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

Fimasartan, a new angiotensin II receptor antagonist, reduces myocyte damage and stabilizes atherosclerotic plaque through its anti-inflammatory effect in animal studies. We investigated the protective effects of pretreatment with fimasartan on ischemia-reperfusion injury (IRI) in a mouse model of ischemic renal damage. C57BL/6 mice were pretreated with or without 5 (IR-F5) or 10 (IR-F10) mg/kg/day fimasartan for 3 days. Renal ischemia was induced by clamping bilateral renal vascular pedicles for 30 min. Histology, pro-inflammatory cytokines, and apoptosis assays were evaluated 24 h after IRI. Compared to the untreated group, blood urea nitrogen and serum creatinine levels were significantly lower in the IR-F10 group. IR-F10 kidneys showed less tubular necrosis and interstitial fibrosis than untreated kidneys. The expression of F4/80, a macrophage infiltration marker, and tumor necrosis factor (TNF)-α, decreased in the IR-F10 group. High-dose fimasartan treatment attenuated the upregulation of TNF-α, interleukin (IL)-1β, and IL-6 in ischemic kidneys. Fewer TUNEL positive cells were observed in IR-F10 compared to control mice. Fimasartan caused a significant decrease in caspase-3 activity and the level of Bax, and increased the Bcl-2 level. Fimasartan preserved renal function and tubular architecture from IRI in a mouse ischemic renal injury model. Fimasartan also attenuated upregulation of inflammatory cytokines and decreased apoptosis of renal tubular cells. Our results suggest that fimasartan inhibited the process of tubular injury by preventing apoptosis induced by the inflammatory pathway.
Animals ; Apoptosis* ; Blood Urea Nitrogen ; Caspase 3 ; Constriction ; Creatinine ; Cytokines ; Fibrosis ; In Situ Nick-End Labeling ; Interleukin-6 ; Interleukins ; Ischemia ; Kidney ; Macrophages ; Mice ; Muscle Cells ; Necrosis ; Plaque, Atherosclerotic ; Receptors, Angiotensin ; Reperfusion Injury* ; Tumor Necrosis Factor-alpha ; Up-Regulation

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

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

BACKGROUND: To determine the associations between serum osteocalcin level and insulin resistance, coronary atherosclerosis by using dual-source coronary computed tomography angiography. METHODS: A total of 98 subjects (24 men and 74 women) were selected for this retrospective cross-sectional study who voluntarily visited a health examination center for routine health check-up including the blood test for serum osteocalcin level and coronary computed tomography angiography. Multiple regression analysis was used to determine which variables were independently related to osteocalcin levels and coronary atherosclerosis. RESULTS: Stepwise multiple regression analysis adjusted for age, sex, menopausal status, body mass index, serum alkaline phosphatase, serum calcium and phosphate showed that osteocalcin negatively correlated with serum glucose (β=-0.145, P=0.001) and homeostasis model assessment of insulin resistance (HOMA-IR) index (β=-1.794, P=0.027) independently. The age, serum glucose, smoking status but not osteocalcin level were independent risk factors for coronary atherosclerosis by use of multiple logistic regression analysis after controlling for other variables. CONCLUSIONS: Serum osteocalcin level was inversely associated with fasting glucose level and insulin resistance measured by HOMA-IR, suggesting that osteocalcin is important for glucose metabolism. However, in this study, no significant difference was observed in the serum osteocalcin level according to the presence of coronary atherosclerotic plaques.
Alkaline Phosphatase ; Angiography ; Blood Glucose ; Body Mass Index ; Calcium ; Coronary Angiography ; Coronary Artery Disease* ; Cross-Sectional Studies ; Fasting ; Glucose ; Hematologic Tests ; Homeostasis ; Humans ; Insulin Resistance* ; Insulin* ; Logistic Models ; Male ; Metabolism ; Osteocalcin* ; Plaque, Atherosclerotic ; Retrospective Studies ; Risk Factors ; Smoke ; Smoking

OBJECTIVETo observe the effects of Danlou Tablet (DT) on inflammatory reaction, and expressions of lipoprotein-associated phospholipase A2 (LP-PLA2), secretory phospholipase A2 (sPLA2), and to analyze potential mechanisms.

METHODSForty male Wistar rats were randomly and equally divided into five groups, i.e., the normal control group, the model group, the Western medicine (WM) group, the low dose DT group, the high dose DT group, 8 in each group. Rats in the normal control group were fed with basic forage for 12 successive weeks, while AS rat model was established in rats of the other four groups by feeding high fat and sugar forage plus intraperitoneal injection of vitamin D₃. Normal saline, atorvastatin calcium suspension (at the daily dose of 1.8 mg/kg), low dose DT suspension (at the daily dose of 450 mg/kg), and high dose DT suspension (at the daily dose of 900 mg/kg) were administered to rats in the model group, the WM group, the low dose DT group, the high dose DT group respectively by gastragavage for 8 successive weeks. The general condition of all rats was observed. Rats were sacrificed after gastric administration and their serum collected. Serum levels of lipids (TC, TG, HDL-C, LDL-C) and inflammatory factors [IL-6, TNF-α, monocyte chemoattractant protein 1 (MCP-1), oxidized low-density lipoprotein (ox-LDL), lipoprotein-associated phospholipase A2 (LP-PLA2), secretory phospholipase A2 (sPLA2)] were detected. Pathological changes of thoracic aorta were observed by HE staining. Protein and gene expressions of LP-PLA2 and sPLA2 in thoracic aorta were measured by Western blot and real-time fluorescent quantitative PCR respectively.

RESULTSCompared with the normal control group, rats in the model group were in low spirits and responded poorly. Typical atherosclerotic plaque could be seen in thoracic aorta of rats in the model group. Serum levels of TC, TG, LDL-C, IL-6, TNF-α, MCP-1, ox-LDL, LP-PLA2, and sPLA2 significantly increased (P < 0.05); protein and gene expressions of LP-PLA2 and sPLA2 in rat thoracic aorta increased (P < 0.05) in the model group. After 8 weeks of intervention, rats in 3 medication groups appeared active, and HE staining showed subsidence of plaque in rat thoracic aorta. Compared with the model group, serum levels of TC, TG, LDL-C, IL-6, TNF-α, MCP-1, ox-LDL, and LP-PLA2 decreased in 3 medication groups (P < 0.01, P < 0.05); serum sPLA2 level decreased, protein and mRNA expressions of LP-PLA2 and sPLA2 in rat thoracic aorta decreased in the WM group (P < 0.01, P < 0.05); protein and mRNA expressions of LP-PLA2 in rat thoracic aorta significantly decreased in the low dose DT group (P < 0.01, P < 0.05), and those of LP-PLA2 and sPLA2 decreased in the high dose DT group (P < 0.01, P < 0.05).

CONCLUSIONDT could fight against inflammatory reaction and AS possibly through inhibiting LP-PLA2 expression and reducing ox-LDL production.

1-Alkyl-2-acetylglycerophosphocholine Esterase ; blood ; Animals ; Aorta, Thoracic ; pathology ; Atherosclerosis ; drug therapy ; Chemokine CCL2 ; blood ; Drugs, Chinese Herbal ; pharmacology ; Inflammation ; drug therapy ; Interleukin-6 ; blood ; Lipids ; blood ; Lipoproteins, LDL ; blood ; Male ; Phospholipases A2 ; blood ; Plaque, Atherosclerotic ; Random Allocation ; Rats ; Rats, Wistar ; Tablets ; Tumor Necrosis Factor-alpha ; blood

BACKGROUND: Progression of atherosclerotic plaques is known to be correlated with elevated circulating homocysteine (Hcy). However, whether the level of Hcy is related with coronary atherosclerosis in the subclinical state is unclear. Therefore, we performed this study to investigate the relationship between blood Hcy levels and subclinical atherosclerosis in asymptomatic self-referred subjects. METHODS: We retrospectively enrolled 2,968 self-referred asymptomatic subjects (1,374 men, 1,594 women) who had undergone both coronary CT angiography (CCTA) and coronary artery calcium scoring. The relationships between atherosclerosis, Hcy, and other clinical factors were assessed. RESULTS: Higher levels of Hcy were related with age, male gender, body mass index (BMI), waist circumference, blood pressure, high density lipoprotein (HDL), triglyceride, blood glucose, HbA1c, hsCRP, and coronary artery calcium score (CACS). Coronary plaque was more frequently found in higher Hcy quartile groups (21.3%, 28.8%, 34.4%, and 34.3%, P<0.001). Significant coronary artery stenosis (stenosis>50%) was also more frequent in higher Hcy quartile groups (1.8%, 5.4%, 5.0%, and 6.6%, P<0.001). The factors associated with CACS included age, male gender, levels of HbA1c, Hcy and hsCRP. Logistic regression analysis adjusted for gender and confounding factors showed that the third- and fourth-quartile Hcy groups had higher odds ratios [odd ratio (OR) 3.980 (1.723-9.194), P=0.001, 7.355 (3.291-16.439), P<0.001, respectively] for high CACS (CACS >400) than the first quartile group. CONCLUSIONS: Blood Hcy levels were associated with an increased risk of the presence and extent of subclinical atherosclerosis in asymptomatic subjects.
Angiography ; Atherosclerosis ; Blood Glucose ; Body Mass Index ; Calcium ; Coronary Artery Disease* ; Coronary Stenosis ; Coronary Vessels ; Homocysteine* ; Humans ; Hypertension ; Lipoproteins ; Logistic Models ; Male ; Odds Ratio ; Plaque, Atherosclerotic ; Retrospective Studies ; Triglycerides ; Waist Circumference

Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on energy metabolism and insulin sensitivity. Besides its antiobese and antidiabetic activity, FGF21 also possesses the protective effects against atherosclerosis. Circulating levels of FGF21 are elevated in patients with atherosclerosis, macrovascular and microvascular complications of diabetes, possibly due to a compensatory upregulation. In apolipoprotein E-deficient mice, formation of atherosclerotic plaques is exacerbated by genetic depletion of FGF21, but is attenuated upon replenishment with recombinant FGF21. However, the blood vessel is not the direct target of FGF21, and the antiatherosclerotic activity of FGF21 is attributed to its actions in adipose tissues and liver. In adipocytes, FGF21 promotes secretion of adiponectin, which in turn acts directly on blood vessels to reduce endothelial dysfunction, inhibit proliferation of smooth muscle cells and block conversion of macrophages to foam cells. Furthermore, FGF21 suppresses cholesterol biosynthesis and attenuates hypercholesterolemia by inhibiting the transcription factor sterol regulatory element-binding protein-2 in hepatocytes. The effects of FGF21 on elevation of adiponectin and reduction of hypercholesterolemia are also observed in a phase-1b clinical trial in patients with obesity and diabetes. Therefore, FGF21 exerts its protection against atherosclerosis by fine-tuning the interorgan crosstalk between liver, brain, adipose tissue, and blood vessels.
Adipocytes ; Adiponectin ; Adipose Tissue ; Animals ; Apolipoproteins ; Atherosclerosis* ; Blood Vessels ; Brain ; Cholesterol ; Energy Metabolism ; Fibroblast Growth Factors* ; Fibroblasts* ; Foam Cells ; Hepatocytes ; Humans ; Hypercholesterolemia ; Insulin Resistance ; Liver ; Macrophages ; Mice ; Myocytes, Smooth Muscle ; Obesity ; Plaque, Atherosclerotic ; Transcription Factors ; Up-Regulation ; Vascular Diseases

PURPOSE: The effects of short-term intensive lipid-lowering treatment on coronary plaque composition have not yet been sufficiently evaluated. We investigated the influence of short-term intensive lipid-lowering treatment on quantitative and qualitative changes in plaque components of non-culprit lesions in patients with acute coronary syndrome. MATERIALS AND METHODS: This was a prospective, randomized, open-label, single-center trial. Seventy patients who underwent both baseline and three-month follow-up virtual histology intravascular ultrasound were randomly assigned to either an intensive lipid-lowering treatment group (ezetimibe/simvastatin 10/40 mg, n=34) or a control statin treatment group (pravastatin 20 mg, n=36). Using virtual histology intravascular ultrasound, plaque was characterized as fibrous, fibro-fatty, dense calcium, or necrotic core. Changes in plaque components during the three-month lipid-lowering treatment were compared between the two groups. RESULTS: Compared with the control statin treatment group, there was a significant reduction in low-density lipoprotein cholesterol in the intensive lipid-lowering treatment group (-20.4±17.1 mg/dL vs. -36.8±17.4 mg/dL, respectively; p<0.001). There were no statistically significant differences in baseline, three-month follow-up, or serial changes of gray-scale intravascular ultrasound parameters between the two groups. The absolute volume of fibro-fatty plaque was significantly reduced in the intensive lipid-lowering treatment group compared with the control group (-1.5±3.4 mm3 vs. 0.8±4.7 mm3, respectively; p=0.024). A linear correlation was found between changes in low-density lipoprotein cholesterol levels and changes in the absolute volumes of fibro-fatty plaque (p<0.001, R2=0.209). CONCLUSION: Modification of coronary plaque may be attainable after only three months of intensive lipid-lowering treatment.
Aged ; Cholesterol, LDL/*blood/drug effects ; Coronary Artery Disease/*diagnostic imaging ; Drug Administration Schedule ; Ezetimibe, Simvastatin Drug Combination/*administration & dosage ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/*administration & dosage ; Male ; Middle Aged ; Plaque, Atherosclerotic/*diagnostic imaging ; Pravastatin/administration & dosage ; Prospective Studies ; Time Factors ; Treatment Outcome ; Ultrasonography, Interventional

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