Atherosclerosis - Articles in Press

Epicardial fat volume and concurrent presence of both myocardial ischemia and obstructive coronary artery disease - Corrected Proof

2012-02-03

Highlights: ► Patients with both ischemia and stenosis had significantly higher CCS. ► Patients with both ischemia and stenosis had significantly higher EFVi. ► EFVi predict concurrent presence of myocardial ischemia and obstructive stenosis.Abstract: Objective: Epicardial fat volume (EFV) is linked to cardiovascular event risk. The aim of this study was to evaluate whether EFV is independently related to concurrent presence of both myocardial ischemia and obstructive coronary stenosis.Methods: We studied 92 consecutive patients without known coronary artery disease (CAD) who underwent Rb-82 PET, coronary calcium scoring (CCS) and invasive coronary angiography (ICA) within 6 months. EFV was computed from non-contrast CT by validated software and indexed to body surface-area (EFVi, cm3/m2). Ischemia was defined by ≥5% difference of total perfusion deficit (quantified by validated software) between stress and rest. Obstructive stenosis was defined ≥50% luminal diameter stenosis.Results: Fifty three patients had both ischemia and stenosis. Compared to those without, patients with both having ischemia and stenosis had significantly higher CCS (1125±1230 vs. 626±690, p=0.02) and EFVi (64.6±20.6 vs. 49.7±14.2cm3/m2, p=0.0002). On multivariable analysis after adjusting age, gender, cardiovascular risk factors, chest pain, and CCS (≥400), only elevated EFVi (>68.1cm3/m2) significantly predicted concurrent presence of both ischemia and stenosis (odds ratio 6.18, 95% confidence interval 1.73–22.01, p=0.005). Area under the receiver-operator-characteristic analysis demonstrated a trend towards improved incremental prediction of concurrent myocardial ischemia and obstructive stenosis over age, gender, chest pain, and high CCS (0.73 vs. 0.65, p=0.09).Conclusions: Our study suggests that elevated EFVi measured using non-contrast CT may be related to concurrent presence of both ischemia and stenosis.

Controversies in dyslipidaemia management - Corrected Proof

Jane Stock — 2012-02-03

While coronary mortality rates have declined over the last few decades, this is challenged by the epidemic of cardiometabolic disease, the major challenge for healthcare providers in the 21st century. This epidemic is not restricted to industrialised countries. China in particular has been in the spotlight. Despite improved access to better treatment, an increasingly Westernised diet has escalated rates of dyslipidaemia () and cardiovascular disease . It is estimated that cardiovascular disease rates in China will increase by more than 50% over the next 20years .

Duration of type 2 diabetes strongly predicts all-cause and cardiovascular mortality in people referred for coronary angiography - Corrected Proof

2012-02-03

Highlights: ► Duration of type 2 diabetes strongly predicts all-cause mortality. ► Duration of type 2 diabetes strongly predicts cardiovascular mortality. ► Considering diabetes duration is important for cardiovascular risk stratification. ► Lifestyle interventions to postpone diabetes onset are encouraged.Abstract: Objective: Type 2 diabetes represents a major cardiovascular risk factor. However, few studies have addressed the impact of the disease duration on mortality. Thus, we aimed to investigate the predictive value of diabetes duration for all-cause and cardiovascular mortality in subjects undergoing coronary angiography.Methods: We studied 2455 participants of the LUdwigshafen RIsk and Cardiovascular health study (1768 males/687 females). They had a mean±standard deviation (SD) age of 63.1±9.0 years (range: 40.0–79.9) and a mean±SD body mass index of 27.7±4.0kg/m2. 704 subjects were newly diagnosed with type 2 diabetes according to the 2010 criteria of the American Diabetes Association and 446 subjects had a known history of type 2 diabetes. The mean±SD duration of the follow-up for all-cause and cardiovascular mortality was 7.7±2.0 years.Results: A total of 543 deaths occurred during the follow-up. Among these, 343 were accounted for by cardiovascular diseases. The duration of type 2 diabetes was strongly and positively correlated with all-cause and cardiovascular mortality (both P<0.001). The multivariate adjusted hazard ratios (95% confidence intervals) for cardiovascular mortality compared to subjects without diabetes were 1.76 (1.34–2.32), 2.86 (2.00–4.08), 2.96 (1.85–4.74), and 4.55 (3.24–6.39) for subjects with new onset type 2 diabetes and subjects with known type 2 diabetes (duration ≤5, >5 and ≤10, >10 years), respectively.Conclusions: The data emphasise the need to consider the diabetes duration for the prediction of mortality in subjects at intermediate to high cardiovascular risk.

The angiographic and clinical outcomes after coronary stenting in patients with metabolic syndrome - Corrected Proof

2012-02-01

Highlights: ► Metabolic syndrome is a risk factor in CAD patients following stent implantation. ► DES implantation decreases angiographic events in metabolic syndrome patients. ► Adequate treatment of MetS is required to improve the outcome in CAD patients.Abstract: Background: Metabolic syndrome (MetS) is regarded as a risk factor for coronary artery disease (CAD). But the influence of MetS on morbidity and mortality after stent implantation in CAD patients remains unknown.Methods: This article presents a meta-analysis of available data on the association between the MetS and the risk of angiographic and clinical outcomes following stent implantation.Results: MetS was associated with a significant increased risk of post-stent all-cause mortality (odd ratio (OR), 2.17, 95% CI, 1.56–3.01), in-lesion restenosis (OR, 1.35, 95% CI, 1.00–1.84) and major adverse cardiac events (MACE) (OR 1.35, 95% CI 1.13–1.61) in CAD patients. Even with drug-eluting stent (DES) implantation, significant increased risk in all-cause mortality (OR, 2.25, 95% CI, 1.61–3.15) and MACE (OR 1.42, 95% CI 1.14–1.76) were remain in patients with MetS. However, the OR of cardiovascular (CV) mortality (1.25, 95% CI 0.71–2.22), MI (1.27, 95% CI 0.87–1.85) and TLR (OR 1.21, 95% CI 0.96–1.53) was not statistically different between the patients with and without metabolic syndrome.Conclusions: Metabolic syndrome is an important risk factor in patients with CAD following stent implantation. Although DES implantation decreased the incidence of angiographic events, further progress in adequate treatment of MetS is still required to improve the clinical outcome.

Effect of Omega-3 fatty acid supplementation on markers of platelet and endothelial function in patients with peripheral arterial disease - Corrected Proof

2012-02-01

Highlights: ► Patient's with intermittent claudication have increased platelet and endothelial activity. ► We performed a cross-over double blind study of 6 week of OMACOR fish oil versus placebo. ► Omega-3 supplementation had no effect on the primary outcome measure von Willebrand factor. ► Omega-3 supplementation had no effect on pulse wave velocity. ► Omega-3 supplementation did not alter platelet aggregation or expression of markers of activation.Abstract: Objective: Omega-3 fatty acids have been shown to reduce platelet and endothelial activation in patients with or at risk of cardiac disease. We aimed to determine if Omega-3 fatty acid supplementation in addition to best medical therapy can reduce the increased platelet and endothelial activity that is present in patients with intermittent claudication.Methods: One hundred and fifty patients who were receiving aspirin and statin therapy were recruited into a randomised cross-over double blind study involving 6 week supplementation with OMACOR fish oil (850–882mg eicosapentaenoic and docosahexaenoic acid) versus placebo. A 12 week washout period occurred between treatments. Patients with diabetes were excluded. For each outcome a random effects model was fitted in which treatment and period were fixed effects and patients were random effects.Results: Omega-3 supplementation had no effect on the primary outcome measure von Willebrand factor. Similarly Omega-3 supplementation resulted in no change in unstimulated or stimulated P-selectin expression and fibrinogen binding, or platelet aggregation (ultegra point of care). Pulse wave velocity was also unchanged. High-sensitivity C-reactive protein, s-ICAM and IL-6 were also unchanged.Conclusion: Supplementation with Omega-3 fatty acids had no affect on platelet and endothelial activation or markers of inflammation in patients with peripheral arterial disease.

Relationship between ambulatory blood pressure and aortic arch atherosclerosis - Corrected Proof

2012-02-01

Highlights: ► The association between BP values and aortic arch atherosclerosis was studied. ► 795 subjects underwent 24-h ambulatory BP monitoring (ABPM) and echocardiography. ► Systolic ABPM variables were associated with the presence of aortic arch plaque. ► Nighttime systolic BP variability was associated with presence of large arch plaque. ► Nighttime systolic BP variability may be associated with arch plaque progression.Abstract: Objective: Atherosclerotic plaque in the aortic arch is an independent risk factor for ischemic stroke. Although high blood pressure (BP) measured at the doctor's office is known to be associated with aortic atherosclerosis, little is known on the association between 24-h ambulatory BP and aortic arch plaque presence and severity. Our objective was to clarify the association between ambulatory BP variables and aortic arch atherosclerosis in a community-based cohort.Methods: The study population consisted of 795 patients (mean age 71±9 years) participating in the Cardiovascular Abnormalities and Brain Lesions (CABL) study who underwent 24-h ambulatory BP monitoring (ABPM). Arch plaque was evaluated by 2D transthoracic echocardiography from a suprasternal window.Results: All systolic ABPM variables (24-h/daytime/nighttime mean systolic BP, daytime/nighttime systolic BP variability) were associated with the presence of any plaque and large (≥4mm) plaque, whereas diastolic BP variables were not associated with aortic atherosclerosis. Multiple regression analysis indicated that nighttime systolic BP variability (expressed as the standard deviation of nighttime systolic BP) remained independently associated with large plaque after adjustment for age, sex, cigarette smoking, history of hypertension, diabetes mellitus, hypercholesterolemia, anti-hypertensive medication and nighttime mean systolic BP (odds ratio 1.39 per 1 standard deviation increase, 95% CI 1.00–1.93, P<0.05).Conclusion: Systolic ABPM variables are significantly associated with the presence of arch plaque. Nighttime systolic BP variability is independently associated with large arch plaque. These findings may have important implications in gaining further insights into the mechanism of arch plaque formation and progression.

Corrigendum to: Cardiovascular actions and therapeutic potential of tanshinone IIA [Atherosclerosis 220 (2012) 3–10] - Corrected Proof

Si Gao, Zhiping Liu, Hong Li, Peter J. Little, Peiqing Liu, Suowen Xu — 2012-02-01

In the above article should have appeared as below.

Publisher's note - Corrected Proof

2012-02-01

Increased leukocyte Rho-associated coiled-coil containing protein kinase activity predicts the presence and severity of coronary vasospastic angina - Corrected Proof

2012-01-31

Highlights: ► ROCK activity increased with the severity of CVA. ► Increased ROCK activity predicted the presence of CVA. ► Treatment with antispastic agents reduced the level of ROCK activity.Abstract: Objective: Although inhibition of Rho-associated coiled-coil containing protein kinase (ROCK) has been shown to prevent coronary vasospastic angina (CVA), direct evidence linking ROCK activity and CVA is lacking. Accordingly, we investigated whether ROCK activity is an independent marker for CVA and is altered after treatment with antispastic medications.Methods and results: We prospectively studied 31 Taiwanese patients who were diagnosed with CVA and 33 control subjects. Subject demographics were recorded, and blood samples were obtained at baseline in all participants and in CVA patients after 3 months of antispastic treatment. Compared with control subjects, leukocyte ROCK activity was greater in CVA patients (136% versus 91%, P<0.001). A cutoff value for leukocyte ROCK activity of 104% predicted the presence of CVA with specificity and sensitivity rates of 88% and 84%, respectively. ROCK activity increased with the severity of CVA (P for trend<0.001). Following 3-month treatment of antispastic agents, leukocyte ROCK activity, high-sensitivity C-reactive protein, and interleukin-6 levels were reduced by 43%, 42% and 27%, respectively (P<0.05 for all).Conclusions: Increased levels of leukocyte ROCK activity independently predicted the presence of CVA and correlated with CVA severity. Treatment with antispastic agents substantially reduced the level of leukocyte ROCK activity.

Sex-specific associations of serum prolactin concentrations with cardiac remodeling: Longitudinal results from the Study of Health Pomerania (SHIP) - Corrected Proof

2012-01-31

Highlights: ► We revealed serum prolactin as a biomarker of cardiac remodeling. ► We examined a population-based observational study with five-year follow-up. ► Prolactin is associated with cardiac remodeling in men but not in women. ► Inverse association of prolactin with left ventricular mass change in men. ► Men with low prolactin had an increased risk of incident left ventricular hypertrophy.Abstract: Background: Previous experimental and patient-based studies suggest that prolactin (PRL) and its 16kDa fragment influence cardiovascular phenotypes by modulating angiogenesis. The association between serum PRL and cardiac remodeling in the general population is unknown.Methods: We evaluated 804 individuals (441 women) from the population-based Study of Health in Pomerania, aged ≥45 years, with available baseline serum PRL who underwent serial echocardiography at baseline and five-year follow-up. Left ventricular mass (LVM) was calculated and left ventricular hypertrophy (LVH) defined by sex-specific distributions of LVM. LV geometry was defined on the basis of relative wall thickness (RWT) and LVH. Sex-specific multivariable regression analyses were performed relating PRL (independent variable modelled as a continuous variable and as sex-specific quartiles) to change in LVM, RWT, and to incident LVH and abnormal geometry.Results: Baseline PRL concentrations were inversely associated with LVM change in men, but not in women (β per 10% decrease in PRL: 0.37; 95% CI, 0.13–0.60 in men and −0.02; 95% CI, −0.21 to 0.17 in women, respectively). In men, baseline PRL concentrations were also inversely associated with incident LVH [first vs. fourth PRL quartile: relative risk (RR) 2.26 (95% CI, 1.20–4.24)] and altered LV geometry on follow-up [RR for incident concentric hypertrophy per 10% decrease in PRL: 1.20 (95% CI, 1.06–1.37)]. None of the longitudinal associations were observed in women.Conclusion: We observed inverse associations of PRL with LVM change, incident LVH, and altered LV geometry in men, but not in women. Additional studies are warranted to confirm our findings and to elucidate the mechanisms underlying these sex-specific associations.

Social disruption stress increases IL-6 levels and accelerates atherosclerosis in ApoE−/− mice - Corrected Proof

Evelina Bernberg, Marcus A. Ulleryd, Maria E. Johansson, Göran M.L. Bergström — 2012-01-30

Abstract: Introduction: We have previously shown that different forms of stress have distinctive effects on atherogenesis in mice. We showed that social stress increase atherosclerosis in ApoE−/− mice, while more physical forms of stress do not. Here we evaluated the effect of social disruption (SDR) stress on atherogenesis and evaluated cytokine release after SDR-stress and five more physical stressors.Methods: Male ApoE−/− mice were exposed to SDR-stress during 12weeks, and atherosclerotic plaque area was assessed in aorta, aortic root and innominate artery. Further, male C57BL/6 mice were exposed to SDR-stress or five physical stressors, and cytokine and corticosterone levels were analyzed in plasma/serum samples immediately after stress.Results: We found a correlation between the level of SDR-stress and atherosclerotic plaque area in aorta and a numerical increased plaque area in aortic root. SDR stress did not affect histological features of plaque composition. However, SDR-stress increased levels of corticosterone, IL-6 and CXCL1. Plasma corticosterone increased for all five physical stressors, but IL-6 and CXCL1 only increased in the group exposed to restraint combined with rat odor.Conclusions: These findings suggest that SDR-stress is indeed atherogenic, in contrast to our previous results using the physical stressors. A possible explanation to this difference is that SDR-stress, but not physical stressors, leads to release of the pro-inflammatory cytokines IL-6 and CXCL1.

DPA n-3, DPA n-6 and DHA improve lipoprotein profiles and aortic function in hamsters fed a high cholesterol diet - Corrected Proof

2012-01-30

Highlights: ► The first report on the cholesterol-lowering activity of isolated docosahexaenoic acid (DPA) n-3 and DPA n-6. ► DPA n-3, DPA n-6 and docosahexaenoic acid (DHA) all reduced plasma cholesterol in hamsters fed a high cholesterol diet. ► Reduction in plasma cholesterol was accompanied by down-regulation of SREBP-2 and HMG-CoA reductase. ► DPA n-3 and DHA improved the aortic function mediated by down-regulation of COX-2.Abstract: The present study examined the cholesterol-lowering activity of omega-3 docosapentaenoic acid (DPA n-3), omega-6 docosapentaenoic acid (DPA n-6) and docosahexaenoic acid (DHA), and their interaction with gene expression of transporters, receptors and enzymes involved in cholesterol absorption and metabolism as well as their effect on aortic function. Forty hamsters were fed either the control diet containing 0.4% stearic acid or one of the three experimental diets containing 0.4% DPA n-3, 0.4% DPA n-6 and 0.4% DHA. Results showed that supplementation of these three fatty acids reduced plasma total cholesterol (TC) and non high-density-lipoprotein cholesterol (non-HDL-C) by 29–33% and 29–50%, respectively, compared with the control. The reduction in TC and non-HDL-C was accompanied by down-regulation of hepatic SREBP-2 and HMG-CoA reductase. Aorta from DPA n-3 and DHA groups was found to have significantly lesser tension and relax better than that from the control and DPA n-6 hamsters, largely mediated by their inhibition on the gene expression of cycloxygense-2 (COX-2). It was concluded that all three fatty acids were beneficial in improving lipoprotein profile with DPA n-3 and DHA having better effect on aortic function.

In vivo assessment of intraplaque and endothelial fibrin in ApoE−/− mice by molecular MRI - Corrected Proof

2012-01-30

Highlights: ► A fibrin-targeted contrast agent (FTCA) allows in vivo imaging of atherosclerosis. ► Late stage plaques show the strongest signal enhancement after FTCA administration. ► FTCA enables the assessment of response to therapy.Abstract: Objective: Molecular magnetic resonance imaging (MRI) has emerged as a promising non-invasive modality to characterize atherosclerotic vessel wall changes on a morphological and molecular level. Intraplaque and endothelial fibrin has recently been recognized to play an important role in the progression of atherosclerosis. This study aimed to investigate the feasibility of intraplaque and endothelial fibrin detection using a fibrin-targeted contrast-agent, FTCA (EPIX Pharmaceuticals, Lexington, MA), in a mouse model of atherosclerosis.Methods: Male apolipoproteinE-knockout mice (ApoE−/−) were fed a high fat diet (HFD) for one to three months. MRI of the brachiocephalic artery was performed prior to and 90min after the administration of FTCA (n=8 per group). Contrast to noise ratios (CNR) and longitudinal relaxation rates (R1) of plaques were determined and compared to ex vivo fibrin density measurements on immunohistological sections stained with a fibrin-specific antibody and gadolinium concentrations measured by inductively coupled mass spectroscopy (ICP-MS).Results: Molecular MRI after FTCA administration demonstrated a significant increase (p<0.05) in contrast agent uptake in brachiocephalic artery plaques. In vivo CNR measurements were in good agreement with ex vivo fibrin density measurements on immunohistochemistry (y=2.4x+11.3, R2=0.82) and ICP-MS (y=0.95x+7.1, R2=0.70). Late stage atherosclerotic plaques displayed the strongest increase in CNR, R1, ex vivo fibrin staining and gadolinium concentration (p<0.05).Conclusion: This study demonstrated the feasibility of intraplaque and endothelial fibrin imaging using FTCA. Direct in vivo fibrin detection and quantification could be useful for characterization and staging of coronary and carotid atherosclerotic lesions, which may aid diagnosis and intervention.

Lymphangiogenesis in aortic valve stenosis—Novel regulatory roles for valvular myofibroblasts and mast cells - Corrected Proof

Suvi Syväranta, Satu Helske, Jani Lappalainen, Markku Kupari, Petri T. Kovanen — 2012-01-27

Highlights: ► Lympatic vessels can be found in human stenotic aortic valves. ► Lymphangiogenic growth factors VEGF-C and VEGF-D are locally produced. ► Myofibroblasts and endothelial cells are their possible sources in aortic valves. ► Mast cells can both induce the expression of VEGF-C and degrade the protein. ► Imbalance between lymphatic and blood vessels may promote disease progression.Abstract: Objective: To investigate mechanisms of lymphangiogenesis in aortic valve stenosis (AS).Methods: Lymphatic vessels were visualized with LYVE-1 staining in 20 control, 5 sclerotic, and 40 stenotic human aortic valves. Vascular endothelial growth factors (VEGFs) VEGF-C and VEGF-D, and their lymphangiogenic receptor VEGFR-3, and the angiogenic VEGFR-2 were analysed by quantitative real-time PCR and immunohistochemistry. Cultured myofibroblasts derived from human stenotic aortic valves, and cultured human mast cells were used to study VEGF-C regulation, and VEGF-C and VEGF-A were quantified from cell culture media by enzyme immunoassays.Results: Lymphatic vessels, VEGF-C, VEGF-D, VEGFR-3 and VEGFR-2 all were present in the aortic valves. In AS, the number of lymphatic vessels and the expression of VEGF-D, VEGFR-3, and VEGFR-2 were increased. Moreover, the numbers of lymphatic vessels correlated positively with those of neovessels (r=0.525, p=0.001) and mast cells (r=0.374, p=0.017). Cultured valvular myofibroblasts produced VEGF-C, and addition of tumour necrosis factor alpha (TNF-α) to the cells augmented its secretion. In contrast, proteases released by activated human mast cells degraded VEGF-C.Conclusion: These results show that lymphangiogenesis is induced in advancing AS. Furthermore, valvular myofibroblasts and activated mast cells were identified as novel regulators of lymphangiogenesis in aortic valves.

The glucagon-like peptide 1 analog liraglutide reduces TNF-α-induced oxidative stress and inflammation in endothelial cells - Corrected Proof

2012-01-27

Highlights: ► Liraglutide can normalize TNF-α-induced pro-oxidant production in HUVEC probably through reduced expression of NADPH oxidase subunit gp91phox and p22phox, reduced membrane translocation of PKC-α, and overexpression of SOD and catalase. ► Liragrutide can also suppress TNF-α-induced NF-kB activation, pentraxin-3 expression and apoptosis of HUVEC. ► In summary, liraglutide can reduce oxidative stress and inflammation in HUVEC.Abstract: Objective: Glucagon-like peptide 1 (GLP-1), one of the incretin hormones, has been reported to increase positive inotropic activity in cardiac myocytes and protect against myocardial injury. However, the effects upon endothelial cells and the mechanisms involved are not fully understood. We assessed the hypothesis that GLP-1 has protective effects against inflammation and oxidative stress on human endothelial cells.Methods and results: The effects of the GLP-1 analog liraglutide upon TNF-α-induced injury of the human umbilical vein endothelial cells (HUVECs) were evaluated. First, ROS induced by TNF-α was measured by staining with CM-H2DCFDA. Intracellular ROS production of HUVECs was significantly decreased in a dose-dependent manner until 30nM while liraglutide inhibited the induction of gp91phox and p22phox, subunit of NADPH oxidase, by TNF-α⋅ In addition, protein levels of SOD-2, catalase and GPx were significantly increased by liraglutide. Second, rapid translocation of PKC-α into the membrane following TNF-α was evident. Liraglutide significantly inhibited this very rapid TNF-α-induced translocation of PKC-α into membrane at 2.5min. Third, liraglutide significantly inhibited NF-κB activation and upregulated I-κB family while phosphorylation of IKK-α/β, which is upstream of NF-κB signaling, was also downregulated after 15min of TNF-α treatment. Finally, liraglutide inhibited apoptosis of HUVEC and expression of Pentraxin-3 induced by TNF-α.Conclusion: Liraglutide exerts marked anti-oxidative and anti-inflammatory effects on endothelial cells with inhibition of PKC-α, NADPH oxidase, NF-κB signaling and upregulation of protective anti-oxidative enzymes.

Functionality of postprandial larger HDL2 particles is enhanced following CETP inhibition therapy - Corrected Proof

2012-01-24

Highlights: ► CETP inhibition preferentially and selectively improves the capacity of large postprandial HDL2b subspecies to mediate cellular FC efflux. ► Postprandial HDL particles from patients treated by CETP inhibitor displayed an elevated ability to deliver CE to hepatic cells. ► Nutritional approach combined with CETP inhibition therapy might represent a promising strategy to modulate anti-atherogenic functions of HDL.Abstract: Objective: To evaluate the impact of CETP inhibition on the capacity of individual postprandial HDL subspecies to promote key steps of the reverse cholesterol transport pathway.Methods: The capacity of HDL particles to mediate cellular free cholesterol efflux and selective hepatic uptake of cholesteryl esters was evaluated throughout postprandial phase (0–8h) following consumption of a standardised mixed meal before and after treatment for 6 weeks with atorvastatin alone (10mg/d) and subsequently with combination torcetrapib/atorvastatin (60/10mg/d) in 16 patients displaying low HDL-C levels (<40mg/dl).Results: The larger HDL2b and HDL2a subfraction displayed a superior capacity to mediate cellular free cholesterol efflux via both SR-BI and ABCG1-dependent pathways than smaller HDL3 subspecies. CETP inhibition specifically enhanced the capacity of HDL2b subfraction for both SR-BI and ABCG1 dependent efflux. However, only the SR-BI-dependent efflux to HDL2b subspecies can be further enhanced during postprandial lipemia following CETP inhibition. Concomitantly, postprandial lipemia was associated with a reduced capacity of total HDL particles to deliver cholesteryl esters to hepatic cells in a drug independent manner.Conclusion: CETP inhibition specifically improves postprandial SR-BI and ABCG1-dependent efflux to larger HDL2b subspecies. In addition, CETP inhibition improves HDL-CE delivery to hepatic cells and maintains an efficient direct return of cholesteryl esters to the liver during postprandial lipemia.

Non-lipid effects of rosuvastatin–fenofibrate combination therapy in high-risk Asian patients with mixed hyperlipidemia - Corrected Proof

2012-01-24

Highlights: ► Rosuvastatin–fenofibrate combination and rosuvastatin monotherapy were compared. ► We randomized 180 Asians with mixed hyperlipidemia with 24-week drug treatment. ► Incidences of muscle or liver enzyme elevation were similar between the two groups. ► The combination changed homocysteine, renal and hematologic parameters more.Abstract: Objective: The aim of this study is to compare the non-lipid effects of rosuvastatin–fenofibrate combination therapy with rosuvastatin monotherapy in high-risk Asian patients with mixed hyperlipidemia.Methods: A total of 236 patients were initially screened. After six weeks of diet and life style changes, 180 of these patients were randomly assigned to receive one of two regimens: rosuvastatin 10mg plus fenofibrate 160mg or rosuvastatin 10mg. The primary outcome variables were the incidences of muscle or liver enzyme elevation. The patients were followed for 24 weeks during drug treatment and for an additional four weeks after drug discontinuation.Results: The rates of the primary outcome variables were similar between the two groups (2.8% and 3.9% in the combination and the rosuvastatin groups, respectively, p=1.00). The combination group had more, but not significantly, common treatment-related adverse events (AEs) (13.3% and 5.6%, respectively) and drug discontinuation due to AEs (10.0% and 3.3%, respectively) than the rosouvastatin group. Combination therapy was associated with higher elevations in homocysteine, blood urea nitrogen, and serum creatinine, whereas elevation in alanine aminotransferase was greater in the rosuvastatin group. Leukocyte count and hemoglobin level decreased to a greater extent in the combination group. The combination group showed greater reductions in TG and elevation in HDL-cholesterol.Conclusion: In our study population, the rosuvastatin–fenofibrate combination resulted in comparable incidences of myo- or hepatotoxicity as rosuvastatin monotherapy. However, this combination may need to be used with caution in individuals with underlying pathologies such as renal dysfunction (NCT01414803).

Dietary fats and dietary cholesterol and risk of stroke in women - Corrected Proof

Susanna C. Larsson, Jarmo Virtamo, Alicja Wolk — 2012-01-24

Abstract: Background: Whether intakes of dietary fat and cholesterol are associated with risk of stroke remain unclear. We examined the associations between intakes of total fat, specific types of fat, and cholesterol and risk of stroke in a prospective cohort of women.Methods: The study population consisted of 34,670 women, aged 49–83 years, in the Swedish Mammography Cohort who were free of cardiovascular disease and completed a food-frequency questionnaire in 1997. Cox proportional hazard regression models were used to estimate relative risks (RR) with 95% confidence intervals (CI).Results: During a mean follow-up of 10.4 years, we ascertained 1680 stroke events, including 1310 cerebral infarctions, 233 hemorrhagic strokes, and 137 unspecified strokes. After adjustment for other stroke risk factors, intake of long-chain omega-3 polyunsaturated fatty acids (PUFA) was inversely associated with risk of total stroke. The multivariable RR of total stroke for the highest compared with the lowest quintile of long-chain omega-3 PUFA intake was 0.84 (95% CI, 0.72–0.99; P for trend=0.04). Dietary cholesterol was positively associated with risk of total stroke (highest versus lowest quintile: RR=1.20; 95% CI, 1.00–1.44; P for trend=0.01) and cerebral infarction (corresponding RR=1.29; 95% CI, 1.05–1.58; P for trend=0.004). Total fat, saturated fat, monounsaturated fat, polyunsaturated fat, α-linolenic acid, and omega-6 PUFA intakes were not associated with stroke.Conclusions: These findings suggest that intake of long-chain omega-3 PUFAs is inversely associated with risk of stroke, whereas dietary cholesterol is positively associated with risk.

A phosphodiesterase 3 inhibitor, K-134, improves hindlimb skeletal muscle circulation in rat models of peripheral arterial disease - Corrected Proof

2012-01-24

Highlights: ► K-134 increases hindlimb muscle blood flow in a rat femoral artery occlusion model. ► K-134 protects against adverse vascular remodeling in ischemic hindlimb muscles. ► K-134 prevents hindlimb necrosis in a laurate-induced peripheral artery injury model. ► K-134 exerts potent antiplatelet and vasodilatory effects.Abstract: Objective: Cilostazol is a phosphodiesterase (PDE)3 inhibitor used to treat peripheral arterial disease with intermittent claudication, as there is clinical evidence that it improves treadmill exercise capacity. However, details of the mechanism underlying this enhanced walking capacity remain to be elucidated.Methods: Based on the hypothesis that PDE3 inhibitors improve peripheral microcirculation in the hindlimbs via vascular smooth muscle relaxation and antiplatelet effects, we examined the effects of a more potent and selective PDE3 inhibitor, K-134, in rat models of peripheral arterial disease (PAD).Results: In a hindlimb ischemia model established by bilateral femoral artery occlusion, oral administration of K-134 for 27 days significantly increased blood flow in hindlimb skeletal muscle after exercise induced by electrical stimulation of the sciatic nerve. Moreover, K-134 enlarged the luminal area of intramuscular arteries and prevented rarefaction of capillary density in the gastrocnemius muscle. These effects were observed without pre-administration on the day following the last administration, suggesting that vasodilatory, antiplatelet and angiogenic activities of K-134 were indirectly responsible for the long-term beneficial effects. In fact, K-134 dose-dependently induced relaxation of rat femoral arteries in vitro, and inhibited rat platelet aggregation ex vivo. Interestingly, in a laurate-induced peripheral vascular injury model, oral administration of K-134 for 6 days prevented progression of hindlimb necrosis.Conclusion: These findings suggest that the beneficial effects of PDE3 inhibitors on walking capacity are due to increased hindlimb skeletal muscle blood flow via intramuscular artery enlargement, and that K-134 is a promising drug for PAD associated with platelet hyperaggregability.

Correlation of peripheral Th17 cells and Th17-associated cytokines to the severity of carotid artery plaque and its clinical implication - Corrected Proof

2012-01-20

Highlights: ► To examine the correlation of Th17 cells and Th17 cytokines to atherosclerotic plaque. ► Th17 cells and Th17 cytokines are correlated to the carotid artery plaque severity. ► Th17 cells and Th17cytokines are correlated to the carotid artery plaque progression.Abstract: Objective: Atherosclerosis is a chronic inflammatory disease regulated by T lymphocyte subsets. Th17 cells reportedly play important roles in the development of inflammatory and autoimmune diseases. In this study, we investigated the contributions of circulating Th17 cells and plasma Th17-associated cytokines to carotid artery plaques.Methods: Based on carotid artery ultrasonography, 280 atherosclerosis patients were categorized both by: (1) 4 levels for extent and severity of plaques (Level 1=least severe; Level 4=most severe) and (2) 5 groups for ultrasound features of carotid artery plaques (none, flat, soft, hard, ulcerated). Peripheral blood Th17 cell frequencies and plasma concentrations of Th17-associated cytokines (IL-17, IL-6, and TNF-α) were also determined.Results: For groups categorized by the extent and severity of carotid artery plaques, Th17 cell frequencies, common carotid artery intima-media thickness (CCA-IMT), and Crouse scores were significantly increased in higher level groups (Levels 3 and 4) than in lower level groups (Levels 1 and 2), and plasma concentrations of IL-17, IL-6, and TNF-α increased with increased levels of plaque severity. The same pattern was found for groups categorized by ultrasound features of carotid artery plaques. The results of Pearson correlation and multiple linear regression analyses showed that both CCA-IMT and Crouse scores for carotid artery plaques were significantly and positively correlated with Th17 cell frequencies and plasma Th17-associated cytokine concentrations.Conclusion: These results suggest that increased frequencies of circulating Th17 cells and Th17-associated cytokines are correlated to the severity and progression of carotid artery plaques.

Plasma osteoprotegerin level on admission is associated with no-reflow phenomenon after primary angioplasty and subsequent left ventricular remodeling in patients with acute ST-segment elevation myocardial infarction - Corrected Proof

2012-01-20

Highlights: ► Osteoprotegerin augments endothelial response to TNF-α by upregulating angiopoietin-2. ► We investigated the relation between OPG, no-reflow and cardiac remodeling. ► TNF-α and Ang-2 had no relation with no-reflow and cardiac remodeling. ► Osteoprotegerin is significantly associated with no-reflow after primary angioplasty. ► Osteoprotegerin is significantly associated with cardiac remodeling at follow-up.Abstract: Objectives: Osteoprotegerin (OPG) upregulates endothelial cell adhesion molecule response to TNF-α by upregulating angiopoietin-2 (Ang-2). The aim of this study was to investigate the association between admission plasma levels of OPG, Ang-2 and TNF-α in patients with acute ST-segment elevation myocardial infarction (STEMI) and no-reflow after primary angioplasty and subsequent left ventricular remodeling (LVR).Methods: Ninety-two patients with first STEMIs, reperfused within 12h of symptom onset, were included. LVR was defined as a >20% increase in LV end-diastolic volume at 6-month follow-up assessed using echocardiography.Results: The incidences of angiographic no-reflow and electrocardiographic no-reflow were 40.2% and 55.4%, respectively. Thirty-six percent of patients subsequently developed LVR. OPG levels were significantly higher in patients who developed angiographic no-reflow (173pg/ml, interquartile range [IQR] 83–416 vs 104pg/ml, IQR 57–235; p=0.04), electrocardiographic no-reflow (160pg/ml, IQR 81–315 vs 102pg/ml, IQR 47–230; p=0.025) and LVR (174pg/ml, IQR 120–342 vs 97pg/ml, IQR 51–219; p=0.004). In multivariable logistic regression, OPG level was an independent predictor of angiographic (OR 1.05: 95% CI 1.01–1.08 [per 10pg/ml increase]; p=0.005) and electrocardiographic (OR 1.04: 95% CI 1.00–1.07 [per 10pg/ml increase]; p=0.04) no-reflow. ROC analysis showed an area under the curve of 0.69 for OPG and LVR. Plasma OPG≥132pg/ml showed a sensitivity of 72% and a specificity of 61% for predicting LVR (OR 4.05: 95% CI 1.06–15.38; p=0.04).Conclusion: High OPG level on admission is significantly associated with no-reflow after primary angioplasty and subsequent LVR at follow-up in patients with STEMI.

Objectively-measured and self-reported physical activity and fitness in relation to inflammatory markers in European adolescents: The HELENA Study - Corrected Proof

2012-01-20

Highlights: ► Atherosclerotic lesions may form during younger years. ► Inflammation plays a key role in atherosclerosis development. ► Physical activity and fitness may be anti-inflammatory factors. ► Fitness plays a direct role on lessening inflammation in adolescence. ► Being active plays an indirect role on inflammation through fitness in adolescence.Abstract: Objective: Atherogenesis involves an inflammatory process that occurs early in life even though clinical symptoms are not observed until adulthood. Two important protective factors for low-grade inflammation may be physical activity (PA) and fitness. We examined the independent associations of objective and subjective measurements of PA and fitness with low-grade inflammation in European adolescents.Methods: A total of 1045 adolescents, aged from 12.5 to 17.5 years old from 10 European cities, were selected from the HELENA-Cross-Sectional Study. Objectively-measured and self-reported PA variables were obtained by accelerometry and the International PA Questionnaire for Adolescents, respectively. Overall, cardiorespiratory, muscular and motor fitness variables were assessed by standardized field-based fitness tests and the International Fitness Scale. C-reactive protein (CRP), complement factors 3 (C3) and 4 (C4), interleukin-6 and TNF-α inflammatory markers were measured.Results: Objectively-measured vigorous PA was inversely associated with C3 (β=−0.094, P=0.021) but it did not remain significant after any objective fitness indicator was included in the model. Other objectively measured or self-reported assessments of PA were not significantly associated with inflammatory markers. All objective measures of fitness were inversely associated with CRP, C3 and C4, whereas only self-reported motor fitness remained significantly associated with C3, C4 and TNF-α. All these observations were independent of age, sex, city and body mass index or waist circumference.Conclusion: High PA in adolescence may play an indirect role on lessening low-grade inflammation through improvements in fitness.

High-resolution radial artery intima-media thickness and cardiovascular risk factors in patients with suspected coronary artery disease – Comparison with common carotid artery intima-media thickness - Corrected Proof

Charlotte Eklund, Peter Friberg, Li-Ming Gan — 2012-01-20

Highlights: ► We explore radial artery IMT and clinical correlates in patients with suspected CAD. ► Very high resolution ultrasound measures radial artery structure with great accuracy. ► Radial artery IMT correlates to traditional risk markers in suspected CAD patients. ► Radial artery IMT might be a novel vascular surrogate marker.Abstract: Objective: The radial artery wall structure can be measured with non-invasive very high-resolution ultrasound with great feasibility and high accuracy. In the present study, we aim to explore clinical correlates of radial artery intima-media thickness (rIMT), in a relatively large patient cohort with suspected coronary artery disease, and further compare those to common carotid artery IMT (cIMT) that is an accepted surrogate marker of atherosclerosis.Methods: Four hundred and sixteen patients referred to myocardial perfusion scintigram (MPS) were recruited, and cIMT and rIMT were scanned using conventional and very high-resolution ultrasound (55MHz transducer), respectively. A number of plasma biomarkers were also measured.Results: Both cIMT and rIMT were similarly correlated with disease history, MPS-verified ischemia, carotid plaque burden, and lipid status. Repeated measurement of rIMT showed acceptable variability.Conclusion: Radial artery IMT may constitute a novel feasible imaging biomarker for systemic atherosclerosis burden, which may be used in future imaging trials to evaluate, e.g. anti-atherosclerotic treatments.

Deviation from Murray's law is associated with a higher degree of calcification in coronary bifurcations - Corrected Proof

2012-01-19

Highlights: ► Associations between Murray's law and plaque composition were studied near coronary bifurcations. ► Patients with smaller daughter vessels in relation to the mother vessel had more dense calcium. ► Deviations from Murray's law may explain why plaque formation often occurs near vessel bifurcations.Abstract: Objective: Murray's law describes the optimal branching anatomy of vascular bifurcations. If Murray's law is obeyed, shear stress is constant over the bifurcation. Associations between Murray's law and intravascular ultrasound (IVUS) assessed plaque composition near coronary bifurcations have not been investigated previously.Methods: In 253 patients plaque components (fibrous, fibro-fatty, necrotic core, and dense calcium) were identified by IVUS in segments proximal and distal to the bifurcation of a coronary side branch. The ratio of mother to daughter vessels was calculated according to Murray's law (Murray ratio) with a high Murray ratio indicating low shear stress. Analysis of variance was used to detect independent associations of Murray ratio and plaque composition.Results: Patients with a high Murray ratio exhibited a higher relative amount of dense calcium and a lower amount of fibrous and fibro-fatty tissue than those with a low Murray ratio. After adjustment for age, sex, cardiovascular risk factors or concomitant medications, the Murray ratio remained significantly associated with fibrous volume distal (F-ratio 4.90, P=0.028) to the bifurcation, fibro-fatty volume distal (F-ratio 4.76, P=0.030) to the bifurcation, and dense calcium volume proximal (F-ratio 5.93, P=0.016) and distal (F-ratio 5.16, P=0.024) to the bifurcation.Conclusion: This study shows that deviation from Murray's law is associated with a high degree of calcification near coronary bifurcations. Individual deviations from Murray's law may explain why some patients are prone to plaque formation near vessel bifurcations.

The removal from plasma of chylomicrons and remnants is reduced in heterozygous familial hypercholesterolemia subjects with identified LDL receptor mutations: Study with artificial emulsions - Corrected Proof

2012-01-18

Highlights: ► Chylomicron-like emulsion can test the plasma catabolism of chylomicrons in men. ► The clearance of chylomicrons was reduced in heterozygous familial hypercholesterolemia. ► No changes in lipolysis were detected.Abstract: Chylomicron remnants bind to both their specific receptors (LRP) and to the LDL receptor (LDLR) in the liver. There is controversy whether disturbances of chylomicron metabolism occur in subjects with familial hypercholesterolemia (FH). The aim of this study was to evaluate whether there are defects on the removal from plasma of chylomicrons and their remnants in heterozygous FH patients with determined LDLR mutations. We studied 20 heterozygous FH patients (43.2±12 years old, 60% males) and 50 normolipidemic subjects matched for age and gender. FH subjects were not in use of LDL-lowering drugs for at least 6 weeks. The removal from plasma of chylomicrons and their remnants was measured by isotopic decay after venous injection of a chylomicron-like emulsion radiolabeled with 14C-cholesteryl ester (14C-CE) and 3H-triolein (3H-TO). These track respectively removal from plasma of chylomicrons and remnants and lipolysis. There was a significant reduction in the fractional catabolic rates (FCR in h−1) of 14C-CE in FH in comparison with normolipidemics: 0.048 (1.46.10−7; 0.57) vs. 0.71(0.049; 1.62), [median (25th–75th percentile)], p=0.003. No differences were found in FCR of 3H-TO between FH and controls, respectively 1.62 (1.02; 2.331) and 1.914 (1.34; 2.878), p=0.405. In conclusion heterozygous FH subjects had a significant decrease on the removal from plasma of chylomicrons and their remnants compared with normolipidemics.

Non-high-density lipoprotein cholesterol is a practical predictor of long-term cardiac death after coronary artery bypass grafting - Corrected Proof

2012-01-16

Highlights: ► We investigated predictive value of non-HDL-C for long-term prognosis after CABG. ► Increased non-HDL-C levels are significantly associated with the cardiac death. ► Non-HDL-C is a practical predictor of cardiac death for secondary prevention. ► Non-HDL-C is an independent predictor of cardiac death beyond other lipids.Abstract: Background: Recent studies have demonstrated that non-high-density lipoprotein cholesterol (non-HDL-C) can predict the risk of cardiovascular events among general population without coronary heart disease (CHD). However, few studies have investigated the predictive value of non-HDL-C for long-term prognosis in patients with CHD. The purpose of this study was to investigate whether non-HDL-C can predict long-term cardiovascular events in patients with CHD who underwent coronary artery bypass grafting (CABG).Methods: We enrolled 1074 consecutive patients who underwent CABG at Juntendo University Hospital between 1984 and 1994, and obtained mortality data through 2000. We divided the patients into 2 groups by the median non-HDL-C level at baseline (180mg/dL) and used Kaplan–Meier method with log-rank test for survival analyses. Cox proportional-hazard regression model was used to calculate the relative risk (RR) of cardiac death.Results: The mean follow-up period was 10.6±3.5 years. The survival rate of cardiac death was significantly lower in the high non-HDL-C group than that in the low non-HDL-C group (log-rank test; p=0.006). Furthermore, in proportional regression analysis adjusted for conventional coronary risk factors, metabolic syndrome, statin treatment, and use of artery bypass graft, the increased levels of non-HDL-C were significant and independent predictor of cardiac death beyond other lipid parameters (RR1.22; by 10mg/dL non-HDL-C increasing, 95% confidence interval 1.03–1.44; p<0.05).Conclusions: The increased levels of non-HDL-C were significantly associated with an increased risk of cardiac death. Baseline non-HDL-C levels may be a practical predictor of long-term cardiac death in patients with CHD after CABG.

Serum albumin as a determinant of cortisol release in patients with acute ischemic stroke - Corrected Proof

Tomasz Dziedzic, Joanna Pera, Marcin Wnuk, Andrzej Szczudlik, Agnieszka Slowik — 2012-01-16

Highlights: ► Protein malnutrition could lead to excessive cortisol release. ► Both hypoalbuminemia and hypercortisolemia are poor prognosticators in ischemic stroke. ► We determine the association between serum albumin and cortisol in ischemic stroke patients. ► Low serum albumin was associated with increased risk of hypercortisolemia.Abstract: Objective: Animal studies demonstrated that protein malnutrition increases pituitary-adrenorcortical activity and leads to excessive cortisol release. The aim of our study was to determine the association between serum albumin and cortisol level in patients with acute ischemic stroke.Methods: Fifty-nine patients with first-ever ischemic stroke were included. Serum albumin level was measured within 36h after stroke symptoms onset. Serum cortisol was measured between 36 and 72h after stroke onset at 6 a.m., 10 a.m., 6 p.m. and 10 p.m.Results: The patients in upper tertile of serum albumin had significantly lower cortisol level measured at 6 a.m. (median with interquartiles: 549.0 [430.4–667.7]nmol/L vs 590.4 [482.8–918.7]nmol/L, P=0.047) and 10 a.m. (402.8 [344.9–510.4]nmol/L vs 634.6 [482.8–827.7]nmol/L, P<0.01) than patients in lower and middle tertiles. On logistic regression analysis adjusted for age and stroke severity, patients in lower and middle tertile of serum albumin had about 7-times higher risk of hypercortisolemia than patients in upper tertile (P<0.01).Conclusions: Low serum albumin level in patients with ischemic stroke is associated with higher serum cortisol level and predisposes to hypercortisolemia.

The potent different risk factors for cerebral infarction in young patients with and without type 2 diabetes: Subanalysis of the Young Cerebral Infarction Study (YCIS) - Corrected Proof

2012-01-16

Highlights: ► We reviewed the clinical features and short-term outcome at discharge of all diabetic and no-diabetic young stroke patients. ► The predictors of short-term outcome were more likely to be TOAST subtype, initial stroke severity and serum uric acid. ► The predictors of diabetic stroke patients were age at onset, dyslipidemia, initial stroke severity and serum fibron levels.Abstract: Background: To compare risk factors, stroke characteristics, and short-term prognosis between diabetic and nondiabetic young ischemic stroke patients to provide information for patient management, counseling, and future research in these patient groups.Methods: All consecutive patients between the ages of 18 and 45 years with first-ever cerebral infarction during 2001–2010 were recruited to participate in the study. Using multivariate logistic regression modeling, demographic characteristics, cerebrovascular risk factors, clinical events, stroke subtypes, and outcome in ischemic stroke patients with and without diabetes were compared.Results: Logistic regression analysis adjusted for confounders confirmed the following independent susceptibility markers: in a substudy of young patients with and without diabetes, the predictors of short-term outcome were more likely to be TOAST subtype, initial stroke severity and serum uric acid, and age at onset, dyslipidemia, initial stroke severity and serum fibron levels correlate with a higher risk for incident stroke in young with diabetes.Conclusion: Our findings suggest that diabetic and nondiabetic ischemic stroke patients exhibit a distinct risk-factor and etiologic profile and may help clinicians to assess prognosis more accurately.

The Barcelona-Asymptomatic Intracranial Atherosclerosis (AsIA) study: Prevalence and risk factors - Corrected Proof

2012-01-16

Highlights: ► We assessed prevalence of intracranial atherosclerosis among stroke-free Caucasians. ► We found a prevalence of 8.6% in a population with moderate-high vascular risk. ► Diabetes and age were independently associated with this condition.Abstract: Background and purpose: The ongoing population-based Barcelona-Asymptomatic Intracranial Atherosclerosis (Barcelona-AsIA) study is a prospective study that plans to investigate the natural history of asymptomatic intracranial atherosclerosis (AsIA) in a Caucasian-Mediterranean population, which remains unknown until now. The present study aims to determine the prevalence of AsIA and associated risk factors in the final study cohort.Methods: Crossover, population-based study of a representative sample (randomly selected from our reference population) older than 50 with a moderate-high vascular risk assessed by the vascular equation REGICOR and prior history of neither stroke nor ischemic heart disease. Anthropometric, demographic, clinical data and blood samples were collected at baseline. All individuals underwent a complete extracranial and transcranial color-coded duplex (TCCD) examination. TCCD criteria were used to identify and classify the degree of intracranial stenoses.Results: A total of 933 subjects (64% men, mean age 66.3 years) were included in the study. One or more intracranial stenoses were detected at baseline in 80 subjects (8.6%) of whom 31 (3.3%) had moderate-severe lesions. The higher the REGICOR scores the greater the prevalence of AsIA (6.6%, 10.2% and 25% for REGICOR scores 5–9, 10–14 and ≥15, p<0.001). Diabetes (OR 2.95; 95% CI (1.68–5.18); p<0.001), age (OR 1.05; 95% CI (1.02–1.08); p=0.001) and hypertension (OR 1.78; 95% CI (1.02–3.13); p=0.04) were independently associated with any degree of AsIA, while diabetes (OR 2.85; 95% CI (1.16–6.96); p=0.02) and age kept independently associated with moderate-severe AsIA.Conclusion: The prevalence of AsIA and moderate-severe AsIA in stroke-free Caucasians with a moderate-high vascular risk were 8.6% and 3.3% respectively. Diabetes and age were independently associated with moderate-severe AsIA.

Molecular characterization of familial hypercholesterolemia in Spain - Corrected Proof

2012-01-16

Abstract: Familial hypercholesterolemia (FH), characterized by isolated elevation of plasmatic low-density lipoprotein (LDL) cholesterol and premature coronary heart disease (CHD), is associated with mutations in three major genes: LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin 9 (PCSK9). We have analyzed 5430 Spanish index cases and 2223 relatives since 2004 with LIPOchip® genetic diagnostic platform, a microarray for the detection of Spanish common mutations in these three genes, including copy number variation (CNV) in LDLR, followed by sequencing analysis of the coding regions of LDLR and exon 26 of APOB, when the result is negative. Samples were received from hospitals of all around Spain. The preferred clinical criterion to diagnose FH was Dutch Lipid Clinic Network (DLCN) score. Our results show that there is a broad spectrum of mutations in the LDLR gene in Spain since about 400 different mutations were detected, distributed along almost the whole LDLR gene. Mutations in APOB (mainly p.Arg3527Gln) covered 6.5% of positive cases and only one PCSK9 mutation was detected. We found correlation between more severe mutations and the clinical diagnosis but also that 28% of FH patients harboring mutations do not have a definite clinical diagnosis. This study analyzes the mutation spectrum in Spain, remarks the importance of genetic diagnosis of FH patients, as well as the cascade screening, and shows how it is being carried out in Spain.

International Atherosclerosis Research School (iARS) 2011 in Prague, Czech Republic - Corrected Proof

Katrin Laatsch — 2012-01-16

Last August, the annual International Atherosclerosis Research School (iARS) took place, for the first time, in Prague, Czech Republic. The organisers were successful in locating a venue comparable to the Elsa-Brändström-Haus in Hamburg, Germany, where the iARS and its predecessors had been held for the last five years. The new site, which fit perfectly with the spirit of the iARS, was the lovely Hotel Nosál, a beautiful, peaceful place in the green outskirts of Prague with excellent public transport connection to the city. It offered a private and quiet location which was ideal for the aims of the iARS and which closely resembled the atmosphere so much appreciated in Hamburg.

Circulating endothelial and platelet derived microparticles reflect the size of myocardium at risk in patients with ST-elevation myocardial infarction - Corrected Proof

2012-01-16

Highlights: ► Microparticles are small membrane vesicles, released from activated, damaged and apoptotic cells. ► Endothelial (EMP) and platelet (PMP) microparticles were quantified in patients with first time ST-elevation myocardial infarction (STEMI). ► The numbers of EMP and PMP correlated to the myocardium at risk, but not to infarct size assessed by cardiac magnetic resonance.Abstract: Objectives: Microparticles (MP) are small membrane vesicles, released from activated, damaged and apoptotic endothelial cells (EMP) or platelets (PMP) that may actively modulate inflammation, coagulation and vascular function. We tested the hypothesis that the number of circulating EMP or PMP in acute myocardial infarction correlates with the myocardium at risk (MaR) and infarct size (IS).Methods: EMP were quantified in plasma samples of 36 patients (age: 63±10 years) with first time ST-elevation myocardial infarction (STEMI) using flow cytometry. EMP were defined as CD31+/CD42− MP and CD144+ MP and PMP as CD31+/CD42+ MP. MaR and IS was determined by cardiovascular magnetic resonance imaging one week after the index event.Results: Plasma levels of CD31+/CD42− EMP were 251.0±178.8/μl and CD144+ 106.3±33.7/μl. PMP levels were 579.2±631.8/μl. MaR was 31.0±11.2% of the left ventricle and IS was 11.4±7.1% of the left ventricle. Patients with STEMI in the left anterior descending artery had higher levels of CD31+/CD42− EMP and PMP than those with other infarct-related arteries (p<0.05). The numbers of CD31+/CD42− EMP and PMP correlated to MaR, but not to IS.Conclusions: Circulating EMP and PMP correlate to the size of MaR in patients with STEMI suggesting that they reflect the severity of the endothelial injury and platelet activation during myocardial ischemia.

Animal models of vascular calcification - Corrected Proof

Ognen Ivanovski, Igor G. Nikolov — 2012-01-16

We read with interest the article by Awan Z et al. entitled “The LDLR deficient mouse as a model for aortic calcification and quantification by micro-computed tomography” . In their study, they explore the effect of age and diet on vascular calcification by micro-computerized tomography (micro-CT) in LDLR deficient (Ldlr−/−) mice. The authors compared chow fed Ldlr−/− mice to controls at 6, 12 and 18 months and on a Western diet (WD) at 6 months and found out that vascular calcification was most prominent in 18-month-old Ldlr−/− mice fed a chow diet and in 6-month-old Ldlr−/− mice fed a western diet. Additionally, they compared controls to Ldlr−/− mice and transgenic mice Tg(Pcsk9) overexpressing PCSK9, which promotes LDLR degradation and found out developed aortic calcifications as well, suggesting that abnormal regulation of the LRP5/Wnt pathway may play a role in the calcification process. The authors developed a novel technique to reliably assess the site and extent of aortic calcification digitally in these animals. We would like to give several comments related to this article.

White blood cell count is associated with carotid and femoral atherosclerosis - Corrected Proof

2012-01-16

Highlights: ► Atherosclerosis is an inflammatory disease. ► Easy-to-measure, low-cost inflammatory markers are needed for CVD risk assessment. ► WBCC, but not CRP, was independently associated with carotid and femoral IMT and plaque. ► The association was similar in normolipidemic and dyslipidemic individuals. ► The association was stronger for increased atherosclerotic burden.Abstract: Objective: Chronic low-grade inflammation is associated with atherosclerosis. Ultrasound imaging allows measurement of intima-media thickness (IMT) and plaque. We investigated the association between inflammatory markers and carotid and femoral atherosclerosis.Methods: We studied 554 subjects with primary dyslipidemia (57% men, median age 49 years) and 246 age- and sex-matched normolipidemic subjects. Carotid and femoral arteries were imaged bilaterally with a standardized protocol. Mean and maximum common carotid IMT (CC-IMT and MaxCC-IMT) and common femoral IMT (F-IMT and MaxF-IMT), and carotid and femoral plaque were assessed. Carotid atherosclerosis was defined by CC-IMT and/or plaque height >75th percentile of a reference population. White blood cell count (WBCC) was measured in all subjects. High-sensitivity C-reactive protein (CRP) was measured in 330 dyslipidemic subjects.Results: The age- and sex-adjusted probability of carotid atherosclerosis and femoral plaque increased by 20% (odds ratio [OR] 1.20; 95% CI, 1.10–1.31) and 25% (1.25; 1.13–1.38), respectively, for each 1000/mm3 WBCC increment. WBCC was associated with age- and sex-adjusted CC-IMT and MaxCC-IMT (p<0.05, both), and F-IMT and MaxF-IMT (p<0.001, both). Adjustment for cardiovascular risk factors did not influence these associations. CRP was associated with CC-IMT and MaxCC-IMT (p<0.05, both), but the associations disappeared after adjustment for body mass index. CRP was unrelated to carotid plaque or measures of femoral atherosclerosis.Conclusions: WBCC, but not CRP, related to early and advanced measures of atherosclerosis independently of risk factors. Our findings support using the heretofore undervalued WBCC as an easy-to-measure, low-cost diagnostic marker of atherosclerosis.

Is the bioresorbable scaffold a sealing device? - Corrected Proof

Nieves Gonzalo, Javier Escaned — 2012-01-13

Over the last 2 decades the relationship between atheromatous plaque structure and composition and acute coronary syndromes has received a great deal of attention. The information gathered from post-mortem and in vivo observations with intracoronary imaging led to the identification of plaque patterns consistently linked to rupture and subsequent thrombosis, the so called high-risk plaques or “vulnerable plaques”. Among them, the predominant type in autopsy studies of patients dying from cardiac cause is the thin-cap fibroatheroma (TCFA). These plaques are characterized by the presence of a large lipid-necrotic core, covered by a thin fibrous cap (<65μm), and frequently present positive remodelling . An uneven distribution of tensile stress resulting from this heterogeneous structure, which typically concentrates in the thin cap shoulders and elicits macrophage infiltration, has been proposed to explain the propensity of these plaques to rupture.

The lipoprotein lipase (LPL) S447X gain of function variant involves increased mRNA translation - Corrected Proof

2012-01-13

Highlights: ► A common LPL gain-of-function variant has favorable clinical features. ► The base change in this LPL variant changes LPL mRNA translation. ► Variant RNA constructs were less susceptible to inhibition by an RNA binding complex.Abstract: Objective: A common gain-of-function LPL variant, LPLS447X, has favorable clinical features and involves a C→G base change at nucleotide 1595 of the LPL cDNA, along with a haplotype, which includes other non-coding SNPs. The mechanism for the LPL gain-in-function is not clear. LPL translation is regulated by epinephrine by an RNA–protein complex, consisting of PKA subunits and an A kinase anchoring protein (AKAP), which targets the 3′UTR.Methods: To examine LPL translation of the LPLS447X variant, in vitro translation of LPL mRNA constructs was studied in the presence of cytoplasmic extracts from 3T3-F442A adipocytes treated with/without epinephrine.Results: When the C→G base change at nucleotide 1595 was introduced, LPL mRNA was less susceptible to inhibition by the adipocyte extract. Similarly, a lessened susceptibility to translation inhibition occurred when the complete haplotype was constructed in the full-length 3.6kb LPL mRNA, when an irrelevant coding sequence was introduced into the LPL mRNA construct, and in response to the use of components of the RNA binding complex (PKA C and R subunits, and KH region of AKAP149).Conclusion: These studies suggest that the LPLS447X gain of function may be due to the base change in the LPL mRNA resulting in a decreased susceptibility to translational inhibition.

Retinal vessel diameter, obesity and metabolic risk factors in school children (JuvenTUM 3) - Corrected Proof

2012-01-13

Abstract: Background: The prevalence of childhood obesity is high and its association with future cardiovascular disease in adulthood is well established. The cross-sectional data presented analyze the prevalence of obesity and the association between metabolic risk factors, physical inactivity and retinal vessel diameter in young school children.Methods: The examination included 578 school children aged 11.1±0.6years from secondary schools in the District of Munich, Germany. Anthropometric measurements and blood sampling were conducted using standard protocols for children. Physical activity was evaluated by use of a questionnaire. Retinal microvascular diameters and the arteriolar to venular ratio (AVR) were assessed with a non-mydriatic vessel analyser (SVA-T) using a computer-based program.Results: In our population, 128 (22.2%) children were overweight (ow) or obese (ob). The mean retinal arteriolar and venular calibres were 208.0±15.6μm and 236.2±16.2μm, respectively, with a mean AVR of 0.88±0.01. Girls had significantly wider arteriolar and venular diameters compared to boys (p<0.001). ow and ob children had a lower AVR compared to normal weight (nw) children (mean(95% CI); nw: 0.89(0.88–0.89); ow: 0.87(0.86–0.88); ob: 0.85(0.83–0.87); p≤0.05). Wider venular diameters were independently associated with higher BMI and higher hsCRP. Blood pressure was associated with retinal vessel constriction. Higher physical inactivity and BMI were independently associated with a reduced AVR (p=0.032 and p<0.001, respectively).Conclusions: Cardiometabolic risk factors and physical inactivity are associated with retinal microvascular alterations in young children, comparable to associations in adults. Retinal vessel imaging seems to be a feasible assessment for the detection of microvascular impairments in children at risk of developing cardiovascular disease in adulthood.

Differential expression of Toll-like receptor 4 and human monocyte subsets in acute myocardial infarction - Corrected Proof

2012-01-13

Highlights: ► The expression levels of TLR4 on CD14+ monocytes were significantly elevated in patients with AMI. ► TLR4 expression levels on CD14+CD16+ monocytes were significantly elevated at culprit site compared with the systemic levels. ► Plasma levels of tumor necrosis factor-α were positively correlated with TLR4 expression levels on monocytes in patients with AMI.Abstract: Objective: To investigate the involvement of Toll-like receptor 4 (TLR4) expression on two monocyte subsets in the pathologic processes related to acute coronary syndrome. How monocytes, which have recently been shown to comprise two distinct subsets, mediate the process of coronary plaque rupture remains to be fully elucidated. Recent studies have shown that TLR4 is involved in monocyte activation of patients with accelerated forms of atherosclerosis.Methods: We enrolled 65 patients with acute myocardial infarction (AMI, n=22), unstable angina pectoris (UAP, n=16), and stable angina pectoris (SAP, n=27) who underwent coronary angiography and 15 healthy controls. The expression of TLR4 on two monocyte subsets (CD14+CD16− and CD14+CD16+) was measured by flow cytometry.Results: In patients with AMI, TLR4 was more expressed on circulating CD14+CD16+ monocytes than on CD14+CD16− monocytes (p<0.001). The expression levels of TLR4 on CD14+CD16+ monocytes were significantly elevated in patients with AMI compared with other 3 groups. TLR4 expression levels on CD14+CD16+ monocytes were significantly elevated at the culprit site compared with the systemic level (p=0.044). The up-regulation of TLR4 on admission was remarkably decreased 12 days after AMI (p<0.001). In addition, plasma levels of tumor necrosis factor-α were positively correlated with TLR4 expression levels on monocytes in patients with AMI (r=0.47, p=0.027).Conclusion: TLR overexpression on CD14+CD16+ monocytes in AMI, as demonstrated both in the circulation and at the coronary culprit site, might be associated with the pathogenesis of AMI.

Uric acid is not an independent predictor of cardiovascular mortality in type 2 diabetes: A population-based study - Corrected Proof

2012-01-12

Abstract: Objective: Although some studies have suggested that uric acid is a risk factor for mortality, this relationship is still uncertain in people with type 2 diabetes.Methods: The study base was the population-based cohort of 1540 diabetic subjects (median age 68.9 years) of the Casale Monferrato Study. The role of serum uric acid on 15-years all-cause, cardiovascular and non-cardiovascular mortality was assessed by multivariate Cox proportional hazards modeling.Results: Baseline levels of serum uric acid were negatively correlated with HbA1c, were higher in men and in the elderly and were independently associated with components of the metabolic syndrome. Out of 14,179 person-years, 1000 deaths (514 due to cardiovascular diseases) were observed. Compared to the lower quartile of uric acid, HRs (95% CI) in the upper quartile were 1.47 (1.22–1.76) for all-cause mortality; 1.40 (1.09–1.80) for cardiovascular mortality and 1.50 (1.15–1.96) for non-cardiovascular mortality. In multiple adjusted models, however, HRs were 1.30 (1.06–1.60) for all-cause mortality, 1.13 (0.85–1.50) for cardiovascular mortality and 1.50 (1.11–2.02) for non-cardiovascular mortality (men 1.87, 1.19–2.95; women 1.20, 0.80–1.80); the latter appeared to be due to neoplastic diseases (HR in all combined quartiles vs. lower quartile: both sexes 1.59, 1.05–2.40; men 1.54, 0.83–2.84, women 1.68, 0.95–2.92).Conclusions: In diabetic people, uric acid is associated with components of the metabolic syndrome but it may not be accounted as an independent risk factor for cardiovascular mortality. The increased all-cause mortality risk with higher levels of uric acid might be due to increased neoplastic mortality and deserves future studies.

Thioredoxin interacting protein genetic variation is associated with diabetes and hypertension in the Brazilian general population - Corrected Proof

2012-01-11

Abstract: Objective: To investigate the relationship between TXNIP polymorphisms, diabetes and hypertension phenotypes in the Brazilian general population.Methods: Five hundred seventy-six individuals randomly selected from the general urban population according to the MONICA-WHO project guidelines were phenotyped for cardiovascular risk factors. A second, independent, sample composed of 487 family-trios from a different site was also selected. Nine TXNIP polymorphisms were studied. The potential association between TXNIP variability and glucose-phenotypes in children was also explored. TXNIP expression was quantified by real-time PCR in 53 samples from human smooth muscle cells primary culture.Results: TXNIP rs7211 and rs7212 polymorphisms were significantly associated with glucose and blood pressure related phenotypes. In multivariate logistic regression models the studied markers remained associated with diabetes even after adjustment for covariates. TXNIP rs7211 T/rs7212 G haplotype (present in approximately 17% of individuals) was significantly associated to diabetes in both samples. In children, the TXNIP rs7211 T/rs7212 G haplotype was associated with fasting insulin concentrations. Finally, cells harboring TXNIP rs7212 G allele presented higher TXNIP expression levels compared with carriers of TXNIP rs7212 CC genotype (p=0.02).Conclusion: Carriers of TXNIP genetic variants presented higher TXNIP expression, early signs of glucose homeostasis derangement and increased susceptibility to chronic metabolic conditions such as diabetes and hypertension. Our data suggest that genetic variation in the TXNIP gene may act as a “common ground” modulator of both traits: diabetes and hypertension.

Interleukin-1 receptor type-1 in non-hematopoietic cells is the target for the pro-atherogenic effects of interleukin-1 in apoE-deficient mice - Corrected Proof

2012-01-11

Highlights: ► We generated apoE/IL-1R1 double knockout (DKO) mice. ► IL-1R1 deficiency in bone marrow-derived cells did not attenuate atherosclerosis. ► DKO transplanted with IL-1R1+/+ cells had reduced lesion area compared to apoE KO. ► Aortas from DKO had lower mRNA levels of inflammatory genes compared to apoE KO. ► IL-1R1 blockade inhibited endothelial cell activation in HUVEC.Abstract: Objectives: Interleukin (IL)-1 produced by vascular and bone marrow-derived cells exerts proinflammatory effects in these cell types by binding to IL-1 receptor type-1 (IL-1R1). We have previously shown that bone marrow-derived IL-1α and IL-1β are critical for atherogenesis in apoE knockout (KO) mice. The aim of the present study was to investigate whether IL-1R1 on vascular wall resident or bone marrow-derived cells mediates IL-1's effects in atherogenesis.Methods and results: We generated apoE−/−/IL-1R1−/− double knockout (DKO) mice and created radiation chimeras. Aortic sinus lesion area was 20–47% lower in DKO compared to apoE KO mice with similar plasma lipids. The production of IL-1α and IL-1β upon stimulation with LPS was not altered in IL-1R1−/− compared to IL-1R1+/+ peritoneal macrophages. DKO mice transplanted with IL-1R1+/+ bone marrow-derived cells had reduced (48%) aortic sinus lesion compared to apoE KO mice while specific deficiency of IL-1R1 in bone marrow-derived cells did not attenuate atherosclerosis. The mRNA levels of genes that promote macrophage recruitment to the vascular wall, namely CD68, VCAM-1, ICAM-1 and MCP-1 were lower in aortas from DKO compared to apoE KO mice. Finally, blockade of IL-1R1 with IL-1R antagonist (IL-1Ra) resulted in complete abrogation of IL-1β-induced expression of adhesion and chemotactic molecules and IL-1α, in isolated human umbilical vein endothelial cells (HUVEC).Conclusions: Vascular wall resident cells are the main targets for the pro-atherogenic effects of bone marrow-derived IL-1 through IL-1R1, partly by induction of adhesion and chemotactic molecules in endothelial cells.

Impaired coronary flow reserve in young patients affected by severe psoriasis - Corrected Proof

2012-01-11

Abstract: Objective: Our study aimed to evaluate the effects of psoriasis (Pso) on coronary microvascular function and whether there is a relationship between disease activity scores and coronary blood flow abnormalities.Methods: 56 young patients (pts) with Pso (42 M, aged 37±3 years) without clinical evidence of cardiovascular diseases, and 56 controls matched for age and gender were studied. Coronary flow velocity in the left anterior descending coronary artery was detected by transthoracic echocardiography at rest and during adenosine infusion. Coronary flow reserve (CFR) was the ratio of hyperaemic diastolic flow velocity (DFV) to resting DFV. A CFR≤2.5 was considered abnormal.Results: In pts with Pso, CFR was lower than in controls (3.2±0.9 vs. 3.7±0.7, p=0.02). CFR was abnormal (≤2.5) in 12 pts (22% vs. 0% controls, p<0.0001). Moreover, in pts with CFR≤2.5, Psoriasis Area Severity Index (PASI), a clinical score for Pso severity, was higher (11±6 vs. 7±3, p=0.006) compared to pts with CFR>2.5. At multivariable analysis PASI remained the only determinant of CFR≤2.5 (p=0.02).Conclusion: CFR in young pts with severe Pso without coronary disease is reduced suggesting a coronary microvascular dysfunction, independently related to the severity and extension of Pso. This early microvascular impairment might be hypothesized as the consequence of prolonged and sustained systemic inflammation and might explain the increased cardiovascular risk conferred by Pso.

Adrenalectomy stimulates the formation of initial atherosclerotic lesions: Reversal by adrenal transplantation - Corrected Proof

2012-01-11

Highlights: ► Adrenalectomy enhances the systemic inflammatory status. ► Adrenalectomy lowers plasma cholesterol and triglyceride levels. ► Adrenal transplantation restores adrenocortical steroid secretion. ► Adrenal-derived steroids protect against development of atherosclerotic lesions.Abstract: Long-term changes in the secretion of immunosuppressive adrenal-derived glucocorticoid hormones influence cardiovascular disease risk. Here we determined the consequences of changes in adrenal steroid metabolism for the development of atherosclerotic lesions in mice.Atherosclerosis-susceptible low-density-lipoprotein (LDL) receptor knockout mice were subjected to adrenalectomy (ADX) or a control (SHAM) operation and subsequently fed an atherogenic diet for 4 weeks. Atherogenic diet feeding raised plasma corticosterone levels in SHAM mice, but not adrenalectomized mice, resulting in an 83% lower (P<0.01) corticosterone level in adrenalectomized mice. Adrenalectomy was associated with a respectively 22% and 29% lower plasma level of cholesterol and triglycerides. In contrast, white blood cell counts were increased 2-fold (P<0.01) in adrenalectomized mice, which could be attributed to a significant 2.1- to 2.6-fold rise in lymphocyte (P<0.05) and monocyte (P<0.05) numbers. Probably as a result of the enhanced systemic inflammatory status, adrenalectomy was associated with a higher susceptibility for diet-induced atherosclerosis (321±18×103μm2 for ADX vs 240±31×103μm2 for SHAM; P<0.05) not withstanding the lowered cholesterol levels. Restoring adrenocortical steroid secretion – but not adrenal medulla function – and the associated downstream glucocorticoid receptor signaling in adrenalectomized mice through adrenal transplantation induced a reversal of the adrenalectomy-associated rise in white blood cell numbers, plasma monocyte chemoattractant protein 1 (MCP-1) levels, and atherosclerotic lesion development (lesion size in transplanted mice: 258±34×103μm2; P<0.05 vs ADX).In conclusion, our studies show that adrenal-derived steroids protect against the development of initial atherosclerotic lesions in LDL receptor knockout mice.

Increased gene dosage of the Ink4/Arf locus does not attenuate atherosclerosis development in hypercholesterolaemic mice - Corrected Proof

2012-01-09

Highlights: ► Increased Ink4/Arf gene dosage augments UV-induced apoptosis in apoE-null macrophages. ► Increased Ink4/Arf dosage does not reduce atherosclerosis burden in apoE-null mice. ► Increased Ink4/Arf dosage does not affect atheroma composition in apoE-null mice.Abstract: Rationale: Human genome-wide association studies have identified genetic variants in the chromosome 9p21 region that confer increased risk of coronary artery disease and other age-related diseases. These variants are located in a block of high linkage disequilibrium with the neighboring Ink4/Arf tumor-suppressor locus (also named CDKN2A/CDKN2B). Since previous studies suggest an atheroprotective role of the Ink4/Arf locus, here we assessed whether gain-of-function of the encoded genes can be exploited therapeutically to reduce atherosclerosis.Methods: Generation and characterization of apolipoprotein E-null mice carrying an additional transgenic copy of the entire Ink4/Arf locus (apoE−/−Super-Ink4/Arf) that reproduces the normal expression and regulation of the endogenous locus.Results: Although liver and aorta of apoE−/−Super-Ink4/Arf mice only showed a trend towards increased Ink4/Arf transcript levels compared to apoE−/− controls, cultured macrophages with increased Ink4/Arf gene dosage exhibited augmented apoptosis induced by irradiation with ultraviolet light, indicating that low level of transgene overexpression can lead to augmented Ink4/Arf function. However, increased Ink4/Arf gene dosage did not affect atherosclerosis development in different vascular regions of both male and female apoE−/− mice fed either normal or high-fat diet. Increased gene dosage of Ink4/Arf similarly had no effect on atheroma cell composition or collagen content, an index of plaque stability.Conclusion: In contrast with previous studies demonstrating cancer resistance in Super-Ink4/Arf mice carrying an additional transgenic copy of the entire Ink4/Arf locus, our results cast doubt on the potential of Ink4/Arf activation as a strategy for the treatment of atherosclerotic disease.

Adiponectin-AdipoR1/2-APPL1 signaling axis suppresses human foam cell formation: Differential ability of AdipoR1 and AdipoR2 to regulate inflammatory cytokine responses - Corrected Proof

2012-01-09

Highlights: ► Adiponectin suppresses foam cell transformation through AdipoR1, AdipoR2 and APPL1. ► AdipoR1 is required by adiponectin to suppress TNFα and MCP-1 gene expression. ► AdipoR2 is the dominant receptor to suppress SR-AI and upregulate IL-1Ra. ► APPL1 is required to inhibit SR-AI and NF-κB gene expression and Akt phosphorylation.Abstract: Objective: Adiponectin is an adipokine that exerts anti-inflammatory and anti-atherogenic effects during macrophage transformation into foam cells. To further understand the signaling pathways of adiponectin involved in macrophage foam cell transformation, we investigated the roles of two adiponectin receptors (AdipoR1 and AdipoR2) and their downstream adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1) in mediating adiponectin action on foam cell transformation.Methods and Results: Transfections were performed to overexpress or knockdown AdipoR1 or AdipoR2 genes in human THP-1 monocytes. Lentiviral-shRNAs were also used to knockdown APPL1 gene in these cells. Foam cell transformation was induced via exposure to oxidized low-density lipoprotein (oxLDL). Our results showed that both AdipoR1 and AdipoR2 were critical for transducing the adiponectin signal that suppresses lipid accumulation and inhibits transformation from macrophage to foam cell. However, AdipoR1 and AdipoR2 were found to have differential effects in diminishing proinflammatory responses. While AdipoR1 was required by adiponectin to suppress tumor necrosis factor alpha (TNFα) and monocyte chemotactic protein 1 (MCP-1) gene expression, AdipoR2 served as the dominant receptor for adiponectin suppression of scavenger receptor A type 1 (SR-AI) and upregulation of interleukin-1 receptor antagonist (IL-1Ra). Knockdown of APPL1 significantly abrogated the ability of adiponectin to inhibit lipid accumulation, SR-AI and nuclear factor-κB (NF-κB) gene expression, and Akt phosphorylation in macrophage foam cells.Conclusions: In current studies, we have demonstrated that adiponectin's abilty to suppress macrophage lipid accumulation and foam cell formation is mediated through AdipoR1 and AdipoR2 and the APPL1 docking protein. However, AdipoR1 and AdipoR2 exhibited a differential ability to regulate inflammatory cytokines and SR-A1. These novel data support the idea that the adiponectin-AdipoR1/2-APPL1 axis may serve as a potential therapeutic target for preventing macrophage foam cell formation and atherosclerosis.

Hepatitis C virus and atherosclerosis in a close and dangerous liason - Corrected Proof

Cristina Vassalle — 2012-01-05

The Framingham risk scores (FRS), proposed more than 50 years ago, is still widely used as a tool for coronary risk stratification. However, a significant proportion of individuals who develop cardiovascular disease (CVD) have average levels of the established risk factors, such as hypertension, diabetes, hypercholesterolemia and smoking habit , and as a result, the sensitivity and specificity of the FRS do not exceed 70% and 82%, respectively . This lack of sensitivity and specificity has focused interest on additional biological determinants that may improve prediction of CVD events, a great number of new emerging determinants are continuously proposed and their relevance debated. Among them, and one with a compelling amount of supportive data is the hypothesized roles of infectious agents in the physiopathology of atherosclerosis.

Prognostic implication of macrocytosis on adverse outcomes after coronary intervention - Corrected Proof

2012-01-05

Highlights: ► The aim of this study was to perform prognostic risk stratification of patients after PCI based on the presence or absence of macrocytosis. ► Significant higher incidence of adverse events, including all-cause and cardiac mortality, was observed in PCI patients with macrocytosis. ► Furthermore, macrocytosis was an independent predictor of cardiac death and composite of adverse cardiovascular events. ► Measuring mean corpuscular volume (MCV) might be helpful for a prognostic risk stratification of patients subjected to PCI.Abstract: Background: Macrocytosis, as a qualitative abnormality of erythrocytes, has not drawn attention as a prognostic indicator after PCI, while anemia, as a quantitative abnormality of erythrocytes, has been recognized as a predictor of adverse outcomes. The aim of this study was to perform prognostic risk stratification of patients after PCI based on the presence or absence of macrocytosis.Methods: The clinical records of 941 consecutive patients who underwent PCI at a single institution were retrospectively reviewed. The prognostic implication of macrocytosis was evaluated by univariate and multivariate Cox's proportional hazard regression analysis.Results: There were 130 (13.8%) patients with macrocytosis. A significantly higher all-cause and cardiac mortality, as well as incidence of composite adverse events were observed in the Macrocytic group. Kaplan–Meier analysis also showed a significantly poorer overall survival in patients with macrocytosis. Even after exclusion of anemic patients, this tendency was still observed. Furthermore, macrocytosis was significantly and independently associated with adverse outcomes after PCI (aHR of cardiac death: 3.45, 95%CI: 1.22–9.80, P=0.019). Interestingly, fewer patients with macrocytosis were prescribed statins compared with those without it (33.8% vs. 47.1%, P=0.005).Conclusions: The results of the study indicate that measuring mean corpuscular volume (MCV) as a qualitative index of erythrocytes might be helpful for a prognostic risk stratification of patients subjected to PCI.

Associations of large artery structure and function with adiposity: Effects of age, gender, and hypertension. The SardiNIA Study - Corrected Proof

2012-01-05

Highlights: ► The relationship between total and visceral adiposity and arterial stiffness, thickness, and diameter is not linear. ► The association between adiposity and arterial properties is steeper in women than in men, in younger than in older subjects. ► Waist correlated with arterial properties better than BMI, and independently of BMI.Abstract: In the context of obesity epidemic, no large population study has extensively investigated the relationships between total and abdominal adiposity and large artery structure and function nor have such relationships been examined by gender, by age, by hypertensive status. We investigated these potential relationships in a large cohort of community dwelling volunteers participating the SardiNIA Study.Methods and results: Total and visceral adiposity and arterial properties were assessed in 6148 subjects, aged 14–102 in a cluster of 4 towns in Sardinia, Italy. Arterial stiffness was measured as aortic pulse wave velocity (PWV), arterial thickness and lumen as common carotid artery (CCA) intima-media thickness (IMT) and diameter, respectively. We reported a nonlinear relationship between total and visceral adiposity and arterial stiffness, thickness, and diameter. The association between adiposity and arterial properties was steeper in women than in men, in younger than in older subjects. Waist correlated with arterial properties better than BMI. Within each BMI quartile, increasing waist circumference was associated with further significant changes in arterial structure and function.Conclusion: The relationship between total or abdominal adiposity and arterial aging (PWV and CCA IMT) is not linear as described in the current study. Therefore, BMI- and/or waist-specific reference values for arterial measurements might need to be defined.

Intra-thoracic fat, cardiometabolic risk factors, and subclinical cardiovascular disease in healthy, recently menopausal women screened for the Kronos Early Estrogen Prevention Study (KEEPS) - Corrected Proof

2012-01-03

Abstract: Objective: To examine the correlations between intra-hepatic and intra-thoracic (total, epicardial, and pericardial) fat deposition with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis burden in healthy, recently postmenopausal women.Methods: Women screened for the Kronos Early Estrogen Prevention Study (mean age 52.9 years) who underwent electron beam or multidetector computed tomography (CT) imaging for the quantification of intra-hepatic fat and thoracic adipose tissue, and coronary artery calcification (CAC) were included (n=650).Results: Higher levels of intra-hepatic and thoracic fat were each associated with CVD risk markers. After adjustment for BMI, the associations for intra-hepatic fat with hs-CRP and insulin persisted (r=0.21 and 0.19, respectively; P<0.001), while those between thoracic fat indices and lipids persisted (r for total thoracic fat with HDL, LDL, and triglycerides=−0.16, 0.11, and 0.11, respectively, P<0.05). Total thoracic fat was associated with CAC after initial multivariable adjustment (odds ratio [OR] of 2nd, 3rd, and 4th vs. 1st quartile and [95% confidence intervals]: 0.8 [0.4–1.6], 1.5 [0.8–2.9], and 1.8 [1.0–3.4]; p for linear trend=0.017) and was only slightly attenuated after additional adjustment for BMI. Associations between total thoracic fat and CVD risk markers and CAC appeared due slightly more to associations with epicardial than pericardial fat.Conclusion: While hepatic fat is related to hs-CRP and insulin, cardiac fat is associated with subclinical atherosclerosis as demonstrated by CAC. Cardiac fat may represent a useful marker for increased CVD risk beyond the standard adiposity measures of BMI and WC.

Effect of folic acid supplementation on the progression of carotid intima-media thickness: A meta-analysis of randomized controlled trials - Corrected Proof

2012-01-03

Abstract: Objectives: We conducted a meta-analysis of relevant randomized trials to assess whether folic acid supplementation reduces the progression of atherosclerosis as measured by carotid intima-media thickness (CIMT).Methods: This analysis included 2052 subjects from ten folic acid randomized trials with the change in CIMT reported as one of the end points. Summary estimates of weighted mean differences (WMDs) and 95% CIs were obtained by using random-effect models. Meta-regression and subgroup analyses were performed to identify the source of heterogeneity.Results: Our analysis showed that folic acid supplementation significantly reduces the progression of CIMT (WMD: −0.04mm; 95%CI: −0.07, −0.02; P<0.001), particularly in subjects with chronic kidney disease (CKD) (WMD: −0.16mm; 95%CI: −0.26, −0.07; P=0.0006) or high cardiovascular disease (CVD) risk (WMD: −0.05mm; 95%CI: −0.11, 0.00; P=0.06) but not in subjects who were generally healthy with only elevated homocysteine concentrations (WMD:0.00mm; 95%CI: −0.01, 0.01; P=0.35). Furthermore, meta-regression analysis of the data showed that the baseline CIMT levels (P=0.011) and the percent reduction of homocysteine (P<0.001) were positively related to the effect size. Consistently, a greater beneficial effect was seen in those trials with baseline CIMT levels ≥0.8mm (WMD: −0.14mm; 95%CI: −0.19, −0.08; P<0.0001), and a reduction in the homocysteine concentration ≥30% (WMD: −0.22mm; 95%CI: −0.38, −0.06; P=0.009). In the corresponding comparison groups, the effect sizes were attenuated and insignificant.Conclusions: Our findings indicate that folic acid supplementation is effective in reducing the progression of CIMT, particularly in subjects with CKD or high CVD risk and among trials with higher baseline CIMT levels or a larger homocysteine reduction.