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• Atherosclerosis and arterial stiffness in obstructive sleep apnea-A cardiovascular magnetic resonance study.

  Authors: Ilias Kylintireas, Sonya Craig, Richard Nethononda, Malcolm Kohler, Jane Francis, Robin Choudhury, John Stradling, Stefan Neubauer

  Atherosclerosis.

  OBJECTIVE: Obstructive sleep apnoea (OSA) has been linked to cardiovascular risk factors, such as hypertension, and clinical cardiovascular endpoints. Our aim was to assess whether OSA isOBJECTIVE: Obstructive sleep apnoea (OSA) has been linked to cardiovascular risk factors, such as hypertension, and clinical cardiovascular endpoints. Our aim was to assess whether OSA is independently associated with atherosclerosis and vascular dysfunction as assessed by cardiovascular magnetic resonance (CMR). METHODS: 58 patients with OSA and 39 matched control subjects without OSA underwent CMR of the aorta and carotid arteries. Carotid and aortic wall thickness and aortic distensibility were measured. Multi-weighted, high resolution CMR imaging was used for carotid atheroma characterization according to the American Heart Association (AHA) atheroma classification, modified for CMR. RESULTS: Carotid [1.47±0.03mm vs. 1.26±0.05mm, (P<0.01)] and aortic wall thickness [2.95±0.09mm vs. 2.05±0.07mm, (P<0.001)] were increased in patients with OSA compared to controls. Aortic distensibility was decreased in patients with OSA [3.62±0.3 vs. 4.75±0.2mmHg(-1)×10(-3), (P<0.05)]. Prevalence of carotid plaque, average carotid atheroma class, and prevalence of high risk features of carotid atheroma were increased in patients with OSA (P<0.005 for all). On multivariate analysis, Oxygen desaturation index (ODI) emerged as an independent predictor of carotid and aortic wall thickness, but not of aortic stiffness. CONCLUSIONS: OSA is associated with increased carotid and aortic atheroma burden and with advanced, high risk carotid atherosclerotic plaques, but not with aortic stiffening.

• Pancreatic β-cell function relates positively to HDL functionality in well-controlled Type 2 diabetes mellitus.

  Authors: Robin P F Dullaart, Wijtske Annema, Jan Freark de Boer, Uwe J F Tietge

  Atherosclerosis.

  BACKGROUND: High density lipoproteins (HDLs) have been implicated in glucose homeostasis. Among subjects with normal fasting glucose (NFG), impaired fasting glucose (IFG) and Type 2 diabetes mellitusBACKGROUND: High density lipoproteins (HDLs) have been implicated in glucose homeostasis. Among subjects with normal fasting glucose (NFG), impaired fasting glucose (IFG) and Type 2 diabetes mellitus (T2DM) we tested whether pancreatic β-cell function relates to HDL functionality, as determined by HDL anti-oxidative capacity and cellular cholesterol efflux to plasma. SUBJECTS AND METHODS: HDL anti-oxidative capacity (inhibition of LDL oxidation in vitro), cellular cholesterol efflux (the ability of plasma to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single human donor), glucose and insulin were determined in fasting plasma samples from 37 subjects with NFG, 36 with IFG and 22 with T2DM (no glucose lowering drug or insulin treatment; HbA1c 6.0±1.0%). Homeostasis model assessment was used to estimate pancreatic β-cell function (HOMA-β) and insulin resistance (HOMAir). RESULTS: HOMA-β was lowest, whereas HOMAir was highest in T2DM (P<0.01 and P<0.001 vs. NFG). HDL anti-oxidative capacity and cellular cholesterol efflux did not differ significantly according to glucose tolerance category. In univariate analysis and after controlling for HOMAir both HDL anti-oxidative capacity (P<0.05) and cellular cholesterol efflux (P<0.01) were positively correlated with HOMA-β in T2DM, but not in NFG and IFG. In age-, sex- and HOMAir-adjusted analyses, T2DM status interacted positively with HDL anti-oxidative capacity (P=0.001) and cellular cholesterol efflux (P=0.042) on HOMA-β. HbA1c interacted similarly with HDL functionality measures on HOMA-β. CONCLUSIONS: Pancreatic β-cell function relates to pathophysiologically relevant measures of HDL function in T2DM, but not in NFG and IFG. Better HDL functionality may contribute to maintenance of β-cell function in subjects with well-controlled T2DM.

• RAGE signaling mediates post-injury arterial neointima formation by suppression of liver kinase B1 and AMPK activity.

  Authors: Weifang Yu, Ru Liu-Bryan, Stephanie Stevens, Jagadeesha K Damanahalli, Robert Terkeltaub

  Atherosclerosis.

  OBJECTIVE: Intima formation involves smooth muscle cell (SMC) proliferation and migration that ultimately drives arterial stenosis, thrombosis, and ischemia in atherosclerosis, hypertension, andOBJECTIVE: Intima formation involves smooth muscle cell (SMC) proliferation and migration that ultimately drives arterial stenosis, thrombosis, and ischemia in atherosclerosis, hypertension, and arterial revascularization. Receptor for advanced glycation endproducts (RAGE) is a transmembrane signaling receptor implicated in diabetic renal and vascular complications, and post-injury intima formation, partly via Signal transducer and activator of transcription 3 (STAT3) activation. The metabolic super-regulator Adenosine monophosphate kinase (AMPK) inhibits SMC proliferation and intima formation. AMPK activation is promoted by liver kinase B1 (LKB1), and LKB1 inhibits STAT3 activation. Here, we tested the hypothesis that RAGE promotes arterial intima formation by modulating both LKB1 and AMPK. METHODS AND RESULTS: RAGE ligands (the calgranulin S100A11, and glycated albumin) suppressed AMPK activation in conjunction with increased proliferation and migration of cultured SMCs. These effects were inhibited both by RAGE deficiency and by prior AMPK activation. In SMCs, RAGE ligands decreased LKB1 activity. Moreover, knockdown of both LKB1 and AMPK were associated with increased STAT3 phosphorylation levels. In response to murine carotid artery ligation, expression of RAGE and S100A11 increased, whereas AMPK and LKB1 activity decreased in situ. Conversely, LKB1 and AMPK activity increased in situ, and neointima formation was attenuated in Rage(-/-) mice. CONCLUSION: The linkage of decreased LKB1 and AMPK activity with increased STAT3 in SMCs mediates the capacity of RAGE ligand-induced signaling to promote neointima formation in response to arterial injury.

• Multiple factors and pathways involved in hepatic very low density lipoprotein-apoB100 overproduction in Otsuka Long-Evans Tokushima fatty rats.

  Authors: Bolin Qin, Richard A Anderson, Teiji Kuzuya, Yasuyuki Kitaura, Yoshiharu Shimomura

  Atherosclerosis.

  AIMS: Overproduction of hepatic very low-density lipoprotein (VLDL) particles is a major abnormality of lipoprotein dysregulation in type 2 diabetes (T2D). We sought to examine the relationshipAIMS: Overproduction of hepatic very low-density lipoprotein (VLDL) particles is a major abnormality of lipoprotein dysregulation in type 2 diabetes (T2D). We sought to examine the relationship between systemic/hepatic inflammation associated with insulin resistance and apolipoprotein (apo)B100-containing VLDL production. METHODS AND RESULTS: At the age of 19 wks, Otsuka Long-Evans Tokushima Fatty (OLETF) rats showed systemic inflammation (plasma TNF-α and interleukin (IL)-6 levels increased), insulin resistance (plasma retinol binding protein 4 and soluble CD36 levels were higher), dyslipidemia and fatty liver (plasma and liver triglyceride and cholesterol levels were higher as well as total VLDL-, VLDL(1)-, VLDL(2)-apoB100 and VLDL-triglycerides were overproduced), compared with the control rats. In livers of OLETF rats, mRNA levels of tnf, il1b and il6 were increased, but an anti-inflammatory protein, zinc finger protein 36, and its mRNA expression were decreased. We also found that the liver mRNA, protein levels, and tyrosine phosphorylation (pY) of insulin receptor (InsR) substrate (IRS) 2, but not IRS1, were decreased in OLETF rats; pY of InsR and Akt protein and phospho-Akt (ser437) were also reduced; but protein tyrosine phosphatase-1B protein was overexpressed. The gene expressions of glucose transporters 1 and 2, and glycogen synthase were decreased, but phosphatase and tensin homolog deleted on chromosome ten and glycogen synthase kinase 3β mRNAs were overexpressed, compared with the controls. Sterol regulatory element binding protein-1c mRNA, ATP-binding cassette transporter A1 mRNA, microsomal triglyceride transfer protein mRNA/protein, and CD36 mRNA/protein levels were increased and lipoprotein lipase and Niemann-Pick c1-like1 mRNA levels were decreased, which are all involved in lipogenesis. Decreased sirtuins1-3 mRNA levels were also observed in OLETF rats. CONCLUSIONS: These abnormal genes, proteins expression and phosphorylation of multiple pathways related to inflammatory, insulin signaling and lipogenesis may be important underlying factors in VLDL-apoB100 particles overproduction observed in T2D. Our data contribute to the further understanding of an association of dyslipoproteinemia with systemic metabolic disorders, fatty liver and dysregulated hepatic metabolic pathways.

• Dietary fatty acids and peripheral artery disease in adults.

  Authors: Asghar Z Naqvi, Roger B Davis, Kenneth J Mukamal

  Atherosclerosis.

  BACKGROUND: Peripheral artery disease (PAD) is a debilitating condition involving atherosclerosis. Although saturated, monounsaturated and polyunsaturated fatty acids have strong associations withBACKGROUND: Peripheral artery disease (PAD) is a debilitating condition involving atherosclerosis. Although saturated, monounsaturated and polyunsaturated fatty acids have strong associations with atherosclerosis, it is unclear if diets high in these fatty acids affect PAD. METHODS: We studied 6352 adults aged 40 years and older who participated in the U.S. National Health and Nutrition Examination Survey between 1999 and 2004. Ankle brachial index (ABI) was assessed by standardized blood pressure measurements, and we defined PAD as an ABI<0.9. Fatty acid intake was assessed by validated 24-h dietary recall. We used multivariable linear and logistic regression to estimate associations between intakes of dietary saturated fatty acids (SFAs), monounsaturated fatty acids (MFAs), marine omega-3 fatty acids (N-3), linolenic acid (LNA), and omega-6 fatty acids (N-6) and ABI/PAD. RESULTS: The prevalence and 95% confidence interval (CI) of PAD was 5.2% (95% CI 4.6-5.8). There were no associations between ABI and intakes of marine N-3 (p=0.83) or N-6 (p=0.19) in adjusted models. In contrast, LNA was associated with higher ABI (p=0.04) and SFA tended to be associated with lower ABI (p=0.06) in adjusted models. In addition, higher SFA was associated with a higher prevalence of PAD: adjusted odds ratio 1.30 (95% CI 1.01-1.67; p=0.04) and a trend toward slower gait speed (p=0.08). CONCLUSION: In this nationally representative sample, higher dietary intakes of LNA and SFAs were associated with higher and lower ABI, respectively. Prospective studies are needed to confirm the potential protective effects of dietary LNA and detrimental effects of dietary SFAs on PAD.

• A simple multiplier to calculate the impact of HDL cholesterol on cardiovascular risk estimation using SCORE.

  Authors: Olivier S Descamps, Marie Therese Cooney, Guy De Backer, Ian Graham

  Atherosclerosis.

  The 2011 ESC-EAS guidelines on the management of dyslipidaemias use four separate charts to illustrate the impact of differing HDL cholesterol levels on risk of cardiovascular disease. We developedThe 2011 ESC-EAS guidelines on the management of dyslipidaemias use four separate charts to illustrate the impact of differing HDL cholesterol levels on risk of cardiovascular disease. We developed an easy way to calculate the effects of differing HDL-C levels on risk by deriving HDL and sex specific multipliers and applying these to various reference charts. Of three strategies explored, one based on a low HDL (0.8mmol/l) reference chart was the simplest and was acceptably accurate. Such an approach simplifies risk estimation by avoiding the need for multiple charts.

• Regulatory T cells and IL-10 levels are reduced in patients with vulnerable coronary plaques.

  Authors: Jacob George, Shmuel Schwartzenberg, Diego Medvedovsky, Michael Jonas, Gideon Charach, Arnon Afek, Ari Shamiss

  Atherosclerosis.

  BACKGROUND: Despite having a similar large extent of atherosclerotic coronary affliction, some patients suffer of recurrent cardiac events, whereas others remain asymptomatic. HYPOTHESIS: WeBACKGROUND: Despite having a similar large extent of atherosclerotic coronary affliction, some patients suffer of recurrent cardiac events, whereas others remain asymptomatic. HYPOTHESIS: We hypothesized the existence of a systemic "signature" that could distinguish "vulnerable" patients with preexisting coronary atherosclerosis from those having similar risk factors and atheromatous burden, but no history of clinically evident plaque rupture/erosion. METHODS: Twenty three patients who had at least two prior myocardial infarctions ("vulnerable group") were matched in respect to their background and coronary atherosclerosis extent with twenty one patients without a history of previous myocardial infarction who underwent routine coronary angiography before valvular surgery. We studied a panel of cytokines, antibodies and hormones including IL-6, IL-10, IL-12, antibodies to β2 glycoprotein I (β2GPI), antibodies to oxidized-LDL, adiponectin and resistin, along with levels of circulating EPCs and Tregs. RESULTS: A significantly higher level of Treg cells was present in the control (73.4%±4) than in the "vulnerable patient" group (62.2%±10.7), p<0.001. IL-10 level was also significantly higher in the control than in the vulnerable patients (2.6±1.2pg/ml versus 0.9±0.1pg/ml respectively, p=0.03). There was no significant difference in the circulating levels of the other cytokines, hormones or EPCs between the two groups. CONCLUSION: Regulatory T cells and serum IL-10 may discriminate "vulnerable" versus stable patients and may have a protective role against plaque rupture in patients with coronary atherosclerosis.

• YKL-40 is elevated in patients with peripheral arterial disease and diabetes or pre-diabetes.

  Authors: Klaudija Batinic, Clemens Höbaus, Milan Grujicic, Angelika Steffan, Finka Jelic, David Lorant, Thomas Hörtenhuber, Florian Hoellerl, Johanna-Maria Brix, Guntram Schernthaner, Renate Koppensteiner, Gerit-Holger Schernthaner

  Atherosclerosis.

  OBJECTIVE: YKL-40 is secreted by macrophages in atherosclerotic lesions and involved in plaque rupture. YKL-40 is elevated in coronary artery disease, and predicts cardiovascular mortality.OBJECTIVE: YKL-40 is secreted by macrophages in atherosclerotic lesions and involved in plaque rupture. YKL-40 is elevated in coronary artery disease, and predicts cardiovascular mortality. Experimental in vivo and in vitro data suggest a role of YKL-40 in tissue remodeling. A disease modulating potency of YKL-40 was not investigated in peripheral arterial disease (PAD). METHODS: We measured YKL-40 in 460 subjects: 316 PAD: 71 normal glucose metabolism (PAD-NGM), 90 pre-diabetes (PAD-PREDM) and 155 diabetes (PAD-DM); 20 diabetes with atherosclerosis but without PAD (AS-DM); 85 diabetes without macro-vascular complications (DM) and 39 healthy controls (CO). RESULTS: YKL-40 is higher in PAD vs. CO (median [25-75 percentile]: 103 [69-159] vs. 43 [30-80]ng/ml; p<0.001). In addition, YKL-40 is elevated in DM (p<0.001), PAD-NGM (p=0.001), PAD-PREDM (p<0.001), PAD-DM (p<0.001) and AS-DM (p=0.002) compared to CO. Among PAD, YKL-40 is increased in PAD-PREDM (p=0.001) and PAD-DM (p=0.01) vs. PAD-NGM. By multivariate regression YKL-40 is significantly associated with age (beta=0.272), triglycerides (beta=0.216), aspartate-amino-transferase (beta=0.177) and c-reactive-protein (beta=0.178). Underpinning its role YKL-40 was found to be associated with micro-/macroalbuminuria (p=0.014/p=008) - a strong remodeling inducer. In addition, YKL-40 was elevated in existence of mediasclerosis (p=0.008), a remodeling process. CONCLUSION: We are first to show that YKL-40 is higher in subjects with peripheral arterial disease. YKL-40 was higher in PAD patients with pre-/diabetes. In addition, YKL-40 was associated with the "severity" of generalized atherosclerosis estimated by affected vascular beds. All our findings point towards a role of YKL-40 in the progression/prognosis of patients with PAD and concomitant diabetes.

• Diastolic function parameters are improved by the addition of simvastatin to enalapril-based treatment in hypertensive individuals.

  Authors: Adenalva L S Beck, Maria E B Otto, Luciana B O D Avila, Fernando M Netto, Marinez K Armendaris, Andrei C Sposito

  Atherosclerosis.

  OBJECTIVE: Diastolic dysfunction (DD) is a frequent condition in hypertensive patients whose presence increases mortality and whose treatment remains unclear. The aim of this study was to investigateOBJECTIVE: Diastolic dysfunction (DD) is a frequent condition in hypertensive patients whose presence increases mortality and whose treatment remains unclear. The aim of this study was to investigate in a prospective, double-blinded, placebo-controlled randomized design the additive effect of simvastatin on DD in enalapril-treated hypertensive patients with average cholesterol levels. METHODS: Hypertensive patients with DD and LDL-cholesterol <160mg/dL underwent a run-in phase to achieve a systolic blood pressure (SBP) <135mmHg and diastolic blood pressure (DBP) <85mmHg with enalapril. Hydrochlorothiazide was added when need to achieve blood pressure control. Four weeks after reaching the optimum anti-hypertensive regimen patients were randomized to receive 80mg simvastatin (n=27) or placebo (n=28) for a period of 20 weeks. Echocardiograms were performed before and after treatment with measurement of maximum left atrial volume (LAV), conventional and tissue Doppler velocities in early diastole (E, e') and late diastole (A, a'). RESULTS: After 20 weeks, the simvastatin group presented reduction in SBP (-4±2mmHg, p=0.02), increase in E/A ratio (1.0±0.05 to 1.2±0.06, p=0.03) and decrease of LAV indexed to body surface area (24.5±0.9 to 21.1±0.8ml/m(2), p=0.048), as compared with placebo arm. No change in systolic function and no correlation between the E/A ratio, LAV and changes in blood pressure or lipid profile were observed. CONCLUSIONS: The addition of simvastatin to enalapril in hypertensive patients with average cholesterol levels improves parameters of diastolic function independently of changes in blood pressure or cholesterol.

• Carotid extra-medial thickness in childhood: Early life effects on the arterial adventitia.

  Authors: Michael R Skilton, Tim R Sullivan, Julian G Ayer, Jason A Harmer, Brett G Toelle, Karen Webb, Guy B Marks, David S Celermajer

  Atherosclerosis.

  OBJECTIVE: Structural modification of the arterial adventitia may be an early event in atherosclerosis. Carotid extra-medial thickness is a new measure of arterial adventitial thickness. We examinedOBJECTIVE: Structural modification of the arterial adventitia may be an early event in atherosclerosis. Carotid extra-medial thickness is a new measure of arterial adventitial thickness. We examined the association of cardiovascular risk factors with extra-medial thickness, in childhood. METHODS: Carotid extra-medial thickness was assessed by high-resolution ultrasound in 389 non-diabetic children aged 8-years. A non-fasting blood sample was collected from 314 participants. Associations of gender, age, lipoproteins, blood pressure, BMI z-score, waist:height ratio and parental history of early vascular disease, with extra-medial thickness were examined. RESULTS: Carotid extra-medial thickness was lower in girls (r=-.163, P=.001) and directly associated with systolic (r=.128, P=.009), diastolic blood pressure (r=.130, P=.009), and height (r=.170, P=.0006). These associations remained after adjustment for carotid intima-media thickness. In multivariable analysis including carotid intima-media thickness, only gender and height were significantly associated with carotid extra-medial thickness. In gender-stratified analysis, the strongest associations with extra-medial thickness were BMI z-score (r=.181, P=.01), height (r=.210, P=.003) and diastolic blood pressure (r=.167, P=.02) for boys; and systolic blood pressure (r=.153, P=.03) and parental history of premature cardiovascular disease (r=.139, P=.05) for girls. The association of BMI z-score with extra-medial thickness differed by gender (P-interaction=.04). CONCLUSIONS: Carotid extra-medial thickness is independently associated with gender and height in childhood. Extra-medial thickness may provide important information concerning early arterial health, particularly related to the arterial adventitia.

• Association between traditional cholesterol parameters, lipoprotein particle concentration, novel biomarkers and carotid plaques in retired National Football League players.

  Authors: Salim S Virani, Lisa Pompeii, Andrew E Lincoln, Reginald E Dunn, Andrew M Tucker, Vijay Nambi, Khurram Nasir, Robert A Vogel, Jeffrey L Boone, Arthur J Roberts, Christie M Ballantyne

  Atherosclerosis.

  OBJECTIVES: We assessed whether low-density lipoprotein particle concentration (LDL-P) and high-sensitivity C-reactive protein [hs-CRP] can identify subclinical atherosclerosis better thanOBJECTIVES: We assessed whether low-density lipoprotein particle concentration (LDL-P) and high-sensitivity C-reactive protein [hs-CRP] can identify subclinical atherosclerosis better than traditional cholesterol parameters in retired National Football League (NFL) players. BACKGROUND: It is not known whether LDL-P and the biomarker hs-CRP can identify subclinical atherosclerosis better than low-density lipoprotein cholesterol (LDL-C) or non-high-density-lipoprotein cholesterol (non-HDL-C) in retired NFL players, given high prevalence of metabolic syndrome in these players. METHODS: Carotid artery plaque screening was performed with traditional lipids, LDL-P, and hs-CRP in 996 retired players. Logistic regression analyses comparing highest with the lowest quartile were performed. RESULTS: Carotid artery plaques were seen in 41%. LDL-C (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.06-2.59), non-HDL-C (OR 1.67, 95% CI 1.04-2.67), and LDL-P (OR 2.21, 95% CI 1.35-3.62) were associated with plaques in adjusted models. Among 187 retired players with metabolic syndrome, LDL-C (OR 1.40, 95% CI 0.53-3.72) was not associated with carotid plaques, whereas LDL-P (OR 3.71, 95% CI 1.16-11.84) and non-HDL-C (OR 2.63, 95% CI 0.91-7.63, p=0.07; borderline significant) were associated with carotid plaques. hs-CRP (OR 1.13, 95% CI 0.71-1.79) was not associated with carotid plaques. CONCLUSION: Carotid artery plaques were common in retired NFL players and were strongly associated with LDL-P, especially among those with metabolic syndrome. hs-CRP was not associated with carotid plaques in this cohort.

• The LDL-cholesterol to HDL-cholesterol ratio and the severity of coronary and aortic atherosclerosis.

  Authors: Yukihiko Momiyama, Reiko Ohmori, Zahi A Fayad, Nobukiyo Tanaka, Ryuichi Kato, Hiroaki Taniguchi, Masayoshi Nagata, Fumitaka Ohsuzu

  Atherosclerosis.

• Assessment of the value of a genetic risk score in improving the estimation of coronary risk.

  Authors: Carla Lluis-Ganella, Isaac Subirana, Gavin Lucas, Marta Tomás, Daniel Muñoz, Mariano Sentí, Eduardo Salas, Joan Sala, Rafel Ramos, Jose M Ordovas, Jaume Marrugat, Roberto Elosua

  Atherosclerosis.

  BACKGROUND: The American Heart Association has established criteria for the evaluation of novel markers of cardiovascular risk. In accordance with these criteria, we assessed the association betweenBACKGROUND: The American Heart Association has established criteria for the evaluation of novel markers of cardiovascular risk. In accordance with these criteria, we assessed the association between a multi-locus genetic risk score (GRS) and incident coronary heart disease (CHD), and evaluated whether this GRS improves the predictive capacity of the Framingham risk function. METHODS AND RESULTS: Using eight genetic variants associated with CHD but not with classical cardiovascular risk factors (CVRFs), we generated a multi-locus GRS, and found it to be linearly associated with CHD in two population based cohorts: The REGICOR Study (n=2351) and The Framingham Heart Study (n=3537) (meta-analyzed HR [95%CI]: ∼1.13 [1.01-1.27], per unit). Inclusion of the GRS in the Framingham risk function improved its discriminative capacity in the Framingham sample (c-statistic: 72.81 vs.72.37, p=0.042) but not in the REGICOR sample. According to both the net reclassification improvement (NRI) index and the integrated discrimination index (IDI), the GRS improved re-classification among individuals with intermediate coronary risk (meta-analysis NRI [95%CI]: 17.44 [8.04; 26.83]), but not overall. CONCLUSIONS: A multi-locus GRS based on genetic variants unrelated to CVRFs was associated with a linear increase in risk of CHD events in two distinct populations. This GRS improves risk reclassification particularly in the population at intermediate coronary risk. These results indicate the potential value of the inclusion of genetic information in classical functions for risk assessment in the intermediate risk population group.

• Estimation of lipoprotein profile in patients with type II diabetes and its relevance to remnant lipoprotein cholesterol levels.

  Authors: Hiroshi Yoshida, Yuji Hirowatari, Hideo Kurosawa, Daisuke Manita, Hidekatsu Yanai, Kumie Ito, Norio Tada

  Atherosclerosis.

  BACKGROUND: Remnant lipoprotein (RLP), associated with atherosclerosis progression, is often elevated in diabetes mellitus. The RLP level is estimated by immune-separation method and agarose-gelBACKGROUND: Remnant lipoprotein (RLP), associated with atherosclerosis progression, is often elevated in diabetes mellitus. The RLP level is estimated by immune-separation method and agarose-gel electrophoresis (AGE). METHODS: The patients were grouped into three groups according to tertile of RLP-cholesterol (RLP-C) levels. The lipoprotein profiles of type II diabetic patients (T2DM) (n=194) were measured by an anion-exchange liquid chromatography (AEX-HPLC) and an AGE with lipid-staining or cholesterol-staining. RESULTS: IDL- and VLDL-cholesterol by the AEX-HPLC, and VLDL-levels by the AGE with lipid-staining and with cholesterol-staining were significantly different in the three groups. In all the subjects, IDL-cholesterol (r=0.531) and VLDL-cholesterol (r=0.880) by the AEX-HPLC method were strongly correlated with RLP-C, but only VLDL levels were correlated with RLP-C in AGE, respectively. CONCLUSION: These results suggest that the AEX-HPLC, which can provide cholesterol levels of not only VLDL but also IDL, is helpful for estimation of lipid profiles in T2DM with high RLP-C.

• IL-1, quo vadis?

  Authors: Alena Grebe, Eicke Latz

  Atherosclerosis.

• PAPP-A negatively regulates ABCA1, ABCG1 and SR-B1 expression by inhibiting LXRα through the IGF-I-mediated signaling pathway.

  Authors: Shi-Lin Tang, Wu-Jun Chen, Kai Yin, Guo-Jun Zhao, Zhong-Cheng Mo, Yun-Cheng Lv, Xin-Ping Ouyang, Xiao-Hua Yu, Huai-Jun Kuang, Zhi-Sheng Jiang, Yu-Chang Fu, Chao-Ke Tang

  Atherosclerosis.

  Pregnancy-associated plasma protein-A (PAPP-A) has been involved in the atherosclerotic process through regulation of local expression of IGF-1 that mediates the activation of thePregnancy-associated plasma protein-A (PAPP-A) has been involved in the atherosclerotic process through regulation of local expression of IGF-1 that mediates the activation of the phosphatidylinositol-3 (PI3-K) and Akt kinase (Akt) signaling cascades which lead to constitutive nitric oxide formation, with its attending vasodilator, antiplatelet and insulin-sensitizing actions. In addition, IGF-1 may decreased cholesterol efflux through reductions of expression in ABCA1 and SR-B1 by the PI3-K/Akt signaling pathway. In the current study, we examined whether PAPP-A was involved in LXRα regulation and in expression of ABCA1, ABCG1 or SR-B1 through the IGF-I-mediated signaling pathway (IGF/PI3-K/Akt). Results showed that PAPP-A significantly decreased expression of ABCA1, ABCG1 and SR-BI at both transcriptional and translational levels in a dose-dependent and time-dependent manner. Cellular cholesterol content was increased while cholesterol efflux was decreased by PAPP-A treatment. Moreover, LXRα which can regulate the expression of ABCA1, ABCG1 and SR-B1, was also down-regulated by PAPP-A treatment. LXRα-specific activation by LXRα agonist almost rescued the down-regulation of ABCA1, ABCG1 and SR-B1 expression by PAPP-A. In addition, PAPP-A can induce the IGF-1/PI3-K/Akt pathway in macrophages. Furthermore, our results indicate that the decreased levels observed in LXRα, ABCA1, ABCG1 and SR-B1 mRNA and protein levels upon treating cells with PAPP-A were strongly impaired with the PI3-K inhibitors or IGF-1R siRNA while the MAPK cascade inhibitor did not execute this effect, indicating that the process of ABCA1, ABCG1 and SR-BI degradation by PAPP-A involves the IGF-1/PI3-K/Akt pathway. In conclusion, PAPP-A may first down-regulate expression of LXRα through the IGF-1/PI3-K/Akt signaling pathway and then decrease expression of ABCA1, ABCG1, SR-B1 and cholesterol efflux in THP-1 macrophage-derived foam cells. Therefore, our study provided one of the mechanisms for understanding the critical effect of PAPP-A in pathogenesis of atherosclerosis.

• Evaluation of possible subclinical atherosclerosis in adolescents with a family history of premature atherosclerosis.

  Authors: Atac Celik, Mustafa Ozcetin, Zekiye Ruken Yuksekkaya Celikyay, Erkan Sogut, Yasemin Yerli, Hasan Kadi, Fatih Koc, Ibrahim Halil Damar, Koksal Ceyhan, Unal Erkorkmaz

  Atherosclerosis.

  OBJECTIVE: To evaluate possible subclinical atherosclerosis using biomarkers and ultrasound-guided methods in a group of adolescents having fathers with premature atherosclerosis. METHODS:OBJECTIVE: To evaluate possible subclinical atherosclerosis using biomarkers and ultrasound-guided methods in a group of adolescents having fathers with premature atherosclerosis. METHODS: Thirty-three subjects whose fathers had a history of premature coronary artery disease and 30 counterparts whose fathers had no history of coronary artery disease were included in the study. RESULTS: The homocysteine levels, high-sensitivity C-reactive protein levels, and cardiac chamber sizes and functions did not differ between the two groups. The carotid stiffness index β (CSI), the intima-media thickness (CIMT) and aortic pulse wave velocity (PWV) values were higher in the group with a family history of coronary artery disease, but only the difference in the CSI was statistically significant (CSI 3.07±1.33 vs 3.88±1.25, P=0.015; CIMT 0.53±0.09mm vs 0.57±0.08mm, P=0.068; PWV 3.49±0.53m/s vs 3.78±0.63m/s, P=0.053). CONCLUSION: Among several markers of subclinical atherosclerosis, the CSI was significantly higher in adolescents who had a family history of premature atherosclerosis. The small sample size, the multifactorial nature of atherosclerosis or the insufficient power of these methods may explain these results.

• Aortic stiffness and calcification in men in a population-based international study.

  Authors: Akira Sekikawa, Chol Shin, J David Curb, Emma Barinas-Mitchell, Kamal Masaki, Aiman El-Saed, Todd B Seto, Rachel H Mackey, Jina Choo, Akira Fujiyoshi, Katsuyuki Miura, Daniel Edmundowicz, Lewis H Kuller, Hirotsugu Ueshima, Kim Sutton-Tyrrell

  Atherosclerosis.

  OBJECTIVES: Aortic stiffness, a hallmark of vascular aging, is an independent risk factor of cardiovascular disease and all-cause mortality. The association of aortic stiffness with aorticOBJECTIVES: Aortic stiffness, a hallmark of vascular aging, is an independent risk factor of cardiovascular disease and all-cause mortality. The association of aortic stiffness with aortic calcification in middle-aged general population remains unknown although studies in patients with end-stage renal disease or elderly subjects suggest that aortic calcification is an important determinant of aortic stiffness. The goal of this study was to examine the association of aortic calcification and stiffness in multi-ethnic population-based samples of relatively young men. METHODS: We examined the association in 906 men aged 40-49 (81 Black Americans, 276 Japanese Americans, 258 White Americans and 291 Koreans). Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV) using an automated waveform analyzer. Aortic calcification from aortic arch to iliac bifurcation was evaluated using electron-beam computed tomography. RESULTS: Aortic calcium score was calculated and was categorized into four groups: zero (n=303), 1-100 (n=411), 101-300 (n=110), and 401+ (n=82). Aortic calcification category had a significant positive association with cfPWV after adjusting for age, race, and mean arterial pressure (mean (standard error) of cfPWV (cm/s) from the lowest to highest categories: 836 (10), 850 (9), 877 (17) and 941 (19), P for trend <0.001). The significant positive association remained after further adjusting for other cardiovascular risk factors. The significant positive association was also observed in each race group. CONCLUSIONS: The results suggest that aortic calcification can be one mechanism for aortic stiffness and that the association of aortic calcification with stiffness starts as early as the 40s.

• Resveratrol inhibits neointimal formation after arterial injury through an endothelial nitric oxide synthase-dependent mechanism.

  Authors: Danna M Breen, Vernon W Dolinsky, Hangjun Zhang, Husam Ghanim, June Guo, Margaret Mroziewicz, Evangelia L Tsiani, Michelle P Bendeck, Paresh Dandona, Jason R B Dyck, Scott P Heximer, Adria Giacca

  Atherosclerosis.

  Revascularization procedures used for treatment of atherosclerosis often result in restenosis. Resveratrol (RSV), an antioxidant with cardiovascular benefits, decreases neointimal formation afterRevascularization procedures used for treatment of atherosclerosis often result in restenosis. Resveratrol (RSV), an antioxidant with cardiovascular benefits, decreases neointimal formation after arterial injury by a mechanism that is still not fully clarified. Our main objective was to address the role of nitric oxide synthases (NOSes) and more specifically the endothelial-NOS (eNOS) isoform as a mediator of this effect. RSV (4mg/kg/day, s.c.) alone or in combination with the NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME) (2mg/kg/day, s.c.) was given to Sprague-Dawley rats beginning at 3 days before arterial (carotid or aortic) injury. RSV reduced neointimal formation by 50% (P<0.01), decreased intimal cell proliferation by 37% (P<0.01) and reduced inflammatory markers such as PECAM and MMP-9 mRNA. These effects of RSV were all abolished by coadministration of l-NAME. Oral RSV (beginning at 5 days before arterial injury) reduced neointimal thickness after femoral wire injury in mice, however this effect was not observed in eNOS knockout mice. This is the first report of RSV decreasing neointimal cell proliferation and neointimal growth through an eNOS-dependent mechanism.

• Evaluation of cytochrome P450-derived eicosanoids in humans with stable atherosclerotic cardiovascular disease.

  Authors: Katherine N Theken, Robert N Schuck, Matthew L Edin, Bryant Tran, Kyle Ellis, Almasa Bass, Fred B Lih, Kenneth B Tomer, Samuel M Poloyac, Michael C Wu, Alan L Hinderliter, Darryl C Zeldin, George A Stouffer, Craig R Lee

  Atherosclerosis.

  OBJECTIVE: Preclinical and genetic epidemiologic studies suggest that modulating cytochrome P450 (CYP)-mediated arachidonic acid metabolism may have therapeutic utility in the management of coronaryOBJECTIVE: Preclinical and genetic epidemiologic studies suggest that modulating cytochrome P450 (CYP)-mediated arachidonic acid metabolism may have therapeutic utility in the management of coronary artery disease (CAD). However, predictors of inter-individual variation in CYP-derived eicosanoid metabolites in CAD patients have not been evaluated to date. Therefore, the primary objective was to identify clinical factors that influence CYP epoxygenase, soluble epoxide hydrolase (sEH), and CYP ω-hydroxylase metabolism in patients with established CAD. METHODS: Plasma levels of epoxyeicosatrienoic acids (EETs), dihydroxyeicosatrienoic acids (DHETs), and 20-hydroxyeicosatetraenoic acid (20-HETE) were quantified by HPLC-MS/MS in a population of patients with stable, angiographically confirmed CAD (N=82) and healthy volunteers from the local community (N=36). Predictors of CYP epoxygenase, sEH, and CYP ω-hydroxylase metabolic function were evaluated by regression. RESULTS: Obesity was significantly associated with low plasma EET levels and 14,15-EET:14,15-DHET ratios. Age, diabetes, and cigarette smoking also were significantly associated with CYP epoxygenase and sEH metabolic activity, while only renin-angiotensin system inhibitor use was associated with CYP ω-hydroxylase metabolic activity. Compared to healthy volunteers, both obese and non-obese CAD patients had significantly higher plasma EETs (P<0.01) and epoxide:diol ratios (P<0.01), whereas no difference in 20-HETE levels was observed (P=NS). CONCLUSIONS: Collectively, these findings suggest that CYP-mediated eicosanoid metabolism is dysregulated in certain subsets of CAD patients, and demonstrate that biomarkers of CYP epoxygenase and sEH, but not CYP ω-hydroxylase, metabolism are altered in stable CAD patients relative to healthy individuals. Future studies are necessary to determine the therapeutic utility of modulating these pathways in patients with CAD.

• Follow-up association study of linkage regions reveals multiple candidate genes for carotid plaque in Dominicans.

  Authors: Chuanhui Dong, Ashley Beecham, Liyong Wang, Susan H Blanton, Tatjana Rundek, Ralph L Sacco

  Atherosclerosis.

  OBJECTIVE: Carotid plaque is a marker of subclinical atherosclerosis with a genetic component. The aim of this follow-up fine mapping study was to identify candidate genes for carotid plaque withinOBJECTIVE: Carotid plaque is a marker of subclinical atherosclerosis with a genetic component. The aim of this follow-up fine mapping study was to identify candidate genes for carotid plaque within four linkage regions. METHODS: We successfully genotyped 3712 single nucleotide polymorphisms (SNPs) under the four linkage regions that were previously identified in 100 extended Dominican families. Family-based association tests were performed to investigate their associations with carotid plaque. Promising SNPs were evaluated in an independent population-based subcohort (N=941, 384 Dominicans) from the Northern Manhattan Study (NOMAS). RESULTS: In the family study, evidence for association (p<0.0005) was found regarding several genes (NAV2, EFCAB11/TDP1, AGBL1, PTPN9, LINGO1 and LOC730118), with the strongest association at rs4143999 near EFCAB11/TDP1 (p=0.00001 for carotid presence and 0.00003 for plaque area, multiple testing corrected p≤0.02). The association in AGBL1 and PTPN9 was mainly driven by the families with linkage evidence (p=0.00008-0.00001 and 0.76-0.32, respectively, in the families with and without linkage evidence). However, these associations explained only a small portion of the observed linkage. In NOMAS, replication (p<0.05 in the whole NOMAS subcohort and p<0.10 in the smaller Dominican subcohort) was found for SNPs within/near EFCAB11, NAV2, AGBL1 and other genes. CONCLUSION: This follow-up study has identified multiple candidate genes for carotid plaque in the Dominican population. Many of these genes have been implicated in neurodegenerative and cardiovascular diseases. Further studies with in-depth re-sequencing are needed to uncover both rare and common functional variants that contribute to the susceptibility to atherosclerosis.

• Statins synergize dexamethasone-induced adipocyte fatty acid binding protein expression in macrophages.

  Authors: Wenquan Hu, Xiaoye Zhou, Meixiu Jiang, Yajun Duan, Yuanli Chen, Xiaoju Li, Zhinan Yin, Guo-Wei He, Zhi Yao, Yan Zhu, David P Hajjar, Jihong Han

  Atherosclerosis.

  OBJECTIVE: Macrophage adipocyte fatty acid binding protein (FABP4) plays an important role in the development of atherosclerosis. We previously reported that dexamethasone induces macrophage FABP4OBJECTIVE: Macrophage adipocyte fatty acid binding protein (FABP4) plays an important role in the development of atherosclerosis. We previously reported that dexamethasone induces macrophage FABP4 mRNA expression. Statins inhibit FABP4 expression. However, it remains unknown that if statins can antagonise dexamethasone-induced macrophage FABP4 expression. METHODS AND RESULTS: We determined the effect of co-treatment of statins and dexamethasone on macrophage FABP4 expression. Unexpectedly, statins did not block the induction of macrophage FABP4 expression by dexamethasone. In contrast, statins synergized dexamethasone-induced FABP4 expression. In vivo, pitavastatin synergized dexamethasone-induced FABP4 expression in both peritoneal macrophages and adipose tissues. Cholesterol and mevalonate, but not farnesylation and geranylgeranylation, inhibited the synergistic induction. Promoter assay disclosed a putative negative glucocorticoid regulatory element (nGRE) in FABP4 gene. Pitavastatin had little effect on expression of glucocorticoid receptor (GR). However, pitavastatin enhanced dexamethasone-mediated GR nuclear translocation but inhibited the binding of GR with nGRE. CONCLUSION: Our study defines an important mechanism involved in the regulation of macrophage FABP4 expression by a glucocorticoid and statins.

• Associations between cellular growth factors and ischemic and hemorrhagic strokes.

  Authors: Yukihiko Momiyama

  Atherosclerosis.

• Asymmetric dimethylarginine in adults with cystathionine β-synthase deficiency.

  Authors: Monica S Rocha, Tom Teerlink, Mirian C H Janssen, Leo A J Kluijtmans, Yvo Smulders, Cornelis Jakobs, Isabel Tavares de Almeida, Isabel Rivera, Rita Castro, Henk J Blom

  Atherosclerosis.

  In hyperhomocysteinemia (HHcy), an independent risk factor for cardiovascular diseases, endothelial dysfunction due to reduced bioavailability of nitric oxide is a consistent finding. However, theIn hyperhomocysteinemia (HHcy), an independent risk factor for cardiovascular diseases, endothelial dysfunction due to reduced bioavailability of nitric oxide is a consistent finding. However, the underlying mechanisms remain unknown. Increased levels of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have been associated with HHcy, and may contribute, at least in part, for the homocysteine-induced endothelial dysfunction, but whether cystathionine β-synthase (CBS) deficiency is associated with increased ADMA has hardly been investigated. To address this question, we measured total homocysteine (tHcy), ADMA and symmetric dimethylarginine (SDMA) in plasma of 22 adult CBS deficient patients, using established HPLC techniques. Results showed that in CBS deficient patients with elevated levels of tHcy (median (total range): 33 (14-237)μmol/L), both ADMA and SDMA levels were normal. Moreover, tHcy and ADMA concentrations were not correlated (r(s)=0.017, p=0.94). Our results favor the hypothesis that the negative vascular effects of HHcy have an ADMA-independent etiology.

• Advances in cell-based therapy for peripheral vascular disease.

  Authors: Arnon Blum, Wayne Balkan, Joshua M Hare

  Atherosclerosis.

  Evidence is accumulating to support cell-based therapies as a new approach for chronic diseases. Perhaps the area of greatest impact, in terms of patient numbers, is cardiovascular disorders. ThisEvidence is accumulating to support cell-based therapies as a new approach for chronic diseases. Perhaps the area of greatest impact, in terms of patient numbers, is cardiovascular disorders. This review considers cell transplantation as a potential treatment for peripheral vascular disease, including ischemic stroke and erectile dysfunction. Bone marrow derived cells are required for endogenous repair in adult individuals affected by angiopathies. Clinical trials using progenitor cells generated from monocytic or non-monocytic cells indicate that both are effective, suggesting that angiogenesis is the result of cross talk between different cells and pathways. Currently, there are 14 registered clinical trials (ClinicalTrials.gov) examining different approaches to stem cell therapy to cure peripheral artery disease, of which 6 have completed enrollment. Here, we will review published clinical studies that used cell transplantation for peripheral vascular ischemic disorders.

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