Extent Of Atherosclerotic Lesions Research Articles

Nanobodies as Diagnostic and Therapeutic Tools for Cardiovascular Diseases (CVDs).

The aim of this review is to summarize some of the most recent work in the field of cardiovascular disease (CVD) diagnosis and therapy, focusing mainly on the role of nanobodies in the development of non-invasive imaging methods, diagnostic devices, and advanced biotechnological therapy tools. In the context of the increased number of people suffering from CVDs due to a variety of factors such as sedentariness, poor nutrition, stress, and smoking, there is an urgent need for new and improved diagnostic and therapeutic methods. Nanobodies can be easily produced in prokaryotes, lower eukaryotes, and plant and mammalian cells, and offer great advantages. In the diagnosis domain, they are mainly used as labeled probes that bind to certain surface receptors or other target molecules and give important information on the severity and extent of atherosclerotic lesions, using imaging methods such as contrast-enhanced ultrasound molecular imaging (CEUMI), positron emission tomography (PET), single-photon emission computed tomography coupled with computed tomography (SPECT/CT), and PET/CT. As therapy tools, nanobodies have been used either for transporting drug-loaded vesicles to specific targets or as inhibitors for certain enzymes and receptors, demonstrated to be involved in various CVDs.

Rosuvastatin Attenuates Progression of Atherosclerosis and Reduces Serum IL6 and CCL2 Levels in Apolipoprotein-E-deficient Mice.

Apolipoprotein E-deficient (Apoe-/-) mice develop atherosclerotic lesions that closely resemble metabolic syndrome in humans. We sought to investigate how rosuvastatin mitigates the atherosclerotic profile of Apoe-/- mice over time and its effects on certain inflammatory chemokines. Eighteen Apoe-/- mice were allocated into three groups of six mice each receiving: standard chow diet (SCD; control group); high-fat diet (HFD); and HFD and rosuvastatin at 5 mg/kg/d orally via gavage for 20 weeks. Analysis of aortic plaques and lipid deposition was conducted by means of en face Sudan IV staining and Oil Red O staining. Serum cholesterol, low-density lipoprotein, high-density lipoprotein, plasma glucose and triglyceride levels were determined at baseline and after 20 weeks of treatment. Serum interleukin 6 (IL6), C-C motif chemokine ligand 2 (CCL2) and tumor necrosis factor-α (TNFα) levels were measured by enzyme-linked immunosorbent assay at the time of euthanasia. The lipidemic profile of Apoe-/- mice on HFD deteriorated over time. Apoe-/- mice on HFD developed atherosclerotic lesions over time. Sudan IV and Oil Red O-stained sections of the aorta revealed increased plaque formation and plaque lipid deposition in HFD-fed mice compared with SCD-fed mice and reduced plaque development in HFD-fed mice treated with rosuvastatin compared with mice not receiving statin treatment. Serum analysis revealed reduced metabolic parameters in HFD-fed mice on rosuvastatin compared with non-statin, HFD-fed mice. At the time of euthanasia, HFD-fed mice treated with rosuvastatin had significantly lower IL6 as well as CCL2 levels when compared with HFD-fed mice not receiving rosuvastatin. TNFα levels were comparable among all groups of mice, irrespective of treatment. IL6 and CCL2 positively correlated with the extent of atherosclerotic lesions and lipid deposition in atherosclerotic plaques. Serum IL6 and CCL2 levels might potentially be used as clinical markers of progression of atherosclerosis during statin treatment for hypercholesterolemia.

Atherosclerotic cardiovascular disease burden in patients with familial hypercholesterolemia: interpretation of data on involvement of different vascular beds.

Familial hypercholesterolemia (FH) is a monogenic, autosomal dominant disorder that results in a rise of low‑density lipoprotein cholesterol (LDL‑C) and markedly increased risk of premature atherosclerotic cardiovascular disease. FH is relatively common, treatable, and its clinical course can be improved through early detection and timely initiation of lipid‑lowering medications. The clinical picture of FH is highly variable, with a heterogeneous phenotype even within a single family, ranging from patients with very early onset of major cardiovascular events to those who do not develop overt cardiovascular disease even at an old age. We summarized studies indicating that atherosclerotic involvement in the coronary arteries and lower extremities is higher in FH patients than in the general population. There is a paucity of data regarding the relationship between FH and the incidence of atherosclerosis in other vascular beds. There are no studies systematically evaluating several vascular beds in asymptomatic patients with FH. Providing a systematic characteristic of patients with FH with respect to the presence and extent of atherosclerotic lesions in different vascular beds may have implications for daily practice not only for patients with FH but also for a larger number of patients with very high plasma LDL‑C concentrations.

Simulating the dynamics of atherosclerosis to the incidence of myocardial infarction, applied to the KORA population.

Analyzing epidemiological data with simplified mathematical models of disease development provides a link between the time-course of incidence and the underlying biological processes. Here we point out that considerable modeling flexibility is gained if the model is solved by simulation only. To this aim, a model of atherosclerosis is proposed: a Markov Chain with continuous state space which represents the coronary artery intimal surface area involved with atherosclerotic lesions of increasing severity. Myocardial infarction rates are assumed to be proportional to the area of most severe lesions. The model can be fitted simultaneously to infarction incidence rates observed in the KORA registry, and to the age-dependent prevalence and extent of atherosclerotic lesions in the PDAY study. Moreover, the simulation approach allows for non-linear transition rates, and to consider at the same time randomness and inter-individual heterogeneity. Interestingly, the fit revealed significant age dependence of parameters in females around the age of menopause, qualitatively reproducing the known vascular effects of female sex hormones. For males, the incidence curve flattens for higher ages. According to the model, frailty explains this flattening only partially, and saturation of the disease process plays also an important role. This study shows the feasibility of simulating subclinical and epidemiological data with the same mathematical model. The approach is very general and may be extended to investigate the effects of risk factors or interventions. Moreover, it offers an interface to integrate quantitative individual health data as assessed, for example, by imaging.

Hydroxytyrosol Plays Antiatherosclerotic Effects through Regulating Lipid Metabolism via Inhibiting the p38 Signal Pathway.

Purpose Hydroxytyrosol (HT) processes multiaspect pharmacological properties such as antithrombosis and antidiabetes. The aim of this study was to explore the antistherosclerotic roles and relevant mechanisms of HT. Methods Male apoE−/− mice were randomly divided into 2 groups: the control group and the HT group (10 mg/kg/day orally). After 16 weeks, blood tissue, heart tissue, and liver tissue were obtained to detect the atherosclerotic lesions, histological analysis, lipid parameters, and inflammation. And the underlying molecular mechanisms of HT were also studied in vivo and in vitro. Results HT administration significantly reduced the extent of atherosclerotic lesions in the aorta of apoE−/− mice. We found that HT markedly lowered the levels of serum TG, TC, and LDL-C approximately by 17.4% (p = 0.004), 15.2% (p = 0.003), and 17.9% (p = 0.009), respectively, as well as hepatic TG and TC by 15.0% (p < 0.001) and 12.3% (p = 0.003), respectively, while inducing a 26.9% (p = 0.033) increase in serum HDL-C. Besides, HT improved hepatic steatosis and lipid deposition. Then, we discovered that HT could regulate the signal flow of AMPK/SREBP2 and increase the expression of ABCA1, apoAI, and SRBI. In addition, HT reduced the levels of serum CRP, TNF-α, IL-1β, and IL-6 approximately by 23.5% (p < 0.001), 27.8% (p < 0.001), 18.4% (p < 0.001), and 19.1% (p < 0.001), respectively, and induced a 1.4-fold increase in IL-10 level (p = 0.014). Further, we found that HT might regulate cholesterol metabolism via decreasing phosphorylation of p38, followed by activation of AMPK and inactivation of NF-κB, which in turn triggered the blockade of SREBP2/PCSK9 and upregulation of LDLR, apoAI, and ABCA1, finally leading to a reduction of LDL-C and increase of HDL-C in the circulation. Conclusion Our results provide the first evidence that HT displays antiatherosclerotic actions via mediating lipid metabolism-related pathways through regulating the activities of inflammatory signaling molecules.

Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice

Background and aimsWe have shown previously that low density lipoprotein (LDL) aggregated by vortexing is internalised by macrophages and oxidised by iron in lysosomes to form the advanced lipid/protein oxidation product ceroid. We have now used sphingomyelinase-aggregated LDL, a more pathophysiological form of aggregated LDL, to study lysosomal oxidation of LDL and its inhibition by antioxidants, including cysteamine (2-aminoethanethiol), which concentrates in lysosomes by several orders of magnitude. We have also investigated the effect of cysteamine on atherosclerosis in mice. MethodsLDL was incubated with sphingomyelinase, which increased its average particle diameter from 26 to 170 nm, and was then incubated for up to 7 days with human monocyte-derived macrophages. LDL receptor-deficient mice were fed a Western diet (19–22 per group) and some given cysteamine in their drinking water at a dose equivalent to that used in cystinosis patients. The extent of atherosclerosis in the aortic root and the rest of the aorta was measured. ResultsConfocal microscopy revealed lipid accumulation in lysosomes in the cultured macrophages. Large amounts of ceroid were produced, which colocalised with the lysosomal marker LAMP2. The antioxidants cysteamine, butylated hydroxytoluene, amifostine and its active metabolite WR-1065, inhibited the production of ceroid. Cysteamine at concentrations well below those expected to be present in lysosomes inhibited the oxidation of LDL by iron ions at lysosomal pH (pH 4.5) for prolonged periods. Finally, we showed that the extent of atherosclerotic lesions in the aortic root and arch of mice was significantly reduced by cysteamine. ConclusionsThese results support our hypothesis that lysosomal oxidation of LDL is important in atherosclerosis and hence antioxidant drugs that concentrate in lysosomes might provide a novel therapy for this disease.

Size distribution of serum extracellular vesicles in mice with atherosclerosis

Background and aimsAtherosclerosis is a prominent vascular lesion, and potentially causing ischemic alterations in the brain and heart. Recent studies have reported that physiological and pathological alterations in atherosclerosis and extracellular vesicles (EV) are related. This study aimed to investigate the association between the extent of atherosclerotic lesions and the number of serum EVs in a mouse model of atherosclerosis (wild-type). MethodsEighteen 3-week-old C57BL/6 N male mice(wild-type) were purchased. Twelve mice were fed a 45% high-fat diet (HFD) for six months. Six mice were provided standard laboratory chow for six months. The entire aorta, from the aortic sinus to the division of the iliac artery, was dissected out from each mouse. Furthermore, the degree of atherosclerosis was microscopically determined. Serum EVs were quantified by size via nanoparticle tracking analysis. ResultsThe number of EVs in the high-atherosclerotic score group (1.43 × 109) was higher than that in the low- atherosclerotic score group (0.7 × 109) in the range of 211.5–222.5 nm (p = 0.033). ConclusionsEnumeration of EVs is a potential method of detecting atherosclerosis.

The extent of atherosclerotic lesions in crural arteries predicts survival of patients with lower limb peripheral artery disease: A new classification of crural atherosclerosis

Background and aimsSeveral studies report correlation of ankle brachial index (ABI) values and mortality. However, no studies exist on the predictive value of anatomical distribution of atherosclerotic lesions and the extent of atherosclerosis at defined arterial segments on life expectancy. The aim of the present study was to evaluate the significance of both extent and localisation of atherosclerotic lesions to mid-term patient survival. MethodsDigital subtraction angiography (DSA) images of 887 consecutive patients admitted to the Department of Vascular Surgery at Turku University Hospital (Turku, Finland) were retrospectively analysed. Each angiography was classified according to the TASC II classification for aorto-iliac and femoro-popliteal segments, and a similar four-grade index was created for crural arteries. Patients were followed until 36-months post DSA. ResultsDuring 36-month follow-up 295 (33%) deaths occurred. Death during follow-up was strongly associated with extensive crural disease, but not with extensive proximal disease (Crural Index III-IV, p = 0.044 and < 0.001, respectively). In a Cox regression analysis incorporating baseline variables, Crural Index IV and most severe atherosclerosis on crural vessels were the strongest predictors of poor prognosis (HR 2.20 95% CI 1.3–3.7, p = 0.003 and HR 2.45 95% CI 1.5–4.0, p < 0.001 respectively). ConclusionsThe extent of crural atherosclerosis is independently associated with poor mid term life expectancy. Therefore, a classification of the extent of crural atherosclerosis could serve as an indicator of mortality among PAD patients and aid in clinical decision making.

Abstract P251: 3-hydroxy-3-methylglutaryl-coenzyme A reductase Inhibition Reduces Intimal Neovascularization and Plaque Growth in Apolipoprotein E-Deficient Mice

Objective: The interactions between the renin-angiotensin system and neovascularization in atherosclerotic plaque development are unclear. We investigated the effects of 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibition with pitavastatin in the pathogenesis of atherosclerosis in ApoE-/- mice with special focus on plaque neovascularization. Methods and Results: Ten-week-old male ApoE-/- mice fed a high-fat diet were randomly assigned into two groups and administered vehicle (0.5% carboxymethyl cellulose) or pitavastatin (PiS, 1 mg/kg daily) for 12 weeks. Quantification of plaque areas at the aortic roots and in the thoracic and abdominal aortas revealed that, in all three regions, AT1R antagonism reduced the intimal neovessel density and the mRNA levels of toll-like receptor (TLR) 2 and TLR4. PiS increased the contents of collagen and elastin, lessened the macrophage component as well as the level of monocyte chemoattractant protein-1 and osteopontin protein in aortic roots, and reduced the mRNA and activity levels of matrix metalloproteinase (MMP)-2 and MMP-9 in aortic roots and thoracic aortas. Neointimal vessel density, the extent of atherosclerotic lesions, and the levels of TLR2 and TLR4 mRNA, were lower in ApoE-/-MMP-2-/- mice than in controls. The amounts of TNF-α and IL-1β protein as well as the levels of MMP2, MMP-9, TLR2, and TLR4 mRNA were increased by exposure to ox-LDL and lipopolysaccharide. These effects were diminished by PiS and small interfering RNAs targeting TLR2 or TLR4 in cultured macrophages. Conclusions: 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibition appears to inhibit intimal neovascularization in ApoE-/- mice, partly by reducing TLR2/TLR4-mediated inflammation and MMP activation, thus decreasing atherogenic plaque growth and instability.

Abstract P259: Endothelial Acid Sphingomyelinase Gene Determines Inflammasome Activation and Atherosclerotic Lesions in Carotid Arteries During Hypercholesterolemia

Nucleotide oligomerization domain (NOD)-like receptor protein with pyrin domain containing 3 (Nlrp3) inflammasome has been reported to be activated by atherogenic factors, thereby triggering endothelial injury and consequent atherosclerotic lesions in the arterial wall. However, the mechanism activating and regulating Nlrp3 inflammasomes remains poorly understood. The present study tested whether membrane raft (MR) signaling platforms associated with acid sphingomyelinase (ASM) and its product ceramide (Ce) importantly contribute to the activation of Nlrp3 inflammasomes and atherosclerotic lesions during hypercholesterolemia (HC). By confocal microscopy and biochemical analyses, we demonstrated the formation and activation of Nlrp3 inflammasomes in the intima of the carotid arteries of Asm +/+ mice with HC (as shown by a 2-fold increase in caspase-1 activity and a 6-fold enhancement of IL-1β positive stain areas), but not in Asm -/- mice. In endothelium-specific ASM transgenic mice (EC-Asm trg ), this inflammasome formation and activation were enhanced. Correspondingly, HC-induced increases in IL-1β production, ASM expression, Ce level and MR-gp91 phox clustering in the carotid intima were abolished in Asm -/- mice, but enhanced in EC-Asm trg mice. Functionally, endothelium-dependent vasodilation (EDVD) in carotid arteries in vivo (by ultrasound flowmetry) and in vitro (in perfused artery) was impaired by HC in Asm +/+ mice by 33% and 54%, respectively. This endothelial dysfunction was not observed in Asm -/- mice. The endothelial tight junction protein, ZO-1 was reduced by HC in both Asm +/+ and EC-Asm trg mice, but not in Asm -/- mice. It was also found that HC-increased neointimal formation, T-cell infiltration, and fibrosis in 2-week partially ligated carotid arteries (PLCA) occurred in Asm +/+ mice, but not in Asm -/- mice with HC. EC-Asm trg mice even exhibited more severe inflammatory and atherosclerotic lesions. All these results suggest that Asm gene and related MR clustering are essential to endothelial inflammasome activation and dysfunction in carotid arteries, ultimately determining the extent of atherosclerotic lesions.

Targeted Knockdown of Hepatic SOAT2 With Antisense Oligonucleotides Stabilizes Atherosclerotic Plaque in ApoB100-only LDLr-/- Mice.

To test the hypothesis that the attenuation of cholesterol oleate packaging into apoB-containing lipoproteins will arrest progression of pre-existing atherosclerotic lesions. Atherosclerosis was induced in apoB-100 only, LDLr(-/-) mice by feeding a diet enriched in cis-monounsaturated fatty acids for 24 weeks. A subset of mice was then euthanized to quantify the extent of atherosclerosis. The remaining mice were continued on the same diet (controls) or assigned to the following treatments for 16 weeks: (1) a diet enriched in n-3 polyunsaturated fatty acids, (2) the cis-monounsaturated fatty acid diet plus biweekly injections of an antisense oligonucleotide specific to hepatic sterol-O-acyltransferase 2 (SOAT2); or (3) the cis-monounsaturated fatty acid diet and biweekly injections of a nontargeting hepatic antisense oligonucleotide. Extent of atherosclerotic lesions in the aorta was monitored morphometrically in vivo with magnetic resonance imaging and ex vivo histologically and immunochemically. Hepatic knockdown of SOAT2 via antisense oligonucleotide treatment arrested lesion growth and stabilized lesions. Hepatic knockdown of SOAT2 in apoB100-only, LDLr(-/-) mice resulted in remodeling of aortic atherosclerotic lesions into a stable phenotype, suggesting SOAT2 is a viable target for the treatment of atherosclerosis.

Abstract 278: Diet-Induced Leukocyte Telomere Shortening Correlates with Extent of Atherosclerosis

Introduction: Cardiovascular disease, the leading cause of death in developed countries, is commonly due to atherosclerosis. Studies have demonstrated association between leukocyte telomere shortening (LTS), extent of atherosclerotic lesions and accelerated cell senescence. Further LTS is associated with dietary intake. However, efforts to link LTS, diet and extent of lesions have been unsuccessful in humans due to difficulties controlling diet in large human population studies. To begin addressing these critical issues, we controlled dietary fat (high-fat, HF) in baboons for 2yrs - a well-developed primate model of human atherosclerosis. This is the first study in primates showing correlation of LTS with both chronic HF diet and atherosclerotic lesions. Hypothesis: We hypothesized that leukocyte telomere length decreased with chronic HF diet in baboons and is correlated with extent of atherosclerotic lesions. Methods and Results: A cohort of pedigreed baboons (n=107; females=46, males=61) was fed a HF diet for 2yrs. Absolute leukocyte telomere lengths (LTL; kb/diploid genome) were quantified by qPCR before and after diet challenge. Total telomere length was calculated by computing the ratio of telomere quantity per single copy gene quantity (baboon LIPG). Mean LTL was significantly shorter after feeding baboons a HF diet for 2 yrs (paired t test, p=0.03). Baboons (n=232) maintained on a low fat diet for 2yrs showed no significant difference in LTL (p=0.47). These findings suggest that a HF diet accelerates LTS. Further we quantified the extent of atherosclerotic lesions in baboons after 2yr HF diet and found that LTL, adjusted for age and sex, were correlated with lesions in descending aorta (Pearson correlation, r=0.19; p=0.03). Interestingly this correlation was significant in females but not in males after adjusting for age (r=0.27, p=0.03). Conclusions: LTS correlates with chronic feeding with a HF diet in baboons, is significantly correlated with arterial lesions and the correlation is sex-specific. These findings suggest that LTS may be a potential biomarker of extent of atherosclerosis.

Abstract 451: PNS-R1 Attenuates the Development of Atherosclerosis in ApoE-Deficient Mouse Model

Atherosclerosis is a chronic pathological condition featured by accumulation of lipids and fibrous elements in the artery. Atherosclerosis remains as the primary cause of cardiovascular diseases and agents that effectively intervenes the development of atherosclerosis are still needed. Panax notoginseng has been extensively used as therapeutic agent in Asia to treat cardiovascular disorders. Panax notoginseng saponins (PNS) is the major class of active components of Panax notoginseng. PNS has been reported to possess anti-atherosclerotic effect. However, which component of PNS is responsible for this effect remains unknown. The current study evaluated the effects of a component unique to PNS, PNS-R1, on atherosclerosis in ApoE-/- mouse model. Histological examination revealed that the extent of atherosclerotic lesion was significantly alleviated in PNS-R1-treated ApoE-/- mice compared to that from the ApoE-/- controls. Meanwhile, PNS-R1 treatment significantly reduced the level of oxidative stress in the atherosclerotic lesion, which was prominently enhanced in ApoE-/- controls. This effect on oxidative stress was corroborated by increased serum level of GSH and SOD and decreased level of MDH in PNS-treated mice. Furthermore, PNS-R1 treatment significantly decreased the levels of total cholesterol, triglycerides and increased the level of HDL without affecting the level of LDL, suggesting an effect of PNS-R1 on lipid metabolism, which could in part contribute to its action in attenuating atherosclerosis. Additionally, the levels of inflammatory factors including IL-2, IL-6, TNF-α, γ-IFN and ox-LDL were markedly reduced in PNS-R1-treated mice compared to that from the ApoE-/- controls, demonstrating a significant anti-inflammatory effect of PNS-R1 in the development of atherosclerosis. Expression of microRNAs known to be involved in the pathogenesis of atherosclerosis was further evaluated and showed that PNS-R1 treatment led to a significant reduction in the expression of miR-122, miR-132 and miR-155. Collectively, our results provided for the first time the experimental evidence supporting the anti-atherosclerotic effects of PNS-R1, which could be a promising therapeutic agent treating atherosclerosis.

A Pathological Study of the Epidemiology of Atherosclerosis in Mexico City

Objective. To examine the frequency and patterns of association of cardiovascular risk factors with atherosclerosis in five different arterial territories at post-mortem in Mexico City. Methods. We obtained five arterial territories arteries (circle of Willis, coronary, carotid, renal, and aorta) of 185 men and women 0 to 90 years of age who underwent autopsy at the Medical Forensic Service of Mexico City. We determined the prevalence and extent of atherosclerotic lesions by histopathology according to the classification of the American Heart Association as early (types I–III) and advanced (types IV–VI), and according to the degree of stenosis and correlated with cardiovascular risk factors. Results. Atherosclerotic lesions were identified in at least one arterial territory in 181 subjects (97.8%), with involvement of two ore more territories in 178 subjects (92.2%). Advanced lesions were observed in 36% and 67% of subjects under 15 and between 16 and 35 years, respectively. Any degree of atherosclerosis was associated with the presence of diabetes mellitus, hypertension, overweight, obesity, and smoking, and to a greater extent with the presence of two or more risk factors (P < 0.001). However, emerging and advanced athersoclerosis was observed in 53% and 20% people with no risk factors. Conclusions. The study shows a high prevalence of atherosclerosis in all age groups and both sexes. There is considerable development of atherosclerotic disease in subjects without known risk factors.

Impact of south asian ethnicity on total plaque volume, calcified plaque volume and non-calcified plaque volume in the coronary arteries: a coronary CT angiography study in East London (UK)

Purpose: The impact of ethnicity on coronary heart disease has received scarce attention. The purpose of this study was to compare the extent and composition of coronary atherosclerosis in South Asian and Caucasian patients with stable chest pain. Methods: Between March 2010 and January 2012 we included 1159 consecutive patients in East London who underwent coronary CT angiography for stable chest pain. The prevalence of diabetes, hypercholesterolemia, hypertension, smoking and family history was obtained. CT angiography was performed using a 128-slice dual-source scanner. For patients with good or excellent image quality atherosclerotic plaques were quantified using an automated algorithm estimating calcified (CPV), non-calcified (NCPV) and total plaque volume (TPV). Severity and extent of atherosclerotic lesions were assessed using degree of vessel disease and segment involvement score. The groups were compared using univariate and multivariate regression analysis. Results: Image quality was good or excellent in 974/1159 (84%) patients. Of these, 550 were SA and 424 were Caucasians. SA patients were younger (50±11 vs. 54±12 years), had higher prevalence of diabetes mellitus (39% vs. 16%), hyperlipidemia (75% vs. 63%), but lower smoking prevalence (37% vs. 59%). After adjustment for confounders, Caucasians had a 1.3-fold [95% CI: 1.1-1.6] higher CPV compared to SA. Ethnicity was not independently associated with NCPV or TPV. Age, gender, diabetes mellitus and hypertension were independently associated with CPV, NCPV and TPV, smoking and hyperlipidemia only with TPV and NCPV. Ethnicity did not predict severity or extent of atherosclerotic lesions. Conclusion: For patients with stable coronary heart disease South Asians had significantly less calcified disease than Caucasians. No difference was observed between the groups for non-calcified and total plaque volume or severity and extent of disease.

Genetic Ablation of Adamts13 Gene Dramatically Accelerates the Formation of Early Atherosclerosis in a Murine Model

ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats-13) cleaves von Willebrand factor, thereby modulating thrombosis and inflammation. Low plasma ADAMTS13 activity is associated with cardiovascular events, including myocardial and cerebral infarction. Here, we investigated the role of ADAMTS13 in the development of early atherosclerosis in a murine model. Apolipoprotein E-null (ApoE(-/-)) and Adamts13-null (Adamts13(-/-)) ApoE(-/-) mice were fed with a high-fat Western diet for 12 weeks. Atherosclerotic lesions in the aorta and aortic roots were quantified after staining. Leukocyte rolling and adhesion onto cremaster venules after oxidative injury were determined by intravital microscopy. Although plasma cholesterol levels were largely similar in both groups, the extent of atherosclerotic lesions in the aorta en face and in the aortic roots in the Adamts13(-/-)ApoE(-/-) mice increased ≈ 5.5-fold (P=0.0017) and ≈ 6.1-fold (P=0.0037), respectively. In addition, the ratio of plasma high- to low-molecular-weight von Willebrand factor multimers increased ≈ 3-fold. The leukocyte rolling velocities were significantly reduced (P<0.001), with an increased number of leukocyte rolling (P=0.0026) and macrophage infiltration into the atherosclerotic lesions in the Adamts13(-/-)ApoE(-/-) mice. Our results suggest that ADAMTS13 plays a critical role in modulating the development of early atherosclerosis, likely through the proteolytic cleavage of ultra-large von Willebrand factor multimers, thereby inhibiting platelet deposition and inflammation.

Effector Memory T cells Are Associated With Atherosclerosis in Humans and Animal Models

Background—Adaptive T-cell response is promoted during atherogenesis and results in the differentiation of naïve CD4+T cells to effector and/or memory cells of specialized T-cell subsets. Aim of this work was to investigate the relationship between circulating CD4+T-cell subsets and atherosclerosis.Methods and Results—We analyzed 57 subsets of circulating CD4+T cells by 10-parameter/8-color polychromatic flow cytometry (markers: CD3/CD4/CD45RO/CD45RA/CCR7/CCR5/CXCR3/HLA-DR) in peripheral blood from 313 subjects derived from 2 independent cohorts. In the first cohort of subjects from a free-living population (n=183), effector memory T cells (TEM: CD3+CD4+CD45RA−CD45RO+CCR7− cells) were strongly related with intima-media thickness of the common carotid artery, even after adjustment for age (r=0.27; P<0.001). Of note, a significant correlation between TEM and low-density lipoproteins was observed. In the second cohort (n=130), TEM levels were significantly increased in patients with chronic stable angina or acute myocardial infarction compared with controls. HLA-DR+TEM were the TEM subpopulation with the strongest association with the atherosclerotic process (r=0.37; P<0.01). Finally, in animal models of atherosclerosis, TEM (identified as CD4+CD44+CD62L−) were significantly increased in low-density lipoprotein receptor and apolipoprotein E deficient mice compared with controls and were correlated with the extent of atherosclerotic lesions in the aortic root (r=0.56; P<0.01).Conclusions—Circulating TEM cells are associated with increased atherosclerosis and coronary artery disease in humans and in animal models and could represent a key CD4+T-cell subset related to the atherosclerotic process. (J Am Heart Assoc. 2012;1:27-41.)

Panax notoginseng Reduces Atherosclerotic Lesions in ApoE-Deficient Mice and Inhibits TNF-α-Induced Endothelial Adhesion Molecule Expression and Monocyte Adhesion

It is widely recognized that atherogenesis is associated with vascular inflammation. Panax notoginseng , a commonly used herb in China, has been shown to possess anti-inflammatory activity. In the present study, the antiatherogenic effect of P. notoginseng saponins (PNS) was examined in apolipoprotein E (apoE)-deficient mice. The molecular mechanisms responsible for the antivascular inflammatory effect of PNS on human coronary artery endothelial cells (HCAECs) were also investigated in vitro. PNS, dissolved in drinking water, was administered orally to two treatment groups at dosages of 4.0 and 12.0 mg/day/mouse, respectively. After 8 weeks, atherosclerosis in the entire aortic area was assessed using an en face method. Compared with the control group, both low- and high-dose PNS-treated groups showed a significant decrease in extent of atherosclerotic lesions by 61.4 and 66.2%, respectively (P < 0.01). PNS also notably reduced serum lipid levels. Serum levels of IL-6 and TNF-alpha in all groups of apoE-deficient mice were below the detection limit. In vitro studies showed that PNS dose-dependently inhibited monocyte adhesion on activated endothelium, as well as the expression of TNF-alpha-induced endothelial adhesion molecules, such as ICAM-1 and VCAM-1. In conclusion, PNS has antiatherogenic activity through, at least in part, its lipid-lowering and antivascular inflammatory mechanisms.

Glucose intolerance, insulin resistance and metabolic syndrome in patients with stable angina pectoris. Obesity predicts coronary atherosclerosis and dysglycemia

Disturbances of glucose regulation and other metabolic disorders, as part of metabolic syndrome, are important risk factors for atherosclerosis. Abnormal glucose metabolism is commonly observed in patients with acute coronary syndrome. However, there is no consistent evidence for subjects with stable angina. To investigate the prevalence of glucose metabolism in patients with stable coronary artery disease (CAD) documented angiographically and to assess correlations of metabolic profile and extent of atherosclerotic lesions. 100 consecutive non-diabetic patients with stable CAD referred to coronary angiography were studied. Total cholesterol and its fractions, triglycerides, uric acid and fasting insulin levels were determined. Oral glucose tolerance test (OGTT) and then coronary angiography were performed. All patients were divided into groups according to glucometabolic and coronary status and insulin resistance. The sum of all lesions in coronary vessels was calculated for each patient (CAD score). After OGTT, 44% of patients presented disturbed glucose metabolism: 9% of patients had newly diagnosed diabetes and 35% patients were in the prediabetic state. There was no correlation between glycemic status and insulin resistance, and severity of coronary heart disease. Obesity, reflected by body mass index, waist circumference and waist-to-hip ratio, was a major metabolic disorder and independent predictor of the extent of coronary atherosclerosis and glucose intolerance. Abnormal glucose regulation is very common in patients with stable CAD. Only obesity was the independent predictor of coronary atherosclerosis and dysglycemia. Other metabolic risk factors are target for prevention and treatment.

The evolving science of atherothrombotic disease

Atherosclerosis is a systemic inflammatory disease characterized by the accumulation of inflammatory cells in the intima of large arteries. The presence of platelets at the site of inflammation and endothelial injury has been known since the early 1960s. In the following years, it was generally accepted that rupture or erosion of advanced atherosclerotic lesions initiates platelet activation and aggregation on the thrombogenic surface of a disrupted atherosclerotic plaque. Thrombotic vascular occlusion is associated with ischaemic episodes in the retina, brain, heart, and other organs. While it is widely accepted that platelets play a significant role in thromboembolic events generated by atherosclerotic lesions (atherothrombosis), their involvement in the initiation of the atherosclerotic process has not been widely recognized by the scientific community. An expanding body of evidence on the role of platelets in the development of atherosclerotic lesions continues to build. Platelets bind to leukocytes and endothelial cells, and initiate the transformation of monocytes into macrophages. Additionally, platelets internalize oxidized phospholipids and promote foam cell formation, as well as recruit progenitor cells that are able to differentiate into foam or endothelial cells. In total, platelets play a key role in the initiation, development, and total extent of atherosclerotic lesions.