Identification of early atherosclerotic lesions in carotid arteries with quantitative characteristics measured by 3D MRI.

PURPOSE: To evaluate the usefulness of quantitative characteristics of morphology and signal intensity of arterial wall measured by 3D multicontrast magnetic resonance vessel wall imaging (MRVWI) in identification of carotid early atherosclerosis (CEAS). MATERIALS AND METHODS: In all, 61 older subjects (mean age 71.8 ± 5.6 years old; 25 males) without cardiovascular symptoms in the last 6 months were recruited. The carotid arteries without advanced plaque features on 3.0T MRI were included for analysis. Ultrasound imaging was used as a reference to identify CEAS. The morphological parameters including lumen area (LA), wall area (WA), wall thickness (WT), and normalized wall index (NWI = WA/[WA+LA] × 100%) and the signal intensity on 3.0T MR T2 -weighted images (T2 SI) of the carotid arterial wall were measured. Three regression models were built to identify CEAS with the following parameters: Model 1 with both morphological and T2 SI parameters; Model 2 with T2 SI parameters; and Model 3 with morphological parameters. All models were adjusted for age and sex. Area under the curve (AUC) was calculated to validate models. RESULTS: Of the 86 carotid arteries without advanced plaques, 47 (54.7%) were found to have early plaques determined by ultrasound. Among three regression models, Model 1 showed the highest AUC values in identifying CEAS (left: AUC = 0.856, P < 0.001; right: AUC = 0.867, P < 0.001), followed by Model 2 (left: AUC = 0.843, P < 0.001; right: AUC = 0.798, P = 0.001), and Model 3 (left: AUC = 0.790, P = 0.002; right: AUC = 0.806, P < 0.001). CONCLUSION: The combination of morphology and normalized T2 SI of arterial wall measured by MRVWI is more effective than each characteristic alone in identification of CEAS. J. Magn. Reson. Imaging 2016;44:1270-1276.

A potential early-atheroprotective target: Irgm1 mediates lymphangiogenesis through LEC autophagy by Tfeb translocation.

Lymphatic dysfunction is a pivotal pathological mechanism underlying the development of early atherosclerotic plaques. Potential targets of lymphatic function must be identified to realize the early prevention and treatment of atherosclerosis (AS). The immunity-related GTPase Irgm1 is involved in orchestrating cellular autophagy and apoptosis. However, the effect of Irgm1 on early AS progression, particularly through alterations in lymphatic function, remains unclear. In this study, we confirmed the protective effect of lymphangiogenesis on early-AS in vivo. Subsequently, an in vivo model of early AS mice with Irgm1 knockdown shows that Irgm1 reduces early atherosclerotic plaque burden by promoting lymphangiogenesis. Given that lymphatic endothelial cell (LEC) autophagy significantly contributes to lymphangiogenesis, Irgm1 may enhance lymphatic circulation by promoting LEC autophagy. Moreover, Irgm1 orchestrates autophagy in LECs by inhibiting mTOR and facilitating nuclear translocation of Tfeb. Collectively, these processes lead to lymphangiogenesis. Thus, this study establishes a link between Irgm1 and early AS, thus revealing a novel mechanism by which Irgm1 exerts an early protective influence on AS within the context of lymphatic circulation. The insights gained from this study have the potential to revolutionize the approach and management of AS onset.

T1-weighted MRI of targeting atherosclerotic plaque based on CD40 expression on engulfed USPIO's cell surface.

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of cholesterol within the arterial wall. Its progression can be monitored via magnetic resonance imaging (MRI). Ultrasmall Superparamagnetic Particles of Iron Oxide (USPIO) (<5 nm) have been employed as T1 contrast agents for MRI applications. In this study, we synthesized USPIO with an average surface carboxylation of approximately 5.28 nm and a zeta potential of -47.8 mV. These particles were phagocytosed by mouse aortic endothelial cells (USPIO-MAECs) and endothelial progenitor cells (USPIO-EPCs), suggesting that they can be utilized as potential contrast agent and delivery vehicle for the early detection of atherosclerosis. However, the mechanism by which this contrast agent is delivered to the plaque remains undetermined. Our results demonstrated that with increasing USPIO concentration during 10-100 µg ml-1, consistent change appeared in signal enhancement on T1-weighted MRI. Similarly, T1-weighted MRI of MAECs and EPCs treated with these concentrations exhibited a regular change in signal enhancement. Prussian blue staining of USPIO revealed substantial absorption into MAECs and EPCs after treatment with 50 µg ml-1USPIO for 24 h. The iron content in USPIO-EPCs was much higher (5 pg Fe/cell) than in USPIO-MAECs (0.8 pg Fe/cell). In order to substantiate our hypothesis that CD40 protein on the cell surface facilitates migration towards inflammatory cells, we utilized AuNPs-PEI (gold nanoparticles-polyethylenimine) carrying siRNACD40to knockout CD40 expression in MAECs. It has been documented that gold nanoparticle-oligonucleotide complexes could be employed as intracellular gene regulation agents for the control of protein level in cells. Our results confirmed that macrophages are more likely to bind to MAECs treated with AuNPs-PEI-siRNANC(control) for 72 h than to MAECs treated with AuNPs-PEI-siRNACD40(reduced CD40 expression), thus confirming CD40 targeting at the cellular level. When USPIO-MAECs and MAECs (control) were delivered to mice (high-fat-fed) via tail vein injection respectively, we observed a higher iron accumulation in plaques on blood vessels in high-fat-fed mice treated with USPIO-MAECs. We also demonstrated that USPIO-EPCs, when delivered to high-fat-fed mice via tail vein injection, could indeed label plaques by generating higher T1-weighted MRI signals 72 h post injection compared to controls (PBS, USPIO and EPCs alone). In conclusion, we synthesized a USPIO suitable for T1-weighted MRI. Our results have confirmed separately at the cellular and tissue andin vivolevel, that USPIO-MAECs or USPIO-EPCs are more accessible to atherosclerotic plaques in a mouse model. Furthermore, the high expression of CD40 on the cell surface is a key factor for targeting and USPIO-EPCs may have potential therapeutic effects.

The effect of gestational diabetes mellitus on carotid artery intima-media thickness in and after pregnancy: a systematic review and meta-analysis.

AIMS: The association between gestational diabetes mellitus (GDM) and common carotid artery (CCA) intima-media thickness (IMT) is still controversial. This systematic review and meta-analysis was performed to assess the correlation between GDM and CCA-IMT in and after pregnancy. METHODS: PubMed and EMBASE databases were systematically reviewed on April 2023. Studies measuring CCA-IMT in both pregnant women with GDM and women with previous history of GDM (pGDM) vs. healthy controls were included. The subtotal and overall standardized mean differences (SMDs) of CCA-IMT were calculated using the random-effect model. RESULTS: Nineteen studies with a total of 302 GDM and 861 pGDM women were analyzed. The average value of CCA-IMT measured in GDM/pGDM (0.59 ± 0.12 mm) was slightly increased in comparison to the accepted reference limits of IMT according to age classes. Substantial heterogeneity was detected for the studies involving both GDM and pGDM women, with an overall statistic I2 of 86.0% (p < 0.001). Large SMDs were obtained for the studies conducted on both GDM and pGDM women, with an overall SMD of 0.89 (95%CI 0.63-1.15, p < 0.001). Egger's test for a regression intercept gave a p-value of 0.37, indicating no publication bias. On meta-regression analysis, all potential confounders (number of patients, age at pregnancy, body mass index, measuring time, follow-up duration and GDM criteria) were not significantly associated with effect modification. CONCLUSIONS: GDM in and after pregnancy is independently associated with subclinical atherosclerosis. The association between GDM and carotid remodeling is potentially mediated by the longstanding underlying risk.

Apolipoproteins as potential communicators play an essential role in the pathogenesis and treatment of early atherosclerosis.

Atherosclerosis as the leading cause of the cardiovascular disease is closely related to cholesterol deposition within subendothelial areas of the arteries. Significantly, early atherosclerosis intervention is the critical phase for its reversal. As atherosclerosis progresses, early foam cells formation may evolve into fibrous plaques and atheromatous plaque, ulteriorly rupture of atheromatous plaque increases risks of myocardial infarction and ischemic stroke, resulting in high morbidity and mortality worldwide. Notably, amphiphilic apolipoproteins (Apos) can concomitantly combine with lipids to form soluble lipoproteins that have been demonstrated to associate with atherosclerosis. Apos act as crucial communicators of lipoproteins, which not only can mediate lipids metabolism, but also can involve in pro-atherogenic and anti-atherogenic processes of atherosclerosis via affecting subendothelial retention and aggregation of low-density lipoprotein (LDL), oxidative modification of LDL, foam cells formation and reverse cholesterol transport (RCT) in macrophage cells. Correspondingly, Apos can be used as endogenous and/or exogenous targeting agents to effectively attenuate the development of atherosclerosis. The article reviews the classification, structure, and relationship between Apos and lipids, how Apos serve as communicators of lipoproteins to participate in the pathogenesis progression of early atherosclerosis, as well as how Apos as the meaningful targeting mass is used in early atherosclerosis treatment.

Early hyperlipidemia triggers metabolomic reprogramming with increased SAH, increased acetyl-CoA-cholesterol synthesis, and decreased glycolysis.

To identify metabolomic reprogramming in early hyperlipidemia, unbiased metabolome was screened in four tissues from ApoE-/- mice fed with high fat diet (HFD) for 3 weeks. 30, 122, 67, and 97 metabolites in the aorta, heart, liver, and plasma, respectively, were upregulated. 9 upregulated metabolites were uremic toxins, and 13 metabolites, including palmitate, promoted a trained immunity with increased syntheses of acetyl-CoA and cholesterol, increased S-adenosylhomocysteine (SAH) and hypomethylation and decreased glycolysis. The cross-omics analysis found upregulation of 11 metabolite synthetases in ApoE‾/‾ aorta, which promote ROS, cholesterol biosynthesis, and inflammation. Statistical correlation of 12 upregulated metabolites with 37 gene upregulations in ApoE‾/‾ aorta indicated 9 upregulated new metabolites to be proatherogenic. Antioxidant transcription factor NRF2-/- transcriptome analysis indicated that NRF2 suppresses trained immunity-metabolomic reprogramming. Our results have provided novel insights on metabolomic reprogramming in multiple tissues in early hyperlipidemia oriented toward three co-existed new types of trained immunity.

Normoxic HIF-1α Stabilization Caused by Local Inflammatory Factors and Its Consequences in Human Coronary Artery Endothelial Cells.

Knowledge about normoxic hypoxia-inducible factor (HIF)-1α stabilization is limited. We investigated normoxic HIF-1α stabilization and its consequences using live cell imaging, immunoblotting, Bio-Plex multiplex immunoassay, immunofluorescence staining, and barrier integrity assays. We demonstrate for the first time that IL-8 and M-CSF caused HIF-1α stabilization and translocation into the nucleus under normoxic conditions in both human coronary endothelial cells (HCAECs) and HIF-1α-mKate2-expressing HEK-293 cells. In line with the current literature, our data show significant normoxic HIF-1α stabilization caused by TNF-α, INF-γ, IL-1ß, and IGF-I in both cell lines, as well. Treatment with a cocktail consisting of TNF-α, INF-γ, and IL-1ß caused significantly stronger HIF-1α stabilization in comparison to single treatments. Interestingly, this cumulative effect was not observed during simultaneous treatment with IL-8, M-CSF, and IGF-I. Furthermore, we identified two different kinetics of HIF-1α stabilization under normoxic conditions. Our data demonstrate elevated protein levels of HIF-1α-related genes known to be involved in the development of atherosclerosis. Moreover, we demonstrate an endothelial barrier dysfunction in HCAECs upon our treatments and during normoxic HIF-1α stabilization comparable to that under hypoxia. This study expands the knowledge of normoxic HIF-1α stabilization and activation and its consequences on the endothelial secretome and barrier function. Our data imply an active role of HIF-1α in vivo in the vasculature in the absence of hypoxia.

Targeting Peptide, Fluorescent Reagent Modified Magnetic Liposomes Coated with Rapamycin Target Early Atherosclerotic Plaque and Therapy.

Atherosclerosis is the leading cause of global morbidity and mortality. Its therapy requires research in several areas, such as diagnosis of early arteriosclerosis, improvement of the pharmacokinetics and bioavailability of rapamycin as its therapeutic agents. Here, we used the targeting peptide VHPKQHR (VHP) (or fluorescent reagent) to modify the phospholipid molecules to target vascular cell adhesion molecule-1 (VCAM-1) and loaded ultrasmall paramagnetic iron oxide (USPIO/Fe3O4) plus rapamycin (Rap) to Rap/Fe3O4@VHP-Lipo (VHPKQHR-modified magnetic liposomes coated with Rap). This nanoparticle can be used for both the diagnosis and therapy of early atherosclerosis. We designed both an ex vivo system with mouse aortic endothelial cells (MAECs) and an in vivo system with ApoE knockout mice to test the labeling and delivering potential of Rap/Fe3O4@VHP-Lipo with fluorescent microscopy, flow cytometry and MRI. Our results of MRI imaging and fluorescence imaging showed that the T2 relaxation time of the Rap/Fe3O4@VHP-Lipo group was reduced by 2.7 times and 1.5 times, and the fluorescence intensity increased by 3.4 times and 2.5 times, respectively, compared with the normal saline group and the control liposome treatment group. It showed that Rap/Fe3O4@VHP-Lipo realized the diagnosis of early AS. Additionally, our results showed that, compared with the normal saline and control liposomes treatment group, the aortic fluorescence intensity of the Rap/Fe3O4@VHP-Lipo treatment group was significantly weaker, and the T2 relaxation time was prolonged by 8.9 times and 2.0 times, indicating that the targeted diagnostic agent detected the least plaques in the Rap/Fe3O4@VHP-Lipo treatment group. Based on our results, the synthesized theragnostic Rap/Fe3O4@VHP-Lipo serves as a great label for both MRI and fluorescence bimodal imaging of atherosclerosis. It also has therapeutic effects for the early treatment of atherosclerosis, and it has great potential for early diagnosis and can achieve the same level of therapy with a lower dose of Rap.

Downregulation of NAGLU in VEC Increases Abnormal Accumulation of Lysosomes and Represents a Predictive Biomarker in Early Atherosclerosis.

Cardiovascular diseases (CVDs), predominantly caused by atherosclerosis (AS), are the leading cause of mortality worldwide. Although a great number of previous studies have attempted to reveal the molecular mechanism of AS, the underlying mechanism has not been fully elucidated. The aberrant expression profiling of vascular endothelial cells (VECs) gene in early atherosclerosis (EAS) was analyzed according to the dataset (GSE132651) downloaded from the Gene Expression Omnibus (GEO) database. We primarily performed functional annotation analysis on the downregulated genes (DRGs). We further identified that α-N-acetylglucosaminidase (NAGLU), one of the DRGs, played a critical role in the progression of EAS. NAGLU is a key enzyme for the degradation of heparan sulfate (HS), and its deficiency could cause lysosomal accumulation and lead to dysfunctions of VECs. We found that siRNA knockdown of NAGLU in human umbilical vein endothelial cell (HUVEC) aggravated the abnormal accumulation of lysosomes and HS. In addition, the expression of NAGLU was reduced in the EAS model constructed by ApoE -/- mice. Furthermore, we also showed that heparin-binding EGF-like growth factor (HB-EGF) protein was upregulated while NAGLU knockdown in HUVEC could specifically bind to vascular endothelial growth factor receptor 2 (VEGFR2) and promote its phosphorylation, ultimately activating the phosphorylation levels of extracellular signal-regulated kinases (ERKs). However, the application of selective VEGFR2 and ERKs inhibitors, SU5614 and PD98059, respectively, could reverse the abnormal lysosomal storage caused by NAGLU knockdown. These results indicated that downregulation of NAGLU in HUVEC increases the abnormal accumulation of lysosomes and may be a potential biomarker for the diagnosis of EAS.

Increased plasma miR-146a levels are associated with subclinical atherosclerosis in newly diagnosed type 2 diabetes mellitus.

AIMS: The association between circulating miR-146a and subclinical atherosclerosis in type 2 diabetes mellitus (T2DM) remains poorly understood. This study aimed to investigate the correlation between plasma miR-146a levels and subclinical atherosclerosis as measured by the carotid intima-media thickness (CIMT) and brachial-ankle pulse wave velocity (baPWV) in patients with newly diagnosed T2DM. METHODS: We studied 100 patients with newly diagnosed T2DM. Subclinical atherosclerosis was defined as a thickened CIMT (≥1.0 mm) and high baPWV defined as a value greater than the 75th percentile. Plasma miR-146a levels and metabolic parameters were measured. RESULTS: Patients with thickened CIMT had higher plasma miR-146a levels than those without thickened CIMT (3.36 ±â€¯1.32 vs 1.38 ±â€¯1.11, P < 0.001). Patients in the high baPWV group had higher plasma miR-146a levels than those in the normal baPWV group (3.43 ±â€¯1.32 vs 1.98 ±â€¯1.48, P < 0.001). Both CIMT (ß = 0.569, P < 0.001) and baPWV (ß = 0.274, P = 0.001) positively correlated with plasma miR-146a levels after adjustment for confounding factors by multiple stepwise regression. On binary logistic regression, plasma miR-146a level was an independent risk factor for thickened CIMT (OR = 3.890, 95% CI 1.415-7.698, P = 0.008) and high baPWV (OR = 1.954, 95% CI 1.256-3.040, P = 0.002) after adjustment for established cardiovascular risk factors. The area under the receiver operating characteristics curve (AUROC) of plasma miR-146a level for predicting thickened CIMT was 0.795 (95%CI 0.708-0.883, P < 0.001) and for predicting high baPWV was 0.773 (95%CI 0.679-0.867, P < 0.001). CONCLUSION: Plasma miR-146a levels correlate with CIMT and baPWV and could act as a biomarker for early diagnosis and as a therapeutic target for atherosclerosis in T2DM.

Coronary Intimal Thickening Begins in Fetuses and Progresses in Pediatric Population and Adolescents to Atherosclerosis.

The prevalence of coronary intimal thickening (IT) was assessed in fetuses and pediatric population. We studied the coronary arteries of 63 hearts obtained from fetuses, infants, children, and adolescents, deceased from noncardiac disease or trauma. Histomorphometric analysis, planimetry, and immunohistochemical studies were conducted. Intimal thickening consisted of proliferation of smooth muscle cells and scarce monocytes embedded in amorphous deposits within the internal elastic membrane (IEM). Intermingled lesions of intimal hyperplasia and parietal nonstenotic plaques were also observed. Intimal thickening was found in 10% of 20 fetuses, in 33.3% of 18 infants, 73.3% of 15 children, and 100% of 10 adolescents. A significant correlation (r = 0.671, P < 0.001) was found between the extent of IT and age. The IEM was duplicated or interrupted in 43% of patients, showing a positive correlation with the degree of IT (P = 0.01). Intimal thickening was predominantly found near bifurcation sites in the left anterior descending coronary artery (55.6%) and in zones free of bifurcation in the right coronary artery (75%). In conclusion, the prevalence and extension of IT lesions are higher at older ages within a young population. Intimal thickening may be regarded as the first event occurring in coronary preatherosclerosis, preceding lipid deposition.

Assessment of biomarkers of inflammation and premature atherosclerosis in adolescents with type-1 diabetes mellitus.

Background Type-1 diabetes mellitus (T1DM) causes endothelial dysfunction and early atherosclerosis, which can result in premature coronary artery disease. The aim of this study was to determine the impact of glycemic control, vascular oxidative stress and inflammation on vascular health in adolescents with T1DM. Methods This was a cross-sectional study in adolescents with age- and sex-matched T1DM who were ≥12 years and were at least 2 years post-diagnosis. Recruitment was balanced to include individuals with hemoglobin A1c (HbA1c) ≤8.5% (n=27) or with HbA1c ≥9.5% (n=25). Biomarkers of inflammation were measured in the blood including C-reactive protein (CRP), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), E-selectin, fibrinogen and tumor necrosis factor-α (TNF-α). Carotid intima media thickness (cIMT) and peripheral arterial tonometry (PAT) were assessed. Results Plasma E-selectin level was significantly different between the two groups with higher levels in the group with HbA1c ≥9.5% (65.0±27.7 ng/mL vs. 48.8±21.5 ng/mL, p=0.02). Though cIMT and PAT were not significantly different between the groups, Pearson correlation showed a significant direct relationship between rising HbA1c and mean right cIMT (p=0.02; r=0.37), PAT (p=0.03, r=0.31) and fibrinogen (p=0.03, r=0.03). Conclusions Elevated E-selectin level is an early marker of oxidative stress in T1DM patients with an elevated HbA1c level. Suboptimal glycemic control as evidenced by a rising HbA1c causes early atherosclerosis.

Cerebral Arterial Stiffness as A New Marker of Early Stage Atherosclerosis of The Cerebral Large Artery in Acute Stroke.

AIM: Carotid-cerebral pulse wave velocity (ccPWV) reflects the segment (C-M segment) stiffness between the common carotid artery and ipsilateral middle cerebral artery. C-M segment atherosclerosis (CMSA) is regarded the most frequent cause of anterior circulation ischemic stroke. We aimed to evaluate the association of ccPWV with early stage CMSA in this study. METHODS: Eighty-one acute ischemic stroke (AIS) patients with 154 C-M segments who were successfully evaluated with digital subtraction angiography, ccPWV, carotid intima-media thickness (cIMT), and brachial-ankle pulse wave velocity were enrolled into this study. Patient demographics and clinical data were retrieved from our AIS databases. RESULTS: Multivariate analyses showed that CMSA was independently associated with higher systolic BP, ccPWV, and cIMT. ccPWV and cIMT presented good diagnostic values for evaluating early stage CMSA in the receiver operating characteristic curve analyses. The areas under the curve (AUCs) of ccPWV were significantly higher than that of cIMT (Z=2.204, P=0.007). The AUC, sensitivity, specificity, Youden index, and cutoff of ccPWV for detecting early stage CMSA were 0.815 (P＜0.001), 86%, 70.7%, 0.567, and 5.4 m/s, respectively. Furthermore, ccPWV was significantly correlated with the stenosis of CMSA at the early stage in Spearman's correlation analyses (r=0.877, P＜0.001) and fractional polynomial plot with 95% confidence intervals. CONCLUSIONS: Cerebral arterial stiffness has the potential to be a new marker of early stage atherosclerosis of the cerebral large artery. This finding may help us prevent the occurrence of stroke and decrease the burden of society from stroke patients.

Increased expression of markers of early atherosclerosis in patients with inflammatory bowel disease.

BACKGROUND & AIMS: Recent studies documented an increased cardiovascular risk in patients with inflammatory bowel disease (IBD). Our study aimed at investigating the prevalence of intima-media thickness (IMT) of the carotid arteries and the arterial stiffness indices as markers of early atherosclerosis in young IBD patients. METHODS: We recruited 68 consecutive IBD patients, and 38 matched healthy controls less than 45years old (median age 31.6±8.1years). Clinical and demographic features, cardiovascular risk factors, history of cardiovascular events, concomitant therapies were registered on a dedicate database. Carotid IMT was evaluated by using high resolution B-mode ultrasonography. Arterial stiffness was assessed by measurement of carotid-femoral Pulse Wave Velocity (PWV) and Augmentation Index (AIx). RESULTS: Total cholesterol (P<0.013) and LDL-cholesterol (P<0.019) levels were significantly lower in IBD patients compared to controls. Carotid IMT was higher in IBD than in controls (P<0.047), but there was no statistically significant difference among Crohn's Disease (CD) and Ulcerative Colitis (UC) patients. Moreover, PWV and AIx were significantly higher in patients as compared to controls (P<0.006 and P<0.004 respectively). No medication seemed to affect vascular measurements, though stiffness parameters were significantly higher in patients treated with 5-ASA (11.9 (9.7) vs 18.2 (10.2), P<0.021), suggesting a lack of efficacy of 5-ASA in protecting IBD patients from early atherogenesis. CONCLUSIONS: Young IBD patients show an increase in subclinical markers of atherosclerosis. Future studies need to address whether these markers result in an increased risk of cardiovascular events in these patient.

Markers of Early Vascular Ageing.

BACKGROUND: Cardiovascular damage is clinically manifested as coronary artery disease, heart failure, stroke and peripheral artery disease. The prevalence of these adverse conditions is higher with advancing age. Although many patients present cardiovascular damage late in their life, it is common to see patients with early atherosclerosis in cardiovascular intensive care units at ages lower than 50 years in men and 55 for women. METHODS AND RESULTS: In this review of the literature we identified risk factors of early vascular damage. The classic risk factors such as age, gender, diabetes mellitus, dyslipidemia, smoking, alcohol, hypertension, obesity, family history and newer biomarkers such as hs-CRP, folic acid, homocysteine, fibrinogen are neither strong nor predictive of the individual patient's risk to present early cardiovascular disease. All these risk factors have been used to propose risk scores for possible future events but we still lack a single strong marker indicating new onset of disease that will predict the future independently of the classical factors. The role of vascular imaging techniques to identify patients with subclinical atherosclerotic vascular damage before clinical disease, including the effect of known and unknown risk factors on the vascular tree, seems to be very important for intensifying preventive measures in high risk patients. Early arteriosclerosis measured from pulse wave velocity is associated with reduced arterial elasticity and is associated with future cardiovascular events. CONCLUSIONS: Vascular measurements may better represent the continuum of cardiovascular disease from a young healthy to an aged diseased vessel that is going to produce adverse clinical events.

Flavonoids from Carya cathayensis Sarg. leaves inhibit carotid artery lesion formation induced by low blood flow.

The aim of the present study was to investigate the protective effect of the total flavonoids (TFs) from the leaves of Carya cathayensis Sarg. against early development of atherosclerosis. An in vivo model of carotid arterial partial ligation was established in mice, and the effects of TFs were investigated by morphometric measurements, Cell proliferation measurement and immunohistochemistry. The results showed that TFs could reduce neointima area by 41%, and the adventitial thickening induced by partial ligation was remarkable inhibited by TFs treatment. medial SMCs proliferation was significantly inhibited in TFs treated group. Immunohistochemistry analyses demonstrated that mice with TFs treatment have significant less macrophages accumulation in adventitia. These findings indicated that TFs have inhibitory effect in early atherosclerosis lesion formation model and strong action on reduce the inflammation in vivo.

Early atherosclerosis in normotensive patients with autosomal dominant polycystic kidney disease: the relation between epicardial adipose tissue thickness and carotid intima-media thickness.

Epicardial adipose tissue thickness (EATT) is suggested as a novel marker of subclinical atherosclerosis. Despite increased carotid intima-media thickness (CIMT) in autosomal dominant polycystic kidney disease (ADPKD) patients, the extent of the relationship between CIMT and EATT is unknown. The main purpose of our study was to evaluate the relation between EATT and CIMT in normotensive ADPKD patients with well-preserved renal function. Fifty-five normotensive ADPKD patients with normal renal function and 50 healthy control subjects were included in the study. EATT and CIMT were measured by echocardiography in all subjects. Correlation between EATT and CIMT was evaluated in ADPKD patients, while multivariate linear regression analysis was performed to determine factors predicting EATT and CIMT. ADPKD patients had significantly higher levels CIMT [0.7 (0.4-1.2) vs. 0.5 (0.4-0.8) mm, p < 0.001] and EATT (6.8 ± 2.7 vs. 4.8 ± 1.2 mm, p < 0.001) as compared with control subjects. Significant positive correlation was found between EATT and CIMT (r = 0.58, p < 0.001). Higher CRP levels (OR 54.7, 95 % CI 37.44-72.01, p < 0.001) and having ADPKD (OR 10.2, 95 % CI 2.53-17.86, p = 0.01) were the only independent factors associated with a higher EATT. A higher age (OR 0.35, 95 % CI -0.02 to 0.71, p = 0.06) tended to be independently associated with a higher EATT. In conclusion, our findings suggest that EATT, being simply measured by echocardiography and correlated with CIMT, can be used to detect subclinical atherosclerosis in normotensive ADPKD patients.

MAS receptors mediate vasoprotective and atheroprotective effects of candesartan upon the recovery of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality.

AT1 antagonists effectively prevent atherosclerosis since AT1 upregulation and angiotensin II-induced proinflammatory actions are critical to atherogenesis. Despite the classic mechanisms underlying the vasoprotective and atheroprotective actions of AT1 antagonists, the cross-talk between angiotensin-converting enzyme-angiotensin II-AT1 and angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axes suggests other mechanisms beyond AT1 blockage in such effects. For instance, angiotensin-converting enzyme 2 activity is inhibited by reactive oxygen species derived from AT1-mediated proinflammatory signaling. Since angiotensin-(1-7) promotes antiatherogenic effects, we hypothesized that the vasoprotective and atheroprotective effects of AT1 antagonists could result from their inhibitory effects on the AT1-mediated negative modulation of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality. Interestingly, our results showed that early atherosclerosis triggered in thoracic aorta from high cholesterol fed-Apolipoprotein E-deficient mice impairs angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality by a proinflammatory-redox AT1-mediated pathway. In such mechanism, AT1 activation leads to the aortic release of tumor necrosis factor-α, which stimulates NAD(P)H oxidase/Nox1-driven generation of superoxide and hydrogen peroxide. While hydrogen peroxide inhibits angiotensin-converting enzyme 2 activity, superoxide impairs MAS functionality. Candesartan treatment restored the functionality of angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis by inhibiting the proinflammatory-redox AT1-mediated mechanism. Candesartan also promoted vasoprotective and atheroprotective effects that were mediated by MAS since A779 (MAS antagonist) co-treatment inhibited them. The role of MAS receptors as the final mediators of the vasoprotective and atheroprotective effects of candesartan was supported by the vascular actions of angiotensin-(1-7) upon the recovery of the functionality of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis.

Nitric Oxide-Enhanced Molecular Imaging of Atheroma using Vascular Cellular Adhesion Molecule 1-Targeted Echogenic Immunoliposomes.

The aim of this study was to determine whether pre-treatment with nitric oxide-loaded echogenic liposomes (NO-ELIP) plus ultrasound can improve highlighting by molecularly targeted (anti-vascular cell adhesion molecule 1 [VCAM-1]) ELIP of atheroma components. Atherosclerotic animals were treated with anti-VCAM-1-ELIP or immunoglobulin (IgG)-ELIP. Each group was selected at random to receive pre-treatment with standard ELIP plus ultrasound, NO-ELIP without ultrasound and NO-ELIP plus ultrasound. Intravascular ultrasound highlighting data for the same arterial segments were collected before and after treatment. Pre-treatment with NO-ELIP plus ultrasound resulted in a significant increase in acoustic enhancement by anti-VCAM-1-ELIP (21.3 ± 1.5% for gray-scale value, 53.9 ± 3.1% for radiofrequency data; p < 0.001 vs. IgG-ELIP, p < 0.05 vs. pre-treatment with standard ELIP plus ultrasound or NO-ELIP without ultrasound). NO-ELIP plus ultrasound can improve highlighting of atheroma by anti-VCAM-1 ELIP. This NO pre-treatment strategy may be useful in optimizing contrast agent delivery to the vascular wall for both diagnostic and therapeutic applications.

[Intima-media thickness in a middle-old age sample of the Spanish general population]. / Grosor íntima-media en una muestra de mediana-avanzada edad de la población general Española.

OBJECTIVES: To ascertain reference values of carotid intima-media thickness (cIMT) in a middle and old-aged sample of the Spanish general population and to establish the 75(th) percentile above which it is necessary to control more strictly other cardiovascular risk factors. To determine cIMT values and the number of carotid plaques in age and sex subgroups, and whether there are differences between them. MATERIAL AND METHODS: Lipids, apolipoproteins, number of carotid atherosclerotic plaques if any, and cIMT of both common carotid arteries were determined in 171 individuals, representative of the adult general population of Burgos (Spain). RESULTS: The median age of the patients was 63 years (interquartile range = 20) and the 75th percentile of carotid IMT was 0,88 mm and 0,81 mm in men and women, respectively. This study shows that the values of cIMT median increase with age and are higher in men than in women in all age groups, except in individuals over 74 years where cIMT median values are similar. The presence or absence of atherosclerotic plaques was not statistically different between men and women at different ages. CONCLUSIONS: This population study shows the reference values of cIMT in a middle and old-aged sample of the Spanish population and shows that age, male gender, systolic blood pressure (SBP) and personal history of coronary heart disease are the main determinants of increased cIMT.