Generation Of Atherosclerosis Research Articles

Association of Cardiovascular Risk Factors with Carotid Intima Media Thickness in Patients with Rheumatoid Arthritis with Low Disease Activity Compared to Controls: A Cross-Sectional Study.

ObjectivesRheumatoid arthritis (RA) has been identified as an independent cardiovascular risk factor. The importance of risk factors such as hypertension and hyperlipidemia in the generation of atherosclerosis in RA patients is unclear. This study analyzed clinical parameters associated with carotid intima media thickness (cIMT) in patients with RA.MethodsSubjects with RA and healthy controls without RA, both without known cardiovascular disease, were included. Participants underwent a standard physical examination and laboratory measurements including a lipid profile. cIMT was measured semi-automatically by ultrasound.ResultsIn total 243 RA patients and 117 controls were included. The median RA disease duration was 7 years (IQR 2–14 years). The median DAS28 was 2.4 (IQR 1.6–3.2) and 114 (50.4%) of the RA patients were in remission. The presence of RA and cIMT were not associated (univariate analysis). Multivariable regression analysis showed that cIMT in RA patients was associated with age (B = 0.006, P<0.001) and systolic blood pressure (B = 0.003, P = 0.003). In controls, cIMT was associated with age (B = 0.006, P<0.001) and smoking (B = 0.097, P = 0.001).ConclusioncIMT values were similar between RA patients and controls. Hypertension was strongly associated with cIMT in RA patients. After adjustment, no association between cIMT and specific RA disease characteristics was found in this well treated RA cohort.

Meaning of the Oral Hygiene in Children, Due to Atherosclerosis Generation

Research focused on association between periodontal diseases and atherosclerosis has been substantial in recent years. It is now well known that chronic inflammation plays an important role in initiation and evolution of atherosclerosis. The bacterial plaque is a key pathology leading to periodontal inflammation. As reported by other authors, bacteria causing periodontal disease were found within the carotid arteries in adults, thus association between periodontal disease in childhood and peripheral vascular disease seem justifiable. The purpose of this study is to investigate the potential link between certain bacteria found in children with periodontal disease and the process of atherosclerosis in adults. Research was carried out in 97 children of which 58 aged between 6-14 comprised an experimental group, whereas 39 children aged of 6-13 comprised the control group. Based on physical examination, the oral hygiene in children of the experimental group was average or bad, while in children of the control group the oral hygiene was good. Blood samples and subgingival plaques were obtained to proceed with microbiological testing by PCR technique. The results of tests showed Aggregatibacter actinomycetemcomitans in 55% and Prevotella intermedia in 79% of children in the experimental group. Only 2 cases of Prevotella intermedia were detected in the control group, however, no cases of Porphyromnas gingivalis were found in either groups. Full blood count, serum homocysteine, CRP, fibrinogen and HDL cholesterol values were normal in both groups. Total cholesterol value was increased in 24,14% in the experimental group vs. 5,15% in the control group, thus increase of total serum cholesterol concentration in children with bad oral hygiene may by a risk factor of atherosclerosis.

Abstract 489: The Role of Hemodynamics in Modulating p120 and Kaiso Expression and Activity in Atherogenesis

Introduction. The generation of atherosclerosis has been shown to be a non-random process, with endothelial cells (ECs) in regions of disturbed hemodynamics developing an atheroprone (pro-inflammatory) phenotype. While a great deal of research has focused on hemodynamic regulation of EC phenotype, the mechanisms that mediate ECs’ response to local shear stress environment remain elusive. p120-catenin (p120) and its transcription factor binding partner Kaiso are expressed in ECs and possess a variety of functions that potentially contribute to the hemodynamic regulation of EC phenotype in atherosclerosis. Specifically, p120 has been shown to regulate adherens junction stability and regulate gene transcription through interaction with Kaiso. Hypothesis. We hypothesize hemodynamic forces modulate the activity of p120 and Kaiso in a manner that alters local endothelial susceptibility to atherogenesis. Methods. Atheroprone/protective hemodynamic profiles obtained by human carotid artery imaging were applied to human ECs in vitro . Protein/gene expression was then analyzed by Western blot, RT-PCR, and imaging. To determine Kaiso-dependent regulation of target gene expression, siRNAs were used to knockdown Kaiso expression. For in vivo validation, vasculature from Apolipoprotein E -/- mice was isolated, fixed, and stained. Results. In vitro, atheroprotective flow upregulates p120 expression and increases its junctional continuity and nuclear accumulation. There is a flow-dependent increase in Kaiso expression over time in both flow conditions, but p120/Kaiso interaction is increased under atheroprone flow. Kaiso knockdown under protective flow results in decreased expression of the anti-inflammatory genes eNOS (0.49 fold) and KLF2 (0.68 fold) and increased expression of the inflammatory marker VCAM (1.44 fold), suggesting a previously unknown anti-atherogenic function of Kaiso. In preliminary mouse studies, Kaiso is expressed in ECs overlying both healthy and diseased regions, as well as being highly expressed within the lesions. Conclusions. p120 and Kaiso expression are regulated in a flow-dependent manner and are potentially a mechanism by which hemodynamics modulate susceptibility to atherogenesis.

Preface to the Festschrift in Honor of Shu Chien’s 80th Birthday

When one examines all of the accomplishments of Shu Chien in his first 80 years, the number and scope of these are truly amazing. This volume focuses on Shu’s seminal impact on the rapidly growing field of ‘‘mechanobiology’’, but when looking over the more than 500 peer reviewed publications in his bibliography one can easily identify many other areas where Shu’s scientific contributions have provided the rich foundation. These include examples such as vascular physiology and the role of blood rheology in human pathologies including sickle cell anemia. Shu Chien has also made tremendous contributions to the development and federal funding of the biological sciences and biomedical engineering. He has served as President of the American Physiological Society, the Federation of American Societies for Experimental Biology (FASEB), the American Institute of Medical and Biological Engineering (AIMBE), and the Biomedical Engineering Society. While President of AIMBE, Shu was instrumental in getting the National Institute of Biomedical Imaging and Bioengineering established within the National Institutes of Health. He has the stature, personality, and integrity to work exceptionally well within the political systems of federal funding agencies and to make everyone feel they won (while in reality Shu’s point of view prevailed). In recognition of all of his achievements, Shu has been elected to the Institute of Medicine, the National Academy of Engineering, the National Academy of Sciences, the Academia Sinica, and as a foreign member of the Chinese Academy of Sciences. Shu Chien was one of the first to recognize the important coupling between cell biology and biomechanics. His early series of papers in Science in 1967 with Gregersen demonstrated the importance of cell membrane properties and intracellular structures on the ability of red cells to traverse small pores. These were followed by several decades of investigations with long time collaborators Richard Skalak and Shelly Weinbaum that probed the biomechanical basis for leukocyte rheology and the generation of atherosclerosis and other vascular pathologies. More recently Shu has taken advantage of the rapid advances in molecular biology, genomics, systems biology, and proteomics to further our understanding of the detailed interacting pathways of mechanotransduction in endothelial cells, osteoclast-like cells and progenitor cells. As an example, in a series of recent papers in the Proceedings of the National Academy of Sciences USA in 2010 and 2011, Shu has probed the role of specific microRNAs in flow regulation of endothelial cell biology. We are getting very close to a real understanding of the molecular basis of mechanotransduction and the role of these pathways in human physiology and pathophysiology. The papers in this Volume demonstrate the range of important problems in human health that are regulated to a large extent by mechanobiology. The authors are colleagues of Shu, many of whom were his students and fellows. With each decade, Shu seems to accelerate the pace of his research and contributions. We can hardly wait to read the next series of papers coming from his group. Our best wishes to you and your wonderful wife K.C. on your 80th birthday and thank you for all of the scientific advances and professional leadership you have given us and will continue to give us. We are all in your debt.

Mannose binding lectin deficiency and triglyceride-rich lipoprotein metabolism in normolipidemic subjects

Mannose binding lectin (MBL) is one of the three initiators of complement activation and is therefore closely linked to inflammation. MBL deficiency has been associated with the generation of atherosclerosis. Since atherosclerosis, the complement system and postprandial lipemia are linked to inflammation, we studied postprandial lipoprotein metabolism in MBL deficiency. An observational study was carried out in 107 volunteers (21% MBL deficient). Classical cardiovascular risk factors were not different between subjects with and without MBL deficiency. Oral fat loading tests in 8 MBL deficient and 14 MBL sufficient subjects showed similar postprandial triglyceride, free fatty acid, hydroxybutyric acid and complement component 3 concentrations. MBL deficient subjects had 2.4 times lower postprandial Sf > 400 (chylomicron)–apoB48 concentrations, but in contrast a 2–3.5 times increased Sf 60–400 (VLDL1–TG) and Sf 60–400–apoB100 response. MBL activity was inversely related to the postprandial Sf 60–400–TG increase. Despite lower postprandial Sf > 400–apoB48 concentrations, MBL deficient subjects show an accumulation of Sf 60–400 lipoproteins.

CX 3 CR1 Deficiency Impairs Dendritic Cell Accumulation in Arterial Intima and Reduces Atherosclerotic Burden

Dendritic cells (DCs) have recently been found in atherosclerosis-predisposed regions of arteries and have been proposed to be causal in atherosclerosis. The chemokine receptor CX3CR1 is associated with arterial injury and atherosclerosis. We sought to determine whether a link exists between arterial DC accumulation, CX3CR1, and atherosclerosis. Mouse aortas were isolated and subjected to en face immunofluorescence analysis. We found that DCs were located predominantly in the intimal regions of arterial branch points and curvatures. Consistent with the increased accumulation of intimal DCs in aged and ApoE-/- aortas compared with young WT aortas (P=0.004 and 0.05, respectively), the incidence of atherosclerosis was 88.9% for aged WT and 100% for ApoE-/- mice compared with 0% for young WT mice. CX3CR1 was expressed on intimal DCs and DC numbers were decreased in CX3CR1-deficient aortas of young, aged, and ApoE-/- mice (P=0.0008, 0.013, and 0.0099). The reduced DC accumulation in CX3CR1-deficiency was also correlated with decreased atherosclerosis in these animals. The accumulation of intimal DC increases in aged and ApoE-/- aortas and correlates with the generation of atherosclerosis. CX3CR1-deficiency impairs the accumulation of DC in the aortic wall and markedly reduces the atherosclerotic burden.

CX3CR1 deficiency impairs the recruitment of dendritic cells to the arterial intima and reduces atherosclerotic burden (98.7)

Abstract Dendritic cells (DCs) have recently been found in atherosclerosis-predisposed regions of arteries and have been proposed to be causal in atherosclerosis. Our previous studies demonstrated that the chemokine receptor CX3CR1 is associated with arterial injury and atherosclerosis. Here we investigated if DC arterial accumulation was correlated with atherosclerosis and the mechanisms by which CX3CR1 may play a role. Mouse aortas were isolated and subjected to en face immunofluorescence analysis. We found that DCs were located predominantly in the intimal regions of arterial branch points and curvature. Consistent with the increased accumulation of intimal DCs in aging (2196.2±154) and ApoE−/−aortas (2697.5±214.3) compared to young WT aortas (904±79.5, p=0.004 and 0.05 respectively), the incidence of atherosclerosis was 88.9% for aging and 100% for ApoE−/− mice. CX3CR1 was expressed on intimal DCs, and DC numbers were decreased in CX3CR1−/− aortas (541.1±93.6 vs. 904±79.5 for WT, p=0.0008). CX3CR1-deficiency decreased atherosclerosis in aortas of ApoE−/−mice by 71% (0.41%±0.11% of aorta surface for ApoE−/−/CX3CR1−/− vs. 1.39%±0.02% for ApoE−/−, p=0.00006). Thus, the accumulation of intimal DC increases in aging and ApoE−/− aortas and correlates with the generation of atherosclerosis. CX3CR1-deficiency impairs the recruitment of DC to the aortic wall and markedly reduces the atherosclerotic burden.

Significance of hemodynamic effects on the generation of atherosclerosis

Atherosclerosis, which is a degenerative vascular disease, is believed to occur in the blood vessels due to deposition of cholesterol or low density hpoprotein (LDL) Atherosclerotic lumen narrowing causes reduction of blood flow due to hemodynamic features Several hypothetical theories related to the hemodynamic effects have been reported. high shear stress theory, low shear stress theory, high shear stress gradient theory, flow separation and turbulence theory, and high pressure theory However, no one theory clearly explains the causes of atherosclerosis The objective of the present study was to investigate the mechanism of the generation of atherosclerosis In the study, the database of Korean carotid and coronary arteries for geometrical and hemodynamic clinical data was established The atherosclerotic sites were predicted by the computer simulations. The results of the computer simulation were compared with the in vivo experimental results, and then the pathogenesis of atherosclerosis by using the clinical data and several hypothetical theories were investigated From the investigation, it was concluded carefully that the mechanism of the generation of atherosclerosis was related to the hemodynamic effects such as flow separation and oscillatory wall shear stress on the vessel walls

Geometry guided data averaging enables the interpretation of shear stress related plaque development in human coronary arteries

The average low shear stress (SS) is known to determine predilection sites of atherosclerotic plaques. However, as plaques encroach into the lumen and thereby increase SS, interpretation of patient-specific data obtained at one moment in time regarding the influence of SS in the generation of atherosclerosis is not straightforward. This study aims to compare two methods of data analysis for the aid of data interpretation: (a) point-wise analysis of the raw data, (b) global analysis: to assess the history related natural SS distribution in coronary arteries by averaging the data in the axial vessel direction. Normal to mildly diseased human coronary arteries were investigated applying a combination of 3-D reconstruction technique and computational fluid dynamics (CFD). Point-wise analysis relating local wall thickness to local SS showed in only 4% of the cases an inverse relationship. In contrast, averaging the data in the axial vessel direction, showed in 38% a significant inverse relation between wall thickness and SS, resulting in an average negative slope of −0.70±0.46mm/Pa. These data suggest that using a geometry guided way of data averaging may reveal history related effects of SS, which in part explains localization of atherosclerotic plaques.

Chlamydial infection and progression of carotid atherosclerosis in patients on regular haemodialysis.

Recent findings have suggested a possible contribution of chlamydial infection to the pathogenesis of atherosclerosis in the general population. However, the role that chlamydial antibody status plays in atherosclerosis generation in haemodialysis (HD) patients remains uncertain. We measured carotid artery intima medial thickness (IMT) over 4 years in 100 HD subjects (age: 58+/-10 years; time on HD: 13+/-7 years; male/female: 67/33) and examined potential associations between Chlamydia pneumoniae (Cp) antibody seropositivity and changes in carotid artery IMT. During 4 years, carotid artery IMT increased significantly from 0.62+/-0.13 to 0.73+/-0.12 mm (P< 0.01). IMT progression was significantly and positively correlated with age (r = 0.37, P<0.01), log-transformed C-reactive protein (CRP; r = 0.33, P<0.01) and log-transformed interleukin-6 (IL-6; r = 0.22, P<0.04), but inversely correlated with blood creatinine (r = -0.36, P<0.01) and albumin (r = -0.24, P<0.02). IMT increases were more prominent in patients positive for IgA antibodies (0.039+/- 0.022 mm/year, n = 52) compared with those without IgA antibodies (0.025+/-0.032 mm/year, n = 48) (P<0.01). IgA seropositivity did not accelerate IMT progression in patients with increased CRP (>0.11 mg/dl, n = 53), but significantly increased IMT to a greater extent in IgA-positive subjects than in IgA-negative subjects having lower CRP (</=0.11 mg/dl, n = 47) (0.017+/-0.024 vs 0.034+/- 0.021 mm/year; P = 0.01). Multivariate regression analysis revealed that serum creatinine, log-transformed CRP and IgA Cp seropositivity were independent risk factors for IMT progression (P<0.01). In contrast, IgG Cp antibody did not affect IMT progression or carotid plaque formation. IMT progression is associated with inflammation and malnutrition. In addition, persistent chlamydial infection may be associated with IMT progression, but only in HD patients having low blood CRP.

Papain-hydrolyzed pork meat reduces serum cholesterol level and premature atherosclerosis in dietary-induced hypercholesterolemic rabbits.

The effects of the low-molecular-weight fraction of papain-hydrolyzed pork meat (LMF) on the plasma cholesterol level and the generation of atherosclerosis were studied in rabbits fed a cholesterol-enriched diet. In LMF-fed rabbits, the plasma and liver cholesterol concentrations were both significantly lower (p<0.0 1) than in rabbits fed untreated pork meat (PM). Similarly, the cholesterol concentrations of the chylomicron and VLDL fractions were significantly lower in LMF-fed rabbits than in rabbits fed PM. Deposition of lipid in transverse sections of the aortic arch was significantly less in rabbits fed LMF than in those fed PM. Electron microscopic studies revealed preventive effects against premature atherosclerotic lesions in the aorta of rabbits fed LME These results indicate that LMF has a hypocholesterolemic action and preventive effects against premature atherosclerosis.

Fibrinogen deficiency reduces vascular accumulation of apolipoprotein(a) and development of atherosclerosis in apolipoprotein(a) transgenic mice.

To test directly whether fibrin(ogen) is a key binding site for apolipoprotein(a) [apo(a)] in vessel walls, apo(a) transgenic mice and fibrinogen knockout mice were crossed to generate fibrin(ogen)-deficient apo(a) transgenic mice and control mice. In the vessel wall of apo(a) transgenic mice, fibrin(ogen) deposition was found to be essentially colocalized with focal apo(a) deposition and fatty-streak type atherosclerotic lesions. Fibrinogen deficiency in apo(a) transgenic mice decreased the average accumulation of apo(a) in vessel walls by 78% and the average lesion (fatty streak type) development by 81%. Fibrinogen deficiency in wild-type mice did not significantly reduce lesion development. Our results suggest that fibrin(ogen) provides one of the major sites to which apo(a) binds to the vessel wall and participates in the generation of atherosclerosis.

Do ACE inhibitors modulate atherosclerosis?

The ACE/angiotensin II/bradykinin system is inextricably linked to some of the processes that contribute to the generation of atherosclerosis at genetic, molecular, biochemical and pharmacological levels. There is a large body of laboratory-derived experimental data that suggests that inhibition of ACE activity has antiproliferative, anti-inflammatory and vasodilatory effects that can modulate this atherosclerotic process from the earliest form of endothelial dysfunction, to delay of lesion formation in primary atherosclerosis or in myointimal proliferation after PTCA. The clinical evidence for these potential benefits is so far sparse. There are several possible explanations for these discrepancies. Firstly, the role of the ACE/bradykinin/angiotensin II system in the local vascular response to either the primary process of atherosclerosis, or to the injury induced by balloon angioplasty is likely to vary between species and models. Secondly, there is a tendency to ensure the presence of ACE inhibitor in high concentration before or during the vascular insult in animal models, whereas this has not been the case in the clinical studies of post-PTCA restenosis. Whilst the animal studies therefore offer potentially valuable insights into the mechanics of local vascular response, the ability of ACE inhibitors to interfere with such mechanisms now needs to be tested in clinical trials that are each aimed at precisely answering specific questions. The experimental data so far lend considerable support to the fact that drugs acting solely by interference with the angiotensin II-receptor complex are at a theoretical disadvantage, when compared with ACE inhibitors, since the former would be expected to have little effect on bradykinin-mediated activities. To the established benefits of ACE inhibitors in left ventricular dysfunction, and the interesting possibility that there may be an anti-ischaemic action in these circumstances, we may add the promise of the TREND study. In the coming years, there is an urgent requirement for intensive investigation into the ability of ACE inhibitors to modulate the various stages of the atherosclerotic spectrum. For now though, the jury remains out.

Viscous boundary layers in reversing flow

The viscous boundary layer on a finite flat plate in a stream which reverses its direction once (at t = 0) is analysed using an improved version of the approximate method described earlier (Pedley 1975). Long before reversal (t &lt; −t1), the flow at a point on the plate will be quasi-steady; long after reversal (t &gt; t2), the flow will again be quasi-steady, but with the leading edge at the other end of the plate. In between (−t1 &lt; t &lt; t2) the flow is governed approximately by the diffusion equation, and we choose a simple solution of that equation which ensures that the displacement thickness of the boundary layer remains constant at t = −t1. The results of the theory, in the form of the wall shear rate at a point as a function of time, are given both for a uniformly decelerating stream, and for a sinusoidally oscillating stream which reverses its direction twice every cycle. The theory is further modified to cover streams which do not reverse, but for which the quasi-steady solution breaks down because the velocity becomes very small. The analysis is also applied to predict the wall shear rate at the entrance to a straight pipe when the core velocity varies with time as in a dog's aorta. The results show positive and negative peak values of shear very much larger than the mean. They suggest that, if wall shear is implicated in the generation of atherosclerosis because it alters the permeability of the wall to large molecules, then an appropriate index of wall shear at a point is more likely to be the r.m.s. value than the mean.