum inflammation and plaque morphology in patients with stable atherosclerotic plaques.

PubMed

Guo, Suxia; Wang, Ruxing; Yang, Zhenyu; Li, Kulin; Wang, Qiang

2012-12-01

Statin treatment in patients with coronary heart disease is associated with a reduced incidence of short-term adverse events and endpoint cardiac events. However, the effects of statin treatment on atherosclerotic plaques, particularly stable plaques, remain poorly defined. In total, 228 consecutive patients with stable atherosclerotic plaques who had undergone coronary arteriography (CAG) and intravascular ultrasound (IVUS) were randomly assigned to receive placebo (placebo group, n=54) or atorvastatin (ATOR) at a single daily dose of 10 mg (ATOR 10 mg group, n=47), 20 mg (ATOR 20 mg group, n=45), 40 mg (ATOR 40 mg group, n=43) or 80 mg (ATOR 80 mg group, n=39). Endpoints, including serum lipids, serum inflammation, plaque volume and percentage of plaque necrosis were assessed after 3-6 months. At baseline, mean low-density lipoprotein (LDL), high-density lipoprotein (HDL) and high-sensitivity C-reactive protein (hs-CRP) levels, as well as plaque volumes and percentages of plaque necrosis, were similar between all groups. At 6 months of follow-up, the LDL levels in the ATOR groups were below those at their respective baselines (P<0.01). HDL levels in the ATOR 80 mg group following treatment were significantly higher compared with baseline (P=0.001). Additionally, they were significantly higher compared with those in the placebo, ATOR 10, 20 and 40 mg groups (P<0.01, P=0.001, P=0.048, P=0.047, respectively). Hs-CRP levels in the placebo group following treatment were higher compared with baseline levels (6.87±2.62 vs. 5.07±1.80, P<0.01), but hs-CRP levels in the ATOR 80 mg group following treatment were lower compared with baseline (3.59±1.07 vs. 6.10±2.12, P<0.01). According to the virtual histology (VH) of IVUS, the percentages of plaque necrosis following treatment in the placebo and ATOR 10 mg groups rose above baseline levels (15.51±12.56 vs. 7.69±1.31%, 13.54±11.76 vs. 7.83±1.43%, P<0.01) and conformed to the diagnostic criteria for unstable plaques (15.51±12.56, 13.54±11.76%). By contrast, in the ATOR 20, 40 and 80 mg groups, percentages of plaque necrosis remained stable following treatment compared with baseline (P=0.069, 0.846 and 0.643, respectively). Plaque volumes following treatment in the placebo, ATOR 10 and 20 mg groups were similar to baseline levels. However, in the ATOR 40 and 80 mg groups, plaque volumes decreased following treatment compared with baseline plaque volumes (30.69±8.12 vs. 37.09±12.01 mm(3), 24.99±1.01 vs. 36.47±14.68 mm(3), P=0.019, P<0.01, respectively). ATOR (20 mg/day) is able to lower LDL to standard levels while ATOR 40 mg/day was superior to 20 mg/day and had similar effects to 80 mg/day. Only ATOR 80 mg/day was able to increase HDL levels. Hs-CRP in patients without ATOR was higher and ATOR 80 mg/day decreased levels. ATOR ≥20 mg/day is able to stabilize plaques and ATOR 80 mg/day was superior to 20 and 40 mg/day. Thus, ATOR 40-80 mg/day reduces the volume of plaques.

Effects of atorvastatin on serum lipids, serum inflammation and plaque morphology in patients with stable atherosclerotic plaques

PubMed Central

GUO, SUXIA; WANG, RUXING; YANG, ZHENYU; LI, KULIN; WANG, QIANG

2012-01-01

Statin treatment in patients with coronary heart disease is associated with a reduced incidence of short-term adverse events and endpoint cardiac events. However, the effects of statin treatment on atherosclerotic plaques, particularly stable plaques, remain poorly defined. In total, 228 consecutive patients with stable atherosclerotic plaques who had undergone coronary arteriography (CAG) and intravascular ultrasound (IVUS) were randomly assigned to receive placebo (placebo group, n=54) or atorvastatin (ATOR) at a single daily dose of 10 mg (ATOR 10 mg group, n=47), 20 mg (ATOR 20 mg group, n=45), 40 mg (ATOR 40 mg group, n=43) or 80 mg (ATOR 80 mg group, n=39). Endpoints, including serum lipids, serum inflammation, plaque volume and percentage of plaque necrosis were assessed after 3–6 months. At baseline, mean low-density lipoprotein (LDL), high-density lipoprotein (HDL) and high-sensitivity C-reactive protein (hs-CRP) levels, as well as plaque volumes and percentages of plaque necrosis, were similar between all groups. At 6 months of follow-up, the LDL levels in the ATOR groups were below those at their respective baselines (P<0.01). HDL levels in the ATOR 80 mg group following treatment were significantly higher compared with baseline (P=0.001). Additionally, they were significantly higher compared with those in the placebo, ATOR 10, 20 and 40 mg groups (P<0.01, P=0.001, P=0.048, P=0.047, respectively). Hs-CRP levels in the placebo group following treatment were higher compared with baseline levels (6.87±2.62 vs. 5.07±1.80, P<0.01), but hs-CRP levels in the ATOR 80 mg group following treatment were lower compared with baseline (3.59±1.07 vs. 6.10±2.12, P<0.01). According to the virtual histology (VH) of IVUS, the percentages of plaque necrosis following treatment in the placebo and ATOR 10 mg groups rose above baseline levels (15.51±12.56 vs. 7.69±1.31%, 13.54±11.76 vs. 7.83±1.43%, P<0.01) and conformed to the diagnostic criteria for unstable plaques (15.51±12.56, 13.54±11.76%). By contrast, in the ATOR 20, 40 and 80 mg groups, percentages of plaque necrosis remained stable following treatment compared with baseline (P=0.069, 0.846 and 0.643, respectively). Plaque volumes following treatment in the placebo, ATOR 10 and 20 mg groups were similar to baseline levels. However, in the ATOR 40 and 80 mg groups, plaque volumes decreased following treatment compared with baseline plaque volumes (30.69±8.12 vs. 37.09±12.01 mm3, 24.99±1.01 vs. 36.47±14.68 mm3, P=0.019, P<0.01, respectively). ATOR (20 mg/day) is able to lower LDL to standard levels while ATOR 40 mg/day was superior to 20 mg/day and had similar effects to 80 mg/day. Only ATOR 80 mg/day was able to increase HDL levels. Hs-CRP in patients without ATOR was higher and ATOR 80 mg/day decreased levels. ATOR ≥20 mg/day is able to stabilize plaques and ATOR 80 mg/day was superior to 20 and 40 mg/day. Thus, ATOR 40–80 mg/day reduces the volume of plaques. PMID:23226776

Mediterranean diet and carotid atherosclerosis in the Northern Manhattan Study

PubMed Central

Gardener, Hannah; Wright, Clinton B.; Cabral, Digna; Scarmeas, Nikolaos; Gu, Yian; Cheung, Ken; Elkind, Mitchell S.V.; Sacco, Ralph L.; Rundek, Tatjana

2015-01-01

Objective Adherence to a Mediterranean-style diet (MeDi) may protect against clinical vascular events by reducing atherosclerosis, but data is limited. This is the first observational study of the association between MeDi adherence and carotid plaque thickness and area. Methods The study included 1374 participants of the population-based Northern Manhattan Study with diet assessed and carotid intima-media thickness (cIMT) and plaque measured using B-mode ultrasound (mean age 66 ± 9 years, 60% female, 60% Hispanic, 18% White, 19% Black). A MeDi adherence score (range = 0–9, 9 representing maximal adherence) was examined continuously and in quintiles (3/4/5/6 –9 vs. 0–2). Results Mean cIMT = 0.9 ± 0.1 mm and 57% had plaque (median plaque thickness = 1.5 mm, 75th percentile = 2.2; median plaque area = 4.2 mm2, 75th percentile = 15.8). There was no association between MeDi and cIMT or plaque presence. MeDi adherence was inversely associated with the 75th percentile of plaque thickness and median of plaque area in quantile regression analyses. These associations persisted after controlling for demographics, smoking, physical activity, and total energy consumption (effect of a 1-point increase in MeDi score on the 75th percentile of plaque thickness = −0.049 mm, p = 0.03; median of plaque area = −0.371 mm2, p = 0.03), and when additionally controlling for vascular disease biomarkers, medication use, BMI, and previous cardiac disease. The protective associations appeared strongest for those with a MeDi score of 5 (4th quintile) vs. 0–2 (bottom quintile). Differential effects of a MeDi on plaque thickness and area across race/ethnic groups was suggested. Conclusions Moderate and strict adherence to a MeDi may protect against a higher burden of carotid atherosclerotic plaque, which may mediate the protection against clinical vascular events. Efforts to improve adherence to a MeDi are critical to reducing the burden of atherosclerotic disease. PMID:24721190

Mediterranean diet and carotid atherosclerosis in the Northern Manhattan Study.

PubMed

Gardener, Hannah; Wright, Clinton B; Cabral, Digna; Scarmeas, Nikolaos; Gu, Yian; Cheung, Ken; Elkind, Mitchell S V; Sacco, Ralph L; Rundek, Tatjana

2014-06-01

Adherence to a Mediterranean-style diet (MeDi) may protect against clinical vascular events by reducing atherosclerosis, but data is limited. This is the first observational study of the association between MeDi adherence and carotid plaque thickness and area. The study included 1374 participants of the population-based Northern Manhattan Study with diet assessed and carotid intima-media thickness (cIMT) and plaque measured using B-mode ultrasound (mean age 66 ± 9 years, 60% female, 60% Hispanic, 18% White, 19% Black). A MeDi adherence score (range = 0-9, 9 representing maximal adherence) was examined continuously and in quintiles (3/4/5/6-9 vs. 0-2). Mean cIMT = 0.9 ± 0.1 mm and 57% had plaque (median plaque thickness = 1.5 mm, 75th percentile = 2.2; median plaque area = 4.2 mm(2), 75th percentile = 15.8). There was no association between MeDi and cIMT or plaque presence. MeDi adherence was inversely associated with the 75th percentile of plaque thickness and median of plaque area in quantile regression analyses. These associations persisted after controlling for demographics, smoking, physical activity, and total energy consumption (effect of a 1-point increase in MeDi score on the 75th percentile of plaque thickness = -0.049 mm, p = 0.03; median of plaque area = -0.371 mm(2), p = 0.03), and when additionally controlling for vascular disease biomarkers, medication use, BMI, and previous cardiac disease. The protective associations appeared strongest for those with a MeDi score of 5 (4th quintile) vs. 0-2 (bottom quintile). Differential effects of a MeDi on plaque thickness and area across race/ethnic groups was suggested. Moderate and strict adherence to a MeDi may protect against a higher burden of carotid atherosclerotic plaque, which may mediate the protection against clinical vascular events. Efforts to improve adherence to a MeDi are critical to reducing the burden of atherosclerotic disease. Copyright © 2014. Published by Elsevier Ireland Ltd.

Detection of Vulnerable Atherosclerotic Plaques in Experimental Atherosclerosis with the USPIO-Enhanced MRI.

PubMed

Qi, Chun-Mei; Du, Lili; Wu, Wei-Heng; Li, Dong-Ye; Hao, Ji; Gong, Lei; Deng, Liangrong; Zhang, Tao; Zhang, Chao; Zhang, Yu

2015-11-01

This study's goal was to assess the diagnostic value of the USPIO-(ultra-small superparamagnetic iron oxide) enhanced magnetic resonance imaging (MRI) in detection of vulnerable atherosclerotic plaques in abdominal aorta in experimental atherosclerosis. Thirty New Zealand rabbits were randomly divided into two groups, Group A and Group B. Each group comprised 15 animals which were fed with high cholesterol diet for 8 weeks and then subjected to balloon-induced endothelial injury of the abdominal aorta. After another 8 weeks, animals in Group B received adenovirus carrying p53 gene that was injected through a catheter into the aortic segments rich in plaques. Two weeks later, all rabbits were challenged with the injection of Chinese Russell's viper venom and histamine. Pre-contrast images and USPIO-enhanced MRI images were obtained after pharmacological triggering with injection of USPIO for 5 days. Blood specimens were taken for biochemical and serological tests at 0 and 18 weeks. Abdominal aorta was histologically studied. The levels of serum ICAM-1 and VCAM-1 were quantified by ELISA. Vulnerable plaques appeared as a local hypo-intense signal on the USPIO-enhanced MRI, especially on T2*-weighted sequences. The signal strength of plaques reached the peak at 96 h. Lipid levels were significantly (p < 0.05) higher in both Group A and B compared with the levels before the high cholesterol diet. The ICAM-1 and VCAM-1 levels were significantly (p < 0.05) higher in Group B compared with Group A. The USPIO-enhanced MRI efficiently identifies vulnerable plaques due to accumulation of USPIO within macrophages in abdominal aorta plaques.

Bone marrow endothelial progenitors augment atherosclerotic plaque regression in a mouse model of plasma lipid lowering

PubMed Central

Yao, Longbiao; Heuser-Baker, Janet; Herlea-Pana, Oana; Iida, Ryuji; Wang, Qilong; Zou, Ming-Hui; Barlic-Dicen, Jana

2012-01-01

The major event initiating atherosclerosis is hypercholesterolemia-induced disruption of vascular endothelium integrity. In settings of endothelial damage, endothelial progenitor cells (EPCs) are mobilized from bone marrow into circulation and home to sites of vascular injury where they aid endothelial regeneration. Given the beneficial effects of EPCs in vascular repair, we hypothesized that these cells play a pivotal role in atherosclerosis regression. We tested our hypothesis in the atherosclerosis-prone mouse model in which hypercholesterolemia, one of the main factors affecting EPC homeostasis, is reversible (Reversa mice). In these mice normalization of plasma lipids decreased atherosclerotic burden; however, plaque regression was incomplete. To explore whether endothelial progenitors contribute to atherosclerosis regression, bone marrow EPCs from a transgenic strain expressing green fluorescent protein under the control of endothelial cell-specific Tie2 promoter (Tie2-GFP+) were isolated. These cells were then adoptively transferred into atheroregressing Reversa recipients where they augmented plaque regression induced by reversal of hypercholesterolemia. Advanced plaque regression correlated with engraftment of Tie2-GFP+ EPCs into endothelium and resulted in an increase in atheroprotective nitric oxide and improved vascular relaxation. Similarly augmented plaque regression was also detected in regressing Reversa mice treated with the stem cell mobilizer AMD3100 which also mobilizes EPCs to peripheral blood. We conclude that correction of hypercholesterolemia in Reversa mice leads to partial plaque regression that can be augmented by AMD3100 treatment or by adoptive transfer of EPCs. This suggests that direct cell therapy or indirect progenitor cell mobilization therapy may be used in combination with statins to treat atherosclerosis. PMID:23081735

Motion Artifact Reduction in Ultrasound Based Thermal Strain Imaging of Atherosclerotic Plaques Using Time Series Analysis

PubMed Central

Dutta, Debaditya; Mahmoud, Ahmed M.; Leers, Steven A.; Kim, Kang

2013-01-01

Large lipid pools in vulnerable plaques, in principle, can be detected using US based thermal strain imaging (US-TSI). One practical challenge for in vivo cardiovascular application of US-TSI is that the thermal strain is masked by the mechanical strain caused by cardiac pulsation. ECG gating is a widely adopted method for cardiac motion compensation, but it is often susceptible to electrical and physiological noise. In this paper, we present an alternative time series analysis approach to separate thermal strain from the mechanical strain without using ECG. The performance and feasibility of the time-series analysis technique was tested via numerical simulation as well as in vitro water tank experiments using a vessel mimicking phantom and an excised human atherosclerotic artery where the cardiac pulsation is simulated by a pulsatile pump. PMID:24808628

Quantifying progression and regression of thrombotic risk in experimental atherosclerosis

PubMed Central

Palekar, Rohun U.; Jallouk, Andrew P.; Goette, Matthew J.; Chen, Junjie; Myerson, Jacob W.; Allen, John S.; Akk, Antonina; Yang, Lihua; Tu, Yizheng; Miller, Mark J.; Pham, Christine T. N.; Wickline, Samuel A.; Pan, Hua

2015-01-01

Currently, there are no generally applicable noninvasive methods for defining the relationship between atherosclerotic vascular damage and risk of focal thrombosis. Herein, we demonstrate methods to delineate the progression and regression of vascular damage in response to an atherogenic diet by quantifying the in vivo accumulation of semipermeable 200–300 nm perfluorocarbon core nanoparticles (PFC-NP) in ApoE null mouse plaques with [19F] magnetic resonance spectroscopy (MRS). Permeability to PFC-NP remained minimal until 12 weeks on diet, then increased rapidly following 12 weeks, but regressed to baseline within 8 weeks after diet normalization. Markedly accelerated clotting (53.3% decrease in clotting time) was observed in carotid artery preparations of fat-fed mice subjected to photochemical injury as defined by the time to flow cessation. For all mice on and off diet, an inverse linear relationship was observed between the permeability to PFC-NP and accelerated thrombosis (P = 0.02). Translational feasibility for quantifying plaque permeability and vascular damage in vivo was demonstrated with clinical 3 T MRI of PFC-NP accumulating in plaques of atherosclerotic rabbits. These observations suggest that excessive permeability to PFC-NP may indicate prothrombotic risk in damaged atherosclerotic vasculature, which resolves within weeks after dietary therapy.—Palekar, R. U., Jallouk, A. P., Goette, M. J., Chen, J., Myerson, J. W., Allen, J. S., Akk, A., Yang, L., Tu, Y., Miller, M. J., Pham, C. T. N., Wickline, S. A., Pan, H. Quantifying progression and regression of thrombotic risk in experimental atherosclerosis. PMID:25857553

MiR-143/145 deficiency attenuates the progression of atherosclerosis in Ldlr-/-mice.

PubMed

Sala, Federica; Aranda, Juan F; Rotllan, Noemi; Ramírez, Cristina M; Aryal, Binod; Elia, Leonardo; Condorelli, Gianluigi; Catapano, Alberico Luigi; Fernández-Hernando, Carlos; Norata, Giuseppe Danilo

2014-10-01

The miR-143/145 cluster regulates VSMC specific gene expression, thus controlling differentiation, plasticity and contractile function, and promoting the VSMC phenotypic switch from a contractile/non-proliferative to a migrating/proliferative state. More recently increased miR-145 expression was observed in human carotid atherosclerotic plaques from symptomatic patients. The goal of this study was to investigate the contribution of miR-143/145 during atherogenesis by generating mice lacking miR-143/145 on an Ldlr-deficient background. Ldlr-/- and Ldlr-/--miR-143/145-/- (DKO) were fed a Western diet (WD) for 16 weeks. At the end of the treatment, the lipid profile and the atherosclerotic lesions were assessed in both groups of mice. Absence of miR-143/145 significantly reduced atherosclerotic plaque size and macrophage infiltration. Plasma total cholesterol levels were lower in DKO and FLPC analysis showed decreased cholesterol content in VLDL and LDL fractions. Interestingly miR-143/145 deficiency per se resulted in increased hepatic and vascular ABCA1 expression. We further confirmed the direct regulation of miR-145 on ABCA1 expression by qRT-PCR, Western blotting and 3'UTR-luciferase reporter assays. In summary, miR-143/145 deficiency significantly reduces atherosclerosis in mice. Therapeutic inhibition of miR-145 might be useful for treating atherosclerotic vascular disease.

Effects of induction/inhibition of endogenous heme oxygenase-1 on lipid metabolism, endothelial function, and atherosclerosis in rabbits on a high fat diet.

PubMed

Liu, Danan; He, Zuoyun; Wu, Lirong; Fang, Ying

2012-01-01

The heme oxygenase-1 (HO-1) / carbon monoxide (CO) system has been presumed as a therapeutic target for preventing atherosclerosis. However, the exact mechanism(s) underlying this system remains largely undefined. This study aims to examine the influence of induction/inhibition of HO-1 on atherosclerotic plaque using pharmacological approaches and to elucidate potential mechanisms. Rabbits were randomly assigned to receive a standard diet (control group), high fat diet (HFD), HFD plus HO inducer hemin (HFD + H group), and HFD plus an HO inhibitor, zinc protoporphyrin-9 (ZnPP9, HFD + Z group). Atherosclerotic plaque was evaluated using oil red O staining and histological analyses. Immunohistochemistry, western blotting, and RT-PCR were employed to study the expression of HO-1 and endothelin-1 (ET-1). Levels of CO, nitric oxide (NO), eNOS/iNOS activities, NF-κB activity, and TNF-α level were determined. No significant differences of serum lipid levels were observed among the HFD, HFD + Z, and HFD + H groups. In rabbits, HFD induced typical atherosclerotic plaque and increased intima/media thickness ratio, which was markedly reduced in the HFD + H group and further aggravated in the HFD + Z group. Furthermore, hemin increased HO-1 expression, CO levels, and eNOS activity, while decreasing iNOS levels, ET-1 expression, NF-κB activity, and TNF-α level. ZnPP9 caused opposite effects. Induction of the endogenous HO-1/CO system by hemin can prevent atherosclerosis though increasing CO levels, regulating eNOS activity, NF-κB activity, TNF-α levels, and ET-1 levels in rabbits. Our results add new evidence for the importance of HO-1 in the genesis and development of atherosclerosis and provide several possible mechanisms underlying the anti-atherosclerosis effects of HO-1.

Applied Imagistics of Ischaemic Heart a Survey. From the Epidemiology of Stable Angina In Order to Better Prevent Sudden Cardiac Death

NASA Astrophysics Data System (ADS)

Petruse, Radu Emanuil; Batâr, Sergiu; Cojan, Adela; Maniţiu, Ioan

2014-11-01

Coronary computed tomography angiography (CCTA) allows coronary artery visualization and the detection of coronary stenoses. In addition; it has been suggested as a novel, noninvasive modality for coronary atherosclerotic plaque detection, characterization, and quantification. Accurate identification of coronary plaques is challenging, especially for the noncalcified plaques, due to many factors such as the small size of coronary arteries, reconstruction artifacts caused by irregular heartbeats, beam hardening, and partial volume averaging. The development of 16, 32, 64 and the latest 320 row multidetector CT not only increases the spatial and the temporal resolution significantly, but also increases the number of images to be interpreted by radiologists substantially. Radiologists have to visually examine each coronary artery for suspicious stenosis using visualization tools such as multiplanar reformatting (MPR) and curved planar reformatting (CPR) provided by the review workstation in clinical practice

The intravenous injection of oxidized LDL- or Apolipoprotein B100 – Coupled splenocytes promotes Th1 polarization in wildtype and Apolipoprotein E – Deficient mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Steinmetz, Martin, E-mail: martin.steinmetz@ukb.uni-bonn.de; Internal Medicine II, University Hospital Bonn, 53105 Bonn; Ponnuswamy, Padmapriya

Background: Th1 responses in atherosclerosis are mainly associated with the aggravation of atherosclerotic plaques, whereas Th2 responses lead to a less pronounced disease in mouse models. The fixation of antigens on cells by means of ethylene carbodiimide (ECDI), and subsequent injection of these antigen-coupled splenocytes (Ag-SP) to induce tolerance against the attached antigens, has been successfully used to treat murine type 1 diabetes or encephalomyelitis in. We analyzed this approach in a mouse model for atherosclerosis. Methods and results: OTII-transgenic mice that were treated with a single dose of 5 × 10{sup 7} OVA-coupled splenocytes (OVA-SP), had decreased splenocyte proliferation, and lowermore » IFNγ production in vitro upon antigen recall. However, in vivo CD4 cell activation was increased. To try lipoprotein-derived, “atherosclerosis-associated” antigens, we first tested human oxidized LDL. In wild type mice, an increase of IFNγ production upon in vitro recall was detected in the oxLDL-SP group. In Apolipoprotein E − deficient (ApoE−/−) mice that received oxLDL-SP every 5 weeks for 20 weeks, we did not find any difference of atherosclerotic plaque burden, but again increased IFNγ production. To overcome xenogenous limitations, we then examined the effects of mouse Apolipoprotein B100 peptides P3 and P6. ApoB100-SP treatment again promoted a more IFNγ pronounced response upon in vitro recall. Flow cytometry analysis of cytokine secreting spleen cells revealed CD4 positive T cells to be mainly the source for IFNγ. In ApoE−/− mice that were administered ApoB100-SP during 20 weeks, the atherosclerotic plaque burden in aortic roots as well as total aorta was unchanged compared to PBS treated controls. Splenocyte proliferation upon antigen recall was not significantly altered in ApoB100-SP treated ApoE−/− mice. Conclusion: Although we did not observe a relevant anti-atherosclerotic benefit, the treatment with antigen-coupled splenocytes in its present form already impacts the immune responses and deserves further exploration. - Highlights: • OVA-SP reduce leucocyte proliferation and IFNγ production in OTII mice. • oxLDL- and ApoB100-splenocytes unexpectedly promote a Th1 response. • Atherosclerotic plaques are unchanged through injections of oxLDL-SP or ApoB100-SP.« less

Open-source telemedicine platform for wireless medical video communication.

PubMed

Panayides, A; Eleftheriou, I; Pantziaris, M

2013-01-01

An m-health system for real-time wireless communication of medical video based on open-source software is presented. The objective is to deliver a low-cost telemedicine platform which will allow for reliable remote diagnosis m-health applications such as emergency incidents, mass population screening, and medical education purposes. The performance of the proposed system is demonstrated using five atherosclerotic plaque ultrasound videos. The videos are encoded at the clinically acquired resolution, in addition to lower, QCIF, and CIF resolutions, at different bitrates, and four different encoding structures. Commercially available wireless local area network (WLAN) and 3.5G high-speed packet access (HSPA) wireless channels are used to validate the developed platform. Objective video quality assessment is based on PSNR ratings, following calibration using the variable frame delay (VFD) algorithm that removes temporal mismatch between original and received videos. Clinical evaluation is based on atherosclerotic plaque ultrasound video assessment protocol. Experimental results show that adequate diagnostic quality wireless medical video communications are realized using the designed telemedicine platform. HSPA cellular networks provide for ultrasound video transmission at the acquired resolution, while VFD algorithm utilization bridges objective and subjective ratings.

Open-Source Telemedicine Platform for Wireless Medical Video Communication

PubMed Central

Panayides, A.; Eleftheriou, I.; Pantziaris, M.

2013-01-01

An m-health system for real-time wireless communication of medical video based on open-source software is presented. The objective is to deliver a low-cost telemedicine platform which will allow for reliable remote diagnosis m-health applications such as emergency incidents, mass population screening, and medical education purposes. The performance of the proposed system is demonstrated using five atherosclerotic plaque ultrasound videos. The videos are encoded at the clinically acquired resolution, in addition to lower, QCIF, and CIF resolutions, at different bitrates, and four different encoding structures. Commercially available wireless local area network (WLAN) and 3.5G high-speed packet access (HSPA) wireless channels are used to validate the developed platform. Objective video quality assessment is based on PSNR ratings, following calibration using the variable frame delay (VFD) algorithm that removes temporal mismatch between original and received videos. Clinical evaluation is based on atherosclerotic plaque ultrasound video assessment protocol. Experimental results show that adequate diagnostic quality wireless medical video communications are realized using the designed telemedicine platform. HSPA cellular networks provide for ultrasound video transmission at the acquired resolution, while VFD algorithm utilization bridges objective and subjective ratings. PMID:23573082

Variogram methods for texture classification of atherosclerotic plaque ultrasound images

NASA Astrophysics Data System (ADS)

Jeromin, Oliver M.; Pattichis, Marios S.; Pattichis, Constantinos; Kyriacou, Efthyvoulos; Nicolaides, Andrew

2006-03-01

Stroke is the third leading cause of death in the western world and the major cause of disability in adults. The type and stenosis of extracranial carotid artery disease is often responsible for ischemic strokes, transient ischemic attacks (TIAs) or amaurosis fugax (AF). The identification and grading of stenosis can be done using gray scale ultrasound scans. The appearance of B-scan pictures containing various granular structures makes the use of texture analysis techniques suitable for computer assisted tissue characterization purposes. The objective of this study is to investigate the usefulness of variogram analysis in the assessment of ultrasound plague morphology. The variogram estimates the variance of random fields, from arbitrary samples in space. We explore stationary random field models based on the variogram, which can be applied in ultrasound plaque imaging leading to a Computer Aided Diagnosis (CAD) system for the early detection of symptomatic atherosclerotic plaques. Non-parametric tests on the variogram coefficients show that the cofficients coming from symptomatic versus asymptomatic plaques come from distinct distributions. Furthermore, we show significant improvement in class separation, when a log point-transformation is applied to the images, prior to variogram estimation. Model fitting using least squares is explored for anisotropic variograms along specific directions. Comparative classification results, show that variogram coefficients can be used for the early detection of symptomatic cases, and also exhibit the largest class distances between symptomatic and asymptomatic plaque images, as compared to over 60 other texture features, used in the literature.

Hematopoietic arginase 1 deficiency results in decreased leukocytosis and increased foam cell formation but does not affect atherosclerosis.

PubMed

Ren, Baoyan; Van Kampen, Erik; Van Berkel, Theo J C; Cruickshank, Sheena M; Van Eck, Miranda

2017-01-01

Arginase1 (Arg1), an M2 macrophage marker, plays a critical role in a number of immunological functions in macrophages, which are the main cell type facilitating atherosclerotic lesion development. Arg1 uses the substrate l-arginine to create l-ornithine, a precursor molecule required for collagen formation and vascular smooth muscle cell differentiation. By reducing l-arginine availability, Arg1 limits the production of nitric oxide (NO), a pro-atherogenic factor in macrophages. In endothelial cells, conversely, NO is strongly anti-atherogenic. However, until now, the role of Arg1 in atherosclerosis is largely unknown. The aim of this study is to specifically investigate the effect of Arg1 deletion in hematopoietic cells on atherosclerosis susceptibility. Ldlr KO mice were transplanted with Arg1 flox/flox ;Tie2-Cre (Arg1 KO) bone marrow (BM) or wildtype (WT) BM. After 8 weeks of recovery on chow diet, recipients mice were fed a Western-Type Diet (WTD) for 10 weeks to induce atherosclerosis. After 10-week WTD challenge, blood leukocyte counts were decreased by 25% (p < 0.001), and spleen leukocytes were decreased by 35% (p = 0.05) in Ldlr KO mice transplanted with Arg1 KO BM compared to mice transplanted with WT BM. The decrease in leukocytes was due to lower B lymphocyte counts. However, oxLDL-specific antibodies were increased in plasma of Ldlr KO mice transplanted with Arg1 KO BM compared to WT BM transplanted controls, whereas oxLDL-specific IgM was not affected. On the other hand, peritoneal foam cells in Arg1 KO BM recipients were increased 3-fold (p < 0.001) compared to WT BM recipients. No change in blood cholesterol was found. Despite changes in leukocyte counts and macrophage foam cell formation, we did not observe differences in atherosclerotic plaque size or plaque macrophage content in the aortic root. Surprisingly, there was also no difference in plaque collagen content, indicating that absence of macrophage Arg1 function does not reduce plaque stability. Deletion of Arg1 in hematopoietic cells adversely affects blood leukocyte counts and increases foam cell formation. However, no effects on atherosclerosis could be demonstrated, indicating that hematopoietic Arg1 function is not a decisive factor in atherosclerotic plaque formation. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

A comparative study of percutaneous atherectomy for femoropopliteal arterial occlusive disease.

PubMed

Gu, Yongquan; Malas, Mahmoud B; Qi, Lixing; Guo, Lianrui; Guo, Jianming; Yu, Hengxi; Tong, Zhu; Gao, Xixiang; Zhang, Jian; Wang, Zhonggao

2017-08-01

SilverHawk™ directional atherectomy has been used to treat more than 300 thousand cases of lower extremity atherosclerotic occlusive disease in the world since it was approved by FDA in 2003. This study aimed to analyze the safety and effectiveness of symptomatic femoral popliteal atherosclerotic disease treated by directional atherectomy (DA). Clinical data of all consecutive patients treated with percutaneous atherectomy utilizing the SilverHawk™ plaque excision was retrospectively analyzed. The anatomic criteria of the atherosclerotic lesions were divided into four types: type I stenosis; type II occlusion; type III in-stent restenosis; type IV stent occlusion. There were 160 patients treated during the study period. Intermittent claudication in 75 patients (47%), rest pain in 55 patients (34.5%) and tissue loss in 30 patients (18.5%). The number of patients was 72, 15, 49 and 24 in type I, II, III and IV lesions, respectively. Technical success rate was 98.6%, 93.3%, 97.9% and 91.7% in type I, II, III and IV lesions, respectively. Debris of intimal plaque was captured by protection device in 92 patients (71.3%). The mean follow-up period was 23.5±10.4 months. Restenosis rate of type I to IV lesions was 21%, 36%, 36% and 40% respectively. Restenosis rate in type I lesion was significantly lower than that in type III and IV lesions (P<0.05). Patients with tissue loss responded to revascularization as follow: type I, 11/13 healed or reduced (84.6%), type II, 3/3 patients improved (100%), type III, 5/6 patients improved (83.3%) and type IV 4/4 healed (100%). In type IV group, four patients had in-stent thrombosis found by postoperative Duplex ultrasonography. They all underwent DA after catheter-directed thrombolysis with good angiographic results. Percutaneous DA is safe and effective for both de-novo atherosclerotic and in-stent stenotic or occlusive lesions. Thrombolysis before plaque excision is recommended in case of in-stenting thrombosis.

Relationship between left main coronary artery plaque burden and nonleft main coronary atherosclerosis: results from the PROSPECT study.

PubMed

Shimizu, Takehisa; Mintz, Gary S; De Bruyne, Bernard; Farhat, Naim Z; Inaba, Shinji; Cao, Yang; Marso, Steven P; Weisz, Giora; Serruys, Patrick W; Stone, Gregg W; Maehara, Akiko

2018-05-17

Whether the severity of left main coronary artery (LMCA) disease reflects LMCA and overall coronary atherosclerotic burden is not known. We aimed to assess nonculprit LMCA disease characteristics and the relationship with atherosclerosis in the rest of the coronary arteries as well as patient outcomes. In the PROSPECT study, 697 patients with acute coronary syndromes underwent three-vessel gray-scale and radiofrequency intravascular ultrasound after percutaneous coronary intervention. Overall, 552 patients with adequate LMCA imaging were compared according to LMCA plaque burden. The tertile with the highest plaque burden in the LMCA had the smallest LMCA minimum lumen area (17.4, 14.2, 10.5, lowest through highest tertiles, respectively, P<0.0001) and the greatest percent necrotic core volume (2.8, 5.6, 9.5%, lowest through highest tertiles, respectively, P<0.0001). Furthermore, the tertile with the highest plaque burden was also significantly associated with the highest overall non-LMCA percent atheroma volume within the major epicardial arteries (48.3, 49.2, 50.8%, lowest through highest tertiles, respectively, P<0.0001). After adjusting for patient background, the LMCA plaque burden was independently associated with non-LMCA percent atheroma volume (P=0.003). Of the three PROSPECT predictors of future nonculprit major adverse cardiac events (MACE) (minimum lumen area≤4 mm, plaque burden≥70%, and virtual histology thin-cap fibroatheroma), the tertile with the highest LMCA plaque burden had the highest number of patients with at least one of three PROSPECT predictors (P=0.03). In multivariable model, though total atheroma volume (per 1%) was an independent predictor of all MACE [hazard ratio (95% confidence interval)=1.06 (1.01-1.11), P=0.02] and strong trend for non-culprit-related MACE [hazard ratio (95% confidence interval)=1.06 (1.00-1.13), P=0.06], plaque burden at LMCA was not (all MACE, P=0.90, non-culprit-related MACE, P=0.85). The severity of atherosclerosis in LMCA predicted the overall atherosclerotic plaque burden as well as the presence of high-risk plaques in the three major epicardial coronary arteries.

Semi-Automated Curation Allows Causal Network Model Building for the Quantification of Age-Dependent Plaque Progression in ApoE-/- Mouse.

PubMed

Szostak, Justyna; Martin, Florian; Talikka, Marja; Peitsch, Manuel C; Hoeng, Julia

2016-01-01

The cellular and molecular mechanisms behind the process of atherosclerotic plaque destabilization are complex, and molecular data from aortic plaques are difficult to interpret. Biological network models may overcome these difficulties and precisely quantify the molecular mechanisms impacted during disease progression. The atherosclerosis plaque destabilization biological network model was constructed with the semiautomated curation pipeline, BELIEF. Cellular and molecular mechanisms promoting plaque destabilization or rupture were captured in the network model. Public transcriptomic data sets were used to demonstrate the specificity of the network model and to capture the different mechanisms that were impacted in ApoE -/- mouse aorta at 6 and 32 weeks. We concluded that network models combined with the network perturbation amplitude algorithm provide a sensitive, quantitative method to follow disease progression at the molecular level. This approach can be used to investigate and quantify molecular mechanisms during plaque progression.

Mast Cells: Pivotal Players in Cardiovascular Diseases

PubMed Central

Bot, Ilze; van Berkel, Theo J.C; Biessen, Erik A.L

2008-01-01

The clinical outcome of cardiovascular diseases as myocardial infarction and stroke are generally caused by rupture of an atherosclerotic plaque. However, the actual cause of a plaque to rupture is not yet established. Interestingly, pathology studies have shown an increased presence of the mast cell, an important inflammatory effector cell in allergy and host defense, in (peri)vascular tissue during plaque progression, which may point towards a causal role for mast cells. Very recent data in mouse models show that mast cells and derived mediators indeed can profoundly impact plaque progression, plaque stability and acute cardiovascular syndromes such as vascular aneurysm or myocardial infarction. In this review, we discuss recent evidence on the role of mast cells in the progression of cardiovascular disorders and give insight in the therapeutic potential of modulation of mast cell function in these processes to improve the resilience of a plaque to rupture. PMID:19936193

Association between serum N-terminal pro-B-type natriuretic peptide levels and characteristics of coronary atherosclerotic plaque detected by coronary computed tomography angiography.

PubMed

Gan, Lu; Feng, Cong; Liu, Chunlei; Tian, Shuping; Song, Xiang; Yang, Li

2016-08-01

The aim of the present study was to explore the association between the levels of serum N-terminal pro-B-type natriuretic peptide (NT-pro BNP) and the characteristics of coronary atherosclerotic plaque detected by coronary computed tomography angiography (CCTA), in patients with unstable angina (UA). A total of 202 patients (age range, 47-82 years) were divided into the following three groups: Non-cardiac disease group (57 patients); stable angina pectoris (SAP) group (62 patients); and UA group (83 patients). There were significant differences between the serum NT-pro BNP levels among the three groups (P=0.007). However, in multivariant diagnoses, NT-pro BNP level was not an independent risk factor for UA. The levels of serum NT-pro BNP were observed to be positively correlated with the number of vessels involved (r=0.462; P<0.001), SIS (r=0.475; P<0.001), segment-stenosis score (r=0.453; P<0.001), coronary calcification score (r=0.412; P=0.001), number of obstructive diseases (r=0.346; P<0.001), and the number of segments with non-calcified plaque (r=0.235; P=0.017), mixed plaque (r=0.234; P=0.017) and calcified plaque (r=0.431; P<0.001). The levels of serum NT-pro BNP were significantly higher in patients with UA and left main-left anterior descending (LM-LAD) disease, compared with UA patients without LM-LAD disease (P<0.001). In addition, serum NT-pro BNP was significantly higher in patients with obstructive disease and UA than in those without obstructive disease (P<0.001). The area under the curve of log(NT-pro BNP) was 0.656 (P=0.006; optimal cut-off value, 1.74; sensitivity, 77.6%; specificity, 51.9%). In conclusion, the levels of serum NT-pro BNP are associated with the burden and severity of coronary artery atherosclerotic disease in patients with UA, and may be helpful in risk stratification of patients with UA.

Association between serum N-terminal pro-B-type natriuretic peptide levels and characteristics of coronary atherosclerotic plaque detected by coronary computed tomography angiography

PubMed Central

Gan, Lu; Feng, Cong; Liu, Chunlei; Tian, Shuping; Song, Xiang; Yang, Li

2016-01-01

The aim of the present study was to explore the association between the levels of serum N-terminal pro-B-type natriuretic peptide (NT-pro BNP) and the characteristics of coronary atherosclerotic plaque detected by coronary computed tomography angiography (CCTA), in patients with unstable angina (UA). A total of 202 patients (age range, 47–82 years) were divided into the following three groups: Non-cardiac disease group (57 patients); stable angina pectoris (SAP) group (62 patients); and UA group (83 patients). There were significant differences between the serum NT-pro BNP levels among the three groups (P=0.007). However, in multivariant diagnoses, NT-pro BNP level was not an independent risk factor for UA. The levels of serum NT-pro BNP were observed to be positively correlated with the number of vessels involved (r=0.462; P<0.001), SIS (r=0.475; P<0.001), segment-stenosis score (r=0.453; P<0.001), coronary calcification score (r=0.412; P=0.001), number of obstructive diseases (r=0.346; P<0.001), and the number of segments with non-calcified plaque (r=0.235; P=0.017), mixed plaque (r=0.234; P=0.017) and calcified plaque (r=0.431; P<0.001). The levels of serum NT-pro BNP were significantly higher in patients with UA and left main-left anterior descending (LM-LAD) disease, compared with UA patients without LM-LAD disease (P<0.001). In addition, serum NT-pro BNP was significantly higher in patients with obstructive disease and UA than in those without obstructive disease (P<0.001). The area under the curve of log(NT-pro BNP) was 0.656 (P=0.006; optimal cut-off value, 1.74; sensitivity, 77.6%; specificity, 51.9%). In conclusion, the levels of serum NT-pro BNP are associated with the burden and severity of coronary artery atherosclerotic disease in patients with UA, and may be helpful in risk stratification of patients with UA. PMID:27446259

Validation of Noninvasive In Vivo Compound Ultrasound Strain Imaging Using Histologic Plaque Vulnerability Features.

PubMed

Hansen, Hendrik H G; de Borst, Gert Jan; Bots, Michiel L; Moll, Frans L; Pasterkamp, Gerard; de Korte, Chris L

2016-11-01

Carotid plaque rupture is a major cause of stroke. Key issue for risk stratification is early identification of rupture-prone plaques. A noninvasive technique, compound ultrasound strain imaging, was developed providing high-resolution radial deformation/strain images of atherosclerotic plaques. This study aims at in vivo validation of compound ultrasound strain imaging in patients by relating the measured strains to typical features of vulnerable plaques derived from histology after carotid endarterectomy. Strains were measured in 34 severely stenotic (>70%) carotid arteries at the culprit lesion site within 48 hours before carotid endarterectomy. In all cases, the lumen-wall boundary was identifiable on B-mode ultrasound, and the imaged cross-section did not move out of the imaging plane from systole to diastole. After endarterectomy, the plaques were processed using a validated histology analysis technique. Locally elevated strain values were observed in regions containing predominantly components related to plaque vulnerability, whereas lower values were observed in fibrous, collagen-rich plaques. The median strain of the inner plaque layer (1 mm thickness) was significantly higher (P<0.01) for (fibro)atheromatous (n=20, strain=0.27%) than that for fibrous plaques (n=14, strain=-0.75%). Also, a significantly larger area percentage of the inner layer revealed strains above 0.5% for (fibro)atheromatous (45.30%) compared with fibrous plaques (31.59%). (Fibro)atheromatous plaques were detected with a sensitivity, specificity, positive predictive value, and negative predictive value of 75%, 86%, 88%, and 71%, respectively. Strain did not significantly correlate with fibrous cap thickness, smooth muscle cell, or macrophage concentration. Compound ultrasound strain imaging allows differentiating (fibro)atheromatous from fibrous carotid artery plaques. © 2016 American Heart Association, Inc.

Frequency of Subclinical Atherosclerosis in Brazilian HIV-Infected Patients.

PubMed

Salmazo, Péricles Sidnei; Bazan, Silméia Garcia Zanati; Shiraishi, Flávio Gobbis; Bazan, Rodrigo; Okoshi, Katashi; Hueb, João Carlos

2018-04-09

AIDS as well as atherosclerosis are important public health problems. The longer survival among HIV-infected is associated with increased number of cardiovascular events in this population, and this association is not fully understood. To identify the frequency of subclinical atherosclerosis in HIV-infected patients compared to control subjects; to analyze associations between atherosclerosis and clinical and laboratory variables, cardiovascular risk factors, and the Framingham coronary heart disease risk score (FCRS). Prospective cross-sectional case-control study assessing the presence of subclinical atherosclerosis in 264 HIV-infected patients and 279 controls. Clinical evaluation included ultrasound examination of the carotid arteries, arterial stiffness by pulse wave velocity (PWV) and augmentation index (AIx), laboratory analysis of peripheral blood, and cardiovascular risk according to FCRS criteria. The significance level adopted in the statistical analysis was p < 0.05. Plaques were found in 37% of the HIV group and 4% of controls (p < 0.001). Furthermore, carotid intima-media thickness was higher in the HIV group than in controls (p < 0.001). Patients with carotid plaque had higher fasting glucose, total cholesterol, low-density lipoprotein cholesterol, and triglycerides than those without plaques. The presence of HIV, adjusted for age, overweight/obesity, and smoking increased by almost fivefold the risk of atherosclerotic carotid plaque (OR: 4.9; 95%CI: 2.5-9.9; p < 0.001). Exposure to protease inhibitors did not influence carotid intima-media thickness, was not associated with carotid plaque frequency, and did not alter the mechanical characteristics of the arterial system (PWV and AIx). HIV-infected patients are at increased risk of atherosclerosis in association with classical cardiovascular risk factors. Treatment with protease inhibitors does not promote functional changes in the arteries, and shows no association with increased frequency of atherosclerotic plaques in carotid arteries. The FCRS may be inappropriate for this population.

Grating interferometry-based phase microtomography of atherosclerotic human arteries

NASA Astrophysics Data System (ADS)

Buscema, Marzia; Holme, Margaret N.; Deyhle, Hans; Schulz, Georg; Schmitz, Rüdiger; Thalmann, Peter; Hieber, Simone E.; Chicherova, Natalia; Cattin, Philippe C.; Beckmann, Felix; Herzen, Julia; Weitkamp, Timm; Saxer, Till; Müller, Bert

2014-09-01

Cardiovascular diseases are the number one cause of death and morbidity in the world. Understanding disease development in terms of lumen morphology and tissue composition of constricted arteries is essential to improve treatment and patient outcome. X-ray tomography provides non-destructive three-dimensional data with micrometer-resolution. However, a common problem is simultaneous visualization of soft and hard tissue-containing specimens, such as atherosclerotic human coronary arteries. Unlike absorption based techniques, where X-ray absorption strongly depends on atomic number and tissue density, phase contrast methods such as grating interferometry have significant advantages as the phase shift is only a linear function of the atomic number. We demonstrate that grating interferometry-based phase tomography is a powerful method to three-dimensionally visualize a variety of anatomical features in atherosclerotic human coronary arteries, including plaque, muscle, fat, and connective tissue. Three formalin-fixed, human coronary arteries were measured using advanced laboratory μCT. While this technique gives information about plaque morphology, it is impossible to extract the lumen morphology. Therefore, selected regions were measured using grating based phase tomography, sinograms were treated with a wavelet-Fourier filter to remove ring artifacts, and reconstructed data were processed to allow extraction of vessel lumen morphology. Phase tomography data in combination with conventional laboratory μCT data of the same specimen shows potential, through use of a joint histogram, to identify more tissue types than either technique alone. Such phase tomography data was also rigidly registered to subsequently decalcified arteries that were histologically sectioned, although the quality of registration was insufficient for joint histogram analysis.

Precision phenotyping, panomics, and system-level bioinformatics to delineate complex biologies of atherosclerosis: rationale and design of the "Genetic Loci and the Burden of Atherosclerotic Lesions" study.

PubMed

Voros, Szilard; Maurovich-Horvat, Pal; Marvasty, Idean B; Bansal, Aruna T; Barnes, Michael R; Vazquez, Gustavo; Murray, Sarah S; Voros, Viktor; Merkely, Bela; Brown, Bradley O; Warnick, G Russell

2014-01-01

Complex biological networks of atherosclerosis are largely unknown. The main objective of the Genetic Loci and the Burden of Atherosclerotic Lesions study is to assemble comprehensive biological networks of atherosclerosis using advanced cardiovascular imaging for phenotyping, a panomic approach to identify underlying genomic, proteomic, metabolomic, and lipidomic underpinnings, analyzed by systems biology-driven bioinformatics. By design, this is a hypothesis-free unbiased discovery study collecting a large number of biologically related factors to examine biological associations between genomic, proteomic, metabolomic, lipidomic, and phenotypic factors of atherosclerosis. The Genetic Loci and the Burden of Atherosclerotic Lesions study (NCT01738828) is a prospective, multicenter, international observational study of atherosclerotic coronary artery disease. Approximately 7500 patients are enrolled and undergo non-contrast-enhanced coronary calcium scanning by CT for the detection and quantification of coronary artery calcium, as well as coronary artery CT angiography for the detection and quantification of plaque, stenosis, and overall coronary artery disease burden. In addition, patients undergo whole genome sequencing, DNA methylation, whole blood-based transcriptome sequencing, unbiased proteomics based on mass spectrometry, as well as metabolomics and lipidomics on a mass spectrometry platform. The study is analyzed in 3 subsequent phases, and each phase consists of a discovery cohort and an independent validation cohort. For the primary analysis, the primary phenotype will be the presence of any atherosclerotic plaque, as detected by cardiac CT. Additional phenotypic analyses will include per patient maximal luminal stenosis defined as 50% and 70% diameter stenosis. Single-omic and multi-omic associations will be examined for each phenotype; putative biomarkers will be assessed for association, calibration, discrimination, and reclassification. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models.

PubMed

Pérez-Medina, Carlos; Binderup, Tina; Lobatto, Mark E; Tang, Jun; Calcagno, Claudia; Giesen, Luuk; Wessel, Chang Ho; Witjes, Julia; Ishino, Seigo; Baxter, Samantha; Zhao, Yiming; Ramachandran, Sarayu; Eldib, Mootaz; Sánchez-Gaytán, Brenda L; Robson, Philip M; Bini, Jason; Granada, Juan F; Fish, Kenneth M; Stroes, Erik S G; Duivenvoorden, Raphaël; Tsimikas, Sotirios; Lewis, Jason S; Reiner, Thomas; Fuster, Valentín; Kjær, Andreas; Fisher, Edward A; Fayad, Zahi A; Mulder, Willem J M

2016-08-01

The goal of this study was to develop and validate a noninvasive imaging tool to visualize the in vivo behavior of high-density lipoprotein (HDL) by using positron emission tomography (PET), with an emphasis on its plaque-targeting abilities. HDL is a natural nanoparticle that interacts with atherosclerotic plaque macrophages to facilitate reverse cholesterol transport. HDL-cholesterol concentration in blood is inversely associated with risk of coronary heart disease and remains one of the strongest independent predictors of incident cardiovascular events. Discoidal HDL nanoparticles were prepared by reconstitution of its components apolipoprotein A-I (apo A-I) and the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine. For radiolabeling with zirconium-89 ((89)Zr), the chelator deferoxamine B was introduced by conjugation to apo A-I or as a phospholipid-chelator (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-deferoxamine B). Biodistribution and plaque targeting of radiolabeled HDL were studied in established murine, rabbit, and porcine atherosclerosis models by using PET combined with computed tomography (PET/CT) imaging or PET combined with magnetic resonance imaging. Ex vivo validation was conducted by radioactivity counting, autoradiography, and near-infrared fluorescence imaging. Flow cytometric assessment of cellular specificity in different tissues was performed in the murine model. We observed distinct pharmacokinetic profiles for the two (89)Zr-HDL nanoparticles. Both apo A-I- and phospholipid-labeled HDL mainly accumulated in the kidneys, liver, and spleen, with some marked quantitative differences in radioactivity uptake values. Radioactivity concentrations in rabbit atherosclerotic aortas were 3- to 4-fold higher than in control animals at 5 days' post-injection for both (89)Zr-HDL nanoparticles. In the porcine model, increased accumulation of radioactivity was observed in lesions by using in vivo PET imaging. Irrespective of the radiolabel's location, HDL nanoparticles were able to preferentially target plaque macrophages and monocytes. (89)Zr labeling of HDL allows study of its in vivo behavior by using noninvasive PET imaging, including visualization of its accumulation in advanced atherosclerotic lesions. The different labeling strategies provide insight on the pharmacokinetics and biodistribution of HDL's main components (i.e., phospholipids, apo A-I). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Optical measurement of arterial mechanical properties: from atherosclerotic plaque initiation to rupture

NASA Astrophysics Data System (ADS)

Nadkarni, Seemantini K.

2013-12-01

During the pathogenesis of coronary atherosclerosis, from lesion initiation to rupture, arterial mechanical properties are altered by a number of cellular, molecular, and hemodynamic processes. There is growing recognition that mechanical factors may actively drive vascular cell signaling and regulate atherosclerosis disease progression. In advanced plaques, the mechanical properties of the atheroma influence stress distributions in the fibrous cap and mediate plaque rupture resulting in acute coronary events. This review paper explores current optical technologies that provide information on the mechanical properties of arterial tissue to advance our understanding of the mechanical factors involved in atherosclerosis development leading to plaque rupture. The optical approaches discussed include optical microrheology and traction force microscopy that probe the mechanical behavior of single cell and extracellular matrix components, and intravascular imaging modalities including laser speckle rheology, optical coherence elastography, and polarization-sensitive optical coherence tomography to measure the mechanical properties of advanced coronary lesions. Given the wealth of information that these techniques can provide, optical imaging modalities are poised to play an increasingly significant role in elucidating the mechanical aspects of coronary atherosclerosis in the future.

Cholesterol, inflammasomes, and atherogenesis

USDA-ARS?s Scientific Manuscript database

Plasma cholesterol levels have been strongly associated with atherogenesis, underscoring the role of lipid metabolism in defining cardiovascular disease risk. However, atherosclerotic plaque is highly dynamic and contains elements of both the innate and adaptive immune system that respond to the abe...

Plaque hemorrhage in carotid artery disease: pathogenesis, clinical and biomechanical considerations.

PubMed

Teng, Zhongzhao; Sadat, Umar; Brown, Adam J; Gillard, Jonathan H

2014-03-03

Stroke remains the most prevalent disabling illness today, with internal carotid artery luminal stenosis due to atheroma formation responsible for the majority of ischemic cerebrovascular events. Severity of luminal stenosis continues to dictate both patient risk stratification and the likelihood of surgical intervention. But there is growing evidence to suggest that plaque morphology may help improve pre-existing risk stratification criteria. Plaque components such a fibrous tissue, lipid rich necrotic core and calcium have been well investigated but plaque hemorrhage (PH) has been somewhat overlooked. In this review we discuss the pathogenesis of PH, its role in dictating plaque vulnerability, PH imaging techniques, marterial properties of atherosclerotic tissues, in particular, those obtained based on in vivo measurements and effect of PH in modulating local biomechanics. Copyright © 2014 Elsevier Ltd. All rights reserved.

Comparison between a new computer program and the reference software for gray-scale median analysis of atherosclerotic carotid plaques.

PubMed

Casella, Ivan Benaduce; Fukushima, Rodrigo Bono; Marques, Anita Battistini de Azevedo; Cury, Marcus Vinícius Martins; Presti, Calógero

2015-03-01

To compare a new dedicated software program and Adobe Photoshop for gray-scale median (GSM) analysis of B-mode images of carotid plaques. A series of 42 carotid plaques generating ≥50% diameter stenosis was evaluated by a single observer. The best segment for visualization of internal carotid artery plaque was identified on a single longitudinal view and images were recorded in JPEG format. Plaque analysis was performed by both programs. After normalization of image intensity (blood = 0, adventitial layer = 190), histograms were obtained after manual delineation of plaque. Results were compared with nonparametric Wilcoxon signed rank test and Kendall tau-b correlation analysis. GSM ranged from 00 to 100 with Adobe Photoshop and from 00 to 96 with IMTPC, with a high grade of similarity between image pairs, and a highly significant correlation (R = 0.94, p < .0001). IMTPC software appears suitable for the GSM analysis of carotid plaques. © 2014 Wiley Periodicals, Inc.

Characterization of human carotid atherosclerotic tissues imaged by combining multiple multiphoton microscopy techniques

NASA Astrophysics Data System (ADS)

Baria, E.; Cicchi, R.; Nesi, G.; Massi, D.; Pavone, F. S.

2017-07-01

We combined Second Harmonic Generation, Two-Photon Fluorescence and Fluorescence Lifetime Imaging Microscopy for studying human carotid ex vivo tissue sections affected by atherosclerosis, resulting in the discrimination of different arterial regions within the plaques.

Relationship of femoral artery ultrasound measures of atherosclerosis with chronic kidney disease.

PubMed

Hsu, Simon; Rifkin, Dena E; Criqui, Michael H; Suder, Natalie C; Garimella, Pranav; Ginsberg, Charles; Marasco, Antoinette M; McQuaide, Belinda J; Barinas-Mitchell, Emma J; Allison, Matthew A; Wassel, Christina L; Ix, Joachim H

2017-12-22

Chronic kidney disease (CKD) is strongly associated with peripheral artery disease (PAD). Detection of subclinical PAD may allow early interventions for or prevention of PAD in persons with CKD. Whether the presence of atherosclerotic plaque and femoral intima-media thickness (IMT) are associated with kidney function is unknown. We performed a cross-sectional observational study of 1029 community-living adults. We measured superficial and common femoral artery IMT and atherosclerotic plaque presence by ultrasound. Estimated glomerular filtration rate (eGFR; continuous) and eGFR <60 mL/min/1.73 m 2 (binary) were evaluated as outcomes. Mean age was 70 ± 10 years, mean eGFR was 78 ± 17 mL/min/1.73 m 2 , and 156 (15%) individuals had eGFR <60 mL/min/1.73 m 2 ; 260 (25%) had femoral artery plaque. In models adjusted for demographics and cardiovascular risk factors, individuals with femoral artery plaque had mean eGFR approximately 3.0 (95% confidence interval, -5.3 to -0.8) mL/min/1.73 m 2 lower than those without plaque (P < .01). The presence of plaque was also associated with a 1.7-fold higher odds of eGFR <60 mL/min/1.73 m 2 (95% confidence interval, 1.1-2.8; P < .02). Associations were similar in persons with normal ankle-brachial index. The directions of associations were similar for femoral IMT measures with eGFR and CKD but were rendered no longer statistically significant with adjustment for demographic variables and cardiovascular disease risk factors. Femoral artery plaque is significantly associated with CKD prevalence in community-living individuals, even among those with normal ankle-brachial index. Femoral artery ultrasound may allow evaluation of relationships and risk factors linking PAD and kidney disease earlier in its course. Copyright © 2017 Society for Vascular Surgery. All rights reserved.

Adherence to a Mediterranean diet is associated with the presence and extension of atherosclerotic plaques in middle-aged asymptomatic adults: The Aragon Workers' Health Study.

PubMed

Mateo-Gallego, Rocío; Uzhova, Irina; Moreno-Franco, Belén; León-Latre, Montserrat; Casasnovas, José A; Laclaustra, Martín; Peñalvo, José L; Civeira, Fernando

The Mediterranean diet (MeDi) is known to prevent cardiovascular events but the mechanisms mediating this association are not fully understood. The objective of the study was to examine the association between MeDi adherence and the presence and extent of atherosclerotic plaques in carotid, femoral, and aorta territories and its relationship with risk factors in asymptomatic middle-aged adults. Cross-sectional analysis of the Aragon Workers' Health Study, a cohort of 2588 subjects (94.9% men aged 51.3 ± 3.89 years) without previous cardiovascular history. Participants underwent carotid, femoral, and aorta ultrasound for the quantification of number and thickness of plaques and intima-media thickness. To estimate the participant's adherence to MeDi, we computed the Alternative MEDiterranean index (aMED). The overall aMED score was 4.19 ± 1.70, representing a moderate adherence to MeDi. aMED score was associated with the presence of plaque in femoral arteries (odds ratio highest vs lowest aMED score quartile: 0.63; 95% confidence interval: 0.48-0.83; P trend = .045) independently of risk factors and mediators. The strongest association between aMED quartiles and presence of plaque was found among smokers, both in femoral (0.39 [0.22-0.69]; P trend = .001) and in any territory (0.33 [0.14-0.79], P trend = .008). aMED was inversely associated with the number of plaques in all territories except for carotids. MeDi adherence showed a dose-dependent protective association with the presence, number, and thickness of plaques independent of other risk factors. The association was strongest for femoral arteries and among smokers. Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Effect of eicosapentaenoic acid/docosahexaenoic acid on coronary high-intensity plaques detected with non-contrast T1-weighted imaging (the AQUAMARINE EPA/DHA study): study protocol for a randomized controlled trial.

PubMed

Nakao, Kazuhiro; Noguchi, Teruo; Asaumi, Yasuhide; Morita, Yoshiaki; Kanaya, Tomoaki; Fujino, Masashi; Hosoda, Hayato; Yoneda, Shuichi; Kawakami, Shoji; Nagai, Toshiyuki; Nishihira, Kensaku; Nakashima, Takahiro; Kumasaka, Reon; Arakawa, Tetsuo; Otsuka, Fumiyuki; Nakanishi, Michio; Kataoka, Yu; Tahara, Yoshio; Goto, Yoichi; Yamamoto, Haruko; Hamasaki, Toshimitsu; Yasuda, Satoshi

2018-01-08

Despite the success of HMG-CoA reductase inhibitor (statin) therapy in reducing atherosclerotic cardiovascular events, a residual risk for cardiovascular events in patients with coronary artery disease (CAD) remains. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are promising anti-atherosclerosis agents that might reduce the residual CAD risk. Non-contrast T1-weighted imaging (T1WI) with cardiac magnetic resonance (CMR) less invasively identifies high-risk coronary plaques as high-intensity signals. These high-intensity plaques (HIPs) are quantitatively assessed using the plaque-to-myocardium signal intensity ratio (PMR). Our goal is to assess the effect of EPA/DHA on coronary HIPs detected with T1WI in patients with CAD on statin treatment. This prospective, controlled, randomized, open-label study examines the effect of 12 months of EPA/DHA therapy and statin treatment on PMR of HIPs detected with CMR and computed tomography angiography (CTA) in patients with CAD. The primary endpoint is the change in PMR after EPA/DHA treatment. Secondary endpoints include changes in Hounsfield units, plaque volume, vessel area, and plaque area measured using CTA. Subjects are randomly assigned to either of three groups: the 2 g/day EPA/DHA group, the 4 g/day EPA/DHA group, or the no-treatment group. This trial will help assess whether EPA/DHA has an anti-atherosclerotic effect using PMR of HIPs detected by CMR. The trial outcomes will provide novel insights into the effect of EPA/DHA on high-risk coronary plaques and may provide new strategies for lowering the residual risk in patients with CAD on statin therapy. The University Hospital Medical Information Network (UMIN) Clinical Trials Registry, ID: UMIN000015316 . Registered on 2 October 2014.

Ultrasound analysis of gray-scale median value of carotid plaques is a useful reference index for cerebro-cardiovascular events in patients with type 2 diabetes.

PubMed

Ariyoshi, Kyoko; Okuya, Shigeru; Kunitsugu, Ichiro; Matsunaga, Kimie; Nagao, Yuko; Nomiyama, Ryuta; Takeda, Komei; Tanizawa, Yukio

2015-01-01

Measurements of plaque echogenicity, the gray-scale median (GSM), were shown to correlate inversely with risk factors for cerebro-cardiovascular disease (CVD). The eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio is a potential predictor of CVD risk. In the present study, we assessed the usefulness of carotid plaque GSM values and EPA/AA ratios in atherosclerotic diabetics. A total of 84 type 2 diabetics with carotid artery plaques were enrolled. On admission, platelet aggregation and lipid profiles, including EPA and AA, were examined. Using ultrasound, mean intima media thickness and plaque score were measured in carotid arteries. Plaque echogenicity was evaluated using computer-assisted quantification of GSM. The patients were then further observed for approximately 3 years. Gray-scale median was found to be a good marker of CVD events. On multivariate logistic regression analysis, GSM <32 and plaque score ≥5 were significantly associated with past history and onset of CVD during the follow-up period, the odds ratios being 7.730 (P = 0.014) and 4.601 (P = 0.046), respectively. EPA/AA showed a significant correlation with GSM (P = 0.012) and high-density lipoprotein cholesterol (P = 0.039), and an inverse correlation with platelet aggregation (P = 0.046) and triglyceride (P = 0.020). Although most patients with CVD had both low GSM and low EPA/AA values, an association of EPA/AA with CVD events could not be statistically confirmed. The present results suggest the GSM value to be useful as a reference index for CVD events in high-risk atherosclerotic diabetics. Associations of the EPA/AA ratio with known CVD risk factors warrant a larger and more extensive study to show the usefulness of this parameter.

Ultrasound analysis of gray-scale median value of carotid plaques is a useful reference index for cerebro-cardiovascular events in patients with type 2 diabetes

PubMed Central

Ariyoshi, Kyoko; Okuya, Shigeru; Kunitsugu, Ichiro; Matsunaga, Kimie; Nagao, Yuko; Nomiyama, Ryuta; Takeda, Komei; Tanizawa, Yukio

2015-01-01

Aims/Introduction Measurements of plaque echogenicity, the gray-scale median (GSM), were shown to correlate inversely with risk factors for cerebro-cardiovascular disease (CVD). The eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio is a potential predictor of CVD risk. In the present study, we assessed the usefulness of carotid plaque GSM values and EPA/AA ratios in atherosclerotic diabetics. Materials and Methods A total of 84 type 2 diabetics with carotid artery plaques were enrolled. On admission, platelet aggregation and lipid profiles, including EPA and AA, were examined. Using ultrasound, mean intima media thickness and plaque score were measured in carotid arteries. Plaque echogenicity was evaluated using computer-assisted quantification of GSM. The patients were then further observed for approximately 3 years. Results Gray-scale median was found to be a good marker of CVD events. On multivariate logistic regression analysis, GSM <32 and plaque score ≥5 were significantly associated with past history and onset of CVD during the follow-up period, the odds ratios being 7.730 (P = 0.014) and 4.601 (P = 0.046), respectively. EPA/AA showed a significant correlation with GSM (P = 0.012) and high-density lipoprotein cholesterol (P = 0.039), and an inverse correlation with platelet aggregation (P = 0.046) and triglyceride (P = 0.020). Although most patients with CVD had both low GSM and low EPA/AA values, an association of EPA/AA with CVD events could not be statistically confirmed. Conclusions The present results suggest the GSM value to be useful as a reference index for CVD events in high-risk atherosclerotic diabetics. Associations of the EPA/AA ratio with known CVD risk factors warrant a larger and more extensive study to show the usefulness of this parameter. PMID:25621138

Development of a Patient-Specific Multi-Scale Model to Understand Atherosclerosis and Calcification Locations: Comparison with In vivo Data in an Aortic Dissection

PubMed Central

Alimohammadi, Mona; Pichardo-Almarza, Cesar; Agu, Obiekezie; Díaz-Zuccarini, Vanessa

2016-01-01

Vascular calcification results in stiffening of the aorta and is associated with hypertension and atherosclerosis. Atherogenesis is a complex, multifactorial, and systemic process; the result of a number of factors, each operating simultaneously at several spatial and temporal scales. The ability to predict sites of atherogenesis would be of great use to clinicians in order to improve diagnostic and treatment planning. In this paper, we present a mathematical model as a tool to understand why atherosclerotic plaque and calcifications occur in specific locations. This model is then used to analyze vascular calcification and atherosclerotic areas in an aortic dissection patient using a mechanistic, multi-scale modeling approach, coupling patient-specific, fluid-structure interaction simulations with a model of endothelial mechanotransduction. A number of hemodynamic factors based on state-of-the-art literature are used as inputs to the endothelial permeability model, in order to investigate plaque and calcification distributions, which are compared with clinical imaging data. A significantly improved correlation between elevated hydraulic conductivity or volume flux and the presence of calcification and plaques was achieved by using a shear index comprising both mean and oscillatory shear components (HOLMES) and a non-Newtonian viscosity model as inputs, as compared to widely used hemodynamic indicators. The proposed approach shows promise as a predictive tool. The improvements obtained using the combined biomechanical/biochemical modeling approach highlight the benefits of mechanistic modeling as a powerful tool to understand complex phenomena and provides insight into the relative importance of key hemodynamic parameters. PMID:27445834

Co-expression of p53 and MDM2 in human atherosclerosis: implications for the regulation of cellularity of atherosclerotic lesions.

PubMed

Ihling, C; Haendeler, J; Menzel, G; Hess, R D; Fraedrich, G; Schaefer, H E; Zeiher, A M

1998-07-01

Atherosclerosis is a fibroproliferative disease of the arterial intima. It was recently found that wild-type p53 (wt p53) accumulates in human atherosclerotic tissue. Wt p53 is a cell cycle regulator involved in DNA repair, DNA synthesis, cell differentiation, and apoptosis and might therefore make an important contribution to the cellularity of atherosclerotic plaques. The product of the MDM2 gene is a nuclear protein which forms a complex with p53, thereby inhibiting the negative regulatory effects of wt p53 on cell cycle progression. In order to address a potential role of the interaction of p53 with MDM2 for the regulation of cellularity in atherosclerotic tissue, 22 carotid atheromatous plaques from patients undergoing endarterectomy were studied to determine the presence of p53 immunoreactivity (IR), MDM2 IR, cell proliferation as evidenced by MIB1/Ki-67 IR and DNA fragmentation by in situ terminal transferase-mediated dUTP 3' end labelling (TUNEL), as a marker for apoptosis. p53 IR localized to areas with evidence of chronic inflammation (22/22) and was observed in virtually all cell types in 68.79 +/- 7.51 per cent of the nuclei. p53 staining in the control tissue from human internal mammary arteries was present in 0.2 +/- 0.29 per cent of the cells (P < or = 0.002). MDM2 IR was present in all cases (22/22) in macrophages and smooth muscle cells (SMCs) in 60.53 +/- 8.32 per cent of the nuclei (controls: 0.8 +/- 0.65 per cent, P < or = 0.002) and co-localized with p53 IR as shown by examination of adjacent sections and by double immunofluorescence labelling. Importantly, co-immunoprecipitation and western blot analysis revealed that p53 and MDM2 were physically associated, indicating that MDM2-p53 complex formation takes place in vivo in human atherosclerotic tissue. Positive TUNEL staining and MIB1/Ki-67 IR present in 3.01 +/- 1.27 per cent of the nuclei (controls: 0 per cent, P < or = 0.002) localized to the same plaque compartments as p53 IR and MDM2 IR. Thus, the fate of cells with p53 accumulation may depend on the interaction and the stoichiometry of the p53 and MDM2 proteins. Cells were indeed found with strong p53 accumulation and nuclear morphology typical for apoptosis and there were a few MIB1/Ki-67-positive cells with co-expression of MDM2, indicating a possible role for MDM2 in reversing the negative regulatory effects of p53 for cell cycle progression. The nuclear co-localization of p53 IR with MDM2 IR and the co-immunoprecipitation assay indicate the presence of p53-MDM2 complex formation in vivo in human atherosclerotic tissue. The destiny of individual p53 and MDM2-co-expressing cells either to undergo p53-dependent apoptosis or to re-enter the cycle of cell proliferation may depend on the relative ratios of the two proteins. p53 and MDM2 may therefore play an important role in regulating cellularity and inflammatory activity in human atherosclerotic plaques.

Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosis

PubMed Central

Mortensen, Martin B.; Kjolby, Mads; Gunnersen, Stine; Larsen, Jakob V.; Palmfeldt, Johan; Falk, Erling; Nykjaer, Anders; Bentzon, Jacob F.

2014-01-01

Genome-wide association studies have identified a link between genetic variation at the human chromosomal locus 1p13.3 and coronary artery disease. The gene encoding sortilin (SORT1) has been implicated as the causative gene within the locus, as sortilin regulates hepatic lipoprotein metabolism. Here we demonstrated that sortilin also directly affects atherogenesis, independent of its regulatory role in lipoprotein metabolism. In a mouse model of atherosclerosis, deletion of Sort1 did not alter plasma cholesterol levels, but reduced the development of both early and late atherosclerotic lesions. We determined that sortilin is a high-affinity receptor for the proinflammatory cytokines IL-6 and IFN-γ. Moreover, macrophages and Th1 cells (both of which mediate atherosclerotic plaque formation) lacking sortilin had reduced secretion of IL-6 and IFN-γ, but not of other measured cytokines. Transfer of sortilin-deficient BM into irradiated atherosclerotic mice reduced atherosclerosis and systemic markers of inflammation. Together, these data demonstrate that sortilin influences cytokine secretion and that targeting sortilin in immune cells attenuates inflammation and reduces atherosclerosis. PMID:25401472

Validation of a time-resolved fluorescence spectroscopy apparatus in a rabbit atherosclerosis model

NASA Astrophysics Data System (ADS)

Fang, Qiyin; Jo, Javier A.; Papaioannou, Thanassis; Dorafshar, Amir; Reil, Todd; Qiao, Jian-Hua; Fishbein, Michael C.; Freischlag, Julie A.; Marcu, Laura

2004-07-01

Time-resolved laser-induced fluorescence spectroscopy (tr-LIFS) has been studied as a potential tool for in vivo diagnosis of atherosclerotic lesions. This study is to evaluate the potential of a compact fiber-optics based tr-LIFS instrument developed in our laboratory for in vivo analysis of atherosclerotic plaque composition. Time-resolved fluorescence spectroscopy studies were performed in vivo on fifteen New Zealand White rabbits (atherosclerotic: N=8, control: N=7). Time-resolved fluorescence spectra were acquired (range: 360-600 nm, increment: 5 nm, total acquisition time: 65 s) from normal aorta wall and lesions in the abdominal aorta. Data were analyzed in terms of fluorescence emission spectra and wavelength specific lifetimes. Following trichrome staining, tissue specimens were analyzed histopathologically in terms of intima/media thickness and biochemical composition (collagen, elastin, foam cells, and etc). Based on intimal thickness, the lesions were divided into thin and thick lesions. Each group was further separated into two categories: collagen rich lesions and foam cell rich lesions based on their biochemical composition. The obtained spectral and time domain fluorescence signatures were subsequently correlated to the histopathological findings. The results have shown that time-domain fluorescence spectral features can be used in vivo to separate atherosclerotic lesions from normal aorta wall as well discrimination within certain types of lesions.

Intravital live cell triggered imaging system reveals monocyte patrolling and macrophage migration in atherosclerotic arteries

NASA Astrophysics Data System (ADS)

McArdle, Sara; Chodaczek, Grzegorz; Ray, Nilanjan; Ley, Klaus

2015-02-01

Intravital multiphoton imaging of arteries is technically challenging because the artery expands with every heartbeat, causing severe motion artifacts. To study leukocyte activity in atherosclerosis, we developed the intravital live cell triggered imaging system (ILTIS). This system implements cardiac triggered acquisition as well as frame selection and image registration algorithms to produce stable movies of myeloid cell movement in atherosclerotic arteries in live mice. To minimize tissue damage, no mechanical stabilization is used and the artery is allowed to expand freely. ILTIS performs multicolor high frame-rate two-dimensional imaging and full-thickness three-dimensional imaging of beating arteries in live mice. The external carotid artery and its branches (superior thyroid and ascending pharyngeal arteries) were developed as a surgically accessible and reliable model of atherosclerosis. We use ILTIS to demonstrate Cx3cr1GFP monocytes patrolling the lumen of atherosclerotic arteries. Additionally, we developed a new reporter mouse (Apoe-/-Cx3cr1GFP/+Cd11cYFP) to image GFP+ and GFP+YFP+ macrophages "dancing on the spot" and YFP+ macrophages migrating within intimal plaque. ILTIS will be helpful to answer pertinent open questions in the field, including monocyte recruitment and transmigration, macrophage and dendritic cell activity, and motion of other immune cells.

Imaging pathobiology of carotid atherosclerosis with ultrasmall superparamagnetic particles of iron oxide: an update.

PubMed

Sadat, Umar; Usman, Ammara; Gillard, Jonathan H

2017-07-01

To provide brief overview of the developments regarding use of ultrasmall superparamagnetic particles of iron oxide in imaging pathobiology of carotid atherosclerosis. MRI is a promising technique capable of providing morphological and functional information about atheromatous plaques. MRI using iron oxide particles, called ultrasmall superparamagnetic iron oxide (USPIO) particles, allows detection of macrophages in atherosclerotic tissue. Ferumoxytol has emerged as a new USPIO agent, which has an excellent safety profile. Based on the macrophage-selective properties of ferumoxytol, there is increasing number of recent reports suggesting its effectiveness to detect pathological inflammation. USPIO particles allow magnetic resonance detection of macrophages in atherosclerotic tissue. Ferumoxytol has emerged as a new USPIO agent, with an excellent safety profile. This has the potential to be used for MRI of the pathobiology of atherosclerosis.

Multiple roles of connexins in atherosclerosis- and restenosis-induced vascular remodelling.

PubMed

Morel, Sandrine

2014-01-01

Endothelial dysfunction is the initial step in atherosclerotic plaque development in large- and medium-sized arteries. This progressive disease, which starts during childhood, is characterized by the accumulation of lipids, macrophages, neutrophils, T lymphocytes and smooth muscle cells in the intima of the vessels. Erosion and rupture of the atherosclerotic plaque may induce myocardial infarction and cerebrovascular accidents, which are responsible for a large percentage of sudden deaths. The most common treatment for atherosclerosis is angioplasty and stent implantation, but these surgical interventions favour a vascular reaction called restenosis and the associated de-endothelialization increases the risk of thrombosis. This review provides an overview of the role of connexins, a large family of transmembrane proteins, in vascular remodelling associated with atherosclerosis and restenosis. The connexins expressed in the vascular wall are Cx37, Cx40, Cx43 and Cx45; their expressions vary with vascular territory and species. Connexins form hemichannels or gap junction channels, allowing the exchange of ions and small metabolites between the cytosol and extracellular space or between neighbouring cells, respectively. Connexins have important roles in vascular physiology; they support radial and longitudinal cell-to-cell communication in the vascular wall, and significant changes in their expression patterns have been described during atherosclerosis and restenosis.

Dual modality instrument for simultaneous optical coherence tomography imaging and fluorescence spectroscopy.

PubMed

Barton, Jennifer Kehlet; Guzman, Francisco; Tumlinson, Alexandre

2004-01-01

We develop a dual-modality device that combines the anatomical imaging capabilities of optical coherence tomography (OCT) with the functional capabilities of laser-induced fluorescence (LIF) spectroscopy. OCT provides cross-sectional images of tissue structure to a depth of up to 2 mm with approximately 10-microm resolution. LIF spectroscopy provides histochemical information in the form of emission spectra from a given tissue location. The OCT subsystem utilizes a superluminescent diode with a center wavelength of 1300 nm, whereas a helium cadmium laser provides the LIF excitation source at wavelengths of 325 and 442 nm. Preliminary data are obtained on eight postmortem aorta samples, each 10 mm in length. OCT images and LIF spectra give complementary information from normal and atherosclerotic portions of aorta wall. OCT images show structures such as intima, media, internal elastic lamina, and fibrotic regions. Emission spectra ratios of 520/490 (325-nm excitation) and 595/635 (442-nm excitation) could be used to identify normal and plaque regions with 97 and 91% correct classification rates, respectively. With miniaturization of the delivery probe and improvements in system speed, this dual-modality device could provide a valuable tool for identification and characterization of atherosclerotic plaques. (c) 2004 Society of Photo-Optical Instrumentation Engineers.

Anti-Atherosclerotic Action of Agmatine in ApoE-Knockout Mice

PubMed Central

Olszanecki, Rafał; Totoń-Żurańska, Justyna; Stachowicz, Aneta; Suski, Maciej; Gębska, Anna; Gajda, Mariusz; Jawień, Jacek; Korbut, Ryszard

2017-01-01

Atherosclerosis is an inflammatory disease in which dysfunction of mitochondria play an important role, and disorders of lipid management intensify this process. Agmatine, an endogenous polyamine formed by decarboxylation of arginine, exerts a protective effect on mitochondria and modulates fatty acid metabolism. We investigated the effect of exogenous agmatine on the development of atherosclerosis and changes in lipid profile in apolipoprotein E knockout (apoE-/-) mice. Agmatine caused an approximate 40% decrease of atherosclerotic lesions, as estimated by en face and cross-section methods with an influence on macrophage but not on smooth muscle content in the plaques. Agmatine treatment did not changed gelatinase activity within the plaque area. What is more, the action of agmatine was associated with an increase in the number of high density lipoproteins (HDL) in blood. Real-Time PCR analysis showed that agmatine modulates liver mRNA levels of many factors involved in oxidation of fatty acid and cholesterol biosynthesis. Two-dimensional electrophoresis coupled with mass spectrometry identified 27 differentially expressed mitochondrial proteins upon agmatine treatment in the liver of apoE-/- mice, mostly proteins related to metabolism and apoptosis. In conclusion, prolonged administration of agmatine inhibits atherosclerosis in apoE-/- mice; however, the exact mechanisms linking observed changes and elevations of HDL plasma require further investigation. PMID:28777310

Anti-Atherosclerotic Action of Agmatine in ApoE-Knockout Mice.

PubMed

Wiśniewska, Anna; Olszanecki, Rafał; Totoń-Żurańska, Justyna; Kuś, Katarzyna; Stachowicz, Aneta; Suski, Maciej; Gębska, Anna; Gajda, Mariusz; Jawień, Jacek; Korbut, Ryszard

2017-08-04

Atherosclerosis is an inflammatory disease in which dysfunction of mitochondria play an important role, and disorders of lipid management intensify this process. Agmatine, an endogenous polyamine formed by decarboxylation of arginine, exerts a protective effect on mitochondria and modulates fatty acid metabolism. We investigated the effect of exogenous agmatine on the development of atherosclerosis and changes in lipid profile in apolipoprotein E knockout (apoE-/-) mice. Agmatine caused an approximate 40% decrease of atherosclerotic lesions, as estimated by en face and cross-section methods with an influence on macrophage but not on smooth muscle content in the plaques. Agmatine treatment did not changed gelatinase activity within the plaque area. What is more, the action of agmatine was associated with an increase in the number of high density lipoproteins (HDL) in blood. Real-Time PCR analysis showed that agmatine modulates liver mRNA levels of many factors involved in oxidation of fatty acid and cholesterol biosynthesis. Two-dimensional electrophoresis coupled with mass spectrometry identified 27 differentially expressed mitochondrial proteins upon agmatine treatment in the liver of apoE-/- mice, mostly proteins related to metabolism and apoptosis. In conclusion, prolonged administration of agmatine inhibits atherosclerosis in apoE-/- mice; however, the exact mechanisms linking observed changes and elevations of HDL plasma require further investigation.

High speed photoacoustic imaging with fast OPO laser at 1.7 μm (Conference Presentation)

NASA Astrophysics Data System (ADS)

Piao, Zhonglie; Teng, Ma; Li, Jiawen; Qu, Yueqiao; Yu, Mingyue; Shung, K. Kirk; Zhou, Qifa; Kim, Chang-Seok; Chen, Zhongping

2016-03-01

Acute cardiovascular events are mostly due to a blood clot or thrombus induced by the sudden rupture of vulnerable atherosclerotic plaques within coronary artery walls. Based on the high optical absorption contrast of the lipid rich plaques within the vessel wall, intravascular photoacoustic (IVPA) imaging at 1.7 μm spectral band has shown promising capabilities for detecting of lipid composition, but the translation of the technology for in vivo application is limited by the slow imaging speed. In this work, we will present a high speed integrated IVPA/US imaging system with a 500 Hz optical parametric oscillator laser at 1725 nm (5 nm linewidth). A miniature catheter with 1.0 mm outer diameter was designed with a polished 200 μm multimode fiber and an ultrasound transducer with 45 MHz center frequency. Two optical illumination methods by gradient-index (GRIN) lens and ball lens are introduced and compared for higher spatial resolution. At 1725 nm, atherosclerotic rabbit abdominal aorta was imaged at two frame per second, which is more than one order of magnitude faster than previous reported IVPA imaging. Furthermore, by wide tuning range of the laser wavelength from 1680 nm to 1770 nm, spectroscopic photoacoustic analysis of lipid-mimicking phantom and an human atherosclerotic artery was performed ex vivo.

Inhalation exposure of gas-metal arc stainless steel welding fume increased atherosclerotic lesions in apolipoprotein E knockout mice.

PubMed

Erdely, Aaron; Hulderman, Tracy; Salmen-Muniz, Rebecca; Liston, Angie; Zeidler-Erdely, Patti C; Chen, Bean T; Stone, Samuel; Frazer, David G; Antonini, James M; Simeonova, Petia P

2011-07-04

Epidemiological studies suggest that welding, a process which generates an aerosol of inhalable gases and metal rich particulates, increases the risk for cardiovascular disease. In this study we analyzed systemic inflammation and atherosclerotic lesions following gas metal arc-stainless steel (GMA-SS) welding fume exposure. Apolipoprotein E knockout (apoE(-/-)) mice, fed a Western diet, were exposed to GMA-SS at 40mg/m(3) for 3h/day for ten days (∼8.26μg daily alveolar deposition). Mice were sacrificed two weeks after exposure and serum chemistry, serum protein profiling and aortic lesion area were determined. There were no significant changes in serum total cholesterol, triglycerides or alanine aminotransferase. Serum levels of uric acid, a potent antioxidant, were decreased perhaps suggesting a reduced capacity to combat systemic oxidative stress. Inflammatory serum proteins interleukin 1 beta (IL-1β) and monocyte chemoattractant protein 3 (MCP-3) were increased two weeks after GMA-SS exposure. Analysis of atherosclerotic plaques showed an increase in lesion area as the result of GMA-SS exposure. In conclusion, GMA-SS exposure showed evidence of systemic inflammation and increased plaque progression in apoE(-/-) mice. These results complement epidemiological and functional human studies that suggest welding may result in adverse cardiovascular effects. Published by Elsevier Ireland Ltd.

N-acetylcysteine inhibits in vivo oxidation of native low-density lipoprotein

PubMed Central

Cui, Yuqi; Narasimhulu, Chandrakala A.; Liu, Lingjuan; Zhang, Qingbin; Liu, Patrick Z.; Li, Xin; Xiao, Yuan; Zhang, Jia; Hao, Hong; Xie, Xiaoyun; He, Guanglong; Cui, Lianqun; Parthasarathy, Sampath; Liu, Zhenguo

2015-01-01

Low-density lipoprotein (LDL) is non-atherogenic, while oxidized LDL (ox-LDL) is critical to atherosclerosis. N-acetylcysteine (NAC) has anti-atherosclerotic effect with largely unknown mechanisms. The present study aimed to determine if NAC could attenuate in vivo LDL oxidation and inhibit atherosclerosis. A single dose of human native LDL was injected intravenously into male C57BL/6 mice with and without NAC treatment. Serum human ox-LDL was detected 30 min after injection, reached the peak in 3 hours, and became undetectable in 12 hours. NAC treatment significantly reduced serum ox-LDL level without detectable serum ox-LDL 6 hours after LDL injection. No difference in ox-LDL clearance was observed in NAC-treated animals. NAC treatment also significantly decreased serum ox-LDL level in patients with coronary artery diseases and hyperlipidemia without effect on LDL level. Intracellular and extracellular reactive oxidative species (ROS) production was significantly increased in the animals treated with native LDL, or ox-LDL and in hyperlipidemic LDL receptor knockout (LDLR−/−) mice that was effectively prevented with NAC treatment. NAC also significantly reduced atherosclerotic plaque formation in hyperlipidemic LDLR−/− mice. NAC attenuated in vivo oxidation of native LDL and ROS formation from ox-LDL associated with decreased atherosclerotic plaque formation in hyperlipidemia. PMID:26536834

Orbital Atherectomy in the Renal Artery: A New Frontier for an Emerging Technology?

PubMed

Valle, Javier A; Armstrong, Ehrin J; Waldo, Stephen W

2017-01-01

Orbital atherectomy has been developed as a method to modify calcified plaque in the peripheral vasculature, with extensive experience and data supporting its use in infrainguinal peripheral arterial disease. However, calcific atherosclerotic disease occurs in other vascular beds and may benefit from the application of this technology. In this case report, we describe the first reported use of orbital atherectomy in a renal artery. A 55-year-old male with severe drug-refractory hypertension was found to have renal artery stenosis, with severe calcification of the right renal artery. Orbital atherectomy was utilized for initial plaque modification, and he underwent stenting of the renal artery lesion with an excellent angiographic and clinical result at follow-up. In conclusion, orbital atherectomy is a safe and effective means of plaque modification for severely calcified lesions. The safe and effective use of orbital atherectomy in the renal vasculature suggests an opportunity for ongoing evaluation into expanded roles for this technology beyond the coronary and lower-extremity arterial beds.

Back-to-back optical coherence tomography-ultrasound probe for co-registered three-dimensional intravascular imaging with real-time display

NASA Astrophysics Data System (ADS)

Li, Jiawen; Ma, Teng; Jing, Joseph; Zhang, Jun; Patel, Pranav M.; Shung, K. Kirk; Zhou, Qifa; Chen, Zhongping

2014-03-01

We have developed a novel integrated optical coherence tomography (OCT)-intravascular ultrasound (IVUS) probe, with a 1.5 mm-long rigid-part and 0.9 mm outer diameter, for real-time intracoronary imaging of atherosclerotic plaques and guiding interventional procedures. By placing the OCT ball lens and IVUS 45MHz single element transducer back-to-back at the same axial position, this probe can provide automatically co-registered, co-axial OCT-IVUS imaging. To demonstrate its capability, 3D OCT-IVUS imaging of a pig's coronary artery in real-time displayed in polar coordinates, as well as images of two major types of advanced plaques in human cadaver coronary segments, was obtained using this probe and our upgraded system. Histology validation is also presented.

Evaluation of low molecular mass thiols content in carotid atherosclerotic plaques.

PubMed

Zinellu, Angelo; Lepedda, Antonio; Sotgia, Salvatore; Zinellu, Elisabetta; Scanu, Bastianina; Turrini, Franco; Spirito, Rita; Deiana, Luca; Formato, Marilena; Carru, Ciriaco

2009-06-01

Despite the evidence that both homocysteine and cysteine are important risk factors for vascular disease and atherosclerosis no information are reported about their effective amount in plaque and on the relationship with the other low molecular weight thiols. We used capillary electrophoresis to measure thiols in both carotid plaque specimens and plasma samples from 37 patients undergoing carotid endarterectomy. Pearson's correlation shows that intraplaque homocysteine, cysteine and cysteinylglycine levels are related to their plasma concentrations. The distribution of intraplaque GSH and Glu-Cys was higher than that of the same thiols in plasma, whereas the other thiols were significantly less prevalent in plaque than in plasma. Intraplaque haemoglobin and GSH levels were correlated, thus suggesting their common origin from erythrocytes lysis. Data suggest that increased levels of intraplaque glutathione may induce important effects on plaque fate by perturbing the normal LMW thiol redox state.

Development of selective laser treatment techniques using mid-infrared tunable nanosecond pulsed laser.

PubMed

Ishii, Katsunori; Saiki, Masayuki; Hazama, Hisanao; Awazu, Kunio

2010-01-01

Mid-infrared (MIR) laser with a specific wavelength can excite the corresponding biomolecular site to regulate chemical, thermal and mechanical interactions to biological molecules and tissues. In laser surgery and medicine, tunable MIR laser irradiation can realize the selective and less-invasive treatments and the special diagnosis by vibrational spectroscopic information. This paper showed a novel selective therapeutic technique for a laser angioplasty of atherosclerotic plaques and a laser dental surgery of a carious dentin using a MIR tunable nanosecond pulsed laser.

ART-ML - a novel XML format for the biological procedures modeling and the representation of blood flow simulation.

PubMed

Karvounis, E C; Tsakanikas, V D; Fotiou, E; Fotiadis, D I

2010-01-01

The paper proposes a novel Extensible Markup Language (XML) based format called ART-ML that aims at supporting the interoperability and the reuse of models of blood flow, mass transport and plaque formation, exported by ARTool. ARTool is a platform for the automatic processing of various image modalities of coronary and carotid arteries. The images and their content are fused to develop morphological models of the arteries in easy to handle 3D representations. The platform incorporates efficient algorithms which are able to perform blood flow simulation. In addition atherosclerotic plaque development is estimated taking into account morphological, flow and genetic factors. ART-ML provides a XML format that enables the representation and management of embedded models within the ARTool platform and the storage and interchange of well-defined information. This approach influences in the model creation, model exchange, model reuse and result evaluation.

Irisin protects against endothelial injury and ameliorates atherosclerosis in apolipoprotein E-Null diabetic mice.

PubMed

Lu, Junyan; Xiang, Guangda; Liu, Min; Mei, Wen; Xiang, Lin; Dong, Jing

2015-12-01

The circulating irisin increases energy expenditure and improves insulin resistance in mice and humans. The improvement of insulin resistance ameliorates atherosclerosis. Therefore, we hypothesized that irisin alleviates atherosclerosis in diabetes. Endothelial function was measured by acetylcholine-induced endothelium-dependent vasodilation using aortic rings in apolipoprotein E-Null (apoE(-/-)) streptozotocin-induced diabetic mice. Atherosclerotic lesion was evaluated by plaque area and inflammatory response in aortas. In addition, the endothelium-protective effects of irisin were also further investigated in primary human umbilical vein endothelial cells (HUVECs) in vitro. The in vivo experiments showed that irisin treatment significantly improved endothelial dysfunction, decreased endothelial apoptosis, and predominantly decreased atherosclerotic plaque area of both en face and cross sections when compared with normal saline-treated diabetic mice. Moreover, the infiltrating macrophages and T lymphocytes within plaque and the mRNA expression levels of inflammatory cytokines in aortas were also significantly reduced by irisin treatment in mice. The in vitro experiments revealed that irisin inhibited high glucose-induced apoptosis, oxidative stress and increased antioxidant enzymes expression in HUVECs, and pretreatment with LY294002, l-NAME, AMPK-siRNA or eNOS-siRNA, attenuated the protection of irisin on HUVECs apoptosis induced by high glucose. In addition, the in vivo and in vitro experiments showed that irisin increased the phosphorylation of AMPK, Akt and eNOS in aortas and cultured HUVECs. The present study indicates that systemic administration of irisin may be protected against endothelial injury and ameliorated atherosclerosis in apoE(-/-) diabetic mice. The endothelium-protective action of irisin was through activation of AMPK-PI3K-Akt-eNOS signaling pathway. Irisin could be therapeutic for atherosclerotic vascular diseases in diabetes. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Diabetic retinopathy is associated with the presence and burden of subclinical carotid atherosclerosis in type 1 diabetes.

PubMed

Carbonell, Marc; Castelblanco, Esmeralda; Valldeperas, Xavier; Betriu, Àngels; Traveset, Alícia; Granado-Casas, Minerva; Hernández, Marta; Vázquez, Federico; Martín, Mariona; Rubinat, Esther; Lecube, Albert; Franch-Nadal, Josep; Fernández, Elvira; Puig-Domingo, Manel; Avogaro, Angelo; Alonso, Núria; Mauricio, Dídac

2018-05-04

Cardiovascular (CV) disease due to atherosclerosis is a major cause of morbidity and mortality in adult patients with diabetes, either type 1 or type 2 diabetes. The aim of the study was to assess the association of the frequency and the burden of subclinical carotid atherosclerotic disease in patients with type 1 diabetes according to the presence and severity of diabetic retinopathy (DR). A cross-sectional study was conducted in 340 patients with type 1 diabetes (41.5% with DR), and in 304 non-diabetic individuals. All participants were free from previous CV disease and chronic kidney disease (CKD). B-mode carotid ultrasound imaging was performed in all the study subjects. Patients with type 1 diabetes underwent a full eye examination, and DR patients were divided into two groups: mild disease and advanced disease. In the group of patients with type 1 diabetes, the percentage of patients with carotid plaques was higher in those with DR compared with those without DR (44.7% vs. 24.1%, p < 0.001). Patients with DR also presented a higher incidence of ≥ 2 carotid plaques (25.5% vs. 11.1%, p < 0.001). Apart from other traditional cardiovascular risk factors, the presence of advanced stages of DR was independently associated with the presence (p = 0.044) and the burden (≥ 2 carotid plaques; p = 0.009) of subclinical carotid atherosclerosis. In patients with type 1 diabetes without previous CV disease or established CKD, the presence of advanced stages of DR is associated with a higher atherosclerotic burden in the carotid arteries. The presence of DR identifies patients at risk for carotid atherosclerotic disease.

Fluid-phase pinocytosis of LDL by macrophages: a novel target to reduce macrophage cholesterol accumulation in atherosclerotic lesions.

PubMed

Kruth, Howar S

2013-01-01

Circulating low-density lipoprotein (LDL) that enters the blood vessel wall is the main source of cholesterol that accumulates within atherosclerotic plaques. Much of the deposited cholesterol accumulates within plaque macrophages converting these macrophages into cholesterol-rich foamy looking cells. Cholesterol accumulation in macrophages contributes to cholesterol retention within the vessel wall, and promotes vessel wall inflammation and thrombogenicity. Thus, how macrophages accumulate cholesterol and become foam cells has been the subject of intense investigation. It is generally believed that macrophages accumulate cholesterol only through scavenger receptor-mediated uptake of modified LDL. However, an alternative mechanism for macrophage foam cell formation that does not depend on LDL modification or macrophage receptors has been elucidated. By this alternative mechanism, macrophages show receptor-independent uptake of unmodified native LDL that is mediated by fluid-phase pinocytosis. In receptor-independent, fluid-phase pinocytosis, macrophages take up LDL as part of the fluid that they ingest during micropinocytosis within small vesicles called micropinosomes, and by macropinocytosis within larger vacuoles called macropinosomes. This produces cholesterol accumulation in macrophages to levels characteristic of macrophage foam cells in atherosclerotic plaques. Fluid-phase pinocytosis of LDL is a plausible mechanism that can explain how macrophages accumulate cholesterol and become disease-causing foam cells. Fluid-phase pinocytosis of LDL is a relevant pathway to target for modulating macrophage cholesterol accumulation in atherosclerosis. Recent studies show that phosphoinositide 3-kinase (PI3K), liver X receptors (LXRs), the macrophage colony-stimulating factor (M-CSF) receptor, and protein kinase C (PKC) mediate macrophage macropinocytosis of LDL, and thus, these may be relevant targets to inhibit macrophage cholesterol accumulation in atherosclerosis.

Rosuvastatin Attenuates CD40L-Induced Downregulation of Extracellular Matrix Production in Human Aortic Smooth Muscle Cells via TRAF6-JNK-NF-κB Pathway

PubMed Central

Wang, Xiao-Lin; Zhou, Yuan-Li; Sun, Wei; Li, Li

2016-01-01

CD40L and statins exhibit pro-inflammatory and anti-inflammatory effects, respectively. They are both pleiotropic and can regulate extracellular matrix (ECM) degeneration in an atherosclerotic plaque. Statins can decrease both the CD40 expression and the resulting inflammation. However, the effects of CD40L and stains on atherosclerotic plaque ECM production and the underlying mechanisms are not well established. Moreover, prolyl-4-hydroxylase α1 (P4Hα1) is involved in collagen synthesis but its correlations with CD40L and statins are unknown. In the present study, CD40L suppressed P4Hα1 expression in human aortic smooth muscle cells (HASMCs) in a dose- and time-dependent manner, with insignificant changes in MMP2 expression and negative enzymatic activity of MMP9. CD40L increased TRAF6 expression, JNK phosphorylation, NF-κB nuclear translocation as well as DNA binding. Furthermore, silencing TRAF6, JNK or NF-κB genes abolished CD40L-induced suppression of P4Hα1. Lower NF-κB nuclear import rates were observed when JNK or TRAF6 silenced HASMCs were stimulated with CD40L compared to HASMCs with active JNK or TRAF6. Together, these results indicate that CD40L suppresses P4Hα1 expression in HASMCs by activating the TRAF6-JNK- NF-κB pathway. We also found that rosuvastatin inhibits CD40L-induced activation of the TRAF6-JNK- NF-κB pathway, thereby significantly rescuing the CD40L stimulated P4Hα1 inhibition. The results from this study will help find potential targets for stabilizing vulnerable atherosclerotic plaques. PMID:27120457

An increased waist-to-hip ratio is a key determinant of atherosclerotic burden in overweight subjects.

PubMed

Scicali, Roberto; Rosenbaum, David; Di Pino, Antonino; Giral, Philippe; Cluzel, Philippe; Redheuil, Alban; Piro, Salvatore; Rabuazzo, Agata Maria; Purrello, Francesco; Bruckert, Eric; Gallo, Antonio

2018-04-21

The association of overweight status and cardiovascular disease is not clear. In this study we aimed to investigate coronary atherosclerotic disease, evaluated as coronary artery calcium score (CACs), in overweight patients with or without abdominal obesity as defined by waist-to-hip ratio (WHR). We enrolled 276 patients aged between 40 and 70 years, with a body mass index of 25-29.9 kg/m 2 and at least one cardiovascular risk factor. Exclusion criteria were history of diabetes, cardiovascular or renal disease. Patients were stratified in high WHR (H-WHR) or low WHR (L-WHR) group according to WHR (≥ 0.85 for women and ≥ 0.90 for men) and underwent multi-detector computed tomography for CACs. Mean carotid intima-media thickness (IMT) and plaque presence were equally assessed. CACs was higher in the H-WHR group compared to L-WHR (9.05 [0.0-83.48] vs 0.0 [0.0-64.7] AU, p < 0.01); the prevalence of CACs > 0 in the H-WHR group was significantly higher than subjects with L-WHR (59.6% vs 38.5%, p < 0.001). Moreover, H-WHR group had higher mean IMT (0.64 [0.56-0.72] vs 0.59 [0.55-0.67] mm, p < 0.05) and higher carotid plaque prevalence (63.7% vs 50.8%, p < 0.05) compared to subjects with L-WHR. Logistic regression showed that H-WHR was associated with presence of CACs and carotid plaque (p < 0.01). In a multiple linear regression, WHR was positively associated with CACs and IMT (p < 0.01). H-WHR is a marker of coronary and peripheral atherosclerotic burden in overweight patients.

Periodontal Pathogens Invade Gingiva and Aortic Adventitia and Elicit Inflammasome Activation in αvβ6 Integrin-Deficient Mice

PubMed Central

Velsko, Irina M.; Chukkapalli, Sasanka S.; Rivera-Kweh, Mercedes F.; Zheng, Donghang; Aukhil, Ikramuddin; Lucas, Alexandra R.; Larjava, Hannu

2015-01-01

The American Heart Association supports an association between periodontal diseases and atherosclerosis but not a causal association. This study explores the use of the integrin β6−/− mouse model to study the causality. We investigated the ability of a polymicrobial consortium of Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Fusobacterium nucleatum to colonize the periodontium and induce local and systemic inflammatory responses. Polymicrobially infected Itgβ6−/− mice demonstrate greater susceptibility to gingival colonization/infection, with severe gingival inflammation, apical migration of the junctional epithelium, periodontal pocket formation, alveolar bone resorption, osteoclast activation, bacterial invasion of the gingiva, a greater propensity for the bacteria to disseminate hematogenously, and a strong splenic T cell cytokine response. Levels of atherosclerosis risk factors, including serum nitric oxide, oxidized low-density lipoprotein, serum amyloid A, and lipid peroxidation, were significantly altered by polybacterial infection, demonstrating an enhanced potential for atherosclerotic plaque progression. Aortic gene expression revealed significant alterations in specific Toll-like receptor (TLR) and nucleotide-binding domain- and leucine-rich-repeat-containing receptor (NLR) pathway genes in response to periodontal bacterial infection. Histomorphometry of the aorta demonstrated larger atherosclerotic plaques in Itgβ6−/− mice than in wild-type (WT) mice but no significant difference in atherosclerotic plaque size between mice with polybacterial infection and mice with sham infection. Fluorescence in situ hybridization demonstrated active invasion of the aortic adventitial layer by P. gingivalis. Our observations suggest that polybacterial infection elicits distinct aortic TLR and inflammasome signaling and significantly increases local aortic oxidative stress. These results are the first to demonstrate the mechanism of the host aortic inflammatory response induced by polymicrobial infection with well-characterized periodontal pathogens. PMID:26371120

Imaging vulnerable plaques by targeting inflammation in atherosclerosis using fluorescent-labeled dual-ligand microparticles of iron oxide and magnetic resonance imaging.

PubMed

Chan, Joyce M S; Monaco, Claudia; Wylezinska-Arridge, Marzena; Tremoleda, Jordi L; Cole, Jennifer E; Goddard, Michael; Cheung, Maggie S H; Bhakoo, Kishore K; Gibbs, Richard G J

2018-05-01

Identification of patients with high-risk asymptomatic carotid plaques remains an elusive but essential step in stroke prevention. Inflammation is a key process in plaque destabilization and a prelude to clinical sequelae. There are currently no clinical imaging tools to assess the inflammatory activity within plaques. This study characterized inflammation in atherosclerosis using dual-targeted microparticles of iron oxide (DT-MPIO) as a magnetic resonance imaging (MRI) probe. DT-MPIO were used to detect and characterize inflammatory markers, vascular cell adhesion molecule 1 (VCAM-1). and P-selectin on (1) tumor necrosis factor-α-treated cells by immunocytochemistry and (2) aortic root plaques of apolipoprotein-E deficient mice by in vivo MRI. Furthermore, apolipoprotein E-deficient mice with focal carotid plaques of different phenotypes were developed by means of periarterial cuff placement to allow in vivo molecular MRI using these probes. The association between biomarkers and the magnetic resonance signal in different contrast groups was assessed longitudinally in these models. Immunocytochemistry confirmed specificity and efficacy of DT-MPIO to VCAM-1 and P-selectin. Using this in vivo molecular MRI strategy, we demonstrated (1) the DT-MPIO-induced magnetic resonance signal tracked with VCAM-1 (r = 0.69; P = .014), P-selectin (r = 0.65; P = .022), and macrophage content (r = 0.59; P = .045) within aortic root plaques and (2) high-risk inflamed plaques were distinguished from noninflamed plaques in the murine carotid artery within a practical clinical imaging time frame. These molecular MRI probes constitute a novel imaging tool for in vivo characterization of plaque vulnerability and inflammatory activity in atherosclerosis. Further development and translation into the clinical arena will facilitate more accurate risk stratification in carotid atherosclerotic disease in the future. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Intraplaque stretch in carotid atherosclerotic plaque--an effective biomechanical predictor for subsequent cerebrovascular ischemic events.

PubMed

Teng, Zhongzhao; Sadat, Umar; Wang, Wenkai; Bahaei, Nasim S; Chen, Shengyong; Young, Victoria E; Graves, Martin J; Gillard, Jonathan H

2013-01-01

Stretch is a mechanical parameter, which has been proposed previously to affect the biological activities in different tissues. This study explored its utility in determining plaque vulnerability. One hundred and six patients with mild to moderate carotid stenosis were recruited in this study (53 symptomatic and 53 asymptomatic). High resolution, multi-sequence magnetic resonance (MR) imaging was performed to delineate various plaque components. Finite element method was used to predict high stretch concentration within the plaque. During a two-year follow-up, 11 patients in symptomatic group and 3 in asymptomatic group experienced recurrent cerebrovascular events. Plaque stretch at systole and stretch variation during one cardiac cycle was greater in symptomatic group than those in the asymptomatic. Within the symptomatic group, a similar trend was observed in patients with recurrent events compared to those without. Plaques with high stretch concentration and large stretch variation are associated with increased risk of future cerebrovascular events.

Local extension of HMGB1 in atherosclerotic lesions of human main cerebral and carotid arteries.

PubMed

Umahara, T; Uchihara, T; Koyama, S; Hashimoto, T; Akimoto, J; Haraoka, J; Iwamoto, T

2014-02-01

High mobility group box 1 protein (HMGB1) is a non-histone chromosomal protein which is highly conserved, ubiquitous, and widely distributed. HMGB1 has multiple functions in the nucleus, including the maintenance of nucleosome structure, the regulation of gene transcription, and involvement in DNA recombination. HMBG1 is currently recognized to have a wide range of potential functions and pathological relevance. HMGB1 is released into the extracellular space from necrotic cells and from activated macrophages. HMGB1 binds to the receptor for advanced glycation end products, resulting in the induction of inflammatory cytokines, and to endothelial cell thrombomodulin. HMGB1 neutralization may also reduce the development of atherosclerosis and ameliorate brain infarction. We investigated the immunolocalization of HMGB1 in atherosclerotic lesions of human cerebral and carotid arteries using a specific antibody, and confirmed the detailed expression and cell type localization using double immunofluorolabeling. In the main cerebral arteries, this anti-HMGB1 antibody intensely immunolabeled both normal morphological vascular smooth muscle cells (VSMCs) within the tunica media and infiltrating VSMCs within the intima of thickened fibrous cap plaques. Endothelial cells were also positive for HMGB1. In carotid plaques, HMGB1-like immunoreactivity (IR) was intense in macrophages, although this IR decreased with increasing cell size. Medium-sized foam cells (50-150 μm) were the most intensely stained. This IR was also observed in the nuclei of foam cells and VSMCs. These findings may provide a basis for understanding the association of HMGB1 with atherosclerotic lesions of the cerebral and carotid arteries, and for constructing strategies to counteract atherosclerosis with anti-HMGB1 antibody.

RNA interference therapy: a new solution for intracranial atherosclerosis?

PubMed Central

Tang, Tao; Wong, Ka-Sing

2014-01-01

Intracranial atherosclerotic stenosis (ICAS) of a major intracranial artery, especially middle cerebral artery (MCA), is reported to be one leading cause of ischemic stroke throughout the world. Compared with other stroke subtypes, ICAS is associated with a higher risk of recurrent stroke despite aggressive medical therapy. Increased understanding of the pathophysiology of ICAS has highlighted several possible targets for therapeutic interventions. Both luminal stenosis and plaque components of ICAS have been found to be associated with ischemic stroke based a post-mortem study. Recent application of high-resolution magnetic resonance imaging (HRMRI) in evaluating ICAS provides new insight into the vascular biology of plaque morphology and component. High signal on T1-weighted fat-suppressed images (HST1) within MCA plaque of HRMRI, highly suggested of fresh or recent intraplaque hemorrhage, has been found to be associated with ipsilateral brain infarction. Thus, the higher prevalence of intraplaque hemorrhage and neovasculature in symptomatic patients with MCA stenosis may provide a potential target for plaque stabilization. We hypothesize that RNA interference (RNAi) therapy delivered by modified nanoparticles may achieve in vivo biomedical imaging and targeted therapy. With the rapid developments in studies about therapeutic and diagnostic nanomaterials, future studies further exploring the molecular biology of atherosclerosis may provide more drug targets for plaque stabilization. PMID:25333054

Lipid detection by intravascular photoacoustic imaging with flexible catheter at 20 fps (Conference Presentation)

NASA Astrophysics Data System (ADS)

Wu, Min; Daeichin, Verya; Springeling, Geert; van der Steen, Antonius F. W.; van Soest, Gijs

2016-02-01

Intravascular Photoacoustic (IVPA) imaging is a promising new technology to assess lipid content of coronary atherosclerotic plaque, an important determinant of the risk associated with the plaque triggering a heart attack. Clinical translation of IVPA imaging requires real-time image acquisition, which has been a technological challenge. In this work, we demonstrate a high-speed, dual-wavelength IVPA imaging system at 1.7 µm wavelength, operating with a flexible catheter of 1.2 mm outer diameter (including outer sheath). The catheter was custom designed and fabricated, and used a 40 MHz transducer for intravascular ultrasound (IVUS) and IVPA imaging. The optical excitation is provided by a dual OPO system, pumped by CW diode-pumped Q-switched Nd:YAG lasers, with a repetition rate of 5 kHz. Each OPO can be tuned to a custom wavelength between 1690 and 1750 nm; two wavelengths only are needed to discriminate between plaque lipids and adipose tissue. The pulse energy is about 80 µJ. We tested the imaging performance of the presented system in a polyvinyl-alcohol (PVA) vessel mimicking phantom and human coronary arteries ex vivo. IVPA identified lipid deposits inside atherosclerotic plaque, while IVUS showed tissue structure. We demonstrated IVPA imaging at a speed of 20 frames per second, with 250 A-scans per frame. This is significantly faster than previous IVPA imaging systems, and will enable the translation of IVPA imaging into clinical practice.

Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis.

PubMed

Borow, Kenneth M; Nelson, John R; Mason, R Preston

2015-09-01

Residual cardiovascular (CV) risk remains in dyslipidemic patients despite intensive statin therapy, underscoring the need for additional intervention. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, is incorporated into membrane phospholipids and atherosclerotic plaques and exerts beneficial effects on the pathophysiologic cascade from onset of plaque formation through rupture. Specific salutary actions have been reported relating to endothelial function, oxidative stress, foam cell formation, inflammation, plaque formation/progression, platelet aggregation, thrombus formation, and plaque rupture. EPA also improves atherogenic dyslipidemia characterized by reduction of triglycerides without raising low-density lipoprotein cholesterol. Other beneficial effects of EPA include vasodilation, resulting in blood pressure reductions, as well as improved membrane fluidity. EPA's effects are at least additive to those of statins when given as adjunctive therapy. In this review, we present data supporting the biologic plausibility of EPA as an anti-atherosclerotic agent with potential clinical benefit for prevention of CV events, as well as its cellular effects and molecular mechanisms of action. REDUCE-IT is an ongoing, randomized, controlled study evaluating whether the high-purity ethyl ester of EPA (icosapent ethyl) at 4 g/day combined with statin therapy is superior to statin therapy alone for reducing CV events in high-risk patients with mixed dyslipidemia. The results from this study are expected to clarify the role of EPA as adjunctive therapy to a statin for reduction of residual CV risk. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Lineage tracing of cells involved in atherosclerosis.

PubMed

Albarrán-Juárez, Julián; Kaur, Harmandeep; Grimm, Myriam; Offermanns, Stefan; Wettschureck, Nina

2016-08-01

Despite the clinical importance of atherosclerosis, the origin of cells within atherosclerotic plaques is not fully understood. Due to the lack of a definitive lineage-tracing strategy, previous studies have provided controversial results about the origin of cells expressing smooth muscle and macrophage markers in atherosclerosis. We here aim to identify the origin of vascular smooth muscle (SM) cells and macrophages within atherosclerosis lesions. We combined a genetic fate mapping approach with single cell expression analysis in a murine model of atherosclerosis. We found that 16% of CD68-positive plaque macrophage-like cells were derived from mature SM cells and not from myeloid sources, whereas 31% of αSMA-positive smooth muscle-like cells in plaques were not SM-derived. Further analysis at the single cell level showed that SM-derived CD68(+) cells expressed higher levels of inflammatory markers such as cyclooxygenase 2 (Ptgs2, p = 0.02), and vascular cell adhesion molecule (Vcam1, p = 0.05), as well as increased mRNA levels of genes related to matrix synthesis such as Col1a2 (p = 0.01) and Fn1 (p = 0.04), than non SM-derived CD68(+) cells. These results demonstrate that smooth muscle cells within atherosclerotic lesions can switch to a macrophage-like phenotype characterized by higher expression of inflammatory and synthetic markers genes that may further contribute to plaque progression. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

The simulation of magnetic resonance elastography through atherosclerosis.

PubMed

Thomas-Seale, L E J; Hollis, L; Klatt, D; Sack, I; Roberts, N; Pankaj, P; Hoskins, P R

2016-06-14

The clinical diagnosis of atherosclerosis via the measurement of stenosis size is widely acknowledged as an imperfect criterion. The vulnerability of an atherosclerotic plaque to rupture is associated with its mechanical properties. The potential to image these mechanical properties using magnetic resonance elastography (MRE) was investigated through synthetic datasets. An image of the steady state wave propagation, equivalent to the first harmonic, can be extracted directly from finite element analysis. Inversion of this displacement data yields a map of the shear modulus, known as an elastogram. The variation of plaque composition, stenosis size, Gaussian noise, filter thresholds and excitation frequency were explored. A decreasing mean shear modulus with an increasing lipid composition was identified through all stenosis sizes. However the inversion algorithm showed sensitivity to parameter variation leading to artefacts which disrupted both the elastograms and quantitative trends. As noise was increased up to a realistic level, the contrast was maintained between the fully fibrous and lipid plaques but lost between the interim compositions. Although incorporating a Butterworth filter improved the performance of the algorithm, restrictive filter thresholds resulted in a reduction of the sensitivity of the algorithm to composition and noise variation. Increasing the excitation frequency improved the techniques ability to image the magnitude of the shear modulus and identify a contrast between compositions. In conclusion, whilst the technique has the potential to image the shear modulus of atherosclerotic plaques, future research will require the integration of a heterogeneous inversion algorithm. Copyright © 2016 Elsevier Ltd. All rights reserved.

Numerical observer for atherosclerotic plaque classification in spectral computed tomography

PubMed Central

Lorsakul, Auranuch; Fakhri, Georges El; Worstell, William; Ouyang, Jinsong; Rakvongthai, Yothin; Laine, Andrew F.; Li, Quanzheng

2016-01-01

Abstract. Spectral computed tomography (SCT) generates better image quality than conventional computed tomography (CT). It has overcome several limitations for imaging atherosclerotic plaque. However, the literature evaluating the performance of SCT based on objective image assessment is very limited for the task of discriminating plaques. We developed a numerical-observer method and used it to assess performance on discrimination vulnerable-plaque features and compared the performance among multienergy CT (MECT), dual-energy CT (DECT), and conventional CT methods. Our numerical observer was designed to incorporate all spectral information and comprised two-processing stages. First, each energy-window domain was preprocessed by a set of localized channelized Hotelling observers (CHO). In this step, the spectral image in each energy bin was decorrelated using localized prewhitening and matched filtering with a set of Laguerre–Gaussian channel functions. Second, the series of the intermediate scores computed from all the CHOs were integrated by a Hotelling observer with an additional prewhitening and matched filter. The overall signal-to-noise ratio (SNR) and the area under the receiver operating characteristic curve (AUC) were obtained, yielding an overall discrimination performance metric. The performance of our new observer was evaluated for the particular binary classification task of differentiating between alternative plaque characterizations in carotid arteries. A clinically realistic model of signal variability was also included in our simulation of the discrimination tasks. The inclusion of signal variation is a key to applying the proposed observer method to spectral CT data. Hence, the task-based approaches based on the signal-known-exactly/background-known-exactly (SKE/BKE) framework and the clinical-relevant signal-known-statistically/background-known-exactly (SKS/BKE) framework were applied for analytical computation of figures of merit (FOM). Simulated data of a carotid-atherosclerosis patient were used to validate our methods. We used an extended cardiac-torso anthropomorphic digital phantom and three simulated plaque types (i.e., calcified plaque, fatty-mixed plaque, and iodine-mixed blood). The images were reconstructed using a standard filtered backprojection (FBP) algorithm for all the acquisition methods and were applied to perform two different discrimination tasks of: (1) calcified plaque versus fatty-mixed plaque and (2) calcified plaque versus iodine-mixed blood. MECT outperformed DECT and conventional CT systems for all cases of the SKE/BKE and SKS/BKE tasks (all p<0.01). On average of signal variability, MECT yielded the SNR improvements over other acquisition methods in the range of 46.8% to 65.3% (all p<0.01) for FBP-Ramp images and 53.2% to 67.7% (all p<0.01) for FBP-Hanning images for both identification tasks. This proposed numerical observer combined with our signal variability framework is promising for assessing material characterization obtained through the additional energy-dependent attenuation information of SCT. These methods can be further extended to other clinical tasks such as kidney or urinary stone identification applications. PMID:27429999

Catheter design optimization for practical intravascular photoacoustic imaging (IVPA) of vulnerable plaques

NASA Astrophysics Data System (ADS)

Iskander-Rizk, Sophinese; Wu, Min; Springeling, Geert; Mastik, Frits; Beurskens, Robert H. S. H.; van der Steen, Antonius F. W.; van Soest, Gijs

2018-02-01

Intravascular photoacoustic/ultrasound imaging (IVPA/US) can image the structure and composition of atherosclerotic lesions identifying lipid-rich plaques ex vivo and in vivo. In the literature, multiple IVPA/US catheter designs were presented and validated both in ex-vivo models and preclinical in-vivo situations. Since the catheter is a critical component of the imaging system, we discuss here a catheter design oriented to imaging plaque in a realistic and translatable setting. We present a catheter optimized for light delivery, manageable flush parameters and robustness with reduced mechanical damage risks at the laser/catheter joint interface. We also show capability of imaging within sheath and in water medium.

Matrix metalloproteinases in acute coronary syndromes: current perspectives.

PubMed

Kampoli, Anna-Maria; Tousoulis, Dimitris; Papageorgiou, Nikolaos; Antoniades, Charalambos; Androulakis, Emmanuel; Tsiamis, Eleftherios; Latsios, George; Stefanadis, Christodoulos

2012-01-01

Matrix metalloproteinases (MMPs) are a family of zinc metallo-endopeptidases secreted by cells and are responsible for much of the turnover of matrix components. Several studies have shown that MMPs are involved in all stages of the atherosclerotic process, from the initial lesion to plaque rupture. Recent evidence suggests that MMP activity may facilitate atherosclerosis, plaque destabilization, and platelet aggregation. In the heart, matrix metalloproteinases participate in vascular remodeling, plaque instability, and ventricular remodelling after cardiac injury. The aim of the present article is to review the structure, function, regulation of MMPs and to discuss their potential role in the pathogenesis of acute coronary syndromes, as well as their contribution and usefullness in the setting of the disease.

Effect of chemical systemic acquired resistance elicitors on avenanthramide biosynthesis in oat (Avena sativa)

USDA-ARS?s Scientific Manuscript database

Oats produce a group of phenolic antioxidants termed avenanthramides. These metabolites are, among food crops, unique to oats and have shown some desirable nutritional characteristics, in experimental systems, such as inhibiting atherosclerotic plaque formation and reducing inflammatory responses. ...

The Effect of Chemical Systemic Acquired Resistance Elicitors on Oat Avenanthramide Biosynthesis

USDA-ARS?s Scientific Manuscript database

Abstract. Oats produce a group of phenolic antioxidants termed “avenanthramides”. These metabolites are, among food crops, unique to oats. They are known to be potent antioxidants and have shown certain desirable nutritional characteristics such as inhibiting atherosclerotic plaque formation and ...

Magnesium intake is inversely associated with coronary artery calcification: the Framingham Heart Study

USDA-ARS?s Scientific Manuscript database

OBJECTIVES: The aim of this study was to examine whether magnesium intake is associated with coronary artery calcification (CAC) and abdominal aortic calcification (AAC). BACKGROUND: Animal and cell studies suggest that magnesium may prevent calcification within atherosclerotic plaques underlying c...

Atorvastatin Improves Inflammatory Response in Atherosclerosis by Upregulating the Expression of GARP.

PubMed

Zhao, Xiaoqi; Liu, Yuzhou; Zhong, Yucheng; Liu, Bo; Yu, Kunwu; Shi, Huairui; Zhu, Ruirui; Meng, Kai; Zhang, Wei; Wu, Bangwei; Zeng, Qiutang

2015-01-01

Regulatory T cells play an important role in the progression of atherosclerosis. GARP is a newly biological membrane molecule existed on activated Tregs, which is related to the release of TGF-β. The antiatherosclerosis effects of statins partly depend on their multiple immune modulatory potencies. In this paper, we present that atorvastatin could upregulate the expression of GARP and TGF-β in CD4+ T cells and increase the numbers of CD4+LAP+ and CD4+Foxp3+ regulatory T cells in ApoE-/- mice. Also, we indicate that atorvastatin promotes the aggregation of GARP+ and Foxp3+ cells and secretory of the TGF-β1 in atherosclerotic plaques. Furthermore, we prove that atorvastatin could delay the procession of atherosclerosis and improve the stability of atherosclerotic plaques. Interestingly, we report that inhibition of GARP distinctly inhibits the anti-inflammatory effects of atorvastatin. We conclude that atorvastatin improves the inflammatory response in atherosclerosis partly by upregulating the expression of GARP on regulatory T cells.

Atorvastatin Improves Inflammatory Response in Atherosclerosis by Upregulating the Expression of GARP

PubMed Central

Zhao, Xiaoqi; Liu, Yuzhou; Zhong, Yucheng; Liu, Bo; Yu, Kunwu; Shi, Huairui; Zhu, Ruirui; Meng, Kai; Zhang, Wei; Wu, Bangwei

2015-01-01

Regulatory T cells play an important role in the progression of atherosclerosis. GARP is a newly biological membrane molecule existed on activated Tregs, which is related to the release of TGF-β. The antiatherosclerosis effects of statins partly depend on their multiple immune modulatory potencies. In this paper, we present that atorvastatin could upregulate the expression of GARP and TGF-β in CD4+ T cells and increase the numbers of CD4+LAP+ and CD4+Foxp3+ regulatory T cells in ApoE−/− mice. Also, we indicate that atorvastatin promotes the aggregation of GARP+ and Foxp3+ cells and secretory of the TGF-β1 in atherosclerotic plaques. Furthermore, we prove that atorvastatin could delay the procession of atherosclerosis and improve the stability of atherosclerotic plaques. Interestingly, we report that inhibition of GARP distinctly inhibits the anti-inflammatory effects of atorvastatin. We conclude that atorvastatin improves the inflammatory response in atherosclerosis partly by upregulating the expression of GARP on regulatory T cells. PMID:26063978

Formation of 3D cholesterol crystals from 2D nucleation sites in lipid bilayer membranes: implications for atherosclerosis.

PubMed

Varsano, Neta; Fargion, Iael; Wolf, Sharon G; Leiserowitz, Leslie; Addadi, Lia

2015-02-04

Atherosclerosis is the major precursor of cardiovascular disease. The formation of cholesterol crystals in atherosclerotic plaques is associated with the onset of acute pathology. The cholesterol crystals induce physical injury in the plaque core, promoting cell apoptosis and triggering an increased inflammatory response. Herein we address the question of how cholesterol crystal formation occurs in atherosclerosis. We demonstrate that three-dimensional (3D) cholesterol crystals can undergo directed nucleation from bilayer membranes containing two-dimensional (2D) cholesterol crystalline domains. We studied crystal formation on supported lipid bilayers loaded with exogenous cholesterol and labeled using a monoclonal antibody that specifically recognizes ordered cholesterol arrays. Our findings show that 3D crystals are formed exclusively on the bilayer regions where there are segregated 2D cholesterol crystalline domains and that they form on the domains. This study has potentially significant implications for our understanding of the crucial step in the mechanism by which atherosclerotic lesions form.

Preintervention lesion remodelling affects operative mechanisms of balloon optimised directional coronary atherectomy procedures: a volumetric study with three dimensional intravascular ultrasound

PubMed Central

von Birgelen, C; Mintz, G; de Vrey, E A; Serruys, P; Kimura, T; Nobuyoshi, M; Popma, J; Leon, M; Erbel, R; de Feyter, P J

2000-01-01

AIMS—To classify atherosclerotic coronary lesions on the basis of adequate or inadequate compensatory vascular enlargement, and to examine changes in lumen, plaque, and vessel volumes during balloon optimised directional coronary atherectomy procedures in relation to the state of adaptive remodelling before the intervention.
DESIGN—29 lesion segments in 29 patients were examined with intravascular ultrasound before and after successful balloon optimised directional coronary atherectomy procedures, and a validated volumetric intravascular ultrasound analysis was performed off-line to assess the atherosclerotic lesion remodelling and changes in plaque and vessel volumes that occurred during the intervention. Based on the intravascular ultrasound data, lesions were classified according to whether there was inadequate (group I) or adequate (group II) compensatory enlargement.
RESULTS—There was no significant difference in patient and lesion characteristics between groups I and II (n = 10 and 19), including lesion length and details of the intervention. Quantitative coronary angiographic data were similar for both groups. However, plaque and vessel volumes were significantly smaller in group I than in II. In group I, 9 (4)% (mean (SD)) of the plaque volume was ablated, while in group II 16 (11)% was ablated (p = 0.01). This difference was reflected in a lower lumen volume gain in group I than in group II (46 (18) mm3 v 80 (49) mm3 (p < 0.02)).
CONCLUSIONS—Preintervention lesion remodelling has an impact on the operative mechanisms of balloon optimised directional coronary atherectomy procedures. Plaque ablation was found to be particularly low in lesions with inadequate compensatory vascular enlargement.


Keywords: intravascular ultrasound; ultrasonics; remodelling; coronary artery disease; atherectomy PMID:10648496

Image and flow cytometric analysis of gold nanoparticle uptake by macrophages

NASA Astrophysics Data System (ADS)

Fixler, Dror; Ankri, Rinat; Weiss, Ronald; Grahnert, Anja; Melzer, Susanne; Tárnok, Attila

2016-03-01

Background/Aim: In atherosclerosis stable and vulnerable atherosclerotic plaque types are distinguished that behave differently concerning rupture, thrombosis and clinical events. The stable are rich in M2 macrophages. The unstable are rich in inflammatory M1 macrophages and are highly susceptible to rupture, setting patients at risk for thrombotic events when they undergo invasive diagnosis such as coronary angiography. Therefore, novel approaches for non-invasive detection and classification of vulnerable plaques in vivo are needed. Whereas classical approaches fail to differentiate between both plaque types, a new biophotonic method (combination of the diffusion reflection (DR) method with flow cytometry (FCM) or image cytometry (IC)) to analyze gold nanoparticle (GNP) loading of plaques could overcome this limitation. Methods: Two types of GNP were used three variants of gold nanorods (GNRI with 40x18 nm, II 65x25 nm and III 52x13 nm in size) and gold nanospheres (GNS with an average diameter of 18.5 nm). The GNS had an absorption peak at 520 nm and the GNR at 630 nm. Monocytes were isolated from human buffy blood samples, differentiated into macrophages and their subtypes and labelled with GNR and GNS for 3 and 24 h. GNS and GNR loading were determined by FCM and/or IC. Macrophages within tissue-like phantoms were analyzed by the DR system. Results: After GNR labelling of macrophages the FCM light scatter values increased up to 3.7 fold and the DR slope changed from an average slope of 0.196 (macrophages only) to an average slope of 0.827 (macrophages labelled with GNR). But, GNRIII did not present much higher DR slopes than the control phantoms, indicating that macrophages take up GNRIII in a lower amount than GNRI or II. IC and microscopy showed that all particle variants were taken up by the cells in a heterogeneous fashion. Conclusion and outlook: The combination of FCM and DR measurements provides a potential novel, highly sensitive and non-invasive method for the identification of atherosclerotic vulnerable plaques, aimed to develop a potential tool for in vivo tracking. Further experiments will show, if different macrophage subtypes (M1 or M2) take up the particles differently and may thereby serve to distinguish stable from vulnerable plaques.

Atheroprotective Properties of Serum IGF-1 in the Carotid and Coronary Territories and Beneficial Role on the Physical Fitness of the Oldest Old.

PubMed

Córdova, Claudio; Boullosa, Daniel A; Custódio, Misael R M; Quaglia, Luiz A; Santos, Simone N; Freitas, Wladimir M; Sposito, Andrei C; Nóbrega, Otávio T

2016-10-01

Our aim was to investigate whether physiological levels of soluble insulin-like growth factor-1 (IGF-1) associate with coronary and carotid atherosclerotic burden and physical fitness in the oldest old by means of a cross-sectional study including 100 community-dwelling individuals with no previous cardiovascular events. Linear correlation was found between IGF-1 and intima-media thickness, number of carotid plaques, and walking speed. Individuals in the upper IGF-1 tertile had smaller right and left intima-media thickness compared with the intermediate and lower tertiles, along with reduced atherosclerotic plaques. Also, walking speed was greater in the upper IGF-1 tertile. On the other hand, a nonlinear correlation was observed between IGF-1 and coronary calcification scores, with the intermediate IGF-1 tertile associated to the lowest scores of calcification and participants with lower circulating levels of IGF-1 showing higher frequency of high-risk morphology plaques. All in all, our report supports a territory-dependent, atherorefractory phenotype in the oldest old carrying middle and/or higher serum levels of IGF-1. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Dark-field imaging in coronary atherosclerosis.

PubMed

Hetterich, Holger; Webber, Nicole; Willner, Marian; Herzen, Julia; Birnbacher, Lorenz; Auweter, Sigrid; Schüller, Ulrich; Bamberg, Fabian; Notohamiprodjo, Susan; Bartsch, Harald; Wolf, Johannes; Marschner, Mathias; Pfeiffer, Franz; Reiser, Maximilian; Saam, Tobias

2017-09-01

Dark-field imaging based on small angle X-ray scattering has been shown to be highly sensitive for microcalcifications, e.g. in breast tissue. We hypothesized (i) that high signal areas in dark-field imaging of atherosclerotic plaque are associated with microcalcifications and (ii) that dark-field imaging is more sensitive for microcalcifications than attenuation-based imaging. Fifteen coronary artery specimens were examined at an experimental set-up consisting of X-ray tube (40kV), grating-interferometer and detector. Tomographic dark-field-, attenuation-, and phase-contrast data were simultaneously acquired. Histopathology served as standard of reference. To explore the potential of dark field imaging in a full-body CT system, simulations were carried out with spherical calcifications of different sizes to simulate small and intermediate microcalcifications. Microcalcifications were present in 10/10 (100%) cross-sections with high dark-field signal and without evidence of calcifications in attenuation- or phase contrast. In positive controls with high signal areas in all three modalities, 10/10 (100%) cross-sections showed macrocalcifications. In negative controls without high signal areas, no calcifications were detected. Simulations showed that the microcalcifications generate substantially higher dark-field than attenuation signal. Dark-field imaging is highly sensitive for microcalcifications in coronary atherosclerotic plaque and might provide complementary information in the assessment of plaque instability. Copyright © 2017 Elsevier B.V. All rights reserved.

Mechanisms of erosion of atherosclerotic plaques.

PubMed

Quillard, Thibaut; Franck, Grégory; Mawson, Thomas; Folco, Eduardo; Libby, Peter

2017-10-01

The present review explores the mechanisms of superficial intimal erosion, a common cause of thrombotic complications of atherosclerosis. Human coronary artery atheroma that give rise to thrombosis because of erosion differ diametrically from those associated with fibrous cap rupture. Eroded lesions characteristically contain few inflammatory cells, abundant extracellular matrix, and neutrophil extracellular traps (NETs). Innate immune mechanisms such as engagement of Toll-like receptor 2 (TLR2) on cultured endothelial cells can impair their viability, attachment, and ability to recover a wound. Hyaluronan fragments may serve as endogenous TLR2 ligands. Mouse experiments demonstrate that flow disturbance in arteries with neointimas tailored to resemble features of human eroded plaques disturbs endothelial cell barrier function, impairs endothelial cell viability, recruits neutrophils, and provokes endothelial cells desquamation, NET formation, and thrombosis in a TLR2-dependent manner. Mechanisms of erosion have received much less attention than those that provoke plaque rupture. Intensive statin treatment changes the characteristic of plaques that render them less susceptible to rupture. Thus, erosion may contribute importantly to the current residual burden of risk. Understanding the mechanisms of erosion may inform the development and deployment of novel therapies to combat the remaining atherothrombotic risk in the statin era.

Quantitative coronary plaque analysis predicts high-risk plaque morphology on coronary computed tomography angiography: results from the ROMICAT II trial.

PubMed

Liu, Ting; Maurovich-Horvat, Pál; Mayrhofer, Thomas; Puchner, Stefan B; Lu, Michael T; Ghemigian, Khristine; Kitslaar, Pieter H; Broersen, Alexander; Pursnani, Amit; Hoffmann, Udo; Ferencik, Maros

2018-02-01

Semi-automated software can provide quantitative assessment of atherosclerotic plaques on coronary CT angiography (CTA). The relationship between established qualitative high-risk plaque features and quantitative plaque measurements has not been studied. We analyzed the association between quantitative plaque measurements and qualitative high-risk plaque features on coronary CTA. We included 260 patients with plaque who underwent coronary CTA in the Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT) II trial. Quantitative plaque assessment and qualitative plaque characterization were performed on a per coronary segment basis. Quantitative coronary plaque measurements included plaque volume, plaque burden, remodeling index, and diameter stenosis. In qualitative analysis, high-risk plaque was present if positive remodeling, low CT attenuation plaque, napkin-ring sign or spotty calcium were detected. Univariable and multivariable logistic regression analyses were performed to assess the association between quantitative and qualitative high-risk plaque assessment. Among 888 segments with coronary plaque, high-risk plaque was present in 391 (44.0%) segments by qualitative analysis. In quantitative analysis, segments with high-risk plaque had higher total plaque volume, low CT attenuation plaque volume, plaque burden and remodeling index. Quantitatively assessed low CT attenuation plaque volume (odds ratio 1.12 per 1 mm 3 , 95% CI 1.04-1.21), positive remodeling (odds ratio 1.25 per 0.1, 95% CI 1.10-1.41) and plaque burden (odds ratio 1.53 per 0.1, 95% CI 1.08-2.16) were associated with high-risk plaque. Quantitative coronary plaque characteristics (low CT attenuation plaque volume, positive remodeling and plaque burden) measured by semi-automated software correlated with qualitative assessment of high-risk plaque features.

Therapies targeting innate immunity for fighting inflammation in atherosclerosis.

PubMed

Mendel, Itzhak; Yacov, Niva; Harats, Dror; Breitbart, Eyal

2015-01-01

Atherosclerosis is a smoldering disease of the vasculature that can lead to the occlusion of the arteries, resulting in ischemia of the heart and brain. For many years, the asserted underlying mechanism of atherosclerosis, supported by its epidemiology, was based on the "cholesterol hypothesis" that people with high blood cholesterol are at higher risk of developing cardiovascular disease. This hypothesis instigated a vigorous search for treatment that yielded the generation of statins, which specifically reduce LDL cholesterol. Since then, statins have revolutionized the way people are treated for the prevention of atherosclerosis. Nonetheless, despite this potent class of drugs, cardiovascular disease continues to be the leading cause of death in many parts of the world, suggesting that additional mechanisms are involved in disease pathogenesis. Intensive research has revealed that the atherosclerotic plaque is enriched with leukocytes, and that macrophages constitute the majority of immune cells in the lesion. Monocytes/macrophages are now recognized as the prime immune cells involved in the development of atherosclerosis and are implicated to affect the size, composition and vulnerability of the atherosclerotic plaque. While many of the macrophage-derived pro-inflammatory mechanisms associated with atherogenesis have been characterized, such as cell adhesion, cytokine production and protease secretion, there is a dearth of drugs that specifically target innate immunity for treating patients with atherosclerosis. This review presents pre-clinical studies, and in most cases following clinical trials with antagonists and agonists that have been designed to counteract inflammation in atherosclerosis and associated diseases, highlighting targets expressed predominantly in monocytes.

Mindin deficiency in macrophages protects against foam cell formation and atherosclerosis by targeting LXR-β.

PubMed

Zhang, Cheng; Qin, Juan-Juan; Gong, Fu-Han; Tong, Jing-Jing; Cheng, Wen-Lin; Wang, Haiping; Zhang, Yan; Zhu, Xueyong; She, Zhi-Gang; Xia, Hao; Zhu, Li-Hua

2018-06-15

Mindin, which is a highly conserved extracellular matrix protein, has been documented to play pivotal roles in regulating angiogenesis, inflammatory processes, and immune responses. The aim of the present study was to assess whether mindin contributes to the development of atherosclerosis. A significant up-regulation of Mindin expression was observed in the serum, arteries and atheromatous plaques of ApoE -/- mice after high-fat diet treatment. Mindin -/- ApoE -/- mice and macrophage-specific mindin overexpression in ApoE -/- mice (Lyz2-mindin-TG) were generated to evaluate the effect of mindin on the development of atherosclerosis. The Mindin -/- ApoE -/- mice exhibited significantly ameliorated atherosclerotic burdens in the entire aorta and aortic root and increased atherosclerotic plaque stability. Moreover, bone marrow transplantation further demonstrated that mindin deficiency in macrophages was largely responsible for the alleviated atherogenesis. The Lyz2-mindin-TG mice exhibited the opposite phenotype. Mindin deficiency enhanced foam cell formation by increasing the expression of cholesterol effectors, including ABCA1 and ABCG1. The mechanistic study indicated that mindin ablation promoted LXR-β expression via a direct interaction. Importantly, LXR-β inhibition largely reversed the ameliorating effect of mindin deficiency on foam cell formation and ABCA1 and ABCG1 expression. The present study demonstrated that mindin deficiency serves as a novel mediator that protects against foam cell formation and atherosclerosis by directly interacting with LXR-β. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Integrated imaging of cardiac anatomy, physiology, and viability.

PubMed

Arrighi, James A

2009-03-01

Technologic developments in imaging will have a significant impact on cardiac imaging over the next decade. These advances will permit more detailed assessment of cardiac anatomy, complex assessment of cardiac physiology, and integration of anatomic and physiologic data. The distinction between anatomic and physiologic imaging is important. For assessing patients with known or suspected coronary artery disease, physiologic and anatomic imaging data are complementary. The strength of anatomic imaging rests in its ability to detect the presence of disease, whereas physiologic imaging techniques assess the impact of disease, such as whether a coronary atherosclerotic lesion limits myocardial blood flow. Research indicates that physiologic data are more prognostically important than anatomic data, but both may be important in patient management decisions. Integrated cardiac imaging is an evolving field, with many potential indications. These include assessment of coronary stenosis, myocardial viability, anatomic and physiologic characterization of atherosclerotic plaque, and advanced molecular imaging.

Intracranial atherosclerosis: current concepts.

PubMed

Arenillas, Juan F

2011-01-01

The most relevant ideas discussed in this article are described here. Intracranial atherosclerotic disease (ICAD) represents the most common cause of ischemic stroke worldwide. Its importance in whites may have been underestimated. New technical developments, such as high-resolution MRI, allow direct assessment of the intracranial atherosclerotic plaque, which may have a profound impact on ICAD diagnosis and therapy in the near future. Early detection of ICAD may allow therapeutic intervention while the disease is still asymptomatic. The Barcelonès Nord and Maresme Asymptomatic Intracranial Atherosclerosis Study is presented here. The main prognostic factors that characterize the patients who are at a higher risk for ICAD recurrence are classified and discussed. The best treatment for ICAD remains to be established. The Stenting Versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis Study is currently ongoing to address this crucial issue. These and other topics will be discussed at the Fifth International Intracranial Atherosclerosis Conference (Valladolid, Spain, autumn 2011).

[Macrophage activation in atherosclerosis. Message 1: Activation of macrophages normally and in atherosclerotic lesions].

PubMed

Nikiforov, N G; Kornienko, V Y; Karagodin, V P; Orekhov, A N

2015-01-01

Macrophages play important role in initiation and progression of inflammation in atherosclerosis. Plaque macrophages were shown to exhibit a phenotypic range that is intermediate between two extremes, M1 (proinflammatory) and M2 (anti-inflammatory). Indeed, in atherosclerosis, macrophages demonstrate phenotypic plasticity to rapidly adjust to changing microenvironmental conditions. In plaque macrophages demonstrate different phenotypes, and besides macrophage phenotypes could be changed. Phenotypes M1, M2, M4, Mhem, HA-mac, M(Hb) u Mox are described in the article. Ability of macrophages change their phenotype also considered.

Ex-vivo UV autofluorescence imaging and fluorescence spectroscopy of atherosclerotic pathology in human aorta

NASA Astrophysics Data System (ADS)

Lewis, William; Williams, Maura; Franco, Walfre

2017-02-01

The aim of our study was to identify fluorescence excitation-emission pairs correlated with atherosclerotic pathology in ex-vivo human aorta. Wide-field images of atherosclerotic human aorta were captured using UV and visible excitation and emission wavelength pairs of several known fluorophores to investigate correspondence with gross pathologic features. Fluorescence spectroscopy and histology were performed on 21 aortic samples. A matrix of Pearson correlation coefficients were determined for the relationship between relevant histologic features and the intensity of emission for 427 wavelength pairs. A multiple linear regression analysis indicated that elastin (370/460 nm) and tryptophan (290/340 nm) fluorescence predicted 58% of the variance in intima thickness (R-squared = 0.588, F(2,18) = 12.8, p=.0003), and 48% of the variance in media thickness (R-squared = 0.483, F(2,18) = 8.42, p=.002), suggesting that endogenous fluorescence intensity at these wavelengths can be utilized for improved pathologic characterization of atherosclerotic plaques.

Tyrosine phosphorylation of platelet derived growth factor β receptors in coronary artery lesions: implications for vascular remodelling after directional coronary atherectomy and unstable angina pectoris

PubMed Central

Abe, J; Deguchi, J; Takuwa, Y; Hara, K; Ikari, Y; Tamura, T; Ohno, M; Kurokawa, K

1998-01-01

Background—Growth factors such as platelet derived growth factor (PDGF) have been postulated to be important mediators of neointimal proliferation observed in atherosclerotic plaques and restenotic lesions following coronary interventions. Binding of PDGF to its receptor results in intrinsic receptor tyrosine kinase activation and subsequent cellular migration, proliferation, and vascular contraction.
Aims—To investigate whether the concentration of PDGF β receptor tyrosine phosphorylation obtained from directional coronary atherectomy (DCA) samples correlate with atherosclerotic plaque burden, the ability of diseased vessels to remodel, coronary risk factors, and clinical events.
Methods—DCA samples from 59 patients and 15 non-atherosclerotic left internal thoracic arteries (LITA) were analysed for PDGF β receptor tyrosine phosphorylation content by receptor immunoprecipitation and antiphosphotyrosine western blot. The amount of PDGF β receptor phosphorylation was analysed in relation to angiographic follow up data and clinical variables.
Results—PDGF β receptor tyrosine phosphorylation in the 59 DCA samples was greater than in the 15 non-atherosclerotic LITA (mean (SD) 0.84 (0.67) v 0.17 (0.08) over a control standard, p < 0.0001). As evaluated by stepwise regression analysis, incorporation of both PDGF β receptor tyrosine phosphorylation and immediate gain correlated strongly (adjusted r2 = 0.579) with late loss, although PDGF β receptor tyramine phosphorylation alone correlated poorly with late loss. Multivariate regression analysis of coronary risk factors and clinical events revealed unstable angina as the most significant correlate of PDGF β receptor tyrosine phosphorylation (F value 20.009, p < 0.0001).
Conclusions—PDGF β receptor tyrosine phosphorylation in atherosclerotic lesions is increased compared with non-atherosclerotic arterial tissues. The association of PDGF β receptor tyrosine phosphorylation with immediate gain strongly correlates with vascular remodelling. PDGF β receptor tyrosine phosphorylation correlates with unstable angina pectoris.

 Keywords: PDGF receptors;  atherosclerosis;  directional coronary atherectomy;  restenosis PMID:9616351

Compound K Attenuates the Development of Atherosclerosis in ApoE−/− Mice via LXRα Activation

PubMed Central

Zhou, Li; Zheng, Yu; Li, Zhuoying; Bao, Lingxia; Dou, Yin; Tang, Yuan; Zhang, Jianxiang; Zhou, Jianzhi; Liu, Ya; Jia, Yi; Li, Xiaohui

2016-01-01

Background: Atherosclerosis is a fundamental pathological process responded to some serious cardiovascular events. Although the cholesterol-lowering drugs are widely prescribed for atherosclerosis therapy, it is still the leading cause of death in the developed world. Here we measured the effects of compound K in atherosclerosis formation and investigated the probably mechanisms of the anti-antherosclerosis roles of compound K. Methods: We treated the atherosclerotic model animals (apoE−/− mice on western diet) with compound K and measured the size of atherosclerotic lesions, inflammatory cytokine levels and serum lipid profile. Peritoneal macrophages were collected in vitro for the foam cell and inflammasome experiments. Results: Our results show that treatment with compound K dose-dependently attenuates the formation of atherosclerotic plaques by 55% through activation of reverse cholesterol transport pathway, reduction of systemic inflammatory cytokines and inhibition of local inflammasome activity. Compound K increases the cholesterol efflux of macrophage-derived foam cells, and reduces the inflammasome activity in cholesterol crystal stimulated macrophages. The activation of LXRα may contribute to the athero-protective effects of compound K. Conclusion: These observations provide evidence for an athero-protective effect of compound K via LXRα activation, and support its further evaluation as a potential effective modulator for the prevention and treatment of atherosclerosis. PMID:27399689

Intra-Arterial Drug and Light Delivery for Photodynamic Therapy Using Visudyne®: Implication for Atherosclerotic Plaque Treatment.

PubMed

Jain, Manish; Zellweger, Matthieu; Frobert, Aurélien; Valentin, Jérémy; van den Bergh, Hubert; Wagnières, Georges; Cook, Stéphane; Giraud, Marie-Noelle

2016-01-01

Photodynamic therapy (PDT), which is based on the activation of photosensitizers with light, can be used to reduce plaque burden. We hypothesized that intra-arterial photosensitizer administration and photo-activation will lead to high and rapid accumulation within the plaque with reduced systemic adverse effects. Thus, this "intra-arterial" PDT would be expected to have less side effects and due to the short time involved would be compatible with percutaneous coronary interventions. We characterized the dose-dependent uptake and efficacy of intra-arterial PDT using Liposomal Verteporfin (Visudyne®), efficient for cancer-PDT but not tested before for PDT of atherosclerosis. Visudyne® (100, 200, and 500 ng/ml) was perfused for 5-30 min in atherosclerotic aorta isolated from ApoE(-/-) mice. The fluorescence Intensity (FI) after 15 min of Visudyne® perfusion increased with doses of 100 (FI-5.5 ± 1.8), 200 (FI-31.9 ± 1.9) or 500 ng/ml (FI-42.9 ± 1.2). Visudyne® (500 ng/ml) uptake also increased with the administration time from 5 min (FI-9.8 ± 2.5) to 10 min (FI-23.3 ± 3.0) and 15 min (FI-42.9 ± 3.4) before reaching saturation at 30 min (FI-39.3 ± 2.4) contact. Intra-arterial PDT (Fluence: 100 and 200 J/cm(2), irradiance-334 mW/cm(2)) was applied immediately after Visudyne® perfusion (500 ng/ml for 15 min) using a cylindrical light diffuser coupled to a diode laser (690 nm). PDT led to an increase of ROS (Dihydroethidium; FI-6.9 ± 1.8, 25.3 ± 5.5, 43.4 ± 13.9) and apoptotic cells (TUNEL; 2.5 ± 1.6, 41.3 ± 15.3, 58.9 ± 6%), mainly plaque macrophages (immunostaining; 0.3 ± 0.2, 37.6 ± 6.4, 45.3 ± 5.4%) respectively without laser irradiation, or at 100 and 200 J/cm(2). Limited apoptosis was observed in the medial wall (0.5 ± 0.2, 8.5 ± 4.7, 15.3 ± 12.7%). Finally, Visudyne®-PDT was found to be associated with reduced vessel functionality (Myogram). We demonstrated that sufficient accumulation of Visudyne® within plaque could be achieved in short-time and therefore validated the feasibility of local intravascular administration of photosensitizer. Intra-arterial Visudyne®-PDT preferentially affected plaque macrophages and may therefore alter the dynamic progression of plaque development.

Scintillating Balloon-Enabled Fiber-Optic System for Radionuclide Imaging of Atherosclerotic Plaques

PubMed Central

Zaman, Raiyan T.; Kosuge, Hisanori; Carpenter, Colin; Sun, Conroy; McConnell, Michael V.; Xing, Lei

2015-01-01

Atherosclerosis underlies coronary artery disease, the leading cause of death in the United States and worldwide. Detection of coronary plaque inflammation remains challenging. In this study, we developed a scintillating balloon-enabled fiber-optic radio-nuclide imaging (SBRI) system to improve the sensitivity and resolution of plaque imaging using 18F-FDG, a marker of vascular inflammation, and tested it in a murine model. Methods The fiber-optic system uses a Complementary Metal-Oxide Silicon (CMOS) camera with a distal ferrule terminated with a wide-angle lens. The novelty of this system is a scintillating balloon in the front of the wide-angle lens to image light from the decay of 18F-FDG emission signal. To identify the optimal scintillating materials with respect to resolution, we calculated the modulation transfer function of yttrium–aluminum–garnet doped with cerium, anthracene, and calcium fluoride doped with europium (CaF2:Eu) phosphors using an edge pattern and a thin-line optical phantom. The scintillating balloon was then fabricated from 10 mL of silicone RTV catalyst mixed with 1 mL of base and 50 mg of CaF2:Eu per mL. The addition of a lutetium oxyorthosilicate scintillating crystal (500 μm thick) to the balloon was also investigated. The SBRI system was tested in a murine atherosclerosis model: carotid-ligated mice (n = 5) were injected with 18F-FDG, followed by ex vivo imaging of the macrophage-rich carotid plaques and nonligated controls. Confirmatory imaging of carotid plaques and controls was also performed by an external optical imaging system and autoradiography. Results Analyses of the different phosphors showed that CaF2:Eu enabled the best resolution of 1.2 μm. The SBRI system detected almost a 4-fold-higher radioluminescence signal from the ligated left carotid artery than the nonligated right carotid: 1.63 × 102 ± 4.01 × 101 vs. 4.21 × 101 ± 2.09 × 100 (photon counts), P = 0.006. We found no significant benefit to adding a scintillating crystal to the balloon: 1.65 × 102 ± 4.07 × 101 vs. 4.44 × 101 ± 2.17 × 100 (photon counts), P = 0.005. Both external optical imaging and autoradiography confirmed the high signal from the 18F-FDG in carotid plaques versus controls. Conclusion This SBRI system provides high-resolution and sensitive detection of 18F-FDG uptake by murine atherosclerotic plaques. PMID:25858046

Prevention of oxLDL uptake leads to decreased atherosclerosis in hematopoietic NPC1-deficient Ldlr-/- mice.

PubMed

Jeurissen, Mike L J; Walenbergh, Sofie M A; Houben, Tom; Gijbels, Marion J J; Li, Jieyi; Hendrikx, Tim; Oligschlaeger, Yvonne; van Gorp, Patrick J; Binder, Christoph J; Donners, Marjo M P C; Shiri-Sverdlov, Ronit

2016-12-01

Atherosclerosis is a chronic inflammatory disease of medium and large vessels and is typically characterized by the predominant accumulation of low-density lipoprotein (LDL)-cholesterol inside macrophages that reside in the vessel walls. Previous studies clearly demonstrated an association specifically between the oxidized type of LDL (oxLDL) and atherosclerotic lesion formation. Further observations revealed that these atherosclerotic lesions displayed enlarged, lipid-loaded lysosomes. By increasing natural antibodies against oxLDL, pneumococcal vaccination has been shown to reduce atherosclerosis in LDL receptor knockout (Ldlr -/- ) mice. Relevantly, loss of the lysosomal membrane protein Niemann-Pick Type C1 (NPC1) led to lysosomal accumulation of various lipids and promoted atherosclerosis. Yet, the importance of lysosomal oxLDL accumulation inside macrophages, compared to non-modified LDL, in atherosclerosis has never been established. By transplanting NPC1 bone marrow into lethally irradiated Ldlr -/- mice, a hematopoietic mouse model for lysosomal cholesterol accumulation was created. Through injections with heat-inactivated pneumococci, we aimed to demonstrate the specific contribution of lysosomal oxLDL accumulation inside macrophages in atherosclerosis development. While there were no differences in plaque morphology, a reduction in plaque size and plaque inflammation was found in immunized NPC1 mut -transplanted mice, compared to non-immunized NPC1 mut -transplanted mice. Lysosomal oxLDL accumulation within macrophages contributes to murine atherosclerosis. Future intervention strategies should focus specifically on preventing oxLDL, unlike non-modified LDL, from being internalized into lysosomes. Such an intervention can have an additive effect to current existing treatments against atherosclerosis. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Characterisation of Atherogenic Effects of Low Carbohydrate, High Protein Diet (LCHP) in ApoE/LDLR-/- Mice.

PubMed

Kostogrys, R B; Johann, C; Czyżyńska, I; Franczyk-Żarów, M; Drahun, A; Maślak, E; Jasztal, A; Gajda, M; Mateuszuk, Ł; Wrobel, T P; Baranska, M; Wybrańska, I; Jezkova, K; Nachtigal, P; Chlopicki, S

2015-08-01

Low Carbohydrate High Protein diet represents a popular strategy to achieve weight loss. The aim of this study was to characterize effects of low carbohydrate, high protein diet (LCHP) on atherosclerotic plaque development in brachiocephalic artery (BCA) in apoE/LDLR-/- mice and to elucidate mechanisms of proatherogenic effects of LCHP diet. Atherosclerosis plaques in brachiocephalic artery (BCA) as well as in aortic roots, lipoprotein profile, inflammation biomarkers, expression of SREBP-1 in the liver as well as mortality were analyzed in Control diet (AIN-93G) or LCHP (Low Carbohydrate High Protein) diet fed mice. Area of atherosclerotic plaques in aortic roots or BCA from LCHP diet fed mice was substantially increased as compared to mice fed control diet and was characterized by increased lipids and cholesterol contents (ORO staining, FT-IR analysis), increased macrophage infiltration (MOMA-2) and activity of MMPs (zymography). Pro-atherogenic phenotype of LCHP fed apoE/LDLR-/- mice was associated with increased plasma total cholesterol concentration, and in LDL and VLDL fractions, increased TG contents in VLDL, and a modest increase in plasma urea. LCHP diet increased SCD-1 index, activated SREBP-1 transcription factor in the liver and triggered acute phase response as evidence by an increased plasma concentration of haptoglobin, CRP or AGP. Finally, in long-term experiment survival of apoE/LDLR-/- mice fed LCHP diet was substantially reduced as compared to their counterparts fed control diet suggesting overall detrimental effects of LCHP diet on health. The pro-atherogenic effect of LCHP diet in apoE/LDLR-/- mice is associated with profound increase in LDL and VLDL cholesterol, VLDL triglicerides, liver SREBP-1 upregulation, and systemic inflammation.

Irgm1 promotes M1 but not M2 macrophage polarization in atherosclerosis pathogenesis and development.

PubMed

Fang, Shaohong; Xu, Yanwen; Zhang, Yun; Tian, Jiangtian; Li, Ji; Li, Zhaoying; He, Zhongze; Chai, Ruikai; Liu, Fang; Zhang, Tongshuai; Yang, Shuang; Pei, Chunying; Liu, Xinxin; Lin, Peng; Xu, Hongwei; Yu, Bo; Li, Hulun; Sun, Bo

2016-08-01

Atherosclerosis is a chronic inflammatory vascular disease related to macrophages uptake of low-density lipoprotein and their subsequent transformation into foam cells. M1 (inflammatory)/M2 (anti-inflammatory) balance was suggested to impact disease progression. In this study, we investigated whether the immunity related GTPase (Irgm1) regulates macrophage polarization during atherosclerosis development. We used apolipoprotein E (ApoE) knockout and Irgm1 haplodeficient mice and induced atherosclerosis with high-cholesterol diet for the indicated months. Atherosclerotic arteries were collected from patients undergoing vascular surgery, to determine the lesional expression of Irgm1 and distribution of M1/M2 populations. Our results showed that IRGM/Irgm1 expression was increased in atherosclerotic artery samples (1.7-fold, p=0.0045) compared with non-atherosclerotic arteries, which was consistent with findings in the murine experimental atherosclerosis model (1.9-fold, p=0.0002). IRGM/Irgm1 expression was mostly found in lesional M1 macrophages. Haplodeficiency of Irgm1 in ApoE(-/-) mice resulted in reduced infiltrating M1 macrophages in atheroma (94%, p=0.0002) and delayed development of atherosclerotic plaques. In vitro experiments also confirmed that Irgm1 haplodeficiency reduced iNOS expression of polarized M1 macrophages (81%, p=0.0034), with negligible impact on the M2 phenotype. Moreover, we found that Irgm1 haplodeficiency in mice significantly reduced expression level of M1 function-related transcription factors, interferon regulatory factor (Irf) 5 and Irf8, but not Irf4, an M2-related transcription factor. This study shows that Irgm1/IRGM participates in the polarization of M1 macrophage and promotes development of atheroma in murine experimental atherosclerosis. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Pleiotrophin (PTN) is expressed in vascularized human atherosclerotic plaques: IFN-γ/JAK/STAT1 signaling is critical for the expression of PTN in macrophages

PubMed Central

Li, Fuqiang; Tian, Fang; Wang, Lai; Williamson, Ian K.; Sharifi, Behrooz G.; Shah, Prediman K.

2010-01-01

Neovascularization is critical to destabilization of atheroma. We previously reported that the angiogenic growth factor pleiotrophin (PTN) coaxes monocytes to assume the phenotype of functional endothelial cells in vitro and in vivo. In this study we show that PTN expression is colocalized with capillaries of human atherosclerotic plaques. Among the various reagents that are critical to the pathogenesis of atherosclerosis, interferon (IFN)-γ was found to markedly induce PTN mRNA expression in a dose-dependent manner in macrophages. Mechanistic studies revealed that the Janus kinase inhibitors, WHI-P154 and ATA, efficiently blocked STAT1 phosphorylation in a concentration- and time-dependent manner. Notably, the level of phosphorylated STAT1 was found to correlate directly with the PTN mRNA levels. In addition, STAT1/STAT3/p44/42 signaling molecules were found to be phosphorylated by IFN-γ in macrophages, and they were translocated into the nucleus. Further, PTN promoter analysis showed that a gamma-activated sequence (GAS) located at −2086 to −2078 bp is essential for IFN-γ-regulated promoter activity. Moreover, electrophoretic mobility shift, supershift, and chromatin immunoprecipitation analyses revealed that both STAT1 and STAT3 bind to the GAS at the chromatin level in the IFN-γ stimulated cells. Finally, to test whether the combined effect of STAT1/STAT3/p44/42 signaling is required for the expression of PTN in macrophages, gene knockdowns of these transcription factors were performed using siRNA. Cells lacking STAT1, but not STAT3 or p42, have markedly reduced PTN mRNA levels. These data suggest that PTN expression in the human plaques may be in part regulated by IFN-γ and that PTN is involved in the adaptive immunity.—Li, F., Tian, F., Wang, L., Williamson, I. K., Sharifi, B. G., Shah, P. K. Pleiotrophin (PTN) is expressed in vascularized human atherosclerotic plaques: IFN-γ/JAK/STAT1 signaling is critical for the expression of PTN in macrophages PMID:19917672

Endothelial Nitric Oxide Synthase Overexpression Restores the Efficiency of Bone Marrow Mononuclear Cell-Based Therapy

PubMed Central

Mees, Barend; Récalde, Alice; Loinard, Céline; Tempel, Dennie; Godinho, Marcia; Vilar, José; van Haperen, Rien; Lévy, Bernard; de Crom, Rini; Silvestre, Jean-Sébastien

2011-01-01

Bone marrow-derived mononuclear cells (BMMNCs) enhance postischemic neovascularization, and their therapeutic use is currently under clinical investigation. However, cardiovascular risk factors, including diabetes mellitus and hypercholesterolemia, lead to the abrogation of BMMNCs proangiogenic potential. NO has been shown to be critical for the proangiogenic function of BMMNCs, and increased endothelial NO synthase (eNOS) activity promotes vessel growth in ischemic conditions. We therefore hypothesized that eNOS overexpression could restore both the impaired neovascularization response and decreased proangiogenic function of BMMNCs in clinically relevant models of diabetes and hypercholesterolemia. Transgenic eNOS overexpression in diabetic, atherosclerotic, and wild-type mice induced a 1.5- to 2.3-fold increase in postischemic neovascularization compared with control. eNOS overexpression in diabetic or atherosclerotic BMMNCs restored their reduced proangiogenic potential in ischemic hind limb. This effect was associated with an increase in BMMNC ability to differentiate into cells with endothelial phenotype in vitro and in vivo and an increase in BMMNCs paracrine function, including vascular endothelial growth factor A release and NO-dependent vasodilation. Moreover, although wild-type BMMNCs treatment resulted in significant progression of atherosclerotic plaque in ischemic mice, eNOS transgenic atherosclerotic BMMNCs treatment even had antiatherogenic effects. Cell-based eNOS gene therapy has both proangiogenic and antiatherogenic effects and should be further investigated for the development of efficient therapeutic neovascularization designed to treat ischemic cardiovascular disease. PMID:21224043

Functional blockage of EMMPRIN ameliorates atherosclerosis in apolipoprotein E-deficient mice.

PubMed

Liu, Hong; Yang, Li-xia; Guo, Rui-wei; Zhu, Guo-Fu; Shi, Yan-Kun; Wang, Xian-mei; Qi, Feng; Guo, Chuan-ming; Ye, Jin-shan; Yang, Zhi-hua; Liang, Xing

2013-10-09

Extracellular matrix metalloproteinase inducer (EMMPRIN), a 58-kDa cell surface glycoprotein, has been identified as a key receptor for transmitting cellular signals mediating metalloproteinase activities, as well as inflammation and oxidative stress. Clinical evidence has revealed that EMMPRIN is expressed in human atherosclerotic plaque; however, the relationship between EMMPRIN and atherosclerosis is unclear. To evaluate the functional role of EMMPRIN in atherosclerosis, we treated apolipoprotein E-deficient (ApoE(-/-)) mice with an EMMPRIN function-blocking antibody. EMMPRIN was found to be up-regulated in ApoE(-/-) mice fed a 12-week high-fat diet in contrast to 12 weeks of normal diet. Administration of a function-blocking EMMPRIN antibody (100 μg, twice per week for 4 weeks) to ApoE(-/-) mice, starting after 12 weeks of high-fat diet feeding caused attenuated and more stable atherosclerotic lesions, less reactive oxygen stress generation on plaque, as well as down-regulation of circulating interleukin-6 and monocyte chemotactic protein-1 in ApoE(-/-) mice. The benefit of EMMPRIN functional blockage was associated with reduced metalloproteinases proteolytic activity, which delayed the circulating monocyte transmigrating into atherosclerotic lesions. EMMPRIN antibody intervention ameliorated atherosclerosis in ApoE(-/-) mice by the down-regulation of metalloproteinase activity, suggesting that EMMPRIN may be a viable therapeutic target in atherosclerosis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

ACE2 activity was increased in atherosclerotic plaque by losartan: Possible relation to anti-atherosclerosis.

PubMed

Zhang, Yue Hui; Hao, Qing Qing; Wang, Xiao Yu; Chen, Xu; Wang, Nan; Zhu, Li; Li, Shu Ying; Yu, Qing Tao; Dong, Bo

2015-06-01

Angiotensin-converting enzyme 2 (ACE2) is a new member of the renin-angiotensin system (RAS) and it has been proposed that ACE2 is a potential therapeutic target for the control of cardiovascular disease. The effect of losartan on the ACE2 activity in atherosclerosis was studied. Atherosclerosis was induced in New Zealand white rabbits by high-cholesterol diet for 3 months. An Angiotensin II (Ang II) receptor blocker (losartan, 25 mg/kg/d) was given for 3 months. ACE2 activity was measured by fluorescence assay and the extent of atherosclerosis was evaluated by H&E and Oil Red O staining. In addition, the effect of losartan on ACE2 activity in smooth muscle cells (SMCs) in vitro was also evaluated. Losartan increased ACE2 activity in atherosclerosis in vivo and SMCs in vitro. Losartan inhibited atherosclerotic evolution. Addition of losartan blocked Ang II-induced down-regulation of ACE2 activity, and blockade of extracellular signal-regulated kinase (ERK1/2) with PD98059 prevented Ang II-induced down-regulation of ACE2 activity. The results showed that ACE2 activity was regulated in atherosclerotic plaque by losartan, which may play an important role in treatment of atherosclerosis. The mechanism involves Ang II-AT1R-mediated mitogen-activated protein kinases, MAPKs (MAPKs) signaling pathway. © The Author(s) 2014.

Sequential colonization of periodontal pathogens in induction of periodontal disease and atherosclerosis in LDLRnull mice.

PubMed

Chukkapalli, Sasanka S; Easwaran, Meena; Rivera-Kweh, Mercedes F; Velsko, Irina M; Ambadapadi, Sriram; Dai, Jiayin; Larjava, Hannu; Lucas, Alexandra R; Kesavalu, Lakshmyya

2017-01-01

Periodontal disease (PD) and atherosclerotic vascular disease (ASVD) are both chronic inflammatory diseases with a polymicrobial etiology and have been epidemiologically associated. The purpose is to examine whether periodontal bacteria that infect the periodontium can also infect vascular tissues and enhance pre-existing early aortic atherosclerotic lesions in LDLRnull mice. Mice were orally infected with intermediate bacterial colonizer Fusobacterium nucleatum for the first 12 weeks followed by late bacterial colonizers (Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia) for the remaining 12 weeks mimicking the human oral microbiota ecological colonization. Genomic DNA from all four bacterial was detected in gingival plaque by PCR, consistently demonstrating infection of mouse gingival surfaces. Infected mice had significant levels of IgG and IgM antibodies, alveolar bone resorption, and showed apical migration of junctional epithelium revealing the induction of PD. These results support the ability of oral bacteria to cause PD in mice. Detection of bacterial genomic DNA in systemic organs indicates hematogenous dissemination from the gingival pockets. Bacterial infection did not alter serum lipid fractions or serum amyloid A levels and did not induce aortic atherosclerotic plaque. This is the first study examining the causal role of periodontal bacteria in induction of ASVD in LDLRnull mice. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Anti-atherogenic activity of wild grape (Vitis thunbergii) extract antagonizing smooth muscle cell proliferation and migration promoted by neighboring macrophages.

PubMed

Kang, Sang-Wook; Kim, Min Soo; Kim, Hyun-Sung; Lee, Yong-Jin; Kang, Young-Hee

2012-06-01

The proliferation and migration of vascular smooth muscle cells (SMCs) play critical roles in intimal thickening and neointimal hyperplasia in early-phase atherosclerosis. This study tested whether wild grape extract (WGE) suppressed the proliferation and migration of human aortic SMCs induced by neighboring macrophages. Cellular expression of fibrogenic connective tissue growth factor (CTGF) and secretion of collagen IV and matrix metalloproteinase (MMP)-2 were determined in SMCs exposed to THP-1-differentiated macrophage-conditioned media. Proliferation was enhanced in SMCs exposed to macrophage-conditioned media collected during the early stage of differentiation, which was attenuated by treatment with ≥ 10 µg/ml WGE. Increased secretion of CTGF and collagen IV macrophage-conditioned media was suppressed in WGE-supplemented SMCs. TGF-β1-promoted production of CTGF and collagen IV was suppressed by blocking TGF-β receptors of R1 and R2 in SMCs. WGE repressed macrophage-conditioned media-upregulated MMP-2 secretion, indicating that WGE had an ability to encumber plaque rupture within atherosclerotic lesions. In addition, ≥ 1 µg/ml WGE ameliorated the migration of SMCs promoted by neighboring macrophages. These results demonstrate that WGE retarded neointimal hyperplasia and thickening within atherosclerotic plaques largely comprising of macrophages and SMCs. Therefore, WGE may be developed as an anti-proliferative and anti-migratory agent targeting SMCs in the proximity of newly differentiated and resident macrophages.

Isorhamnetin Attenuates Atherosclerosis by Inhibiting Macrophage Apoptosis via PI3K/AKT Activation and HO-1 Induction

PubMed Central

Luo, Yun; Sun, Guibo; Dong, Xi; Wang, Min; Qin, Meng; Yu, Yingli; Sun, Xiaobo

2015-01-01

Background and Purpose Isorhamnetin (Iso) is a flavonoid compound extracted from the Chinese herb Hippophae rhamnoides L. Previous studies have revealed its anti-cancer, anti-inflammatory, and anti-oxidant activities. This study investigated the ability of Iso to inhibit oxidized low-density lipoprotein (ox-LDL)-induced cell apoptosis in THP-1-derived macrophages. The effects of Iso on atherosclerosis in vivo were also evaluated in apolipoprotein E knockout (ApoE-/-) mice fed a high fat diet. Methods and Results Iso showed significant inhibitory effects on ox-LDL-induced THP-1-derived macrophage injuries via decreasing reactive oxygen species levels, lipid deposition, and caspase-3 activation, restoring mitochondrial membrane potential, reducing the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells, and regulating apoptosis-related proteins. We also determined the protective effects of Iso by PI3K/AKT activation and HO-1 induction. Iso reduced the atherosclerotic plaque size in vivo in ApoE-/- mice as assessed by oil red O, Sudan IV staining, and CD68-positive cells, and reduced macrophage apoptosis as assessed by caspase-3 and TUNEL assays in lesions. Conclusion In conclusion, our results show that Iso inhibited atherosclerotic plaque development in ApoE-/- mice by PI3K/AKT activation and HO-1 induction. PMID:25799286

Euterpe oleracea (açai) modifies sterol metabolism and attenuates experimentally-induced atherosclerosis.

PubMed

Feio, Claudine A; Izar, Maria C; Ihara, Silvia S; Kasmas, Soraia H; Martins, Celma M; Feio, Max N; Maués, Luís A; Borges, Ney C; Moreno, Ronilson A; Póvoa, Rui M; Fonseca, Francisco A

2012-01-01

Euterpe Oleracea (açai) is a fruit from the Amazon region whose chemical composition may be beneficial for individuals with atherosclerosis. We hypothesized that consumption of Euterpe Oleracea would reduce atherosclerosis development by decreasing cholesterol absorption and synthesis. Male New Zealand rabbits were fed a cholesterol-enriched diet (0.5%) for 12 weeks, when they were randomized to receive Euterpe Oleracea extract (n = 15) or water (n = 12) plus a 0.05% cholesterol-enriched diet for an additional 12 weeks. Plasma phytosterols and desmosterol were determined by ultra-performance liquid chromatography and mass spectrometry. Atherosclerotic lesions were estimated by computerized planimetry and histomorphometry. At sacrifice, animals treated with Euterpe Oleracea had lower levels of total cholesterol (p =0.03), non-HDL-cholesterol (p = 0.03) and triglycerides (p = 0.02) than controls. These animals had smaller atherosclerotic plaque area in their aortas (p = 0.001) and a smaller intima/media ratio (p = 0.002) than controls, without differences in plaque composition. At the end of the study, campesterol, β-sitosterol, and desmosterol plasma levels did not differ between groups; however, animals treated with Euterpe Oleracea showed lower desmosterol/campesterol (p = 0.026) and desmosterol/ β-sitosterol (p =0.006) ratios than controls. Consumption of Euterpe Oleracea extract markedly improved the lipid profile and attenuated atherosclerosis. These effects were related in part to a better balance in the synthesis and absorption of sterols.

Association between cardiovascular risk profiles and the presence and extent of different types of coronary atherosclerotic plaque as detected by multidetector computed tomography.

PubMed

Bamberg, Fabian; Dannemann, Nina; Shapiro, Michael D; Seneviratne, Sujith K; Ferencik, Maros; Butler, Javed; Koenig, Wolfgang; Nasir, Khurram; Cury, Ricardo C; Tawakol, Ahmed; Achenbach, Stephan; Brady, Thomas J; Hoffmann, Udo

2008-03-01

To assess the association between cardiovascular risk factors and extent of noncalcified- (NCAP), mixed- (MCAP), and calcified coronary atherosclerotic plaque (CAP). In this cross-sectional study, we included consecutive subjects who presented with chest pain but had no history of coronary artery disease (CAD) and did not develop acute coronary syndrome. Contrast-enhanced 64-slice coronary MDCT was performed to determine the presence of NCAP, MCAP, and CAP for each coronary segment. Among 195 patients (91 women, mean age: 54.6+/-12.0) exclusively NCAP was detected in 11 patients (5.6%). The extent of NCAP decreased and the extent of MCAP and CAP increased with age (P=0.06, P=0.02, and P=0.13, respectively). Hyperlipidemia and family history of CAD were associated with the extent of NCAP after adjusting for other risk factors (P=0.02 and P=0.04, respectively) or for the extent of MCAP and CAP (P=0.02 and P=0.05, respectively). Our data suggest that only a small proportion of individuals have exclusively NCAP and indicate that the relation of NCAP and CAP changes with age. Among individual risk factors, hyperlipidemia and family history of CAD may be associated with the extent of NCAP. Larger observational trials are necessary to confirm our findings.

Tissue-specific insulin signaling, metabolic syndrome and cardiovascular disease

PubMed Central

Rask-Madsen, Christian; Kahn, C. Ronald

2012-01-01

Summary Impaired insulin signaling is central to the development of the metabolic syndrome and can promote cardiovascular disease indirectly through development of abnormal glucose and lipid metabolism, hypertension and a proinflammatory state. However, insulin action directly on vascular endothelium, atherosclerotic plaque macrophages, and in the heart, kidney, and retina has now been described, and impaired insulin signaling in these locations can alter progression of cardiovascular disease in the metabolic syndrome and affect development of microvascular complications of diabetes. Recent advances in our understanding of the complex pathophysiology of insulin’s effects on vascular tissues offer new opportunities for preventing these cardiovascular disorders. PMID:22895666

CXCL4-induced macrophages in human atherosclerosis.

PubMed

Domschke, Gabriele; Gleissner, Christian A

2017-09-09

Atherosclerosis is considered an inflammatory disease of the arterial wall. Monocytes and monocyte-derived cells (most often termed macrophages) play an essential role in the formation of atherosclerotic lesions, as they take up lipids leading to subsequent foam cell formation accompanied by release of pro-inflammatory cytokines. Similarly, platelets have been discovered to represent an important cell type mediating inflammatory and immune processes in atherogenesis, mainly by secreting chemokines, which are stored in the platelets' alpha granules, upon platelet activation. Therefore, the interaction between monocyte-derived cells and platelets is of exceptional importance. In this review, we specifically focus on the chemokine (platelet factor-4, PF4) and its effects on monocytes and monocyte-derived cells. By formation of heterodimers dimers and -oligomers with CCL5, CXCL4 induces binding of monocytes cells to endothelial cell and thereby promotes diapedesis of monocytes into the subendothelial space. CXCL4 also affects the differentiation of monocytes as it induces a specific macrophage phenotype, which we suggested to term "M4". For example, CXCL4-induced macrophages irreversibly lose the hemoglobin-haptoglobin scavenger receptor CD163. The combination of CD68, S100A8, and MMP7 turned out to reliably identify M4 macrophages both in vitro and in vivo within atherosclerotic lesions. In human atherosclerotic plaques, M4 macrophages are predominantly present in the adventitia and the intima and their prevalence is associated with plaque instability suggesting that they are a marker of pro-inflammatory activity. Overall, CXCL4-induced M4 macrophages may represent a target for diagnostic and therapeutic interventions in human atherosclerotic disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation*

PubMed Central

Gregory, Jill C.; Buffa, Jennifer A.; Org, Elin; Wang, Zeneng; Levison, Bruce S.; Zhu, Weifei; Wagner, Matthew A.; Bennett, Brian J.; Li, Lin; DiDonato, Joseph A.; Lusis, Aldons J.; Hazen, Stanley L.

2015-01-01

Recent studies indicate both clinical and mechanistic links between atherosclerotic heart disease and intestinal microbial metabolism of certain dietary nutrients producing trimethylamine N-oxide (TMAO). Here we test the hypothesis that gut microbial transplantation can transmit choline diet-induced TMAO production and atherosclerosis susceptibility. First, a strong association was noted between atherosclerotic plaque and plasma TMAO levels in a mouse diversity panel (n = 22 strains, r = 0.38; p = 0.0001). An atherosclerosis-prone and high TMAO-producing strain, C57BL/6J, and an atherosclerosis-resistant and low TMAO-producing strain, NZW/LacJ, were selected as donors for cecal microbial transplantation into apolipoprotein e null mice in which resident intestinal microbes were first suppressed with antibiotics. Trimethylamine (TMA) and TMAO levels were initially higher in recipients on choline diet that received cecal microbes from C57BL/6J inbred mice; however, durability of choline diet-dependent differences in TMA/TMAO levels was not maintained to the end of the study. Mice receiving C57BL/6J cecal microbes demonstrated choline diet-dependent enhancement in atherosclerotic plaque burden as compared with recipients of NZW/LacJ microbes. Microbial DNA analyses in feces and cecum revealed transplantation of donor microbial community features into recipients with differences in taxa proportions between donor strains that were transmissible to recipients and that tended to show coincident proportions with TMAO levels. Proportions of specific taxa were also identified that correlated with plasma TMAO levels in donors and recipients and with atherosclerotic lesion area in recipients. Atherosclerosis susceptibility may be transmitted via transplantation of gut microbiota. Gut microbes may thus represent a novel therapeutic target for modulating atherosclerosis susceptibility. PMID:25550161

SASH1, a new potential link between smoking and atherosclerosis.

PubMed

Weidmann, Henri; Touat-Hamici, Zahia; Durand, Herve; Mueller, Christian; Chardonnet, Solenne; Pionneau, Cedric; Charlotte, Frédéric; Janssen, Klaus-Peter; Verdugo, Ricardo; Cambien, Francois; Blankenberg, Stefan; Tiret, Laurence; Zeller, Tanja; Ninio, Ewa

2015-10-01

We have previously reported that SASH1 expression is increased in circulating human monocytes from smokers and was positively correlated with the number of carotid atherosclerotic plaques. The aim of this study was to further validate the link between smoking, SASH1 and atherosclerosis within the vascular wall and to assess the impact of SASH1 expression on endothelial cell functions. Human carotids with atherosclerotic plaques were obtained from 58 patients (45 of them with known smoking status: smoker, non-smoker, ex-smokers), and were processed for gene expression analyses and immunostaining. To investigate its function, SASH1 was silenced in human aortic endothelial cells (HAECs) using two different siRNA and subcellular localization of SASH1 was determined by immunostaining and subcellular fractionation. Subsequently the transcriptomic analyses and functional experiments (wound healing, WST-1 proliferation or Matrigel assays) were performed to characterize SASH1 function. SASH1 was expressed in human vascular cells (HAECs, smooth muscle cells) and in monocytes/macrophages. Its tissue expression was significantly higher in the atherosclerotic carotids of smokers compared to non-smokers (p < 0.01). In HAECs, SASH1 was expressed mostly in the cytoplasm and SASH1 knockdown resulted in an increased cell migration, proliferation and angiogenesis. Transcriptomic and pathway analyses showed that SASH1 silencing results in a decreased CYP1A1 expression possibly through the inhibition of TP53 activity. We showed that SASH1 expression is increased in atherosclerotic carotids in smokers and its silencing affects endothelial angiogenic functions; therefore we provide a potential link between smoking and atherosclerosis through SASH1 expression. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

MCS-18, a natural product isolated from Helleborus purpurascens, inhibits maturation of dendritic cells in ApoE-deficient mice and prevents early atherosclerosis progression.

PubMed

Dietel, Barbara; Muench, Rabea; Kuehn, Constanze; Kerek, Franz; Steinkasserer, Alexander; Achenbach, Stephan; Garlichs, Christoph D; Zinser, Elisabeth

2014-08-01

Inflammation accelerates both plaque progression and instability in the pathogenesis of atherosclerosis. The inhibition of dendritic cell (DC) maturation is a promising approach to suppress excessive inflammatory immune responses and has been shown to be protective in several autoimmune models. The aim of this study was to investigate the immune modulatory effects of the natural substance MCS-18, an inhibitor of DC maturation, regarding the progression of atherosclerosis in ApoE-deficient mice. ApoE-deficient mice were fed for twelve weeks with a Western-type diet (n = 32) or normal chow (control group; n = 16). Animals receiving high-fat diet were treated with MCS-18 (500 μg/kg body weight, n = 16) or saline (n = 16) twice a week. After 12 weeks, animals were transcardially perfused and sacrificed. The percentage of mature DCs (CD3(-)/CD19(-)/CD14(-)/NK1.1(-)/CD11c(+)/MHCII(+)/CD83(+)/CD86(+)) and T cell subpopulations (CD4(+)/CD25(+)/Foxp3(+), CD3/CD4/CD8) was analyzed in peripheral blood and in the spleen using flow cytometry. Plaque size was determined in the aortic root and the thoracoabdominal aorta using en-face staining. Immunohistochemical stainings served to detect inflammatory cells in the aortic root. Several cytokines and chemokines were determined in serum using multiplex assays. In splenic cells derived from saline-treated atherosclerotic mice an increased DC maturation, reflected by the upregulation of CD83 and CD86 expression, was observed. The enhanced expression of both maturation markers was absent in MCS-18 treated atherosclerotic mice. While the percentage of splenic Foxp3 expressing Treg was increased in animals receiving MCS-18 compared to saline-treated atherosclerotic mice, cytotoxic T cells were reduced in the spleen and in atherosclerotic lesions of the aortic root. Furthermore, proatherogenic cytokines (e.g. IL-6 and IFN-γ) and chemokines (e.g. MIP-1β) were decreased in serum of MCS-18-treated animals when compared to saline-treated atherosclerotic mice. Also plaque size in the aortic root and the thoracoabdominal aorta was significantly lower following administration of MCS-18. This study provides for the first time evidence that MCS-18 is able to prevent the onset of atherosclerosis in ApoE-deficient mice. The observed anti-atherogenic effect is associated with the suppression of DC maturation and an inhibited migration and proliferation of cytotoxic T cells. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Metalloproteinases and atherothrombosis: MMP-10 mediates vascular remodeling promoted by inflammatory stimuli.

PubMed

Rodriguez, Jose A; Orbe, Josune; Martinez de Lizarrondo, Sara; Calvayrac, Olivier; Rodriguez, Cristina; Martinez-Gonzalez, Jose; Paramo, Jose A

2008-01-01

Atherosclerosis is the common pathophysiological substrate of ischemic vascular diseases and their thrombotic complications. The unbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) has been hypothesized to be involved in the growth, destabilization, and eventual rupture of atherosclerotic lesions. Different MMPs have been assigned relevant roles in the pathology of vascular diseases and MMP-10 (stromelysin-2) has been involved in vascular development and atherogenesis. This article examines the pathophysiological role of MMPs, particularly MMP-10, in the onset and progression of vascular diseases and their regulation by pro-inflammatory stimuli. MMP-10 over-expression has been shown to compromise vascular integrity and it has been associated with aortic aneurysms. MMP-10 is induced by C-reactive protein in endothelial cells, and it is over-expressed in atherosclerotic lesions. Additionally, higher MMP-10 serum levels are associated with inflammatory markers, increased carotid intima-media thickness and the presence of atherosclerotic plaques. We have cloned the promoter region of the MMP-10 gene and studied the effect of inflammatory stimuli on MMP-10 transcriptional regulation, providing evidences further supporting the involvement of MMP-10 in the pathophysiology of atherothrombosis.

CXCR6 regulates the recruitment of pro-inflammatory IL-17A-producing T cells into atherosclerotic aortas

PubMed Central

Butcher, Matthew J.; Wu, Chih-I; Waseem, Tayab

2016-01-01

The adaptive immune response is involved in the development and progression of atherosclerosis and IL-17A+ cells play a role in this disease. Although elevated number of CD4+ IL-17A+ (Th17) and IL-17A+TCRγδ+ T cells are found within murine atherosclerotic aortas and human plaques, the mechanisms governing IL-17A+ T-cell migration to atherosclerotic lesions are unclear. The chemokine receptor CXCR6 is expressed on several T-cell subsets and plays a pro-atherogenic role in atherosclerosis. Here, we used CXCR6-deficient (Cxcr6 GFP/GFP) apolipoprotein E-deficient (Apoe −/−) mice to investigate the involvement of CXCR6 in the recruitment IL-17A+ T cells to atherosclerotic aortas. Flow cytometric analyses revealed reductions in Th17 and IL-17A+TCRγδ+ T cells within aged Cxcr6 GFP/GFP Apoe −/− aortas, in comparison with age-matched Cxcr6 GFP/+ Apoe −/− aortas. Although CXCR6-sufficient IL-17A+ T cells efficiently migrated toward CXCL16, the migration of CXCR6-deficient IL-17A+ T cells was abolished in transwell assays. Importantly, the recruitment of Cxcr6 GFP/GFP Apoe −/− IL-17A+ T cells into the aortas of Apoe −/− recipients was markedly reduced in short-term adoptive transfer experiments. Altogether these results demonstrate an important role of CXCR6 in the regulation of pathological Th17 and IL-17A+TCRγδ+ T-cell recruitment into atherosclerotic lesions. PMID:26614640

CXCR6 regulates the recruitment of pro-inflammatory IL-17A-producing T cells into atherosclerotic aortas.

PubMed

Butcher, Matthew J; Wu, Chih-I; Waseem, Tayab; Galkina, Elena V

2016-05-01

The adaptive immune response is involved in the development and progression of atherosclerosis and IL-17A(+) cells play a role in this disease. Although elevated number of CD4(+) IL-17A(+) (Th17) and IL-17A(+)TCRγδ(+) T cells are found within murine atherosclerotic aortas and human plaques, the mechanisms governing IL-17A(+) T-cell migration to atherosclerotic lesions are unclear. The chemokine receptor CXCR6 is expressed on several T-cell subsets and plays a pro-atherogenic role in atherosclerosis. Here, we used CXCR6-deficient (Cxcr6 (GFP/GFP) ) apolipoprotein E-deficient (Apoe (-/-) ) mice to investigate the involvement of CXCR6 in the recruitment IL-17A(+) T cells to atherosclerotic aortas. Flow cytometric analyses revealed reductions in Th17 and IL-17A(+)TCRγδ(+) T cells within aged Cxcr6 (GFP/GFP) Apoe (-/-) aortas, in comparison with age-matched Cxcr6 (GFP/+) Apoe (-/-) aortas. Although CXCR6-sufficient IL-17A(+) T cells efficiently migrated toward CXCL16, the migration of CXCR6-deficient IL-17A(+) T cells was abolished in transwell assays. Importantly, the recruitment of Cxcr6 (GFP/GFP) Apoe (-/-) IL-17A(+) T cells into the aortas of Apoe (-/-) recipients was markedly reduced in short-term adoptive transfer experiments. Altogether these results demonstrate an important role of CXCR6 in the regulation of pathological Th17 and IL-17A(+)TCRγδ(+) T-cell recruitment into atherosclerotic lesions. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Erythrocyte membrane cholesterol and lipid core growth in a rabbit model of atherosclerosis: modulatory effects of rosuvastatin.

PubMed

Tziakas, Dimitrios; Chalikias, Georgios; Kapelouzou, Alkistis; Tentes, Ioannis; Schäfer, Katrin; Karayannakos, Panagiotis; Kostakis, Alkiviadis; Boudoulas, Harissios; Konstantinides, Stavros

2013-12-10

Lipid core expansion is partly responsible for the conversion of a stable atherosclerotic lesion to a rupture-prone plaque. Intraplaque hemorrhage contributes to the accumulation of cholesterol within unstable plaques. In the present study, we investigated, using a rabbit model of atherosclerosis, the extent to which diet-induced increases in cholesterol content of erythrocyte membranes (CEM) contribute to lipid core expansion and the modulatory effect of rosuvastatin use. Rabbits fed with atherogenic diet (0.75% cholesterol) for 5 months exhibited advanced atherosclerotic lesions (mean plaque area, 0.39 ± 0.03 mm(2)), and lipid core size was associated with the concentration-time integral (CTI) of CEM levels (r=0.567, P=0.004) independent of other established predictors of lipid core size. Further experiments were performed by feeding rabbits atherogenic diet (1% cholesterol) for 3 months, followed by either normal diet or normal diet plus rosuvastatin for the next 3 months. Although no differences were observed in total plaque area between both groups, administration of rosuvastatin was associated with significantly smaller lipid cores, fewer macrophages within the lipid core, less microvessels as well as with lower CTI of CEM levels compared to normal diet alone. Moreover, intraplaque erythrocyte membranes covered a smaller lipid core area in rabbits under rosuvastatin plus normal diet as opposed to rabbits under diet alone. Increased CEM levels, induced by high-cholesterol diet, are associated with lipid core growth. Ingestion of a potent HMG-CoA reductase inhibitor (rosuvastatin) may decrease CEM levels, and this effect may contribute to regression of the lipid core. © 2013.

Early improvement in carotid plaque echogenicity by acarbose in patients with acute coronary syndromes.

PubMed

Hirano, Mitsumasa; Nakamura, Takamitsu; Obata, Jyun-ei; Fujioka, Daisuke; Saito, Yukio; Kawabata, Ken-ichi; Watanabe, Kazuhiro; Watanabe, Yosuke; Kugiyama, Kiyotaka

2012-01-01

The resolution of hyperglycemia is associated with suppression of in-hospital cardiac complications in patients with acute coronary syndromes (ACS). This study evaluated carotid artery plaque echolucency using ultrasound in patients with ACS and type 2 diabetes mellitus (DM) to determine whether acarbose, an α-glucosidase inhibitor, may rapidly stabilize unstable atherosclerotic plaques. ACS patients with type 2 DM and carotid plaques (n=44) were randomly assigned to treatment with acarbose (150 or 300 mg/day, n=22) or a control group (no acarbose, n=22). Acarbose treatment was initiated within 5 days after the onset of ACS. Unstable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) before, and at 2 weeks, 1 and 6 months after the initiation of treatment. An increase in the IBS value reflected an increase in carotid plaque echogenicity. As results, the IBS value of echolucent carotid plaques showed a significant increase at 1 month and a further increase at 6 months after treatment in the acarbose group, but there was minimal change in the control group. The increase in IBS values was significantly correlated with a decrease in C-reactive protein levels. Acarbose rapidly improved carotid plaque echolucency within 1 month of therapy in patients with ACS and type 2 DM.

Mast cells in atherosclerotic cardiovascular disease - Activators and actions.

PubMed

Kovanen, Petri T; Bot, Ilze

2017-12-05

Mast cells are potent actors involved in inflammatory reactions in various tissues, including both in the intimal and the adventitial layers of atherosclerotic arteries. In the arterial intima, the site of atherogenesis, mast cells are activated to degranulate, and thereby triggered to release an abundance of preformed inflammatory mediators, notably histamine, heparin, neutral proteases and cytokines stored in their cytoplasmic secretory granules. Depending on the stimulus, mast cell activation may also launch prolonged synthesis and secretion of single bioactive molecules, such as cytokines and derivatives of arachidonic acid. The mast cell-derived mediators may impede the functions of different types of cells present in atherosclerotic lesions, and also compromise the structural and functional integrity of the intimal extracellular matrix. In the adventitial layer of atherosclerotic coronary arteries, mast cells locate next to peptidergic sensory nerve fibers, which, by releasing neuropeptides may activate mast cells to release vasoactive compounds capable of triggering local vasoconstriction. The concerted actions of arterial mast cells have the potential to contribute to the initiation and progression of atherosclerosis, and ultimately to destabilization and rupture of an advanced atherosclerotic plaque with ensuing atherothrombotic complications. Copyright © 2017 Elsevier B.V. All rights reserved.

Smooth muscle cells in atherosclerosis originate from the local vessel wall and not circulating progenitor cells in ApoE knockout mice.

PubMed

Bentzon, Jacob F; Weile, Charlotte; Sondergaard, Claus S; Hindkjaer, Johnny; Kassem, Moustapha; Falk, Erling

2006-12-01

Recent studies of bone marrow (BM)-transplanted apoE knockout (apoE-/-) mice have concluded that a substantial fraction of smooth muscle cells (SMCs) in atherosclerosis arise from circulating progenitor cells of hematopoietic origin. This pathway, however, remains controversial. In the present study, we reexamined the origin of plaque SMCs in apoE-/- mice by a series of BM transplantations and in a novel model of atherosclerosis induced in surgically transferred arterial segments. We analyzed plaques in lethally irradiated apoE-/- mice reconstituted with sex-mismatched BM cells from eGFP+ apoE-/- mice, which ubiquitously express enhanced green fluorescent protein (eGFP), but did not find a single SMC of donor BM origin among approximately 10,000 SMC profiles analyzed. We then transplanted arterial segments between eGFP+ apoE-/- and apoE-/- mice (isotransplantation except for the eGFP transgene) and induced atherosclerosis focally within the graft by a recently invented collar technique. No eGFP+ SMCs were found in plaques that developed in apoE-/- artery segments grafted into eGFP+ apoE-/- mice. Concordantly, 96% of SMCs were eGFP+ in plaques induced in eGFP+ apoE-/- artery segments grafted into apoE-/- mice. These experiments show that SMCs in atherosclerotic plaques are exclusively derived from the local vessel wall in apoE-/- mice.

Chemokine receptors CXCR2 and CX3CR1 differentially regulate functional responses of bone-marrow endothelial progenitors during atherosclerotic plaque regression.

PubMed

Herlea-Pana, Oana; Yao, Longbiao; Heuser-Baker, Janet; Wang, Qiongxin; Wang, Qilong; Georgescu, Constantin; Zou, Ming-Hui; Barlic-Dicen, Jana

2015-05-01

Atherosclerosis manifests itself as arterial plaques, which lead to heart attacks or stroke. Treatments supporting plaque regression are therefore aggressively pursued. Studies conducted in models in which hypercholesterolaemia is reversible, such as the Reversa mouse model we have employed in the current studies, will be instrumental for the development of such interventions. Using this model, we have shown that advanced atherosclerosis regression occurs when lipid lowering is used in combination with bone-marrow endothelial progenitor cell (EPC) treatment. However, it remains unclear how EPCs home to regressing plaques and how they augment atherosclerosis reversal. Here we identify molecules that support functional responses of EPCs during plaque resolution. Chemokines CXCL1 and CX3CL1 were detected in the vascular wall of atheroregressing Reversa mice, and their cognate receptors CXCR2 and CX3CR1 were observed on adoptively transferred EPCs in circulation. We tested whether CXCL1-CXCR2 and CX3CL1-CX3CR1 axes regulate functional responses of EPCs during plaque reversal. We show that pharmacological inhibition of CXCR2 or CX3CR1, or genetic inactivation of these two chemokine receptors interfered with EPC-mediated advanced atherosclerosis regression. We also demonstrate that CXCR2 directs EPCs to regressing plaques while CX3CR1 controls a paracrine function(s) of these cells. CXCR2 and CX3CR1 differentially regulate EPC functional responses during atheroregression. Our study improves understanding of how chemokines and chemokine receptors regulate plaque resolution, which could determine the effectiveness of interventions reducing complications of atherosclerosis. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Chemokine receptors CXCR2 and CX3CR1 differentially regulate functional responses of bone-marrow endothelial progenitors during atherosclerotic plaque regression

PubMed Central

Herlea-Pana, Oana; Yao, Longbiao; Heuser-Baker, Janet; Wang, Qiongxin; Wang, Qilong; Georgescu, Constantin; Zou, Ming-Hui; Barlic-Dicen, Jana

2015-01-01

Aims Atherosclerosis manifests itself as arterial plaques, which lead to heart attacks or stroke. Treatments supporting plaque regression are therefore aggressively pursued. Studies conducted in models in which hypercholesterolaemia is reversible, such as the Reversa mouse model we have employed in the current studies, will be instrumental for the development of such interventions. Using this model, we have shown that advanced atherosclerosis regression occurs when lipid lowering is used in combination with bone-marrow endothelial progenitor cell (EPC) treatment. However, it remains unclear how EPCs home to regressing plaques and how they augment atherosclerosis reversal. Here we identify molecules that support functional responses of EPCs during plaque resolution. Methods and results Chemokines CXCL1 and CX3CL1 were detected in the vascular wall of atheroregressing Reversa mice, and their cognate receptors CXCR2 and CX3CR1 were observed on adoptively transferred EPCs in circulation. We tested whether CXCL1–CXCR2 and CX3CL1–CX3CR1 axes regulate functional responses of EPCs during plaque reversal. We show that pharmacological inhibition of CXCR2 or CX3CR1, or genetic inactivation of these two chemokine receptors interfered with EPC-mediated advanced atherosclerosis regression. We also demonstrate that CXCR2 directs EPCs to regressing plaques while CX3CR1 controls a paracrine function(s) of these cells. Conclusion CXCR2 and CX3CR1 differentially regulate EPC functional responses during atheroregression. Our study improves understanding of how chemokines and chemokine receptors regulate plaque resolution, which could determine the effectiveness of interventions reducing complications of atherosclerosis. PMID:25765938

Correlation of calcified carotid plaques detected by panoramic radiograph with risk factors for stroke development.

PubMed

Griniatsos, John; Damaskos, Spyros; Tsekouras, Nikolaos; Klonaris, Chris; Georgopoulos, Sotirios

2009-10-01

The aim was to evaluate whether patients with calcifications in the carotid region detectable by panoramic radiograph differ in the prevalence of risk factors for stroke development compared with those without calcifications. Forty consecutive individuals suffering from proven carotid artery atherosclerotic occlusive disease were submitted to carotid endarterectomy. Seventeen patients were symptomatic at the time of referral, having suffered at least 1 episode of ischemic cerebral event during the preceding 6 months, mainly transient ischemic attacks or amaurosis fugax, and the remaining 23 patients were asymptomatic and the diagnosis was reached during a thorough investigation of coexisting coronary or peripheral vascular disease. Preoperatively, all patients had undergone panoramic radiograph examination, as the presurgical protocol commanded. Based on the panoramic radiograph results, patients in whom calcifications were detected either unilaterally (n = 10) or bilaterally (n = 18) constituted group A (n = 28) and patients in whom no calcifications were detected constituted group B (n = 12) of this study. Univariate analysis among several risk factors for stroke development between the 2 groups of patients disclosed a stastistically significant lower incidence of diabetes mellitus (P = .005) but a higher incidence of symptomatic plaques (P < .030) in the group of patients with detectable calcifications in the panoramic radiograph. Patients with calcified carotid plaques detectable by panoramic radiography are more likely to have suffered cerebrovascular events. Therefore, patients with detectable carotid plaque in panoramic radiographs require referral to their physician for further investigation.

Complement Activation: An Emerging Player in the Pathogenesis of Cardiovascular Disease

PubMed Central

Carter, Angela M.

2012-01-01

A wealth of evidence indicates a fundamental role for inflammation in the pathogenesis of cardiovascular disease (CVD), contributing to the development and progression of atherosclerotic lesion formation, plaque rupture, and thrombosis. An increasing body of evidence supports a functional role for complement activation in the pathogenesis of CVD through pleiotropic effects on endothelial and haematopoietic cell function and haemostasis. Prospective and case control studies have reported strong relationships between several complement components and cardiovascular outcomes, and in vitro studies and animal models support a functional effect. Complement activation, in particular, generation of C5a and C5b-9, influences many processes involved in the development and progression of atherosclerosis, including promotion of endothelial cell activation, leukocyte infiltration into the extracellular matrix, stimulation of cytokine release from vascular smooth muscle cells, and promotion of plaque rupture. Complement activation also influences thrombosis, involving components of the mannose-binding lectin pathway, and C5b-9 in particular, through activation of platelets, promotion of fibrin formation, and impairment of fibrinolysis. The participation of the complement system in inflammation and thrombosis is consistent with the physiological role of the complement system as a rapid effector system conferring protection following vessel injury. However, in the context of CVD, these same processes contribute to development of atherosclerosis, plaque rupture, and thrombosis. PMID:24278688

Increased activity of vascular adenosine deaminase in atherosclerosis and therapeutic potential of its inhibition.

PubMed

Kutryb-Zajac, Barbara; Mateuszuk, Lukasz; Zukowska, Paulina; Jasztal, Agnieszka; Zabielska, Magdalena A; Toczek, Marta; Jablonska, Patrycja; Zakrzewska, Agnieszka; Sitek, Barbara; Rogowski, Jan; Lango, Romuald; Slominska, Ewa M; Chlopicki, Stefan; Smolenski, Ryszard T

2016-11-01

Extracellular nucleotides and adenosine that are formed or degraded by membrane-bound ecto-enzymes could affect atherosclerosis by regulating the inflammation and thrombosis. This study aimed to evaluate a relation between ecto-enzymes that convert extracellular adenosine triphosphate to adenine dinucleotide phosphate, adenosine monophosphate, adenosine, and inosine on the surface of the vessel wall with the severity or progression of experimental and clinical atherosclerosis. Furthermore, we tested whether the inhibition of adenosine deaminase will block the development of experimental atherosclerosis. Vascular activities of ecto-nucleoside triphosphate diphosphohydrolase 1, ecto-5'-nucleotidase, and ecto-adenosine deaminase (eADA) were measured in aortas of apolipoprotein E-/- low density lipoprotein receptor (ApoE-/-LDLR-/-) and wild-type mice as well as in human aortas. Plaques were analysed in the entire aorta, aortic root, and brachiocephalic artery by Oil-Red O and Orcein Martius Scarlet Blue staining and vascular accumulation of macrophages. The cellular location of ecto-enzymes was analysed by immunofluorescence. The effect of eADA inhibition on atherosclerosis progression was studied by a 2-month deoxycoformycin treatment of ApoE-/-LDLR-/- mice. The vascular eADA activity prominently increased in ApoE-/-LDLR-/- mice when compared with wild type already at the age of 1 month and progressed along atherosclerosis development, reaching a 10-fold difference at 10 months. The activity of eADA correlated with atherosclerotic changes in human aortas. High abundance of eADA in atherosclerotic vessels originated from activated endothelial cells and macrophages. There were no changes in ecto-nucleoside triphosphate diphosphohydrolase 1 activity, whereas ecto-5'-nucleotidase was moderately decreased in ApoE-/-LDLR-/- mice. Deoxycoformycin treatment attenuated plaque development in aortic root and brachiocephalic artery of ApoE-/-LDLR-/- mice, suppressed vascular inflammation and improved endothelial function. This study highlights the importance of extracellular nucleotides and adenosine metabolism in the atherosclerotic vessel in both experimental and clinical setting. The increased eADA activity marks an early stage of atherosclerosis, contributes to its progression and could represent a novel target for therapy. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.

High-resolution magnetic resonance imaging of carotid atherosclerotic plaques - a correlation study with histopathology.

PubMed

Xia, Zhangyong; Yang, Hua; Yuan, Xiaochun; Wang, Jiyue; Zhang, Shigang; Zhang, Liyong; Qu, Yang; Chen, Jun; Jiao, Liqun; Wang, Le-Xin; Du, Yifeng

2017-07-01

This study aimed to utilize high-resolution magnetic resonance imaging (MRI) to investigate the characteristics of stable and vulnerable carotid arteriosclerotic plaques, with correlations to histopathological findings. High-resolution MRI was performed in 817 patients, using three-dimensional magnetic resonance angiography. Plaque composition was evaluated by measuring the areas occupied by calcification, a lipid-rich necrotic core, intra-plaque haemorrhage, and fibrous cap rupture. Plaque morphology was analysed by measuring vessel wall area, thickness, and luminal area at the bifurcation of the common carotid artery. Plaque tissues were sampled during carotid endarterectomy and examined using haematoxylin-eosin, Oil Red O, Masson trichrome staining, and immunohistochemical staining for CD68. Patients were divided into stable plaque group (n = 462) and vulnerable plaque group (n = 355), based on intraoperative observations and postoperative histopathological findings. Compared to the stable plaque group, the vulnerable plaque group exhibited increased vessel wall areas and thickness, and decreased mean luminal areas (P < 0.001). The vulnerable plaque group also had a lower collagen content, a higher lipid content, and higher CD68 expression in plaque tissues on histological examinations (P < 0.01). Incidences of lipid-rich necrotic core (38.1 % vs. 34.3 %), intra-plaque haemorrhage (26.9 % vs. 22.8 %), plaque calcification (45.2 % vs. 40.9 %), and fibrous cap rupture (36.0 % vs 39.8 %) in the plaques were concordant with MRI observations and histopathological findings (p > 0.05). Stable and vulnerable carotid plaques had different morphologies and compositions. High-resolution MRI can assess such differences qualitatively and quantitatively in vivo and provide guidance for risk stratification and management.

MRI-based patient-specific human carotid atherosclerotic vessel material property variations in patients, vessel location and long-term follow up

PubMed Central

Wang, Qingyu; Canton, Gador; Guo, Jian; Guo, Xiaoya; Hatsukami, Thomas S.; Billiar, Kristen L.; Yuan, Chun; Wu, Zheyang

2017-01-01

Background Image-based computational models are widely used to determine atherosclerotic plaque stress/strain conditions and investigate their association with plaque progression and rupture. However, patient-specific vessel material properties are in general lacking in those models, limiting the accuracy of their stress/strain measurements. A noninvasive approach of combining in vivo 3D multi-contrast and Cine magnetic resonance imaging (MRI) and computational modeling was introduced to quantify patient-specific carotid plaque material properties for potential plaque model improvements. Vessel material property variation in patients, along vessel segment, and between baseline and follow up were investigated. Methods In vivo 3D multi-contrast and Cine MRI carotid plaque data were acquired from 8 patients with follow-up (18 months) with written informed consent obtained. 3D thin-layer models and an established iterative procedure were used to determine parameter values of the Mooney-Rivlin models for the 81slices from 16 plaque samples. Effective Young’s Modulus (YM) values were calculated for comparison and analysis. Results Average Effective Young’s Modulus (YM) and circumferential shrinkage rate (C-Shrink) value of the 81 slices was 411kPa and 5.62%, respectively. Slice YM value varied from 70 kPa (softest) to 1284 kPa (stiffest), a 1734% difference. Average slice YM values by vessel varied from 109 kPa (softest) to 922 kPa (stiffest), a 746% difference. Location-wise, the maximum slice YM variation rate within a vessel was 311% (149 kPa vs. 613 kPa). The average slice YM variation rate for the 16 vessels was 134%. The average variation of YM values for all patients from baseline to follow up was 61.0%. The range of the variation of YM values was [-28.4%, 215%]. For plaque progression study, YM at follow-up showed negative correlation with plaque progression measured by wall thickness increase (WTI) (r = -0.7764, p = 0.0235). Wall thickness at baseline correlated with WTI negatively, with r = -0.5253 (p = 0.1813). Plaque burden at baseline correlated with YM change between baseline and follow-up, with r = 0.5939 (p = 0.1205). Conclusion In vivo carotid vessel material properties have large variations from patient to patient, along the diseased segment within a patient, and with time. The use of patient-specific, location specific and time-specific material properties in plaque models could potentially improve the accuracy of model stress/strain calculations. PMID:28715441

Three-dimensional quantitative T1 and T2 mapping of the carotid artery: Sequence design and in vivo feasibility.

PubMed

Coolen, Bram F; Poot, Dirk H J; Liem, Madieke I; Smits, Loek P; Gao, Shan; Kotek, Gyula; Klein, Stefan; Nederveen, Aart J

2016-03-01

A novel three-dimensional (3D) T1 and T2 mapping protocol for the carotid artery is presented. A 3D black-blood imaging sequence was adapted allowing carotid T1 and T2 mapping using multiple flip angles and echo time (TE) preparation times. B1 mapping was performed to correct for spatially varying deviations from the nominal flip angle. The protocol was optimized using simulations and phantom experiments. In vivo scans were performed on six healthy volunteers in two sessions, and in a patient with advanced atherosclerosis. Compensation for patient motion was achieved by 3D registration of the inter/intrasession scans. Subsequently, T1 and T2 maps were obtained by maximum likelihood estimation. Simulations and phantom experiments showed that the bias in T1 and T2 estimation was < 10% within the range of physiological values. In vivo T1 and T2 values for carotid vessel wall were 844 ± 96 and 39 ± 5 ms, with good repeatability across scans. Patient data revealed altered T1 and T2 values in regions of atherosclerotic plaque. The 3D T1 and T2 mapping of the carotid artery is feasible using variable flip angle and variable TE preparation acquisitions. We foresee application of this technique for plaque characterization and monitoring plaque progression in atherosclerotic patients. © 2015 Wiley Periodicals, Inc.

Progranulin expression in advanced human atherosclerotic plaque.

PubMed

Kojima, Yoji; Ono, Koh; Inoue, Katsumi; Takagi, Yasushi; Kikuta, Ken-ichiro; Nishimura, Masaki; Yoshida, Yoshinori; Nakashima, Yasuhiro; Matsumae, Hironobu; Furukawa, Yutaka; Mikuni, Nobuhiro; Nobuyoshi, Masakiyo; Kimura, Takeshi; Kita, Toru; Tanaka, Makoto

2009-09-01

Progranulin (PGRN) is a unique growth factor that plays an important role in cutaneous wound healing. It has an anti-inflammatory effect and promotes cell proliferation. However, when it is degraded to granulin peptides (GRNs) by neutrophil proteases, a pro-inflammatory reaction occurs. Since injury, inflammation and repair are common features in the progression of atherosclerosis, it is conceivable that PGRN plays a role in atherogenesis. Immunohistochemical analysis of human carotid endoatherectomy specimens indicated that vascular smooth muscle cells (vSMCs) in the intima expressed PGRN. Some macrophages in the plaque also expressed PGRN. We assessed the effect of PGRN on a human monocytic leukemia cell line (THP-1) and human aortic smooth muscle cells (HASMCs). PGRN alone had no effect on HASMC or THP-1 proliferation or migration. However, when THP-1 cells were stimulated with MCP-1, the number of migrated cells decreased in a PGRN-dose-dependent manner. TNF-alpha-induced HASMC migration was enhanced only at 10nM of PGRN. Interleukin-8 (IL-8) secretion from HASMCs was reduced by forced expression of PGRN and increased by RNAi-mediated knockdown of PGRN. While exogenous treatment with recombinant PGRN decreased IL-8 secretion, degraded recombinant GRNs increased IL-8 secretion from HASMCs. The expression of PGRN mainly reduces inflammation and its degradation into GRNs enhances inflammation in atherosclerotic plaque and may contribute to the progression of atherosclerosis.

Comparison of the inflammatory burden of truly asymptomatic carotid atheroma with atherosclerotic plaques contralateral to symptomatic carotid stenosis: an ultra small superparamagnetic iron oxide enhanced magnetic resonance study

PubMed Central

Tang, Tjun Y; Howarth, Simon P S; Miller, Sam R; Graves, Martin J; U‐King‐Im, Jean‐Marie; Trivedi, Rikin A; Li, Zhi Yong; Walsh, Stewart R; Brown, Andrew P; Kirkpatrick, Peter J; Gaunt, Michael E; Gillard, Jonathan H

2007-01-01

Background Inflammation is a recognised risk factor for the vulnerable atherosclerotic plaque. The aim of this study was to explore whether there is a difference in the degree of magnetic resonance (MR) defined inflammation using ultra small superparamagnetic iron oxide (USPIO) particles within carotid atheroma in completely asymptomatic individuals and the asymptomatic carotid stenosis contralateral to the symptomatic side. Methods 20 symptomatic patients with contralateral disease and 20 completely asymptomatic patients underwent multi‐sequence MR imaging before and 36 h after USPIO infusion. Images were manually segmented into quadrants and signal change in each quadrant was calculated following USPIO administration. Mean signal change was compared across all quadrants in the two groups. Results The mean percentage of quadrants showing signal loss was 53% in the contralateral group compared with 31% in completely asymptomatic individuals (p = 0.025). The mean percentages showing enhancement were 44% and 65%, respectively (p = 0.024). The mean signal difference between the two groups was 8.6% (95% CI 1.6% to 15.6%; p = 0.017). Conclusions Truly asymptomatic plaques seem to demonstrate inflammation but not to the extent of the contralateral asymptomatic stenosis to the symptomatic side. Inflammatory activity may be a significant risk factor in asymptomatic disease. PMID:17578854

Topographic association of angioscopic yellow plaques with coronary atherosclerotic plaque: assessment with quantitative colorimetry in human coronary artery autopsy specimens.

PubMed

Ishibashi, Fumiyuki; Lisauskas, Jennifer B; Kawamura, Akio; Waxman, Sergio

2008-01-01

Yellow plaques seen during coronary angioscopy are thought to be the surrogates for superficial intimal lipids in coronary plaque. Given diffuse and heterogeneous nature of atherosclerosis, yellow plaques in coronaries may be seen as several yellow spots on diffuse coronary plaque. We examined the topographic association of yellow plaques with coronary plaque. In 40 non-severely stenotic ex-vivo coronary segments (average length: 52.2 +/- 3.1 mm), yellow plaques were examined by angioscopy with quantitative colorimetry. The segments were cut perpendicular to the long axis of the vessel at 2 mm intervals, and 1045 slides with 5 microm thick tissue for whole segments were prepared. To construct the plaque surface, each tissue slice was considered to be representative of the adjacent 2 mm. The circumference of the lumen and the lumen border of plaque were measured in each slide, and the plaque surface region was constructed. Coronary plaque was in 37 (93%) of 40 segments, and consisted of a single mass [39.9 +/- 3.9 (0-100) mm, 311.3 +/- 47.4 (0.0-1336.2) mm2]. In 30 (75%) segments, multiple (2-9) yellow plaques were detected on a mass of coronary plaque. The number of yellow plaques correlated positively with coronary plaque surface area (r = 0.77, P < 0.0001). Yellow plaques in coronaries detected by angioscopy with quantitative colorimetry, some of them are associated with lipid cores underneath thin fibrous caps, may be used to assess the extent of coronary plaque. Further research using angioscopy could be of value to study the association of high-risk coronaries with acute coronary syndromes.