Oxysterols and symptomatic versus asymptomatic human atherosclerotic plaque

Atherosclerosis is the most common cause of mortality in the Western world, contributing to about 50% of all deaths. Atherosclerosis is characterized by deposition of lipids onto the coronary or carotid arterial wall and formation of an atherosclerotic plaque. Atherosclerotic plaques are categorized into two groups: symptomatic and asymptomatic. The symptomatic plaques tend to be unstable and prone to rupture, and are associated with an increase in ischemic events. Oxysterols, products of cholesterol oxidation, are cytotoxic materials. Their level and type may be associated with plaque formation, development and stability. Oxysterols stimulate the formation of foam cells, advance atherosclerotic plaque progression, and contribute to plaque vulnerability and instability due to their cytotoxicity and their ability to induce cell apoptosis. Studies indicate that plasma 7β-OH CH level can be used as a biomarker for detecting carotid and coronary artery disease. Further clinical studies are needed to evaluate the potential of oxysterols for use as biomarkers for plaque vulnerability and instability. The identification of biomarkers in the blood that can distinguish between symptomatic and asymptomatic plaques remains an unresolved issue.     

Differential effects of insulin-like growth factor-1 and atheroma-associated cytokines on cell proliferation and apoptosis in plaque smooth muscle cells of symptomatic and asymptomatic patients with carotid stenosis

Morbidity and mortality from atherosclerosis are associated with complicated atherosclerotic lesions due to plaque rupture, which is regulated by a balance between proliferation and apoptosis of vascular smooth muscle cells (VSMC). We examined insulin-like growth factor-1 (IGF-1)-induced survival of plaque VSMC from carotid endarterectomy specimens and investigated the underlying cellular mechanisms in the presence and absence of IL-12 and IFN-gamma. Both IL-12 and IFN-gamma were strongly expressed in symptomatic atherosclerotic plaques as compared with asymptomatic plaques. In asymptomatic plaque VSMC, IGF-1 induced the survival and proliferation of VSMC and accelerated VSMC into S-phase. IL-12 or IFN-gamma inhibited proliferation and VSMC were arrested in the G0-G1 phase. IGF-1 markedly inhibited the expression of p27(kip) and p21(cip) and significantly induced cyclin E and cyclin D. Both cytokines by themselves increased the expression of p27(kip) and p21(cip) and inhibited cyclin E and cyclin D. On the contrary, in symptomatic VSMC there was already increased apoptosis of VSMC and there was no significant effect of IGF-1 or inflammatory cytokines on proliferation, apoptosis or the expression of p27(kip) and p21(cip) and cyclin D and E. These data suggest that IGF-1 is more potent in inducing the survival of VSMC from the endarterectomy specimens of asymptomatic patients as compared to that of symptomatic subjects and cytokines associated with atheroma lesions decrease the activity of IGF-1-induced survival in the VSMC of asymptomatic plaques. The different expression and activity of cell cycle regulatory proteins could be responsible for apoptosis of VSMC and destabilization of atherosclerotic plaques.     

Age-related model for estimating the symptomatic and asymptomatic transmissibility of COVID-19 patients

Estimation of age-dependent transmissibility of COVID-19 patients is critical for effective policymaking. Although the transmissibility of symptomatic cases has been extensively studied, asymptomatic infection is understudied due to limited data. Using a dataset with reliably distinguished symptomatic and asymptomatic statuses of COVID-19 cases, we propose an ordinary differential equation model that considers age-dependent transmissibility in transmission dynamics. Under a Bayesian framework, multi-source information is synthesized in our model for identifying transmissibility. A shrinkage prior among age groups is also adopted to improve the estimation behavior of transmissibility from age-structured data. The added values of accounting for age-dependent transmissibility are further evaluated through simulation studies. In real-data analysis, we compare our approach with two basic models using the deviance information criterion (DIC) and its extension. We find that the proposed model is more flexible for our epidemic data. Our results also suggest that the transmissibility of asymptomatic infections is significantly lower (on average, 76.45% with a credible interval (27.38%, 88.65%)) than that of symptomatic cases. In both symptomatic and asymptomatic patients, the transmissibility mainly increases with age. Patients older than 30 years are more likely to develop symptoms with higher transmissibility. We also find that the transmission burden of asymptomatic cases is lower than that of symptomatic patients.     

Carotenoids and asymptomatic carotid atherosclerosis

High plasma concentrations of lycopene and beta-carotene have been associated with reduced prevalence of cardiovascular disease. The aim of this study is to compare plasma concentrations of these carotenoids in subjects with or without ultrasonic evidence of asymptomatic carotid atherosclerosis. One hundred and sixty-five subjects underwent physical examination and ultrasonic measurement of common carotid artery intima-media thickness. Analysis of variance and logistic regression methods were used to determine whether differences existed between participants with or without ultrasonic evidence of asymptomatic carotid atherosclerosis. Of the 165 participants, 80 exhibited evidence of carotid atherosclerosis (carotid intima-media thickness>0.8 mm), while 85 did not (carotid intima-media thickness>0.8 mm), while 85 did not (carotid intima-media thickness<0.8 mm). Participants with ultrasonic evidence of carotid atherosclerosis exhibited significantly greater body mass index, significantly higher serum concentrations of total cholesterol, LDL-associated cholesterol and triglycerides, and significantly higher plasma concentrations of uric acid, C-reactive protein and fibrinogen. In contrast, participants with ultrasonic evidence of carotid atherosclerosis exhibited significantly lower plasma concentrations of lycopene and beta-carotene. These results suggest that lycopene and beta-carotene may play important roles in delaying the development of the early asymptomatic stage of carotid atherosclerosis. Encouraging adequate intakes of antioxidant carotenoids may provide an important public health service.     

Markers of inflammation collocate with increased wall stress in human coronary arterial plaque

In this study, we hypothesized that spatial relationships exist between the local mechanical environment and inflammatory marker expression in atherosclerotic plaques, and that these relationships are plaque-progression dependent. Histologic cross-sections were collected at regular intervals along the length of diseased human coronary arteries and classified as early, intermediate, advanced, or mature based on their morphological features. For each cross-section, the spatial distribution of stress was determined using a 2D heterogeneous finite element model, and the corresponding distribution of selected inflammatory markers (macrophages, matrix metalloproteinase-1 [MMP-1], and nuclear factor-kappa B [NF-κB]) were determined immunohistochemically. We found a monotonic spatial relationship between mechanical stress and activated NF-κB that was consistent in all stages of plaque progression. We also identified progression-dependent relationships between stress and both macrophage presence and MMP-1 expression. These findings add to our understanding of the role of mechanical stress in stimulating the inflammatory response, and help explain how mechanical factors may regulate complex biological changes in remodeling.     

Protease activity in Giardia duodenalis trophozoites of axenic strains isolated from symptomatic and asymptomatic patients

We have examined by gelatin-SDS-PAGE the protease activity in cell lysates of Giardia duodenalis trophozoites of two axenic strains isolated in Brazil from a symptomatic patient (BTU-11) and an asymptomatic carrier (BTU-10), and the reference strain Portland 1 (P1). The proteolysis band patterns showed differences among strains isolated from asymptomatic and symptomatic individuals. The lysate of the strain BTU-10, showed only five hydrolysis bands, while a greater number of bands (10-11 bands) was seen in strains BTU-11 and P1. The protease activity in all lysates was inhibited by cysteine (E-64 and iodoacetamide) and serine proteases (TPCK and TLCK) inhibitors, but not by PMSF and EDTA. In general, the results revealed protease activities in G. duodenalis trophozoites of Brazilian axenic strains and the predominance of cysteine proteinases. It should be stressed the inter-strain difference in hydrolysis band patterns observed between strains isolated from symptomatic patients and the strain obtained from an asymptomatic carrier.     

Immunoglobulin allotypes in symptomatic and asymptomatic pigeon breeders.

Comparison of immunoglobulin allotypes were studied in a group of patients with pigeon breeder's disease and in similarly exposed by asymptomatic individuals. The study revealed that the disease is not correlated with immunoglobulin allotypes. Furthermore, the phenotype Gm(a;g) was not associated with high levels of serum antibodies to pigeon antigens.     

Lipids and carotid plaque in the Northern Manhattan Study (NOMAS)

Background

Heterogeneity in B-type natriuretic peptide (BNP) levels, especially among individuals with acute heart failure with normal left ventricular ejection fraction (HFNEF), can cause confusion in interpreting results. We investigated the characteristics of cases of acute HFNEF with only modestly elevated BNP.

Methods

One hundred forty-two patients with acute or acute exacerbation of chronic HFNEF were divided into two groups by BNP level: BNP < 100 pg/ml (NB group, n = 45) and BNP ≥ 100 pg/ml (B group, n = 97). We compared clinical findings, echocardiography results, and neurohormonal factors between these two groups.

Results

In the NB group, a history of open-heart surgery (OHS) was more frequent (71% vs. 22%, p < 0.0001) and hypertension was less frequent (p = 0.0005). Left atrial diameter (LAd) was higher (p = 0.0026), while interventricular septal thickness, posterior wall thickness, relative wall thickness, left ventricular mass index were lower (p = 0.0005, p = 0.0225, p = 0.0114, p = 0.0051, respectively) in the NB group. In patients with HFNEF, a history of OHS remained an independent predictor of BNP level (< 100 pg/ml) after adjustment for hypertension, age, LAd, and interventricular septal thickness (odds ratio 3.6, p = 0.0252).

Conclusion

We found associations between acute HFNEF with less elevated BNP and a history of OHS. In a patient suspected of HFNEF, a history of OHS is considered diagnostic evidence of presence of diastolic heart failure when plasma levels of BNP are less elevated.     

Common carotid wall shear stress and carotid atherosclerosis in end-stage renal disease patients

Decrease of arterial wall shear stress (WSS) is associated with higher probability of atherosclerotic plaque development in many disease conditions. End-stage renal diseases (ESRD) patients suffer from vascular disease frequently, but its nature differs from general population. This study was aimed at proving an association between common carotid wall shear stress and the presence of carotid bifurcation plaques in a group of ESRD patients. ESRD subjects, planned for the creation of a dialysis access and therapy were included. Wall shear rate (WSR) was used as a surrogate of WSS and was analyzed in the common carotid arteries by duplex ultrasonography. Intima media thickness (IMT) was measured at the same site. The presence/absence of carotid bifurcation plaques was recorded. The endothelial function was estimated by the levels of von Willebrand factor (vWf). 35 ESRD patients were included (19 females, 17 diabetics). Atherosclerotic plaque was present in 53 % of bifurcations. Wall shear rate was lower in arteries with plaques (349+/-148 vs. 506+/-206 s(-1), p=0.005) and was directly related to the height of IMT and inversely to the activity of vWf (r= -0.65, p=0.016). Lower wall shear rate in the common carotid arteries is linked to the endothelial dysfunction and to the presence of atherosclerotic plaques in carotid bifurcations in ESRD subjects. Faster arterial dilatation may facilitate this process in ESRD subjects.     

双歧杆菌三联活菌胶囊对动脉粥样硬化患者血脂、颈动脉斑块和肠道菌群的影响

目的 探讨双歧杆菌三联活菌胶囊辅助治疗颈动脉粥样硬化患者及其对患者血脂、颈动脉斑块和肠道菌群的影响。方法 选择2017年1月至2017年10月在我院门诊治疗的颈动脉粥样硬化患者84例,随机分为观察组和对照组各42例。对照组患者均予以瑞舒伐他汀（10 mg/次,1次/d）+肠溶阿司匹林片（100 mg/次,1次/d）口服治疗,并根据病情酌情给予降压、降糖等治疗。观察组患者在对照组基础上加用双歧杆菌三联活菌胶囊630 mg/次,3次/d,温水口服。两组患者疗程均为6个月。观察两组患者治疗前后血脂指标[总胆固醇（TC）、甘油三脂（TG）、高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C）]水平、颈动脉斑块指标[颈动脉斑块内‒中膜厚度（IMT）及斑块面积）及肠道菌群数量（双歧杆菌、乳杆菌和大肠埃希菌）的变化。结果 治疗6个月后,两组患者TC、TG和LDL-C水平较治疗前均明显下降,HDL-C水平较治疗前均有明显上升（P<0.05）,且观察组变化幅度较对照组更明显（P<0.05）;两组患者颈动脉IMT及斑块面积较治疗前均明显下降（P<0.05）,且观察组下降幅度幅度较对照组更明显（P<0.05）;两组患者肠道双歧杆菌和乳杆菌数量较治疗前明显上升,大肠埃希菌数量较治疗前明显下降（P<0.05或P<0.01）,且观察组变化幅度幅度较对照组更明显（P<0.05）。结论 双歧杆菌三联活菌胶囊对颈动脉粥样硬化患者具有良好的协同降脂作用,并能延缓和逆转颈动脉粥样硬化,降低IMT及斑块面积。其作用机制可能与其能纠正肠道菌群紊乱,增加肠道有益菌数量,减少致病菌数量密切相关。     

Relevant sonographic parameters of a painful shoulder in symptomatic dialyzed patients versus asymptomatic dialyzed and healthy volunteers

The aim of this study is to find dialysis relevant sonographic parameters of painful shoulder of the symptomatic dialyzed patients comparing them with parameters in asymptomatic dialyzed patients and healthy volunteers. Significant difference in all metric parameters (thickness of supraspinatus tendon, diameter of biceps tendon sheet and capsula-bone distance) were noticed between all groups and the symptomatic had the highest values. Asymptomatic had the higher values then volunteers. Inhomogenicity of the tendon and biceps tendon sheet effusion in the symptomatic patients were the most often occurred. Subdeltoid effusion, deposits and tendon rupture were found only in symptomatic patients. No difference in presence of calcifications between symptomatic and asymptomatic was found. Metric parameters are relevant and associated with dialysis, as well as biceps tendon effusion tendon inhomogenicity, deposits and subdeltoid effusion. Tendon ruptures are relatively rare and nonspecific.     

A negative correlation between human carotid atherosclerotic plaque progression and plaque wall stress: in vivo MRI-based 2D/3D FSI models

It is well accepted that atherosclerosis initiation and progression correlate positively with low and oscillating flow wall shear stresses (FSS). However, this mechanism cannot explain why advanced plaques continue to grow under elevated FSS conditions. In vivo magnetic resonance imaging (MRI)-based 2D/3D multi-component models with fluid-structure interactions (FSI, 3D only) for human carotid atherosclerotic plaques were introduced to quantify correlations between plaque progression measured by wall thickness increase (WTI) and plaque wall (structure) stress (PWS) conditions. A histologically validated multi-contrast MRI protocol was used to acquire multi-year in vivo MRI images. Our results using 2D models (200-700 data points/patient) indicated that 18 out of 21 patients studied showed significant negative correlation between WTI and PWS at time 2 (T2). The 95% confidence interval for the Pearson correlation coefficient is (-0.443,-0.246), p<0.0001. Our 3D FSI model supported the 2D correlation results and further indicated that combining both plaque structure stress and flow shear stress gave better approximation results (PWS, T2: R(2)=0.279; FSS, T1: R(2)=0.276; combining both: R(2)=0.637). These pilot studies suggest that both lower PWS and lower FSS may contribute to continued plaque progression and should be taken into consideration in future investigations of diseases related to atherosclerosis.     

Longitudinal MRI study on the natural history of carotid artery plaques in symptomatic patients

Purpose

To investigate the natural history of carotid atherosclerosis in patients who experienced a TIA or ischemic stroke.

Patients and Methods

Ninety-two TIA/stroke patients (57 men, mean age 67.7±9.8 years) with ipsilateral <70% carotid stenosis underwent multisequence MRI of the plaque ipsilateral to the symptomatic side at baseline and after one year. For each plaque, several parameters were assessed at both time points.

Results

Carotid lumen, wall and total vessel ( = carotid lumen and wall) volume did not significantly change. Forty-four patients had a plaque with a lipid-rich necrotic core (LRNC) at baseline, of which 34 also had a LRNC after one year. In three patients a LRNC appeared after one year. Thirty patients had a plaque with a thin and/or ruptured fibrous cap (FC) at both time points. In seven patients, FC status changed from thin and/or ruptured into thick and intact. In three patients, FC status changed from thick and intact into thin and/or ruptured. Twenty patients had intraplaque hemorrhage (IPH) at both time points. In four patients, IPH disappeared, whereas in three patients, new IPH appeared at follow-up.

Conclusion

In TIA/stroke patients, carotid plaque morphology does not significantly change over a one-year period. IPH and FC status change in a minority of patients.     

Maximal wall shear stress in arterial stenoses: application to the internal carotid arteries

Maximal wall shear stress (MWSS) in the convergent part of a stenosis is calculated by the interactive boundary-layer theory. A dimensional analysis of the problem shows that MWSS depends only on a few measurable parameters. A simple relationship between MWSS and these parameters is obtained, validated, and used to calculate the magnitude of MWSS in a carotid stenosis, as a function of the patency of the circle of Willis and the stenotic pattern. This demonstrates the huge effect of collateral pathways. Elevated MWSS are observed even in moderate stenoses, provided they are associated with a contralateral occlusion, a large anterior, and narrow posterior communicating arteries, suggesting a potential risk of embolus release in this configuration.     

Iron in arterial plaque: modifiable risk factor for atherosclerosis

It has been proposed that iron depletion protects against cardiovascular disease. There is increasing evidence that one mechanism for this protection may involve a reduction in iron levels within atherosclerotic plaque. Large increases in iron concentration are seen in human atherosclerotic lesions in comparison to levels in healthy arterial tissue. In animal models, depletion of lesion iron levels in vivo by phlebotomy, systemic iron chelation treatment or dietary iron restriction reduces lesion size and/or increases plaque stability. A number of factors associated with increased arterial disease or increased cardiovascular events is also associated with increased plaque iron. In rats, infusion of angiotensin II increases ferritin levels and arterial thickness which are reversed by treatment with the iron chelator deferoxamine. In humans, a polymorphism for haptoglobin associated with increased cardiovascular disease is also characterized by increased lesional iron. Heme oxygenase 1 (HO1) is an important component of the system for mobilization of iron from macrophages. Human HO1 promoter polymorphisms causing weaker upregulation of the enzyme are associated with increased cardiovascular disease and increased serum ferritin. Increased cardiovascular disease associated with inflammation may be in part caused by elevated hepcidin levels that promote retention of iron within plaque macrophages. Defective retention of iron within arterial macrophages in genetic hemochromatosis may explain why there is little evidence of increased atherosclerosis in this disorder despite systemic iron overload. The reviewed findings support the concept that arterial plaque iron is a modifiable risk factor for atherogenesis.     

Biomechanical correlates of symptomatic and asymptomatic neurophysiological impairment in high school football

Concussion is a growing public health issue in the United States, and chronic traumatic encephalopathy (CTE) is the chief long-term concern linked to repeated concussions. Recently, attention has shifted toward subconcussive blows and the role they may play in the development of CTE. We recruited a cohort of high school football players for two seasons of observation. Acceleration sensors were placed in the helmets, and all contact activity was monitored. Pre-season computer-based neuropsychological tests and functional magnetic resonance imaging (fMRI) tests were also obtained in order to assess cognitive and neurophysiological health. In-season follow-up scans were then obtained both from individuals who had sustained a clinically-diagnosed concussion and those who had not. These changes were then related through stepwise regression to history of blows recorded throughout the football season up to the date of the scan. In addition to those subjects who had sustained a concussion, a substantial portion of our cohort who did not sustain concussions showed significant neurophysiological changes. Stepwise regression indicated significant relationships between the number of blows sustained by a subject and the ensuing neurophysiological change. Our findings reinforce the hypothesis that the effects of repetitive blows to the head are cumulative and that repeated exposure to subconcussive blows is connected to pathologically altered neurophysiology.     

Antioxidant status and purine bases in carotid artery plaque

Free radical excess and oxidative stress are implicated in the formation and progression of atherosclerotic plaque through actions on susceptible vascular cells, such as by activating xanthine oxidase. Purine bases and other antioxidant compounds could play important protective roles in atherogenesis, as could nonenzymatic low molecular weight thiol defenses, not previously evaluated in carotid artery plaque. Therefore, we measured purine catabolites (hypoxanthine, xanthine, uric acid, allantoin) and antioxidant compounds (total sulphydryl groups, homocysteine, cysteine, and glutathione) in advanced carotid artery plaque and found a high ratio of allantoin to uric acid, suggesting a ongoing local oxidative stress.