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1.
Dong C Della-Morte D Wang L Cabral D Beecham A McClendon MS Luca CC Blanton SH Sacco RL Rundek T 《PloS one》2011,6(11):e27157
Objective
Sirtuins (SIRTs) and mitochondrial uncoupling proteins (UCPs) have been implicated in cardiovascular diseases through the control of reactive oxygen species production. This study sought to investigate the association between genetic variants in the SIRT and UCP genes and carotid plaque.Methods
In a group of 1018 stroke-free subjects from the Northern Manhattan Study with high-definition carotid ultrasonography and genotyping, we investigated the associations of 85 single nucleotide polymorphisms (SNPs) in the 11 SIRT and UCP genes with the presence and number of carotid plaques, and evaluated interactions of SNPs with sex, smoking, diabetes and hypertension as well as interactions between SNPs significantly associated with carotid plaque.Results
Overall, 60% of subjects had carotid plaques. After adjustment for demographic and vascular risk factors, T-carriers of the SIRT6 SNP rs107251 had an increased risk for carotid plaque (odds ratio, OR = 1.71, 95% CI = 1.23–2.37, Bonferroni-corrected p = 0.03) and for a number of plaques (rate ratio, RR = 1.31, 1.18–1.45, Bonferroni-corrected p = 1.4×10−5), whereas T-carriers of the UCP5 SNP rs5977238 had an decreased risk for carotid plaque (OR = 0.49, 95% CI = 0.32–0.74, Bonferroni-corrected p = 0.02) and plaque number (RR = 0.64, 95% CI = 0.52–0.78, Bonferroni-corrected p = 4.9×10−4). Some interactions with a nominal p≤0.01 were found between sex and SNPs in the UCP1 and UCP3 gene; between smoking, diabetes, hypertension and SNPs in UCP5 and SIRT5; and between SNPs in the UCP5 gene and the UCP1, SIRT1, SIRT3, SIRT5, and SIRT6 genes in association with plaque phenotypes.Conclusion
We observed significant associations between genetic variants in the SIRT6 and UCP5 genes and atherosclerotic plaque. We also found potential effect modifications by sex, smoking and vascular risk factors of the SIRT/UCP genes in the associations with atherosclerotic plaque. Further studies are needed to validate our observations. 相似文献2.
Herder C Baumert J Zierer A Roden M Meisinger C Karakas M Chambless L Rathmann W Peters A Koenig W Thorand B 《PloS one》2011,6(6):e19852
Background
This study compares inflammation-related biomarkers with established cardiometabolic risk factors in the prediction of incident type 2 diabetes and incident coronary events in a prospective case-cohort study within the population-based MONICA/KORA Augsburg cohort.Methods and Findings
Analyses for type 2 diabetes are based on 436 individuals with and 1410 individuals without incident diabetes. Analyses for coronary events are based on 314 individuals with and 1659 individuals without incident coronary events. Mean follow-up times were almost 11 years. Areas under the receiver-operating characteristic curve (AUC), changes in Akaike''s information criterion (ΔAIC), integrated discrimination improvement (IDI) and net reclassification index (NRI) were calculated for different models. A basic model consisting of age, sex and survey predicted type 2 diabetes with an AUC of 0.690. Addition of 13 inflammation-related biomarkers (CRP, IL-6, IL-18, MIF, MCP-1/CCL2, IL-8/CXCL8, IP-10/CXCL10, adiponectin, leptin, RANTES/CCL5, TGF-β1, sE-selectin, sICAM-1; all measured in nonfasting serum) increased the AUC to 0.801, whereas addition of cardiometabolic risk factors (BMI, systolic blood pressure, ratio total/HDL-cholesterol, smoking, alcohol, physical activity, parental diabetes) increased the AUC to 0.803 (ΔAUC [95% CI] 0.111 [0.092–0.149] and 0.113 [0.093–0.149], respectively, compared to the basic model). The combination of all inflammation-related biomarkers and cardiometabolic risk factors yielded a further increase in AUC to 0.847 (ΔAUC [95% CI] 0.044 [0.028–0.066] compared to the cardiometabolic risk model). Corresponding AUCs for incident coronary events were 0.807, 0.825 (ΔAUC [95% CI] 0.018 [0.013–0.038] compared to the basic model), 0.845 (ΔAUC [95% CI] 0.038 [0.028–0.059] compared to the basic model) and 0.851 (ΔAUC [95% CI] 0.006 [0.003–0.021] compared to the cardiometabolic risk model), respectively.Conclusions
Inclusion of multiple inflammation-related biomarkers into a basic model and into a model including cardiometabolic risk factors significantly improved the prediction of type 2 diabetes and coronary events, although the improvement was less pronounced for the latter endpoint. 相似文献3.
LJ Schurgers IA Joosen EM Laufer ML Chatrou M Herfs MH Winkens R Westenfeld V Veulemans T Krueger CM Shanahan W Jahnen-Dechent E Biessen J Narula C Vermeer L Hofstra CP Reutelingsperger 《PloS one》2012,7(8):e43229
Background
Vitamin K-antagonists (VKA) are treatment of choice and standard care for patients with venous thrombosis and thromboembolic risk. In experimental animal models as well as humans, VKA have been shown to promote medial elastocalcinosis. As vascular calcification is considered an independent risk factor for plaque instability, we here investigated the effect of VKA on coronary calcification in patients and on calcification of atherosclerotic plaques in the ApoE−/− model of atherosclerosis.Methodology/Principal Findings
A total of 266 patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users) underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD). VKA-users developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE−/− mice (10 weeks) received a Western type diet (WTD) for 12 weeks, after which mice were fed a WTD supplemented with vitamin K1 (VK1, 1.5 mg/g) or vitamin K1 and warfarin (VK1&W; 1.5 mg/g & 3.0 mg/g) for 1 or 4 weeks, after which mice were sacrificed. Warfarin significantly increased frequency and extent of vascular calcification. Also, plaque calcification comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased apoptosis and, surprisingly outward plaque remodeling, without affecting overall plaque burden.Conclusions/Significance
VKA use is associated with coronary artery plaque calcification in patients with suspected CAD and causes changes in plaque morphology with features of plaque vulnerability in ApoE−/− mice. Our findings underscore the need for alternative anticoagulants that do not interfere with the vitamin K cycle. 相似文献4.
Zhang H Zhang L Myerson J Bibee K Scott M Allen J Sicard G Lanza G Wickline S 《PloS one》2011,6(10):e26385
Rationale
Acute atherothrombotic occlusion in heart attack and stroke implies disruption of the vascular endothelial barrier that exposes a highly procoagulant intimal milieu. However, the evolution, severity, and pathophysiological consequences of vascular barrier damage in atherosclerotic plaque remain unknown, in part because quantifiable methods and experimental models are lacking for its in vivo assessment.Objective
To develop quantitative nondestructive methodologies and models for detecting vascular barrier disruption in advanced plaques.Methods and Results
Sustained hypercholesterolemia in New Zealand White (NZW) rabbits for >7–14 months engendered endothelial barrier disruption that was evident from massive and rapid passive penetration and intimal trapping of perfluorocarbon-core nanoparticles (PFC-NP: ∼250 nm diameter) after in vivo circulation for as little as 1 hour. Only older plaques (>7 mo), but not younger plaques (<3 mo) demonstrated the marked enhancement of endothelial permeability to these particles. Electron microscopy revealed a complex of subintimal spongiform channels associated with endothelial apoptosis, superficial erosions, and surface-penetrating cholesterol crystals. Fluorine (19F) magnetic resonance imaging and spectroscopy (MRI/MRS) enabled absolute quantification (in nanoMolar) of the passive permeation of PFC-NP into the disrupted vascular lesions by sensing the unique spectral signatures from the fluorine core of plaque-bound PFC-NP.Conclusions
The application of semipermeant nanoparticles reveals the presence of profound barrier disruption in later stage plaques and focuses attention on the disrupted endothelium as a potential contributor to plaque vulnerability. The response to sustained high cholesterol levels yields a progressive deterioration of the vascular barrier that can be quantified with fluorine MRI/MRS of passively permeable nanostructures. The possibility of plaque classification based on the metric of endothelial permeability to nanoparticles is suggested. 相似文献5.
Marc Frerix Johannes Stegbauer Alexander Kreuter Stefan Markus Weiner 《Arthritis research & therapy》2014,16(1):R54
Introduction
The objective of this cross-sectional and retrospective cohort study was (1) to determine the usefulness of intima-media thickness (IMT) in contrast to plaque assessment, (2) to examine the value of additive femoral artery sonography and (3) to identify potential risk factors for atherosclerosis and incident cardiovascular events in systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) patients.Methods
In this study, 90 SSc and 100 SLE patients were examined by duplexsonography. IMT was measured in common carotid and common femoral arteries, plaques were assessed in common, internal and external carotid and common, proximal superficial and deep femoral arteries. Different definitions of pathological IMT (pIMT) were compared with the presence of plaque. Results were evaluated in relation to traditional and non-traditional risk factors for baseline atherosclerosis (logistic regression) and their predictive value for cardiovascular events during follow-up (cox regression).Results
Definite atherosclerosis occurred frequently without signs of subclinical atherosclerosis in both diseases: pIMT >0.9 mm was present in only 17/59 (28.9%) SSc and 13/49 (26.5%) SLE patients with already present atherosclerotic plaques. Using age-adjusted pIMT definitions, this rate was even lower (5.1-10.3% in SSc, 14.3-26.5% in SLE). Plaques were located only at the carotid or only at the femoral arteries in 26 (13.7%) and 24 (12.6%) patients, respectively. Age and nicotine pack-years were independently associated with atherosclerotic plaques in SLE and SSc patients, as well as the cumulative prednisolone dose in SSc subgroup, and ssDNA positive SLE patients had a lower risk for atherosclerotic plaque. During follow-up (available for 129/190 (67.9%) patients, 650 person-years), cardiovascular events occurred more often in patients with coronary heart disease (adjusted-hazards ratio (HR) 10.19, 95% confidence interval (CI) 3.04 to 34.17, P <0.001), male patients (adjusted-HR 8.78, 95% CI 2.73 to 28.19, P <0.001) and in patients with coexistent carotid and femoral plaques (adjusted-HR 5.92, 95% CI 1.55 to 22.67, P = 0.009). Patients with solely carotid or femoral plaque were not at higher risk.Conclusion
Atherosclerotic plaque lesions can be found frequently in absence of intima-media thickening in both SSc and SLE patients. As well as routine sonography of carotid arteries, the sonography of femoral arteries is recommended to identify additional atherosclerotic lesions and to detect patients at a high risk for cardiovascular events. 相似文献6.
Caglayan E Romeo GR Kappert K Odenthal M Südkamp M Body SC Shernan SK Hackbusch D Vantler M Kazlauskas A Rosenkranz S 《PloS one》2010,5(10):e13608
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, ) or Src-family kinases (SU6656, PP2), but not PLCγ ( LY294002), 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). U73122Conclusions
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. 相似文献7.
Background
Platelet-derived chemokines are implicated in several aspects of vascular biology. However, for the chemokine platelet factor 4 variant (PF-4var/CXCL4L1), released by platelets during thrombosis and with different properties as compared to PF-4/CXCL4, its role in heart disease is not yet studied. We evaluated the determinants and prognostic value of the platelet-derived chemokines PF-4var, PF-4 and RANTES/CCL5 in patients with stable coronary artery disease (CAD).Methodology/Principal Findings
From 205 consecutive patients with stable CAD and preserved left ventricular (LV) function, blood samples were taken at inclusion and were analyzed for PF-4var, RANTES, platelet factor-4 and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Patients were followed (median follow-up 2.5 years) for the combined endpoint of cardiac death, non-fatal acute myocardial infarction, stroke or hospitalization for heart failure. Independent determinants of PF-4var levels (median 10 ng/ml; interquartile range 8–16 ng/ml) were age, gender and circulating platelet number. Patients who experienced cardiac events (n = 20) during follow-up showed lower levels of PF-4var (8.5 [5.3–10] ng/ml versus 12 [8–16] ng/ml, p = 0.033). ROC analysis for events showed an area under the curve (AUC) of 0.82 (95% CI 0.73–0.90, p<0.001) for higher NT-proBNP levels and an AUC of 0.32 (95% CI 0.19–0.45, p = 0.009) for lower PF-4var levels. Cox proportional hazard analysis showed that PF-4var has an independent prognostic value on top of NT-proBNP.Conclusions
We conclude that low PF-4var/CXCL4L1 levels are associated with a poor outcome in patients with stable CAD and preserved LV function. This prognostic value is independent of NT-proBNP levels, suggesting that both neurohormonal and platelet-related factors determine outcome in these patients. 相似文献8.
Holm S Ueland T Dahl TB Michelsen AE Skjelland M Russell D Nymo SH Krohg-Sørensen K Clausen OP Atar D Januzzi JL Aukrust P Jensen JK Halvorsen B 《PloS one》2011,6(12):e28785
Background and Purpose
Fatty acid binding protein 4 (FABP4) has been shown to play an important role in macrophage cholesterol trafficking and associated inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in carotid atherosclerosis and ischemic stroke.Methods
We examined plasma FABP4 levels in asymptomatic (n = 28) and symptomatic (n = 31) patients with carotid atherosclerosis, as well as in 202 subjects with acute ischemic stroke. In a subgroup of patients we also analysed the expression of FABP4 within the atherosclerotic lesion. In addition, we investigated the ability of different stimuli with relevance to atherosclerosis to regulate FABP4 expression in monocytes/macrophages.Results
FABP4 levels were higher in patients with carotid atherosclerosis, both systemically and within the atherosclerotic lesion, with particular high mRNA levels in carotid plaques from patients with the most recent symptoms. Immunostaining of carotid plaques localized FABP4 to macrophages, while activated platelets and oxidized LDL were potent stimuli for FABP4 expression in monocytes/macrophages in vitro. When measured at the time of acute ischemic stroke, high plasma levels of FABP4 were significantly associated with total and cardiovascular mortality during follow-up, although we did not find that addition of FABP4 to the fully adjusted multivariate model had an effect on the prognostic discrimination for all-cause mortality as assessed by c-statistics.Conclusions
FABP4 is linked to atherogenesis, plaque instability and adverse outcome in patients with carotid atherosclerosis and acute ischemic stroke. 相似文献9.
David G. Zacharias Sung Gyun Kim Alfonso Eirin Massat Adi R. Bachar Yun K. Oh Joerg Herrmann Martin Rodriguez-Porcel Pinchas Cohen Lilach O. Lerman Amir Lerman 《PloS one》2012,7(2)
Objective
The mechanism of atherosclerotic plaque progression leading to instability, rupture, and ischemic manifestation involves oxidative stress and apoptosis. Humanin (HN) is a newly emerging endogenously expressed cytoprotective peptide. Our goal was to determine the presence and localization of HN in carotid atherosclerotic plaques.Methods and Results
Plaque specimens from 34 patients undergoing carotid endarterectomy were classified according to symptomatic history. Immunostaining combined with digital microscopy revealed greater expression of HN in the unstable plaques of symptomatic compared to asymptomatic patients (29.42±2.05 vs. 14.14±2.13% of plaque area, p<0.0001). These data were further confirmed by immunoblot (density of HN/β-actin standard symptomatic vs. asymptomatic 1.32±0.14 vs. 0.79±0.11, p<0.01). TUNEL staining revealed a higher proportion of apoptotic nuclei in the plaques of symptomatic patients compared to asymptomatic (68.25±3.61 vs. 33.46±4.46% of nuclei, p<0.01). Double immunofluorescence labeling revealed co-localization of HN with macrophages (both M1 and M2 polarization), smooth muscle cells, fibroblasts, and dendritic cells as well as with inflammatory markers MMP2 and MMP9.Conclusions
The study demonstrates a higher expression of HN in unstable carotid plaques that is localized to multiple cell types within the plaque. These data support the involvement of HN in atherosclerosis, possibly as an endogenous response to the inflammatory and apoptotic processes within the atheromatous plaque. 相似文献10.
Sílvia Collado Elisabeth Coll Carlos Nicolau Mercedes Pons Josep M Cruzado Julio Pascual Aleix Cases 《PloS one》2015,10(6)
Background
To evaluate the predictive value of carotid atherosclerotic disease (CAD) and intima-media thickness (IMT) on incident cardiovascular disease and mortality in hemodialysis patients.Methods
Multicenter, observational, prospective study including 110 patients, followed-up to 6 years. Carotid doppler ultrasonographic findings were classified in 4 degrees of severity: 1) IMT <0.9 mm, 2) IMT >0.9 mm, 3) carotid plaque with stenosis <50% and 4) plaque with stenosis >50%. The associations between IMT and CAD and cardiovascular events, total and cardiovascular mortality were assessed.Results
83% of the patients had atherosclerotic plaques (CAD degrees 3-4). During follow-up, 29.1% of patients experienced cardiovascular events, and 28.2% died, 38.7% of cardiovascular origin. The presence of plaques was associated with cardiovascular events (p = 0.03) while calcified plaques were associated with both cardiovascular events (p = 0.01), cardiovascular mortality (p = 0.03) and non-significantly with overall mortality (p = 0.08) in the survival analysis. Carotid IMT was not associated with outcomes. Cardiovascular events correlated with CAD severity (HR 2.27, 95% CI 1.13-4.54), age (HR 1.04, 1.01-1.06), previous cardiovascular disease (HR 1.75, 1.05-4.42), dyslipidemia (HR 2.25, 1.11-4.53), lipoprotein (a) (HR 1.01, 1.00-1.02), troponin I (HR 3.89, 1.07-14.18), fibrinogen levels (HR 1.38, 0.98-1.94) and antiplatelet therapy (HR 2.14, 1.04-4.4). In an age-adjusted multivariate model, cardiovascular events were independently associated with previous coronary artery disease (HR 3.29, 1.52-7.15) and lipoprotein (a) (HR 1.01, 1.00-1.02).Conclusions
The presence of carotid plaques and, especially, calcified plaques, are predictors of new cardiovascular events and cardiovascular mortality in hemodialysis patients, while IMT was not. The prognostic value of calcified plaques should be confirmed in future studies. 相似文献11.
Yasumi Uchida Yuko Maezawa Yasuto Uchida Nobuyuki Hiruta Ei Shimoyama Seiji Kawai 《PloS one》2013,8(2)
Objectives
Oxidized low-density lipoprotein (oxLDL) plays a key role in the formation of atherosclerotic plaques. However, its localization in human coronary arterial wall is not well understood. The present study was performed to visualize deposition sites and patterns of native oxLDL and their relation to plaque morphology in human coronary artery.Methods
Evans blue dye (EB) elicits a violet fluorescence by excitation at 345-nm and emission at 420-nm, and a reddish-brown fluorescence by excitation at 470-nm and emission at 515-nm characteristic of oxLDL only. Therefore, native oxLDL in excised human coronary artery were investigated by color fluorescent microscopy (CFM) using EB as a biomarker.Results
(1) By luminal surface scan with CFM, the % incidence of oxLDL in 38 normal segments, 41 white plaques and 32 yellow plaques that were classified by conventional angioscopy, was respectively 26, 44 and 94, indicating significantly (p<0.05) higher incidence in the latter than the former two groups. Distribution pattern was classified as patchy, diffuse and web-like. Web-like pattern was observed only in yellow plaques with necrotic core. (2) By transected surface scan, oxLDL deposited within superficial layer in normal segments and diffusely within both superficial and deep layers in white and yellow plaques. In yellow plaques with necrotic core, oxLDL deposited not only in the marginal zone of the necrotic core but also in the fibrous cap.Conclusion
Taken into consideration of the well-known process of coronary plaque growth, the results suggest that oxLDL begins to deposit in human coronary artery wall before plaque formation and increasingly deposits with plaque growth, exhibiting different deposition sites and patterns depending on morphological changes. 相似文献12.
Levula M Oksala N Airla N Zeitlin R Salenius JP Järvinen O Venermo M Partio T Saarinen J Somppi T Suominen V Virkkunen J Hautalahti J Laaksonen R Kähönen M Mennander A Kytömäki L Soini JT Parkkinen J Pelto-Huikko M Lehtimäki T 《PloS one》2012,7(4):e33787
Background
Atherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed.Methodology/Principal Findings
We characterized the genes generally involved in human advanced atherosclerotic (AHA type V–VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non-atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value <0.05), 235 genes were up-regulated and 68 genes down-regulated in the carotid plaques, 242 genes up-regulated and 116 down-regulated in the femoral plaques and 256 genes up-regulated and 49 genes down-regulated in the aortic plaques. Nine genes were found to be specifically induced predominantly in aortic plaques, e.g., lactoferrin, and three genes in femoral plaques, e.g., chondroadherin, whereas no gene was found to be specific for carotid plaques. In pathway analysis, a total of 28 pathways or gene sets were found to be significantly dysregulated in atherosclerotic plaques (false discovery rate [FDR] <0.25).Conclusions
This study describes comprehensively the gene expression changes that generally prevail in human atherosclerotic plaques. In addition, site specific genes induced only in femoral or aortic plaques were found, reflecting that atherosclerotic process has unique features in different vascular beds. 相似文献13.
Azhar Abbas P?l Aukrust David Russell Kirsten Krohg-S?rensen Trine Alm?s Dorte Bundgaard Vigdis Bjerkeli Ellen Lund Sagen Annika E. Michelsen Tuva B. Dahl Sverre Holm Thor Ueland Mona Skjelland Bente Halvorsen 《PloS one》2014,9(1)
Background
Atherosclerosis is a major cause of cerebrovascular disease. Matrix metalloproteinases (MMPs) play an important role in matrix degradation within the atherosclerotic lesion leading to plaque destabilization and ischemic stroke. We hypothesized that MMP-7 could be involved in this process.Methods
Plasma levels of MMP-7 were measured in 182 consecutive patients with moderate (50–69%) or severe (≥70%) internal carotid artery stenosis, and in 23 healthy controls. The mRNA levels of MMP-7 were measured in atherosclerotic carotid plaques with different symptomatology, and based on its localization to macrophages, the in vitro regulation of MMP-7 in primary monocytes was examined.Results
Our major findings were (i) Patients with carotid atherosclerosis had markedly increased plasma levels of MMP-7 compared to healthy controls, with particularly high levels in patients with recent symptoms (i.e., within the last 2 months). (ii) A similar pattern was found within carotid plaques with markedly higher mRNA levels of MMP-7 than in non-atherosclerotic vessels. Particularly high protein levels of MMP-7 levels were found in those with the most recent symptoms. (iii) Immunhistochemistry showed that MMP-7 was localized to macrophages, and in vitro studies in primary monocytes showed that the inflammatory cytokine tumor necrosis factor-α in combination with hypoxia and oxidized LDL markedly increased MMP-7 expression. (iv) During the follow-up of patients with carotid atherosclerosis, high plasma levels of MMP-7 were independently associated with total mortality.Conclusion
Our findings suggest that MMP-7 could contribute to plaque instability in carotid atherosclerosis, potentially involving macrophage-related mechanisms. 相似文献14.
Bert Rutten Claudia Tersteeg Joyce E. P. Vrijenhoek Thijs C. van Holten Ellen H. A. M. Elsenberg Elske M. Mak-Nienhuis Gert Jan de Borst J. Wouter Jukema Nico H. J. Pijls Johannes Waltenberger Anton Jan van Zonneveld Frans L. Moll Elizabeth McClellan Andrew Stubbs Gerard Pasterkamp Imo Hoefer Philip G. de Groot Mark Roest 《PloS one》2014,9(8)
Objective
Platelet reactivity, platelet binding to monocytes and monocyte infiltration play a detrimental role in atherosclerotic plaque progression. We investigated whether platelet reactivity was associated with levels of circulating platelet-monocyte complexes (PMCs) and macrophages in human atherosclerotic carotid plaques.Methods
Platelet reactivity was determined by measuring platelet P-selectin expression after platelet stimulation with increasing concentrations of adenosine diphosphate (ADP), in two independent cohorts: the Circulating Cells cohort (n = 244) and the Athero-Express cohort (n = 91). Levels of PMCs were assessed by flow cytometry in blood samples of patients who were scheduled for percutaneous coronary intervention (Circulating Cells cohort). Monocyte infiltration was semi-quantitatively determined by histological examination of atherosclerotic carotid plaques collected during carotid endarterectomy (Athero-Express cohort).Results
We found increased platelet reactivity in patients with high PMCs as compared to patients with low PMCs (median (interquartile range): 4153 (1585–11267) area under the curve (AUC) vs. 9633 (3580–21565) AUC, P<0.001). Also, we observed increased platelet reactivity in patients with high macrophage levels in atherosclerotic plaques as compared to patients with low macrophage levels in atherosclerotic plaques (mean±SD; 8969±3485 AUC vs. 7020±3442 AUC, P = 0.02). All associations remained significant after adjustment for age, sex and use of drugs against platelet activation.Conclusion
Platelet reactivity towards ADP is associated with levels of PMCs and macrophages in human atherosclerotic carotid plaques. 相似文献15.
Stephanie Maiwald Suthesh Sivapalaratnam Mahdi M. Motazacker Julian C. van Capelleveen Ilze Bot Saskia C. de Jager Miranda van Eck Jennifer Jolley Johan Kuiper Jonathon Stephens Cornelius A. Albers C. Ruben Vosmeer Heleen Kruize Daan P. Geerke Allard C. van der Wal Chris M. van der Loos John J. P. Kastelein Mieke D. Trip Willem H. Ouwehand Geesje M. Dallinga-Thie G. Kees Hovingh 《PloS one》2014,9(5)
Aims
Genetic factors explain a proportion of the inter-individual variation in the risk for atherosclerotic events, but the genetic basis of atherosclerosis and atherothrombosis in families with Mendelian forms of premature atherosclerosis is incompletely understood. We set out to unravel the molecular pathology in a large kindred with an autosomal dominant inherited form of premature atherosclerosis.Methods and Results
Parametric linkage analysis was performed in a pedigree comprising 4 generations, of which a total of 11 members suffered from premature vascular events. A parametric LOD-score of 3.31 was observed for a 4.4 Mb interval on chromosome 12. Upon sequencing, a non-synonymous variant in KERA (c.920C>G; p.Ser307Cys) was identified. The variant was absent from nearly 28,000 individuals, including 2,571 patients with premature atherosclerosis. KERA, a proteoglycan protein, was expressed in lipid-rich areas of human atherosclerotic lesions, but not in healthy arterial specimens. Moreover, KERA expression in plaques was significantly associated with plaque size in a carotid-collar Apoe−/− mice (r2 = 0.69; p<0.0001).Conclusion
A rare variant in KERA was identified in a large kindred with premature atherosclerosis. The identification of KERA in atherosclerotic plaque specimen in humans and mice lends support to its potential role in atherosclerosis. 相似文献16.
Background
Few studies reported the associations between decreased glomerular filtration rate (GFR) and mortality, coronary heart disease (CHD), and stroke in hypertensive patients. We aim to assess the associations between GFR and mortality, CHD, and stroke in hypertensive patients and to evaluate whether low GFR can improve the prediction of these outcomes in addition to conventional cardiovascular risk factors.Methods and Findings
This is an observational prospective study and 3,711 eligible hypertensive patients aged ≥5 years from rural areas of China were used for the present analysis. The associations between eGFR and outcomes, followed by a median of 4.9 years, were evaluated using Cox proportional hazards models adjusting for other potential confounders. Low eGFR was independently associated with risk of all-cause mortality, cardiovascular mortality, and incident stroke [multivariable adjusted hazard ratios (95% confidence intervals) for eGFR <60 ml/min/1.73 m2 relative to eGFR ≥90 ml/min/1.73 m2 were 1.824 (1.047–3.365), 2.371 (1.109–5.068), and 2.493 (1.193–5.212), respectively]. We found no independent association between eGFR and the risk of CHD. For 4-year all-cause and cardiovascular mortality, integrated discrimination improvement (IDI) was positive when eGFR were added to traditional risk factors (1.51%, P = 0.016, and 1.99%, P = 0.017, respectively). For stroke and CHD events, net reclassification improvements (NRI) were 5.9% (P = 0.012) and 1.8% (P = 0.083) for eGFR, respectively.Conclusions
We have established an inversely independent association between eGFR and all-cause mortality, cardiovascular mortality, and stroke in hypertensive patients in rural areas of China. Further, addition of eGFR significantly improved the prediction of 4-year mortality and stroke over and above that of conventional risk factors. We recommend that eGFR be incorporated into prognostic assessment for patients with hypertension in rural areas of China.Limitations
We did not have sufficient information on atrial fibrillation to control for the potential covariate. These associations should be further confirmed in future. 相似文献17.
Wagner Serra e Silva Filho Renato C. V. Casarin Eduardo L. Nicolela Junior Humberto M. Passos Ant?nio W. Sallum Reginaldo B. Gon?alves 《PloS one》2014,9(10)
Background and Objective
The immune and infectious alterations occurring in periodontitis have been shown to alter the development and severity of cardiovascular disease. One of these relationships is the translocation of oral bacteria to atheroma plaques, thereby promoting plaque development. Thus, the aim of this study was to assess, by 16s cloning and sequencing, the microbial diversity of the subgingival environment and atheroma plaques of patients concomitantly suffering from periodontitis and obstructive coronary artery atherosclerosis (OCAA).Methods
Subgingival biofilm and coronary balloons used in percutaneous transluminal coronary angioplasty were collected from 18 subjects presenting with generalized moderate to severe periodontitis and OCAA. DNA was extracted and the gene 16S was amplified, cloned and sequenced.Results
Significant differences in microbial diversity were observed between both environments. While subgingival samples mostly contained the phylum Firmicutes, in coronary balloons, Proteobacteria (p<0.05) was predominant. In addition, the most commonly detected genera in coronary balloons were Acinetobacter, Alloprevotella, Pseudomonas, Enterobacter, Sphingomonas and Moraxella, while in subgingival samples Porphyromonas, Filifactor, Veillonella, Aggregatibacter and Treponema (p<0.05) were found. Interestingly, 17 identical phylotypes were found in atheroma and subgingival samples, indicating possible bacterial translocation between periodontal pockets and coronary arteries.Conclusion
Periodontal pockets and atheromatous plaques of cardiovascular disease patients can present similarities in the microbial diversity. 相似文献18.
Hägg S Salehpour M Noori P Lundström J Possnert G Takolander R Konrad P Rosfors S Ruusalepp A Skogsberg J Tegnér J Björkegren J 《PloS one》2011,6(4):e18248
Background
The stability of atherosclerotic plaques determines the risk for rupture, which may lead to thrombus formation and potentially severe clinical complications such as myocardial infarction and stroke. Although the rate of plaque formation may be important for plaque stability, this process is not well understood. We took advantage of the atmospheric 14C-declination curve (a result of the atomic bomb tests in the 1950s and 1960s) to determine the average biological age of carotid plaques.Methodology/Principal Finding
The cores of carotid plaques were dissected from 29 well-characterized, symptomatic patients with carotid stenosis and analyzed for 14C content by accelerator mass spectrometry. The average plaque age (i.e. formation time) was 9.6±3.3 years. All but two plaques had formed within 5–15 years before surgery. Plaque age was not associated with the chronological ages of the patients but was inversely related to plasma insulin levels (p = 0.0014). Most plaques were echo-lucent rather than echo-rich (2.24±0.97, range 1–5). However, plaques in the lowest tercile of plaque age (most recently formed) were characterized by further instability with a higher content of lipids and macrophages (67.8±12.4 vs. 50.4±6.2, p = 0.00005; 57.6±26.1 vs. 39.8±25.7, p<0.0005, respectively), less collagen (45.3±6.1 vs. 51.1±9.8, p<0.05), and fewer smooth muscle cells (130±31 vs. 141±21, p<0.05) than plaques in the highest tercile. Microarray analysis of plaques in the lowest tercile also showed increased activity of genes involved in immune responses and oxidative phosphorylation.Conclusions/Significance
Our results show, for the first time, that plaque age, as judge by relative incorporation of 14C, can improve our understanding of carotid plaque stability and therefore risk for clinical complications. Our results also suggest that levels of plasma insulin might be involved in determining carotid plaque age. 相似文献19.
MF Hughes O Saarela J Stritzke F Kee K Silander N Klopp J Kontto J Karvanen C Willenborg V Salomaa J Virtamo P Amouyel D Arveiler J Ferrières PG Wiklund J Baumert B Thorand P Diemert DA Trégouët C Hengstenberg A Peters A Evans W Koenig J Erdmann NJ Samani K Kuulasmaa H Schunkert 《PloS one》2012,7(7):e40922
Background
More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design.Methods
Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5–18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived.Results
Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50–59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events.Conclusions
Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men. 相似文献20.
Kirshberg S Izhar U Amir G Demma J Vernea F Beider K Shlomai Z Wald H Zamir G Shapira OM Peled A Wald O 《PloS one》2011,6(9):e24856