OBJECTIVEAtherosclerosis is an inflammatory process that results in complex lesions or plaques that protrude into the arterial lumen. Carotid atherosclerotic plaque rupture, with distal atheromatous debris embolization, causes cerebrovascular events. This review aimed to explore research progress on the risk factors and outcomes of human carotid atherosclerotic plaques, and the molecular and cellular mechanisms of human carotid atherosclerotic plaque vulnerability for therapeutic intervention.

DATA SOURCESWe searched the PubMed database for recently published research articles up to June 2016, with the key words of "risk factors", "outcomes", "blood components", "molecular mechanisms", "cellular mechanisms", and "human carotid atherosclerotic plaques".

STUDY SELECTIONThe articles, regarding the latest developments related to the risk factors and outcomes, atherosclerotic plaque composition, blood components, and consequences of human carotid atherosclerotic plaques, and the molecular and cellular mechanisms of human carotid atherosclerotic plaque vulnerability for therapeutic intervention, were selected.

RESULTSThis review described the latest researches regarding the interactive effects of both traditional and novel risk factors for human carotid atherosclerotic plaques, novel insights into human carotid atherosclerotic plaque composition and blood components, and consequences of human carotid atherosclerotic plaque.

CONCLUSIONCarotid plaque biology and serologic biomarkers of vulnerability can be used to predict the risk of cerebrovascular events. Furthermore, plaque composition, rather than lesion burden, seems to most predict rupture and subsequent thrombosis.

Biomarkers ; blood ; Carotid Stenosis ; blood ; epidemiology ; metabolism ; pathology ; Humans ; Plaque, Atherosclerotic ; blood ; complications ; metabolism ; pathology ; Risk Factors

The effects of polarized-light therapy (PLT) on high-cholesterol diet (HCD)-induced hypercholesterolemia and atherosclerosis were investigated in comparison with that of lovastatin in rabbits. Hypercholesterolemia was induced by feeding male New Zealand white rabbits with 1% cholesterol in diet for 2 weeks and maintained with 0.5% cholesterol for 6 weeks, followed by normal diet for 2 weeks for recovery. Lovastatin (0.002% in diet) or daily 5-min or 20-min PLT on the outside surface of ears was started 2 weeks after induction of hypercholesterolemia. Hypercholesterolemic rabbits exhibited great increases in serum cholesterol and low-density lipoproteins (LDL) levels, and finally severe atheromatous plaques formation covering 57.5% of the arterial walls. Lovastatin markedly reduced both the cholesterol and LDL, but the reducing effect (47.5%) on atheroma formation was relatively low. By comparison, 5-min PLT preferentially decreased LDL, rather than cholesterol, and thereby potentially reduced the atheroma area to 42.2%. Notably, 20-min PLT was superior to lovastatin in reducing both the cholesterol and LDL levels as well as the atheromatous plaque formation (26.4%). In contrast to the increases in blood alanine transaminase and aspartate transaminase following lovastatin treatment, PLT did not cause hepatotoxicity. In addition, PLT decreased platelets and hematocrit level. The results indicate that PLT attenuates atherosclerosis not only by lowering blood cholesterol and LDL levels, but also by improving blood flow without adverse effects. Therefore, it is suggested that PLT could be a safe alternative therapy for the improvement of hypercholesterolemia and atherosclerosis.
Alanine Transaminase ; Aspartate Aminotransferases ; Atherosclerosis ; Blood Platelets ; Cholesterol ; Diet ; Ear ; Hematocrit ; Humans ; Hypercholesterolemia ; Lipoproteins, LDL ; Lovastatin ; Male ; Plaque, Atherosclerotic ; Rabbits

BACKGROUND AND OBJECTIVES: Studies on the stability of atheromatous plaques, as a determinant of the cause of complications, have been reported. Among the functional features of plaques related with vulnerability, inflammation has emerged as a leading cause of clinical presentation. The purpose of this study was to find the source of the inflammatory response in the patients with acute myocardial infarction (AMI). SUBJECTS AND METHODS: Patients with AMI, whose lesion of in either the left anterior descending artery (LAD group, n=13) or the right coronary artery (RCA group, n=11), were selected. The levels of interleukin-6 (IL-6) and P-selectin were measured in blood from the aortic root (A), great cardiac vein (G) and peripheral vein (V). The control group (n=15) included patients with either stable or variant angina. RESULTS: The levels of IL-6 were 4.77+/-6.0 (A), 11.32+/-7.8 (G) and 4.39+/-5.0 pg/mL (V) in the LAD group, and 3.64+/-2.1 (A), 6.05+/-4.9 (G) and 3.84+/-3.2 pg/mL (V) in the RCA group. Unrelated to the infarction related artery, the level of IL-6 in the great cardiac vein was significantly increased in patients with AMI. The percentages of platelet expressed P-selectin were 6.03+/-7.0 (A), 8.14+/-8.1 (G) and 8.83+/-7.9 (V) in the LAD group and 6.46+/-8.4 (A), 5.80+/-6.0 (G) and 5.91+/-6.9 (V) in the RCA group. CONCLUSION: These findings suggest that the generalized inflammatory response is activated across the coronary vascular bed in patients with AMI, regardless of the infarction related artery site. Therefore, systemic therapy, as well as local management for vulnerable plaque, would be required.
Arteries ; Blood Platelets* ; Coronary Vessels ; Humans ; Infarction ; Inflammation ; Interleukin-6 ; Myocardial Infarction* ; P-Selectin ; Plaque, Atherosclerotic ; Platelet Activation* ; Veins

Dendritic cells (DCs), first identified in 1973, have been shown to be the principal cells involved in antigen presentation to T cells, and are more potent in the presentation of antigen than B cells or macrophages. Atherosclerosis is a representative chronic vascular inflammatory disease in which various immune cells have been implicated in the formation of atherosclerotic plaque. Thus, the quantification and elucidation of activity of immune populations in atherosclerotic vessels are very important in understanding the pathogenesis of atherosclerosis. Several current studies demonstrate that DCs which exist in atherosclerotic lesion appear to play several important roles in atherosclerosis. This review summarizes current understandings on the function of DCs in atherosclerosis, and also suggests future directions for research of DC function in inflammatory atherosclerotic vascular disease.
Antigen Presentation ; Atherosclerosis ; B-Lymphocytes ; Blood Vessels ; Dendritic Cells ; Inflammation ; Macrophages ; Plaque, Atherosclerotic ; T-Lymphocytes ; Vascular Diseases

BACKGROUND: Inflammation is an important underlying mechanism in the pathogenesis of atherosclerosis, and an elevated resting heart rate underlies the process of atherosclerotic plaque formation. We hypothesized an association between resting heart rate and subclinical inflammation. METHODS: Resting heart rate was recorded at baseline in the KoGES-ARIRANG (Korean Genome and Epidemiology Study on Atherosclerosis Risk of Rural Areas in the Korean General Population) cohort study, and was then divided into quartiles. Subclinical inflammation was measured by white blood cell count and high-sensitivity C-reactive protein. We used progressively adjusted regression models with terms for muscle mass, body fat proportion, and adiponectin in the fully adjusted models. We examined inflammatory markers as both continuous and categorical variables, using the clinical cut point of the highest quartile of white blood cell count (≥7,900/mm³) and ≥3 mg/dL for high-sensitivity C-reactive protein. RESULTS: Participants had a mean age of 56.3±8.1 years and a mean resting heart rate of 71.4±10.7 beats/min; 39.1% were men. In a fully adjusted model, an increased resting heart rate was significantly associated with a higher white blood cell count and higher levels of high-sensitivity C-reactive protein in both continuous (P for trend <0.001) and categorical (P for trend <0.001) models. CONCLUSION: An increased resting heart rate is associated with a higher level of subclinical inflammation among healthy Korean people.
Adiponectin ; Adipose Tissue ; Atherosclerosis ; Blood Cell Count* ; Blood Cells* ; C-Reactive Protein ; Cohort Studies ; Epidemiology ; Genome ; Heart Rate* ; Heart* ; Humans ; Inflammation ; Leukocyte Count ; Leukocytes ; Male ; Plaque, Atherosclerotic

BACKGROUND/AIMS: Both the farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) play important roles in lipid metabolism and atherosclerosis. We investigated the interaction between FXR and PPARgamma. METHODS: Apolipoprotein E knockout (ApoE-/-) mice and FXR knockout (FXR-/-) mice were crossed to generate ApoE-/-FXR-/- mice. The mice were divided into ApoE-/-, ApoE-/-FXR-/-, and ApoE-/-FXR-/- + pioglitazone groups. All mice were fed a high-fat, high-cholesterol diet for 12 weeks. The ApoE-/-FXR-/- + pioglitazone group was also treated with pioglitazone, 20 mg/kg body weight. Body weight, blood glucose level, lipid profile, and liver enzyme levels were measured. To evaluate atherosclerotic lesions, the aorta was stained with Oil red O. RESULTS: There were no differences in body weight or blood glucose level among the three groups. The serum lipid concentration and liver enzyme levels increased in the ApoE-/-FXR-/- group compared with the ApoE-/- group (p < 0.01). The ApoE-/-FXR-/- + pioglitazone group had lower high-density lipoprotein (HDL) (55 +/- 4 vs. 28 +/- 2 mg/dL, p < 0.01) and low-density lipoprotein (LDL) (797 +/- 26 vs. 682 +/- 47 mg/dL, p = 0.04) cholesterol than the ApoE-/-FXR-/- group. The respective percentages of aortic atherosclerotic plaques in the ApoE-/-, ApoE-/-FXR-/-, and ApoE-/-FXR-/- + pioglitazone groups were 2.7 +/- 0.2%, 7.7 +/- 1.2%, and 18.6 +/- 1.0%. In ApoE-/-FXR-/- mice, the administration of pioglitazone significantly increased the number of atherosclerotic lesions (p = 0.02). CONCLUSIONS: Pioglitazone increased the number of atherosclerotic plaques in ApoE-/-FXR-/- mice. This suggests that when FXR is inhibited, the activation of PPARgamma can aggravate atherosclerosis.
Animals ; Aorta ; Apolipoproteins ; Atherosclerosis ; Blood Glucose ; Body Weight ; Cholesterol ; Diet ; Lipid Metabolism ; Lipoproteins ; Liver ; Mice ; Peroxisome Proliferator-Activated Receptors ; Peroxisomes ; Plaque, Atherosclerotic ; PPAR gamma ; Receptors, Cytoplasmic and Nuclear ; Thiazolidinediones

OBJECTIVETo investigate the pathologies of aortic root atherosclerotic lesion in uremic apoE-/- mice and explore the effect of serum from patients with chronic renal insufficiency (CRI) and the uremic toxin, indoxyl sulfate (IS), on the expression of cholesterol transporting receptors and lipid accumulation in macrophages in vitro.

METHODSThe uremic apoE-/- mouse model was established by surgical operation. Frozen sections of the aortic root were collected from uremic apoE-/- mice, sham-operated apoE-/- mice and C57BL/6J mice and stained with oil red O to calculate the relative area of atherosclerotic plaque. Murine macrophage RAW264.7 cell line was treated for 12 h with different concentrations of IS or serum samples from CRI patients and healthy individuals, and the mRNA expressions of cholesterol transporting receptors (SR-A1, CD36, ABCA1, ABCG1 and SR-B1) were detected. After treatment for 24 h, the cells were induced into foam cells to determine lipid contents using oil red O staining.

RESULTSThe relative area of the atherosclerotic plaques in the aortic root increased significantly in uremic apoE-/- mice compared with that in sham-operated apoE-/- mice. CRI serum (5%) and IS (250 µmol/L) obviously increased the mRNA expression of CD36 and lipid accumulation in the macrophages, but did not affect the mRNA expression of other cholesterol transporting receptors.

CONCLUSIONCRI can accelerate the progression of atherosclerosis through the mechanism that IS in CRI serum promotes lipid accumulation in macrophages by enhancing the mRNA expression of CD36, which contributes to the formation of foam cells.

Animals ; Apolipoproteins E ; Cell Line ; Foam Cells ; chemistry ; Humans ; Indican ; pharmacology ; Lipids ; chemistry ; Macrophages ; chemistry ; Mice ; Mice, Inbred C57BL ; Plaque, Atherosclerotic ; pathology ; Renal Insufficiency, Chronic ; blood

Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Early detection of subclinical atherosclerosis is important for reduction of cardiovascular risk. However, the current diagnostic strategy, which focuses on traditional risk factors or the use of risk scoring, is unsatisfactory. Arterial walls thicken and stiffen with age, a process known as arteriosclerosis. There is a close interaction between arterial stiffness and atherosclerosis. Increased luminal pressure and shear stress caused by arterial stiffening result in endothelial dysfunction, accelerate the formation of atheromas, and stimulate excessive collagen production and deposition in the arterial wall. Carotid intima-media thickness (CIMT) has been shown to predict cardiovascular risk in many large studies. However, there is controversy regarding the value of CIMT for prediction of cardiovascular risk because of differences in study design, specifically with respect to CIMT measurements. Pulse wave velocity (PWV) is the most widely used measure of arterial stiffness; measurement of PWV is simple, non-invasive, and reproducible. Many clinical studies and meta-analyses have shown that PWV has predictive value in cardiovascular disease beyond traditional risk factors, both in the general population and in patients with various diseases. Brachial pressure has been a poor surrogate for aortic pressure for more than 50 years. However, recent studies have shown a closer relationship between central blood pressure and intermediate cardiovascular phenotypes or cardiovascular target organ damage, compared to the respective relationships with brachial blood pressure. Considering the non-invasiveness and ability to collect multiple types of clinical data, measurement of CIMT, PWV, and central blood pressure may be useful to identify patients at high risk for development of cardiovascular disease.
Arterial Pressure ; Arteriosclerosis ; Atherosclerosis ; Blood Pressure ; Cardiovascular Diseases ; Carotid Intima-Media Thickness ; Collagen ; Humans ; Mortality ; Phenobarbital ; Phenotype ; Plaque, Atherosclerotic ; Pulse Wave Analysis ; Risk Factors ; Vascular Stiffness

OBJECTIVETo observe the therapeutic effects of Rongban Tongmai granule on oxidative stress in atherosclerotic rabbits.

METHODThe experimental rabbits were randomly divided into control group and hyperlipidemic group. The model of experimental atherosclerosis was prepared by feeding high cholesterol and lipid diet for weeks. After 4 weeks, hyperlipidemic rabbits were randomly divided into five groups, model group, high, medium and low doses of Rongban Tongmai granule and Shujiangzhi group, taking medicine for 8 weeks. The level of NO, ox-LDL, LP(a), SOD and MDA in the serum was measured before experiment, after treatment, treated for 4 weeks and for 8 weeks. After treated for 8 weeks, the level of MDA, GSH and NO, as well as activity of SOD and GSH-Px in the liver of rabbits was determined, meanwhile, the pathologic morphology of aortas was observed by light microscope.

RESULTCompared with control group, aortic intima of rabbits in model group had obviously thickened and developed atherosclerotic plaque. The serum level of MDA and LP(a) in model group had increased (P < 0.01) at 12 weeks after feeding high cholesterol and lipid diet, but the activity of SOD and level of NO were decreased (P < 0.01, P < 0.001). At the same time, the level of MDA in the liver had been elevated (P < 0.01), but the activity of SOD, GSH and NO was decreased (P < 0.01, P < 0.001) in 12 weeks. Rongban Tong-mai granule could inhibit atherosclerotic lesion in aorta, decrease the level of MDA and LP(a) (P < 0.05), increase the activity of SOD and NO (P < 0.05) after treated for 8 weeks in serum, moreover, the activity of SOD, GSH and NO content in the liver were increased (P < 0.05), as well as MDA was decreased (P < 0.05).

CONCLUSIONRongban Tongmai granule can prevent atherosclerosis by antioxidative stress and correcting unbalance of redox.

Animals ; Antioxidants ; administration & dosage ; Atherosclerosis ; blood ; drug therapy ; metabolism ; pathology ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; Glutathione ; blood ; Humans ; Lipoproteins, LDL ; blood ; Malondialdehyde ; blood ; Oxidative Stress ; drug effects ; Plaque, Atherosclerotic ; Rabbits ; Random Allocation ; Superoxide Dismutase ; blood

OBJECTIVE: To explore the expression of CyPA and CD147 in rabbit models of vulnerable carotid atherosclerotic plaque and the therapeutic effect of atorvastatin.
 METHODS: Twenty-four male New Zealand rabbits were randomly divided into 3 groups. Eight rabbits were served as a normal diet group (Group A), and the remaining 16 rabbits underwent balloon-induced endothelial injury in the right carotid artery and thereafter were fed on high-cholesterol diet (1% cholesterol) for 12 weeks, then they were divided into 2 groups: a AS group (Group B), an atorvastatin group [Group C, 2.5 mg/(kg.d)]. 4 weeks later, plaque disrupture was triggered by China Russell's viper venom and histamine. Serum levels of TC, TG, LDL-C and HDL-C were measured at different timepoint. The damaged carotid arteries were collected to undergo pathological examination. The macrophage, expression of CyPA and CD147 were detected by immuno-histochemical analysis, and the mRNA levels of CyPA and CD147 were examined by reverse transcription polymerase chain reaction (RT-PCR).
 RESULTS: Compared with the Group A, the serum levels of TC and LDL-c in the Group B and Group C were significantly increased (all P<0.01). Compared with the Group B, the serum levels of TC and LDL-c in the Group C were reduced significantly after atorvastatin intervention for 4 weeks (all P<0.01). The plaques disruption and thrombosis occurred in 4 out of the 6 rabbits in the Group B, while only 1 rabbit demonstrated plaques disruption and thrombosis in the Group C. Compared with the Group B, the levels of CyPA, CD147 and macrophage in carotid atherosclerotic plaque in the Group C were decreased significantly (all P<0.01).
 CONCLUSION The up-regulation of CyPA and CD147 may be involved in pathogenesis of vulnerable carotid atherosclerotic plaque. Atorvastatin could stabilize the plaque through inhibiting the CyPA and CD147 expression.
Animals ; Atorvastatin ; pharmacology ; Basigin ; metabolism ; Carotid Artery, Common ; pathology ; Cholesterol ; blood ; Cholesterol, Dietary ; administration & dosage ; Cyclophilin A ; metabolism ; Macrophages ; cytology ; Male ; Plaque, Atherosclerotic ; drug therapy ; metabolism ; Rabbits ; Random Allocation ; Thrombosis ; pathology ; Triglycerides ; blood