Atherosclerosis

Editorial Board

2010-03-01

Lipid transfer proteins: Past, present and perspectives

Eder C.R. Quintão, Patrícia M. Cazita — 2009-09-07

Abstract: Lipid transfer proteins (PLTP and CETP) play roles in atherogenesis by modifying the arterial intima cholesterol content via altering the concentration and function of plasma lipoproteins and influencing inflammation. In this regard, endotoxins impair the reverse cholesterol transport (RCT) system in an endotoxemic rodent model, supporting a pro-inflammatory role of HDL reported in chronic diseases where atherosclerosis is premature. High PLTP activity related to atherosclerosis in some clinical studies, but the mechanisms involved could not be ascertained. In experimental animals the relation of elevated plasma PLTP concentration with atherosclerosis was confounded by HDL-C lowering and by unfavorable effects on several inflammatory markers. Coincidently, PLTP also increases in human experimental endotoxemia and in clinical sepsis. Human population investigations seem to favor low CETP as atheroprotective; this is supported by animal models where overexpression of huCETP is atherogenic, most likely due to increased concentration of apoB-lipoprotein-cholesterol. Thus, in spite of CETP facilitating the HDL-C-mediated RCT, the reduction of apoB-LP-cholesterol concentration is the probable antiatherogenic mechanism of CETP inhibition. On the other hand, experimental huCETP expression protects mice from the harmful effects of a bacterial polysaccharide infusion and the mortality rate of severely ill patients correlates with reduction of the plasma CETP concentration. Thus, the roles played by PLTP and CETP on atherosclerosis and acute inflammation seem contradictory. Therefore, the biological roles of PLTP and CETP must be carefully monitored when investigating drugs that inhibit their activity in the prevention of atherosclerosis.

Autologous stem cell therapy for peripheral arterial disease: Meta-analysis and systematic review of the literature

Gian Paolo Fadini, Carlo Agostini, Angelo Avogaro — 2009-09-10

Abstract: Background: Peripheral arterial disease (PAD) is a common cause of disability and mortality. Up to one third of patients are not susceptible to traditional revascularization and may benefit from stem cell therapies.Objective: In this meta-analysis, we sought to determine whether autologous cell therapy is effective in the treatment of PAD.Methods: We searched the English literature in Medline, Excerpta Medica and the Cochrane database for trials of autologous cell therapy in patients with PAD published before 31 January 2009. We included controlled and non-controlled, randomized and non-randomized trials using autologous bone marrow or granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood cells to treat PAD. We also collected data from trials of G-CSF monotherapy, as a control treatment.Results: In a meta-analysis of 37 trials, autologous cell therapy was effective in improving surrogate indexes of ischemia, subjective symptoms and hard endpoints (ulcer healing and amputation). On the contrary, G-CSF monotherapy was not associated with significant improvement in the same endpoints. Patients with thromboangiitis obliterans showed some larger benefits than patients with atherosclerotic PAD. The intramuscular route of administration and the use of bone marrow cells seemed somehow more effective than intrarterial administration and the use of mobilized peripheral blood cells. The procedures were well tolerated and generally safe.Conclusion: This meta-analysis indicates that intramuscular autologous bone marrow cell therapy is a feasible, relatively safe and potentially effective therapeutic strategy for PAD patients, who are not candidate for traditional revascularization. Larger, placebo-controlled, randomized multicenter trials need to be planned and conducted to confirm these findings.

An approach to molecular imaging of atherosclerosis, thrombosis, and vascular inflammation using microparticles of iron oxide

2009-11-02

Abstract: The rapidly evolving field of molecular imaging promises important advances in the diagnosis, characterization and pharmacological treatment of vascular disease. Magnetic resonance imaging (MRI) provides a modality that is well suited to vascular imaging as it can provide anatomical, structural and functional data on the arterial wall. Its capabilities are further enhanced by the use of a range of increasingly sophisticated contrast agents that target specific molecules, cells and biological processes. This article will discuss one such approach, using microparticles of iron oxide (MPIO).MPIO have been shown to create highly conspicuous contrast effects on T2*-weighted MR images. We have developed a range of novel ligand-conjugated MPIO for molecular MRI of endothelial adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and P-selectin expressed in vascular inflammation, as well as activated platelet thrombosis. This review discusses the application of ligand-targeted MPIO for in vivo molecular MRI in a diverse range of vascular disease models including acute vascular inflammation, atherosclerosis, thrombosis, ischemia-reperfusion injury and ischemic stroke. The exceptionally conspicuous contrast effects of ligand-conjugated MPIO provide a versatile and sensitive tool for quantitative vascular molecular imaging that could refine diagnosis and measure response to treatment. The potential for clinical translation of this new class of molecular contrast agent for clinical imaging of vascular syndromes is discussed.

The haptoglobin 2–2 genotype is associated with increased redox active hemoglobin derived iron in the atherosclerotic plaque

Shiri Kalet-Litman, Pedro R. Moreno, Andrew P. Levy — 2010-03-01

In man the haptoglobin (Hp) gene is polymorphic with two common alleles denoted 1 and 2 . We have recently demonstrated in multiple independent longitudinal studies that there is an up to 500% increase in the incidence of cardiovascular disease in individuals with the Hp 2–2 genotype and diabetes mellitus (DM) . The normal function of Hp is to bind extracorpuscular hemoglobin (Hb) and promote its clearance after it is released into either the blood secondary to red cell intravascular hemolysis (6g per day in a normal man) or into the extravascular compartment after hemorrhage (i.e., after hemorrhage into the atherosclerotic plaque) . We and others have previously demonstrated that the Hp 1 allele protein product is superior to the Hp 2 allele protein product in blocking Hb induced oxidation of multiple substrates including LDL and HDL . The major pathway for clearance of the Hp–Hb complex from the blood as well as from the atherosclerotic plaque is via the monocyte/macrophage CD163 receptor . We have demonstrated that the Hp 1–Hb complex is cleared more rapidly by the CD163 receptor than the Hp 2–Hb complex . Furthermore, the amount of the CD163 receptor expressed on monocyte/macrophages is decreased in Hp 2–2 and DM individuals . In this study we set out to test the hypothesis that the Hp genotype regulates the turnover and oxidative activity of Hb in the atherosclerotic plaque.

Apolipoprotein H: Its relevance to cardiovascular disease

M.A. Crook — 2010-01-04

Apolipoprotein H (Apo H) is a single chain glycoprotein consisting of 326 amino acid residues with a molecular weight of about 50kDa and is involved in clotting mechanisms and lipid pathways . Castro and colleagues report in this journal that plasma concentrations of Apo H are strongly associated with the metabolic syndrome and cardiovascular disease in type 2 diabetic patients and could be considered as a clinical marker of cardiovascular risk. The increased Apo H concentration in these patients was due to its increased liver synthesis. Apo H is attracting interest in the field of cardiovascular disease, diabetes mellitus, haemostasis and lipidology and may provide an exciting link between them but why is this?

Telomere length in atherosclerosis and diabetes

Klelia D. Salpea, Steve E. Humphries — 2010-01-18

The Nobel Prize in Medicine in 2009 was awarded to Elizabeth Blackburn, Carol Greider and Jack Szostak for discovering the molecular structure of the far ends of chromosomes, called telomeres (), and how these protect chromosomes from degradation. Their discoveries shed light on a basic biological mechanism which stimulated research in a new exciting field aiming to explore the role of telomeres in normal ageing, cancer and age-related disease pathology.

An alternative pathway of reverse cholesterol transport: The oxysterol 27-hydroxycholesterol

Oliver Weingärtner, Ulrich Laufs, Michael Böhm, Dieter Lütjohann — 2009-10-05

Abstract: Reverse cholesterol transport, although not well understood, is an important mechanism in the pathophysiology of atherosclerosis. Macrophages can eliminate some cholesterol from atherosclerotic lesions by an oxidative mechanism involving sterol 27-hydroxylase. Patients with inherited “cerebrotendinous xanthomatosis” lack sterol 27-hydroxylase (CYP27A1) and develop severe premature atherosclerosis despite normal serum cholesterol concentrations. Thus, it has been speculated that sterol 27-hydroxylase is an anti-atherosclerotic enzyme. Here, we report the case of a 25-year-old patient who presented to our emergency room with an acute non-ST elevation myocardial infarction due to severe coronary heart disease. Lipid analysis revealed dramatically increased 27-hydroxycholesterol and low high-density lipoprotein (HDL)-cholesterol levels. Previous reports suggest that 27-hydroxylase is upregulated to protect peripheral cells from severe cholesterol accumulation, especially in cases of ineffective reverse cholesterol transport due to low HDL-cholesterol levels. Our findings indicate that oxysterols could play an important and so far underestimated role in reverse cholesterol transport.

Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation

2009-11-04

Abstract: Objective: High oxidative stress potentially leads to accelerated telomere shortening and consequent premature cell senescence, implicated in type 2 diabetes (T2D) development. Therefore, we studied the association of leukocyte telomere length (LTL) with the presence of T2D, as well as the effect on the patients’ LTL of plasma oxidative stress and of variation in UCP2, a gene involved in the mitochondrial production of reactive oxygen species.Methods: Mean LTL was determined in 569 Caucasian, 103 South Asian and 70 Afro-Caribbean T2D patients aged from 24 to 92 years, 81 healthy Caucasian male students aged from 18 to 28 years and 367 healthy Caucasian men aged from 40 to 61 years by real-time PCR. Plasma total antioxidant status (TAOS) was measured in the T2D patients by a photometric microassay. The patients were also genotyped for the UCP2 functional variants −866G>A and A55V.Results: Afro-Carribeans had 510bp longer mean length compared to Caucasians (p<0.0001) and 500bp longer than South Asians (p=0.004). T2D subjects displayed shorter age-adjusted LTL compared to controls [6.94(6.8–7.03) vs. 7.72(7.53–7.9), p<0.001] with subjects in the middle and the lowest tertile of LTL having significantly higher odds ratios for T2D compared to those in the highest tertile [1.50(1.08–2.07) and 5.04(3.63–6.99), respectively, p<0.0001]. In the patients, LTL was correlated negatively with age (r=−0.18, p<0.0001) and positively with TAOS measures (r=0.12, p=0.01) after adjusting for age, while carriers of the UCP2 −866A allele had shorter age-adjusted LTL than common homozygotes [6.86(6.76–6.96)kb vs. 7.03(6.91–7.15)kb, p=0.04].Conclusion: The present data suggest that shorter LTL is associated with the presence of T2D and this could be partially attributed to the high oxidative stress in these patients. The association of the UCP2 functional promoter variant with the LTL implies a link between mitochondrial production of reactive oxygen species and shorter telomere length in T2D.

EMMPRIN and its ligand cyclophilin A regulate MT1-MMP, MMP-9 and M-CSF during foam cell formation

2009-09-16

Abstract: Upon coincubation with platelets, CD34+ progenitor cells have the potential to differentiate into foam cells, and thereby may promote the progression of atherosclerosis. The exact mechanism of MMP-regulation during the cellular differentiation process to foam cells is still unclear. Thus, we investigated the role of EMMPRIN (CD147) and its ligand cyclophilin A (CyPA) during foam cell formation originating from both monocytes/macrophages and CD34+ progenitor cells.Methods and results: Differentiation of CD34+ progenitor to foam cells was analyzed in a coculture model of progenitor cells and platelets. While CD34+ cells did not express EMMPRIN or MT1-MMP, mature foam cells strongly expressed EMMPRIN, which was associated with MT1-MMP expression as well as MMP-9. Gene silencing of EMMPRIN by siRNA during the cell differentiation process hindered not only the upregulation of MMPs (MT1-MMP, MMP-9), but also the secretion of the cytokine M-CSF. During the differentiation process CyPA was substantially released into the supernatant. The presence of the CyPA inhibitor NIM811 significantly reduced MMP-9 secretion during the differentiation process. Similar results were obtained using the classical pathway of foam cell formation by coincubating human macrophages with AcLDL. Additionally, the presence of soluble EMMPRIN ligands (CyPA, recombinant EMMPRIN) further enhanced MMP-9 secretion by mature foam cells. Consistently, CyPA and EMMPRIN were found in atherosclerotic plaques of ApoE-deficient mice by immunohistochemistry.Conclusion: EMMPRIN is upregulated during the differentiation process from CD34+ progenitor cells to foam cells, whereas its ligand, CyPA, is released. The CyPA/EMMPRIN activation pathway may play a relevant role in promoting the vulnerability of atherosclerotic plaques.

Cellular factors involved in CXCL8 expression induced by glycated serum albumin in vascular smooth muscle cells

2009-09-07

Abstract: Glycated serum albumin (GSA) promotes vascular complications in diabetes. The aim of this study was to determine if GSA induces chemokine, particularly CXCL8 (IL-8), and to determine intracellular signaling pathways activated by GSA in vascular smooth muscle cells (VSMCs). GSA increased IL-8 transcription via promoter activation and enhanced CXCL8 release from VSMCs. GSA-induced promoter activation of the IL-8 gene was suppressed by dominant-negative mutants of TLR-4, MyD88, and TRIF, but not by a dominant-negative form of TLR-2. In addition, IL-8 up-regulation in response to GSA was inhibited by resveratrol, curcumin, diphenyleneiodium, U0126, and SB202190. Mutation at the NF-κB- or C/EBP-binding site, but not at the AP-1-binding site, in the IL-8 promoter region suppressed GSA-induced promoter activation. Moreover, gene delivery of IκB suppressed CXCL8 release. This study suggests that GSA induces expression of IL-8 in VSMCs and that TLR-4, mitogen-activated protein kinases, NF-κB, and NADPH oxidase are involved in that process.

Ex vivo gene transferring of human dimethylarginine dimethylaminohydrolase-2 improved endothelial dysfunction in diabetic rat aortas and high glucose-treated endothelial cells

Chang-Wu Lu, Zheng Guo, Mei Feng, Zhong-Zu Wu, Zhi-Min He, Yan Xiong — 2010-03-01

Abstract: Objectives: Elevated level of asymmetric dimethylarginine (ADMA) is an independent risk factor for endothelial dysfunction. Dimethylarginine dimethylaminohydrolase (DDAH) is the key enzyme responsible for the degradation of endogenous ADMA. The purposes of this study were to determine whether suppressed DDAH2 expression would implicate in endothelial dysfunction associated with diabetes mellitus and further to investigate whether adenovirus-mediated DDAH2 gene overexpression could improve the hyperglycemia-induced endothelial dysfunction.Methods: Diabetic model was induced by intraperitoneal injection of streptozotocin to male Sprague–Dawley rats. Recombinant adenoviral vector encoding human DDAH2 gene driven by a cytomegalovirus promoter was constructed to overexpress hDDAH2 gene in isolated rat aortas and endothelial cells. Changes in DDHA/ADMA/nitric oxide (NO) pathway in diabetic rats and high glucose-treated endothelial cells were examined.Results: DDAH2 expression was distinctly suppressed, which was accompanied by inhibited DDAH activity and impaired endothelium-dependent relaxation in aortas, and elevated ADMA concentrations in serum of diabetic rats compared to control rats. Suppressions of DDAH2 expression and DDAH activity, accumulation of ADMA, and inhibition of NO synthesis were observed in high glucose-treated endothelial cells. DDAH2 overexpression not only improved endothelial dysfunction in diabetic aortas but also attenuated hyperglycemia-induced changes in DDAH/ADMA//NO pathway in endothelial cells.Conclusion: These results indicate that suppression of DDAH2 expression contributes to hyperglycemia-induced endothelial dysfunction, which can be improved by DDAH2 overexpression. This study suggests that targeted modulation of DDAH2 gene in vascular endothelium may be a novel approach for the treatment of endothelial dysfunction in diabetes mellitus.

Vaccination against Foxp3+ regulatory T cells aggravates atherosclerosis

2009-09-18

Abstract: Objective: Regulatory T cells are crucial for immune homeostasis and an impaired regulatory T cell function results in many pathological conditions. Regulatory T cells have already been described to be protective in atherosclerosis. However the exact contribution of Foxp3-expressing natural regulatory T cells in atherosclerosis has not been elucidated yet.Methods and results: In this study we vaccinated LDL receptor deficient mice with dendritic cells which are transfected with Foxp3 encoding mRNA and studied the effect on initial atherosclerosis. Vaccination against Foxp3 resulted in a reduction of Foxp3+ regulatory T cells in several organs and in an increase in initial atherosclerotic lesion formation. Furthermore we observed an increase in plaque cellularity and increased T cell proliferation in the Foxp3 vaccinated mice.Conclusion: We further establish the protective role of Tregs in atherosclerosis. The results illustrate the important role for Foxp3-expressing regulatory T cells in atherosclerosis, thereby providing a potential opportunity for therapeutic intervention against this disease.

ADRP/ADFP and Mal1 expression are increased in macrophages treated with TLR agonists

2009-09-14

Abstract: Activation of macrophages by TLR agonists enhances foam cell formation, but the underlying mechanisms are not understood. We examined the effects of TLR agonists on ADRP/ADFP, a protein associated with forming lipid droplets, and Mal1 a fatty acid-binding protein, in two mouse macrophage cell lines and human monocytes. Low doses of LPS, a TLR4 agonist increased both mRNA and protein levels of ADRP/ADFP and Mal1 in RAW 264.7 macrophages. Following pretreatment with Intralipid, fatty acids, or acetyl-LDL to increase triglyceride or cholesterol ester storage, LPS treatment still increased ADRP/ADFP and Mal1 mRNA levels. LPS also induced ADRP/ADFP and Mal1 in J774 macrophages and ADRP/ADFP in human monocytes. Zymosan, a fungal product that activates TLR2, poly-I:C, a viral mimetic that activates TLR3, and imiquimod, a TLR7 agonist, also increased ADRP/ADFP. Zymosan, but not poly-I:C or imiquimod, induced Mal1. In contrast, neither gene was induced by TNFα, IL-1β, IL-6, or interferon-γ. Thus TLR agonists induce ADRP/ADFP and Mal1, which likely contributes to macrophage triglyceride and cholesterol ester storage leading to foam cell formation.

Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin

2009-09-25

Abstract: Objective: A major site of action for the atheroprotective drug nicotinic acid (NA) is adipose tissue, via the G-protein-coupled receptor, GPR109A. Since, adipose tissue is an active secretory organ that contributes both positively and negatively to systemic inflammatory processes associated with cardiovascular disease, we hypothesized that NA would act directly upon adipocytes to alter the expression of pro-inflammatory chemokines, and the anti-inflammatory adipokine adiponectin.Methods and results: TNF-α treatment (1.0ng/mL) of 3T3-L1 adipocytes resulted in an increase in gene expression of fractalkine (9±3.3-fold, P<0.01); monocyte chemoattractant protein-1 (MCP-1) (24±1.2-fold, P<0.001), ‘regulated upon activation, normal T cell expressed and secreted’ (RANTES) (500±55-fold, P<0.001) and inducible nitric oxide synthase (iNOS) (200±70-fold, P<0.05). The addition of NA (10−4M) to TNF-α-treated adipocytes attenuated expression of fractalkine (50±12%, P<0.01); MCP-1 (50±6%, P<0.01), RANTES (70±3%, P<0.01) and iNOS (60±16%). This pattern was mirrored in protein released from the adipocytes into the surrounding media. The effect on gene expression was neutralised by pre-treatment with pertussis toxin. NA attenuated macrophage chemotaxis (by 27±3.5%, P<0.001) towards adipocyte conditioned media. By contrast, NA, (10−6–10−3M) increased, in a dose-dependent manner, mRNA of the atheroprotective hormone adiponectin (3–5-fold n=6, P<0.01).Conclusions: NA suppresses pro-atherogenic chemokines and upregulates the atheroprotective adiponectin through a G-protein-coupled pathway. Since adipose tissue has the potential to contribute to both systemic and local (perivascular) inflammation associated with atherosclerosis our results suggest a new “pleiotropic” role for NA.

Cathepsin K gene disruption does not affect murine aneurysm formation

2009-09-24

Abstract: Cathepsin K (catK), a lysosomal cysteine protease, exerts strong elastinolytic and collagenolytic activity and is implicated in a range of pathological disorders including cardiovascular disease. CatK expression was found to be elevated in human aortic aneurysm pointing to a role in this vasculopathy. In the angiotensin II (Ang II)-induced mouse model for aneurysm formation, catK, S and C expression was strongly upregulated. Therefore, we investigated the effect of catK deficiency on Ang II-induced aneurysm formation in the abdominal aorta of apoE−/− mice.Contrary to our expectations, catK deficiency did not protect against aneurysm formation, nor did it affect medial elastin breaks. Proteolytic activity in abdominal aortic lysates were comparable between apoE−/− and catK−//−apoE−/− mice. Adventitial presence of catS- and catC-expressing cells was significantly increased in catK−/−//apoE−/− versus apoE−/− mice, which might have compensated for the deficiency of catK-derived proteolysis in the aneurysm tissue of catK deficient apoE−/− mice. Circulating granulocytes and activated T cell numbers were significantly increased in Ang II-infused catK−/−//apoE−/− mice, which is consistent with the borderline significant increase in adventitial leukocyte content in catK−/−//apoE−/− compared to apoE−/− mice. Strikingly, despite unchanged proteolytic activity in AAA lesions, collagen content in the aneurysm was significantly increased in catK−//−apoE−/− mice. In conclusion, while catK deficiency has major impact on various vasculopathies, it did not affect murine aneurysm formation.

Contribution of apolipoprotein E genotype and docosahexaenoic acid to the LDL-cholesterol response to fish oil

2009-09-14

Abstract: Objectives: To investigate the impact of apolipoprotein E (apoE) genotype on the response of the plasma lipoprotein profile to eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) intervention in humans.Methods and results: 38 healthy normolipidaemic males, prospectively recruited on the basis of apoE genotype (n=20 E3/E3 and n=18 E3/E4), completed a double-blind placebo-controlled cross-over trial, consisting of 3×4 week intervention arms of either control oil, EPA-rich oil (ERO, 3.3g EPA/day) or DHA-rich oil (DRO, 3.7g DHA/day) in random order, separated by 10 week wash-out periods. A significant genotype-independent 28% and 19% reduction in plasma triglycerides in response to ERO and DRO was observed. For total cholesterol (TC), no significant treatment effects were evident; however a significant genotype by treatment interaction emerged (P=0.045), with a differential response to ERO and DRO in E4 carriers. Although the genotype×treatment interaction for LDL-cholesterol (P=0.089) did not reach significance, within DRO treatment analysis indicated a 10% increase in LDL (P=0.029) in E4 carriers with a non-significant 4% reduction in E3/E3 individuals. A genotype-independent increase in LDL mass was observed following DRO intervention (P=0.018). Competitive uptake studies in HepG2 cells using plasma very low density lipoproteins (VLDL) from the human trial, indicated that following DRO treatment, VLDL2 fractions obtained from E3/E4 individuals resulted in a significant 32% (P=0.002) reduction in LDL uptake relative to the control.Conclusions: High dose DHA supplementation is associated with increases in total cholesterol in E4 carriers, which appears to be due to an increase in LDL-C and may in part negate the cardioprotective action of DHA in this population subgroup.

Berberine and plant stanols synergistically inhibit cholesterol absorption in hamsters

2009-09-27

Abstract: The present study was conducted to determine the efficacy and underlying mechanism of berberine (BBR), plant stanols (PS) and their combination on plasma lipids. Male Golden Syrian hamsters were randomly divided into 4 groups (n=15/group) and fed a cornstarch–casein–sucrose-based diet containing 0.15% cholesterol and 5% fat. Three treatment groups were supplemented with 0.17% (equivalent to 100mgkg−1d−1) BBR, 1% PS, or a combination of both (BBRPS) for 4wk. At the end of the study, plasma lipids were analyzed with enzymatic methods, cholesterol absorption and synthesis using stable isotope tracer methodology, and gene and protein expressions in the liver and small intestine using real-time PCR and Western blot, respectively. BBR and PS significantly lowered plasma total- and nonHDL-cholesterol levels, and BBRPS markedly improved cholesterol-lowering efficacy compared to BBR or PS alone. Further examinations revealed that BBR and PS both inhibited cholesterol absorption and by contrast, increased cholesterol synthesis, and exerted a synergistic action when they were combined. Plasma total or nonHDL-cholesterol levels were significantly correlated with cholesterol absorption rates. BBR upregulated sterol 27-hydroxlase gene expression and BBRPS increased both cholesterol-7α-hydroxylase and sterol 27-hydroxlase gene expressions. BBR and PS also synergistically decreased plasma triacylglycerides. These findings suggest that the cholesterol-lowering action of BBR might involve a combination of inhibition of cholesterol absorption and stimulation of bile acid synthesis. The combination of BBR and PS improves cholesterol-lowering efficacy through a synergistic action on cholesterol absorption, in addition to synergistically reducing plasma triacylglycerols in hamsters.

Palmitic acid enhances lectin-like oxidized LDL receptor (LOX-1) expression and promotes uptake of oxidized LDL in macrophage cells

Junichi Ishiyama, Ryoko Taguchi, Akiko Yamamoto, Koji Murakami — 2009-09-28

Abstract: Objective: Elevated levels of nonesterified fatty acids (NEFA) in obesity and type 2 diabetes may contribute to the development of atherosclerosis. Therefore, we examined whether NEFA could regulate expression of scavenger receptors responsible for uptake of oxidized LDL (oxLDL) in macrophages, a critical step in atherogenesis.Methods and results: Expression level of scavenger receptors in NEFA-treated macrophage-like THP-1 and Raw264.7 cells were analyzed by real-time PCR. Palmitic acid showed the greatest enhancement of expression of lectin-like oxidized LDL receptor (LOX-1) among 7 NEFA examined (4 saturated and 3 unsaturated fatty acids). Upregulation of LOX-1 was selective as increases in expression level of other scavenger receptors (CD36, SR-AI, SR-BI, and CD68) were not observed. Western blotting analysis indicated that upregulation of LOX-1 also occurred at the protein level. Uptake of oxLDL by Raw264.7 cells was promoted by palmitic acid, and the enhanced uptake was abrogated when the cells were transfected with siRNA against LOX-1. Downregulation of Toll-like receptor (TLR) 2, TLR4, or IRAK4 with siRNA did not prevent LOX-1 upregulation, whereas inhibitors of p38 MAPK (p38) and reactive oxygen species (ROS) signal inhibited the upregulation of LOX-1 induced by palmitic acid.Conclusions: These results suggest that elevated level of palmitic acid may contribute to development of atherosclerosis through enhanced uptake of oxLDL via upregulation of LOX-1 in macrophages. The effects of palmitic acid may be mediated by ROS-p38 pathway rather than TLRs.

The role of carotid intima-media thickness assessment in cardiovascular risk evaluation in patients with polyvascular atherosclerosis

2009-09-17

Abstract: In populational studies, carotid intima-media thickness (CIMT) is a valuable tool in the evaluation of cardiovascular (CV) risk. However, there is not much evidence on the relation between CIMT, and CV events in patients who have already undergone revascularization procedures.Aim: To evaluate the relationship between CIMT, atherosclerosis extent and CV event rates in patients with established atherosclerosis.Methods and Results: Baseline mean-CIMT was assessed in 652 patients, including 195; 191; 112; 29 with angiographic arterial stenosis ≥50% in 1; 2; 3 or 4 territories (coronary, supraaortic, renal and/or lower limb arteries), who underwent revascularization procedure in ≥1 arterial territory, and in 125 control subjects without significant lesions. For CIMT ≥1.25mm (≥3rd quartile), the sensitivity and specificity of ≥2-territory involvement were 81.6% and 81.9%. CV events occurred in 91(14%) subjects. The Kaplan–Meier 2-year CV event-free survival was 95.6%; 93.1%; 83.8%; 77% in patients with mean-CIMT values in the 1st; 2nd; 3rd and 4th quartile. The independent CV adverse event predictors identified in the multivariate Cox proportional hazard model were: mean-CIMT ≥1.25mm (RR=2.52; CI=1.5–4.24; p=0.001); hs-CRP (RR=1.02; CI=1.0–1.03; p=0.011), claudication (RR=1.58; CI=0.98–2.57; p=0.062), accumulation of ≥4 traditional risk factors (RR=2.02; CI=1.31–3.12; p=0.002), 2-3-vessel coronary artery disease (RR=1.95; CI=1.21–3.14; p=0.006). Inclusion of CIMT into the stratification model significantly improved the prediction of CV event risk (ΔChi2=13.27, p=0.0003).Conclusions: In patients undergoing revascularization procedure(s), CIMT has an important and independent contribution to further CV risk stratification. The mean-CIMT value ≥1.25mm is associated with 2.5-fold increased risk of adverse CV events.

Thoracic aorta calcification detected by electron beam tomography predicts all-cause mortality

2009-09-27

Abstract: Background: The presence of coronary artery calcium (CAC) is an independent marker of increased risk of cardiovascular disease (CVD) events and mortality. However, the predictive value of thoracic aorta calcification (TAC), which can be additionally identified without further scanning during assessment of CAC, is unknown.Methods: We followed a cohort of 8401 asymptomatic individuals (mean age: 53±10 years, 69% men) undergoing cardiac risk factor evaluation and TAC and CAC testing with electron beam computed tomography. Multivariable Cox proportional hazards models were developed to predict all-cause mortality based on the presence of TAC.Results: During a median follow-up period of 5 years, 124 (1.5%) deaths were observed. Overall survival was 96.9% and 98.9% for those with and without detectable TAC, respectively (p<0.0001). Compared to those with no TAC, the hazard ratio for mortality in the presence of TAC was 3.25 (95% CI: 2.28–4.65, p<0.0001) in unadjusted analysis. After adjusting for age, gender, hypertension, dyslipidemia, diabetes mellitus, smoking and family history of premature coronary artery disease, and presence of CAC the relationship remained robust (HR 1.61, 95% CI: 1.10–2.27, p=0.015). Likelihood ratio χ2 statistics demonstrated that the addition of TAC contributed significantly in predicting mortality to traditional risk factors alone (χ2=13.62, p=0.002) as well as risk factors+CAC (χ2=5.84, p=0.02) models.Conclusion: In conclusion, the presence of TAC was associated with all-cause mortality in our study; this relationship was independent of conventional CVD risk factors as well as the presence of CAC.

Computer-aided non-contrast CT-based quantification of pericardial and thoracic fat and their associations with coronary calcium and metabolic syndrome

2009-09-14

Abstract: Introduction: Pericardial fat is emerging as an important parameter for cardiovascular risk stratification. We extended previously developed quantitation of thoracic fat volume (TFV) from non-contrast coronary calcium (CC) CT scans to also quantify pericardial fat volume (PFV) and investigated the associations of PFV and TFV with CC and the Metabolic Syndrome (METS).Methods: TFV is quantified automatically from user-defined range of CT slices covering the heart. Pericardial fat contours are generated by spline interpolation between 5–7 control points, placed manually on the pericardium within this cardiac range. Contiguous fat voxels within the pericardium are identified as pericardial fat. PFV and TFV were measured from non-contrast CT for 201 patients. In 105 patients, abdominal visceral fat area (VFA) was measured from an additional single-slice CT. In 26 patients, images were quantified by two readers to establish inter-observer variability. TFV and PFV were examined in relation to Body Mass Index (BMI), waist circumference and VFA, standard coronary risk factors (RF), CC (Agatston score >0) and METS.Results: PFV and TFV showed excellent correlation with VFA (R=0.79, R=0.89, p<0.0001), and moderate correlation with BMI (R=0.49, R=0.48, p<0.0001). In 26 scans, the inter-observer variability was greater for PFV (8.0±5.3%) than for TFV (4.4±3.9%, p=0.001). PFV and TFV, but not RF, were associated with CC [PFV: p=0.04, Odds Ratio 3.1; TFV: p<0.001, OR 7.9]. PFV and TFV were also associated with METS [PFV: p<0.001, OR 6.1; TFV p<0.001, OR 5.7], unlike CC [OR=1.0 p=NS] or RF. PFV correlated with low-HDL and high-glucose; TFV correlated with low-HDL, low-adiponectin, and high glucose and triglyceride levels.Conclusions: PFV and TFV can be obtained easily and reproducibly from routine CC scoring scans, and may be important for risk stratification and monitoring.

Relationship between common carotid intima-media thickness and thoracic aortic calcification: The Multi-Ethnic Study of Atherosclerosis

2009-09-28

Abstract: Background: Mean maximum carotid intima-media thickness (CIMT) is associated with both coronary artery disease and cerebral thromboembolism. Thoracic aortic calcification (TAC) detected by computed tomography (CT) is also highly associated with vascular disease and cardiovascular risk. No previous study has examined the relationship between CIMT and TAC in a large patient cohort. We performed a cross-sectional study to determine whether, at baseline, there is a relationship between CIMT and CT-determined TAC score.Methods: In the Multi-Ethnic Study of Atherosclerosis, the study cohort included a population based sample of four ethnic groups (Chinese, White, Hispanic and African-American) of 6814 women and men ages 45–84 years. After exclusion of 198 persons due to incomplete information, we compared results of 6616 participants with both CIMT and TAC. TAC was measured from the lower edge of the pulmonary artery bifurcation to the cardiac apex. CIMT at the common carotid artery site was represented as the mean maximal CIMT of the right and left near and far walls, respectively. Multivariable relative risk regression analysis was used to evaluate relationships between TAC and CIMT.Results: The prevalence of TAC was 28% (n=1846) and the mean maximum (+SD) CIMT was 0.87±0.19mm. A higher prevalence of TAC was noted across increasing CIMT quartiles (1st: 12%, 2nd: 21%, 3rd: 30%, 4th: 49%, p<0.0001). One standard deviation increase in CIMT was associated with a 16% higher likelihood for presence of TAC after adjusting for demographics and cardiovascular disease (CVD) risk factors (95% CI: 1.12–1.26). In addition, individuals with CIMT in the highest quartile, as compared to those with CIMT in the first quartile, had a 76% higher likelihood for presence of TAC (prevalence ratio [PR]: 1.76, 95% CI: 1.37–2.26). In race-ethnic stratified analyses, similar associations were seen in all groups. Among those with TAC>0, a higher CIMT was significantly associated with continuous TAC scores (log transformed) in the overall population as well as among all ethnic-racial groups.Conclusions: Our study demonstrates that TAC is associated with increasing severity of carotid atherosclerotic burden as measured by CIMT. The combined utility of these two noninvasive measures of subclinical atherosclerosis for CVD risk assessment needs to be determined in future studies.

Increased intima thickness of the radial artery in individuals with prehypertension and hypertension

Anna Myredal, Li Ming Gan, Walter Osika, Peter Friberg, Mats Johansson — 2009-10-05

Abstract: Background: We have used a novel ultra high-frequency (55MHz) ultrasound technique to non-invasively measure the radial arterial vessel wall and separate the intima–media (IMT) complex into measurements of intima and media thickness (IT and MT). Since no previous study has measured IT and MT separately in individuals with prehypertension and hypertension, the aim of the current study was to measure IT and MT thickness of the radial arteries among individuals with prehypertension, hypertension and healthy subjects.Methods and results: Individuals with prehypertension (n=32), hypertension (n=34) and healthy subjects (n=29) underwent ultra high-resolution ultrasound of the radial artery. Individuals with prehypertension showed a 14% increase in IT compared to healthy subjects (0.083±0.020mm versus 0.073±0.015mm; p<0.05), whereas no difference was seen in MT. Individuals with hypertension showed a 12% increase of in IT compared to healthy subjects (0.082±0.018mm versus 0.073±0.015mm, p<0.05), whereas no differences were seen regarding MT. Prehypertensive and hypertensive individuals did not differ regarding IT and MT.Conclusion: Both prehypertension and hypertension are associated with thickening of the intimal layer of the radial artery. The present data indicates that intima thickening appears early during the development of hypertension even when blood pressure is only slightly elevated.

A study of the role of the myocyte-specific enhancer factor-2A gene in coronary artery disease

2009-09-28

Abstract: We evaluated the role of the MEF2A as a risk factor for coronary artery disease (CAD) in 1186 subjects with angiographically documented disease compared with 885 CAD-free individuals in the Saudi population. Screening the gene revealed exon 11 as the most polymorphic of all coding regions, harbouring several substitution polymorphisms and insertion/deletions (indels) at a locus containing an 11 CAG trinucleotide chain and a CCGCCGCCA sequence, which introduced frameshifts and premature stop codons at nt146637 and nt146647, nt146780 or nt146783. While these indels were not significantly associated with CAD, a causative relationship was established for rs1059759 G>C [1.21(1.02–1.43); p=0.029], and a borderline one for rs34851361 A>G [1.22(0.9–1.54); p=0.088]. Importantly, a haplotype 1A-2G-3G-4A-5C-6G-7G-8A constructed from the studied SNPs was also associated with CAD [6.39(0.93–43.75); p=0.0052]. These results identify MEF2A gene as a susceptibility gene for CAD.

Associations between COX-2 polymorphisms, blood cholesterol and risk of acute coronary syndrome

2009-09-14

Abstract: Background: The use of specific COX-2 inhibitors in cancer prevention has been associated with higher risk of acute coronary syndrome (ACS) and myocardial infarction. The aim of this study was to investigate if the polymorphisms COX2 T8473C (rs5275), and COX2 A-1195G (rs689466), which modify the enzyme levels of COX-2, were associated with risk of ACS and if alcohol intake, smoking, and use of NSAID would modify the associations. We also wanted to investigate associations with blood lipid levels.Methods: A case–cohort study including 1031 ACS cases and a sub-cohort of 1703 persons was nested within the population-based prospective study Diet, Cancer and Health of 57,053 individuals aged 55–64 at recruitment 1993–1997.Results: Male variant allele carriers of COX-2 T8473C were at lower risk of ACS (IRR=0.75, CI=0.61–0.93, p=0.008) than homozygous wildtype carriers. There were no statistically significant interactions between genotypes and alcohol intake, smoking and NSAID use in relation to risk of ACS. Among males, there was interaction between COX-2 T8473C and alcohol in relation to total cholesterol, non-HDL cholesterol and LDL levels (p for interaction: 0.003, 0.007 and 0.01, respectively), such that variant allele carriers with low alcohol intake had the lowest lipid levels. No statistically significant associations were observed in females.Conclusion: This study suggests that genetically determined COX-2 levels are associated with risk of ACS and blood lipid levels among males. No consistent associations were found for females.

Tangier disease caused by compound heterozygosity for ABCA1 mutations R282X and Y1532C

2009-09-18

Abstract: Background: Inherited low levels of high density lipoprotein (HDL) cholesterol may be due to mutations in the genes encoding the ATP-binding cassette transporter A1 (ABCA1), apolipoprotein (apo) A-I or lecithin:cholesterol acyltransferase (LCAT).Methods: The ABCA1, apoA-I and LCAT genes of a 40-year-old male subject with serum HDL cholesterol of 0.06mmol/l were subjected to DNA sequencing. The proband's family was examined for co-segregation between mutations and levels of HDL cholesterol. Cholesterol efflux in fibroblasts from the proband and a normocholesterolemic subject was compared. The effects of an ABCA1 mutation on cholesterol efflux and membrane localization of ABCA1 were studied in transfected HEK293 and HeLa cells, respectively.Results: The proband was a compound heterozygote for ABCA1 mutations R282X (c.844 C>T) and Y1532C (c.4595 A>G). Relatives who were heterozygous for one of these mutations, had about half-normal HDL cholesterol levels. Cholesterol efflux was reduced in fibroblasts from the proband, as was cholesterol efflux from HEK293 cells transfected with an human (h) ABCA1 expression plasmid harboring the Y1532C mutation. Confocal microscopy of HeLa cells transfected with the Y1532C–hABCA1 plasmid revealed that the Y1532C mutation inhibits ABCA1 from reaching the cellular membrane.Conclusion: Compound heterozygosity for the nonsense mutation R282X and the missense mutation Y1532C in the ABCA1 gene causes Tangier disease. R282X has a detrimental effect on the function of ABCA1 since a premature stop codon is introduced. Mutation Y1532C disrupts the normal function of ABCA1 as determined by in vitro analyses.

Impact of implanted bone marrow progenitor cell composition on limb salvage after cell implantation in patients with critical limb ischemia

2009-09-14

Abstract: Objective: The aim of this study is to identify which factors influence limb salvage after bone marrow mononuclear cell implantation (BMI) in patients with chronic critical limb ischemia (CLI).Methods: Thirteen no-option CLI patients treated with BMI were enrolled in the present study. Limb ischemia was assessed using the ankle-brachial index (ABI), transcutaneous oxygen tension (TcO2), and rest pain score. The cell populations among the implanted cells were determined by May-Giemsa staining and flow cytometry.Results: Major lower extremity amputations after BMI were performed in seven patients. Before implantation, there were no significant differences between the amputation group (n=7) and the salvage group (n=6) in clinical characteristics, the ABI, the TcO2 level, or the rest pain score. After implantation, there were no differences between the groups in the serum levels of angiogenic or inflammatory cytokines. The number of implanted BM cells was the same in the two groups, but the cells implanted in the limb salvage group were composed of significantly higher numbers of hematopoietic progenitors (erythroblasts and myeloblasts) and lymphocytes (p<0.05, respectively). The number of CD34-positive cells was somewhat greater in the salvage group than in the amputation group (p=0.09) and was positively associated with the number of erythroblasts (r2=0.29, p=0.06) and the number of myeloblasts (r2=0.59, p<0.01).Conclusions: The cellular composition of the BM cells injected may affect limb salvage after the implantation in patients with severe CLI. The favorable effects of BMI appear to reflect the impact of the progenitor cell doses.

Effects of atorvastatin on serum soluble receptors for advanced glycation end-products in type 2 diabetes

H.L. Tam, S.W.M. Shiu, Y. Wong, W.S. Chow, D.J. Betteridge, K.C.B. Tan — 2009-09-07

Abstract: Objective: The receptor for advanced glycation end-products (RAGE) plays an important role in the pathogenesis of diabetic complications and atherosclerosis. Interfering with the activation of RAGE by using a soluble form of the receptor (sRAGE) ameliorates the vascular complications of diabetes in animal models. We have investigated whether statin can influence the expression of sRAGE and esRAGE (a splice variant of sRAGE) in vitro and in vivo.Methods: THP-1 cells were incubated with atorvastatin in vitro and sRAGE and esRAGE in the medium was measured by Western immunoblot. Serum levels of sRAGE and esRAGE were measured by ELISA in archived serum samples from a previous randomized double-blind placebo-controlled clinical trial that explored the cardiovascular effects of atorvastatin in hypercholesterolemic Chinese type 2 diabetic patients.Results: sRAGE and esRAGE were induced by atorvastatin in a time- and dose-dependent manner in THP-1 cells. In the diabetic patients, there was a significant increase in serum sRAGE (p<0.05) and esRAGE (p<0.01) in the atorvastatin group at 6-month, but no change in placebo group. Serum esRAGE was higher in atorvastatin group than placebo group [median 240.5pg/ml (interquartile range 186.5–377.3) vs 194.8pg/ml (124.1–347.9) respectively, p<0.01] at 6-month, whereas the differences in sRAGE did not reach statistical significance (p=0.051). There was a correlation between the increase of serum esRAGE and reduction of serum LDL (r=−0.36, p=0.001).Conclusions: Statins are known to have pleiotropic effects and we have shown that atorvastatin can increase circulating esRAGE levels in type 2 diabetic patients.

Low-dose atorvastatin improves dyslipidemia and vascular function in patients with primary biliary cirrhosis after one year of treatment

2009-09-28

Abstract: Objective: Primary biliary cirrhosis (PBC) is frequently associated with hypercholesterolemia and with an increased cardiovascular morbidity and mortality. Statins lower serum cholesterol levels and may thus improve the cardiovascular risk in PBC patients. The aim of our study was to prospectively examine the efficacy of low-dose atorvastatin on cholestasis as well as cardiovascular risk markers such as dyslipidemia and vascular function in patients with PBC.Methods: Nineteen patients with early-stage (biopsy proven and AMA positive) PBC and low-density lipoprotein cholesterol (LDL-C) above 130mg/dL were included in this single-center study and treated with atorvastatin 10mg per day for one year.Results: Concentrations of total cholesterol, LDL-C, LDL triglycerides, oxLDL, IgG and sVCAM-1 decreased significantly after 48 weeks of atorvastatin treatment. Flow-mediated dilation (FMD) of the brachial artery as an indicator of vascular function significantly increased, while carotid artery intima-media thickness and vascular wall stiffness did not progress under treatment. No statistical differences in liver enzymes were observed except a transient increase of alkaline phosphatase.Conclusion: Treatment with low-dose atorvastatin is safe in early-stage PBC, effectively reduces total cholesterol, LDL-C, LDL triglycerides, oxLDL and sVCAM-1 and improves vascular function as reflected by FMD, without affecting cholestasis progression. Therefore, statin therapy should be considered in PBC patients with additional risk factors for cardiovascular disease.

Angiotensin II receptor blocker and statins lower elevated levels of osteopontin in essential hypertension—Results from the EUTOPIA trial

2009-10-05

Abstract: Background: Osteopontin is a pleiotropic cytokine that has been implicated as a key factor in the development of atherosclerosis, a major complication of hypertension. We have earlier shown that olmesartan reduces mediators of vascular inflammation in patients with hypertension and cardiovascular disease. We aimed at studying the effect of olmesartan and/or pravastatin on osteopontin plasma levels, and the association between vascular inflammation markers and osteopontin in hypertensive patients.Methods: We assessed a panel of vascular inflammation markers and osteopontin during 12 weeks of therapy with 20mg olmesartan (n=94) or placebo (n=96) in a prospective, double-blind, multi-center study in patients with essential hypertension (re-evaluation of the EUTOPIA trial blood samples). Pravastatin (20mg) was added to the double-blind therapy at week 6 in both arms. The association of demographic variables and inflammation markers with osteopontin has been analyzed as well.Results: Baseline osteopontin plasma concentrations in the study population were elevated compared to healthy controls (32.85±19.04ng/mL vs. 23.82±3.69ng/mL, p=0.027). Mono-therapy with olmesartan and co-therapy with pravastatin reduced levels of circulating osteopontin (p<0.001). The addition of pravastatin to the placebo treatment-arm resulted in a reduction of osteopontin levels as well (p<0.01). osteopontin plasma levels correlated with VCAM-1 (r=0.27; p=0.0002), ICAM-1 (r=0.18; p=0.015), IL-6 (r=0.35; p<0.0001) and hsCRP (r=0.22; p=0.0022).Conclusion: We show, for the first time, that olmesartan significantly decreases osteopontin concentrations. Co-therapy with pravastatin also reduces osteopontin levels. Elevated osteopontin levels in hypertensive patients correlate with adhesion molecules and inflammation markers.

Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands

2009-10-12

Abstract: Background: Heterozygous familial hypercholesterolemia (heFH) is a common autosomal dominant hereditary disorder caused by mutations in the LDL-receptor gene that lead to elevated plasma levels of low-density lipoprotein-cholesterol (LDL-c). Robust lowering of LDL-c levels is essential for risk reduction of premature cardiovascular diseases and early death. European and Dutch guidelines recommend to treat LDL-c to plasma levels <2.5mmol/l. In the present study we evaluated the treatment of heFH patients in The Netherlands.Methods: A cross-sectional study was conducted in outpatient lipid clinics of three Academic Centers and two regional hospitals. Patient records of known heFH patients were retrieved and data were reviewed on the use of lipid-lowering medication, plasma lipids and lipoproteins, safety laboratory results and reasons for not achieving treatment goals.Results: The data of 1249 patients with heFH were available. Nearly all patients (96%) were on statin treatment. The treatment goal for LDL-c <2.5mmol/l was achieved in 261 (21%) patients. Among those who did not reach LDL-c goals, 261 (27%) were on combination therapy of maximum statin dose and ezetimibe. Main reason (32%) why patients did not use maximum therapy despite an LDL-c ≥2.5mmol/l, was acceptance of a higher target LDL-c level by the treating physician. An alternative treatment goal of >50% LDL-c reduction, as recommended in the NICE guidelines, was achieved in 47% of patients with an LDL-c ≥2.5mmol/l and not using maximum therapy.Conclusion: Only a small proportion of patients with heFH reaches the LDL-c treatment target of <2.5mmol/l. These results emphasize the need for better monitoring, better utilization of available medication and for new treatment options in heFH to further decrease LDL-c levels.

The high 2D:4D finger length ratio effects on atherosclerotic plaque development

2009-09-04

Abstract: Background: The index finger to ring finger length ratio (2D:4D) of the right hand are affected by prenatal testosterone levels in male. To date, it has been determined that the high 2D:4D ratio is related to the myocardial infarction, however no research has revealed the relationship between the high 2D:4D ratio whose coronary artery shows atherosclerotic plaque development.Objective: The aim of this study was to display the relationship between the 2D:4D ratio and atherosclerosis formation in male autopsy cases.Methods: We designed a study in 100 heterosexual male autopsies whose mean age was 21.4±2.47 (range between 17 and 25). The 2nd and 4th digits were measured on the palmar surface of the right hand and taken the right coronary artery to show the atherosclerotic plaque development.Results and conclusion: Grade 3 group had significantly higher 2D:4D ratio compared to Grade 1 and Grade 2 groups (p=0.02 for both).

Relationship between coronary endothelial function and coronary calcification in early atherosclerosis

2009-12-07

Abstract: Background: The relationship between coronary endothelial function and coronary calcification is not well established.Methods: Forty-six patients 17 men [37%]; age, 47.4±11.4 years prospectively underwent testing for coronary endothelial function and measurement of coronary artery calcification (CAC).Results: Log CAC scores were not significantly different between patients with normal (n=31) and abnormal (n=15) response of epicardial coronary artery diameter to acetylcholine (%CADAch) (median (25, 75 percentile) 1.1 (0.0, 3.7) vs. 0.3 (0.0, 2.4), P=.32) and with normal (n=28) and abnormal (n=18) response of coronary blood flow to acetylcholine (%CBFAch) (0.5 (0.0, 3.6) vs. 0.5 (0.0, 3.2), P=.76). Log CAC scores did not correlate with %CADAch (r=0.08, P=.59), %CBFAch (r=0.14, P=.35).Conclusions: In patients without significant coronary artery disease, coronary endothelial dysfunction showed no apparent association with coronary calcification. Our findings suggest that these 2 markers may represent separate, independent processes in the progression of coronary atherosclerosis.

APOH is increased in the plasma and liver of type 2 diabetic patients with metabolic syndrome

2009-10-30

Abstract: Objective: To assess the association of APOH with metabolic and cardiovascular risk markers in type 2 diabetic patients.Methods: In a cohort of 169 type 2 diabetic subjects, plasma levels of APOH, antibodies anti-APOH, lipoprotein subfractions, oxidation, inflammatory and insulin resistance markers and the Trp316Ser and Val247Leu variations in the APOH gene were analyzed. Apo H mRNA levels and protein content were measured in hepatic and adipose tissue (subcutaneous and visceral) samples obtained during bariatric surgery from three diabetics who fulfilled metabolic syndrome (MS) criteria and three non-diabetic, non-MS.Results: APOH plasma levels were significantly associated with triglycerides (p<0.001), all the components of triglyceride-rich lipoproteins (p<0.001) and RBP4 (p<0.001) levels. APOH was higher in type 2 diabetic patients with MS (p=0.003) and with clinical evidence of macrovascular disease (p=0.012). The Trp316Ser and Val247Leu APOH gene variants did not modulate APOH plasma values. Neither Apo H mRNA nor protein was detected in the adipose tissue. Liver from patients with diabetes and MS showed a significant increase of both Apo H mRNA and protein respect to the non-diabetic, non-MS patients.Conclusion: APOH plasma concentrations are strongly associated to MS alterations and vascular disease in type 2 diabetic patients and could be considered as a clinical marker of cardiovascular risk. The enhanced APOH levels in these patients are due to an increased liver synthesis. If APOH plays a major causal role in macrovascular lesions associated to diabetes and MS need further studies.

High plasma levels of matrix metalloproteinase-8 in patients with unstable angina

2009-08-12

Abstract: Matrix metalloproteinases (MMPs) play a role in collagen breakdown, leading to plaque instability. High levels of MMPs mRNA and proteins, especially MMP-1, MMP-2, MMP-8, MMP-9, and MMP-13, were shown in human atherosclerotic plaques. However, among various MMPs, only MMP-1, MMP-8 and MMP-13, so-called interstitial collagenases, can initiate collagen breakdown. To elucidate whether MMP-1, MMP-8 and MMP-13 levels in blood were high in patients with unstable angina (UAP), we measured serum MMP-1 and plasma MMP-8 and MMP-13 levels in 45 patients with UAP, 175 with stable coronary artery disease (CAD), and 45 controls. Plasma C-reactive protein levels tended to be higher in patients with UAP than in those with stable CAD and controls (median 0.94 vs. 0.69 and 0.51mg/l). Regarding blood levels of MMPs, MMP-13 levels were above the lower detection limit in only one patient with UAP (2%), one with stable CAD (1%), and none in controls. MMP-1 levels did not differ among patients with UAP, stable CAD, and controls (median 4.8, 5.3, and 5.4ng/ml). Notably, MMP-8 levels were higher in patients with stable CAD than in controls (median 3.5ng/ml vs. 2.8ng/ml, P<0.005), however, MMP-8 levels in patients with UAP were much higher than those in stable CAD (3.9ng/ml vs. 3.5ng/ml, P<0.05). In multivariate analysis, MMP-8 level was an independent factor for UAP. Thus, plasma MMP-8 levels were found to be high in patients with UAP, suggesting that MMP-8 levels in UAP may reflect coronary plaque instability and that MMP-8 is a promising biomarker for UAP.

A role for plasma transforming growth factor-β and matrix metalloproteinases in aortic aneurysm surveillance in Marfan syndrome?

2009-09-01

Abstract: Background: We have previously shown that the angiotensin-converting enzyme (ACE) inhibitor perindopril reduced aortic diameter by 3–7mm in Marfan syndrome (MFS) patients. Excessive signalling by the transforming growth factor-β (TGF-β) has been implicated in the development of aortic dilatation. We hypothesised that reduction in aortic diameter would correlate with reduction in plasma TGF-β and matrix metalloproteinase (MMP) levels.Methods: 17 MFS patients (aged 33±5 (mean±SD)) on standard β-blocker therapy were randomised to also receive perindopril (n=10) or placebo (n=7) for 24 weeks in a double blind study. Aortic root diameters were assessed at four sites via transthoracic echocardiography. Venous blood samples were analysed for latent and active TGF-β, MMP-2 and MMP-3 levels.Results: Perindopril significantly reduced aortic root diameters relative to placebo in both end-systole and end-diastole (by 1.2–3mm/m2, p<0.001). In addition, compared to placebo perindopril significantly reduced latent TGF-β levels by 14.0±4.5ng/ml (p=0.01), active TGF-β levels by 4±1ng/ml (p=0.02), MMP-2 levels by 22±6ng/ml (p<0.001), and MMP-3 levels by 5±1ng/ml (p<0.001). There were moderately strong correlations between the pre/post intervention change in aortic diameters and the change in both latent (r=0.49–0.76, p=0.001–0.04) and active TGF-β (r=0.59–0.73, p=0.002–0.02), MMP-2 (r=0.63–0.75, p=0.001–0.007), and MMP-3 plasma levels (r=0.81–0.83, p<0.0001).Conclusions: Plasma TGF-β, MMP-2 and MMP-3 should be further explored in longitudinal trials as potential prognostic indicators of progression of aortic dilatation and response to therapy in MFS.

Is uric acid protective or deleterious in acute ischemic stroke? A prospective cohort study

2009-09-16

Abstract: Contrasting observations have been made between serum urate and ischemic stroke outcomes in studies involving Caucasian populations. To assess the hypothesis that urate is associated with stroke outcomes, a prospective follow-up study was performed in a cohort of Asian patients with ischemic stroke. Patients diagnosed with transient ischemic attack, first or recurrent ischemic stroke were included in this study. Serum urate, measured using high-performance liquid chromatography, was correlated with 12-month functional and vascular stroke outcomes. Poor functional outcome was defined as a modified Rankin scale exceeding 2 and vascular outcome was defined as a composite of recurrent stroke, myocardial infarction or vascular death during the study period. A total of 503 patients of mean age 63 (SD 12) years were included. A U-shaped relationship between urate quartiles and poor functional outcomes was demonstrated. More patients with low (<280μM) and high (>410μM) urate levels had poor functional outcomes (36% and 27% respectively), compared to those with urate levels between 340 and 410μM (14%). No significant relationship was observed between urate and vascular outcomes. Depending on its level, serum urate may exhibit protective and deleterious effects on stroke outcomes.

Leptin, adiponectin, their ratio and risk of coronary heart disease: Results from the MONICA/KORA Augsburg Study 1984–2002

2009-09-07

Abstract: Objective: Despite modulating a number of metabolic processes linked to atherosclerosis, including glucose regulation, hematopoiesis, fatty acid catabolism and angiogenesis, the potential association of adiponectin and leptin with coronary heart disease is still a matter of controversy.Methods: We conducted a population-based case-cohort study within the MONICA/KORA Augsburg studies. Serum levels of adipokines were measured in 333 case subjects with incident CHD and 1,728 non-case subjects selected from a source population of 9300 middle-aged men and women. Mean follow-up was 10.8±4.6 years. We sought to analyze the association of leptin and adiponectin and their ratio with CHD.Results: After adjustment for various confounding factors the hazard ratios and 95% confidence intervals comparing tertile extremes were 0.79 (0.53–1.17) for leptin (top vs bottom tertile) and 0.87 (0. 62–1.23) for adiponectin (bottom vs top tertile), respectively. Furthermore, the ratio of leptin/adiponectin also showed no association with CHD (HR 1.01 (0.68–1.51)).Conclusions: The present study reports the association of leptin and adiponectin with incident CHD in a large population-based cohort. In contrast to fairly strong associations previously reported, our findings indicate no clinically relevant association between leptin, adiponectin and their ratio with the risk of CHD after adjustment for potential confounders.

Associations of inflammatory markers with coronary artery calcification: Results from the Multi-Ethnic Study of Atherosclerosis

2009-09-22

Abstract: Objective: Inflammatory markers predict coronary heart disease (CHD). However, associations with coronary artery calcium (CAC), a marker of subclinical CHD, are not established.Methods: We examined cross-sectional associations of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with CAC presence (Agatston score>0 by computed tomography) in 6783 Multi-Ethnic Study of Atherosclerosis (MESA) participants.Results: In all participants, those in the highest, compared to lowest, quartile of CRP had a relative risk (RR, 95% confidence interval) of 1.13 (1.06–1.19; p<0.01) for CAC in age, sex and ethnicity adjusted models. For highest versus lowest quartiles, relative risks were 1.22 (1.15–1.30; p<0.01) for IL-6 and 1.18 (1.11–1.24; p<0.01) for fibrinogen. Adjusting for CHD risk factors (smoking, diabetes, blood pressure, obesity and dyslipidemia) attenuated RRs. RRs for CAC were 1.05 (0.99–1.12; p=0.63) for CRP, 1.12 (1.06–1.20; p<0.01) for IL-6 and 1.09 (1.02–1.16; p=0.01) for fibrinogen in multivariable adjusted models. Results were similar for men and women and across ethnic groups.Conclusion: Inflammatory markers were weakly associated with CAC presence and burden in MESA. Our data support the hypothesis that inflammatory biomarkers and CAC reflect distinct pathophysiology.

Association of low glomerular filtration rate and albuminuria with peripheral arterial disease: The National Health and Nutrition Examination Survey, 1999–2004

2009-09-14

Abstract: Microalbuminuria may be an early sign of intra-renal vascular dysfunction and a marker of vascular risk in the general population as well as in high-risk individuals. However, the association between albuminuria and PAD has been demonstrated only in few small studies. The aim of current study is to evaluate the relative impact of albuminuria and glomerular filtration rate on the risk of peripheral artery disease (PAD) in a nationally representative sample population.Data (ankle brachial index [ABI], urine albumin, fasting glucose, and glomerular filtration rate [GFR] estimated using the Modification of Diet in Renal Disease [MDRD] Study equation) were collected on 7068 adults from the National Health and Nutrition Examination Survey (NHANES 1999–2004). PAD was defined as ABI <0.9 or >1.4. There was a trend towards an association between the presence of abnormal renal function (GFR<60mL/min/1.73m2) and PAD in the non-diabetic patients (OR of 1.43, 95% CI: 0.98–2.09; P=0.07) where as the presence of abnormal renal function was strongly associated PAD in the diabetic patients (OR of 2.3, 95% CI: 1.34–3.95; P=0.046). On the contrary, albuminuria was independently associated with PAD in the non-diabetic (OR, 1.87; 95% CI, 1.38–2.52; P=0.0003) but not in the diabetic patients (OR: 1.08, 95% CI: 0.68–1.73, P=0.7411).We concluded that albuminuria, independent of renal function, is strongly associated with PAD in non-diabetic subjects. As diabetes develops and HbA1c level increases, the predictive value of albuminuria gradually diminishes after adjustment for renal function.

Interrelationships of factor VII activity and plasma leptin with insulin resistance in coronary heart disease

Rubina A. Karatela, Gurmukh S. Sainani — 2009-09-25

Abstract: Objective: An increase of FVII activity (FVIIc) has been proposed to be an independent cardiovascular risk factor. Whether FVII is associated with insulin resistance in coronary heart disease (CHD) is still unknown. We tested the hypothesis that plasma FVII activity and leptin are associated with insulin resistance independently.Methods: We studied 130 subjects, of which 65 were CHD subjects and 65 were non-CHD control subjects. Fasting plasma levels of leptin, insulin, glucose, FVIIc activity, fibrinogen, lipid parameters were estimated for all the subjects. Body mass index (BMI), waist circumference (WC) and blood pressure levels were also determined.Results: We observed significantly raised plasma levels of FVIIc activity, leptin and insulin resistance among the CHD subjects compared to the non-CHD subjects. Raised FVIIc activity levels in CHD were significantly positively correlated with insulin resistance. Raised plasma leptin levels in CHD were correlated with insulin resistance, BMI and WC. Multivariate regression analysis showed that elevated levels of FVII activity in CHD was significantly associated with insulin resistance, independent of dyslipidemia, leptin, blood pressure levels, BMI, WC, gender and age. Furthermore, raised leptin levels in CHD subjects were significantly associated with insulin resistance and BMI, independently of each other and of dyslipidemia, FVIIc, blood pressure levels, WC, gender and age.Conclusion: Raised FVII and leptin levels in CHD patients were independently associated with insulin resistance, this was not observed among the non-CHD subjects.

Pentraxin 3 and complement cascade activation in the failure of arteriovenous fistula

2009-09-23

Abstract: Objective: Pentraxin-3 (PTX3) has been suggested to play a role in the development of vascular pathology. Stenosis of arteriovenous fistula (AVF) leading to its failure is the major cause of morbidity in hemodialysis patients. To date, little is known on the pathogenesis of AVF stenosis. The aim of the present study was to investigate the potential role of PTX3 in this setting.Methods and results: A sample of venous wall was collected at the time of AVF formation in 44 patients with end stage renal disease. Ten patients developed AVF stenosis and from these patients a second portion of the venous wall was obtained during surgical revision of the AVF. Confocal laser scanning microscopy demonstrated that PTX3 immunostaining, hardly detectable in native AVF, was significantly increased in failed AVF, showing a specific co-localization with endothelial cell markers. Circulating mononuclear cells isolated at the time of AVF revision presented a significantly higher PTX3 mRNA expression than those collected during AVF creation. Interestingly, a significant deposition of C5b-9 on endothelial cells, co-localizing with PTX3, was observed in stenotic AVF.Conclusion: The present study demonstrates for the first time a close association between PTX3 deposition and complement activation at the endothelial cell level in failed AVF and suggests a role for PTX3 in modulating innate immunity in the pathogenesis of AVF stenosis.

High expression level of Toll-like receptor 2 on monocytes is an important risk factor for arteriosclerotic disease

2009-09-22

Abstract: Background: Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns to initiate an innate immune response. We previously reported upregulation of TLR2 expression level on monocytes of stable angina pectoris patients with significant coronary artery disease (CAD) relative to control patients without significant CAD. In this study we aimed to determine whether high level of Toll-like receptor 2 (TLR2) is a risk factor for atherogenesis, independent of established risk factors including smoking, diabetes mellitus (DM), hypertension (HT), and hyperlipidemia (HL).Methods: TLR2 expression level on circulating monocyte surfaces was measured by using our developed flow cytometry assay. Patients were classified into two groups: “Arteriosclerotic disease” group (n=108) and “Control” group (n=70). Patients of the first group had arteriosclerotic disease such as CAD, aortic aneurysm, or peripheral arterial disease (PAD). The “Control” group was sex- and age-matched to the “Arteriosclerotic disease” group.Results: TLR2 expression was significantly higher in the “Arteriosclerotic disease” group than in the “Control” group (p<0.001). Multivariate ordinal logistic regression analysis was performed; other known risk factors, which were represented to two nominal score points, 0 or 1, for patients with and without it, respectively, and TLR2 level, which was treated as a metric variable. DM (p=0.002), HT (p=0.001), HL (p<0.001), and TLR2 level (p<0.001) were identified as significant contributors for arteriosclerotic disease.Conclusions: High TLR2 expression level on monocytes may be an independent risk factor for atherogenesis.

Target organ damage in patients with rheumatoid arthritis: The role of blood pressure and heart rate

2009-09-25

Abstract: Background: Rheumatoid arthritis (RA) is characterised by increased cardiovascular morbidity and mortality. Even though hypertension (HT) is highly prevalent in RA, the extent of target organ damage (TOD) caused by it remains unknown. Inflammation and sympathetic overdrive may also associate with TOD. We investigated the prevalence and associations of TOD in RA.Methods: In this cross-sectional, observational study, 251 RA patients with no overt cardiovascular or renal disease had extensive clinical and laboratory evaluations, including a 12-lead electrocardiogram and urine albumin:creatinine ratio. Pulse pressure (PP) was used as a proxy of arterial stiffness and heart rate (HR) of autonomic activity. TOD was defined as described in the European guidelines for the management of arterial hypertension. Binary logistic regression analysis was used to evaluate the independence of the variables that associated with the presence of TOD.Results: TOD prevalence was 23.5% (59/251). Of the 59 patients with TOD, 45.8% had suboptimally controlled HT, whereas 32.3% had undiagnosed HT. In univariable analysis, TOD was significantly associated with higher age (64.2±11.7 years vs. 58.0±12.4 years, p=0.001), HT prevalence (89.8% vs. 60.4%, p<0.001), systolic blood pressure (SBP) (150.3±18.8mmHg vs. 139.7±20.7mmHg, p=0.001), PP (70.6±16.6mmHg vs. 60.3±17.3mmHg, p<0.001), HR (77.1±15.4bpm vs. 72.2±12.2bpm, p<0.001), serum uric acid (320.6±88.8μmol/l vs. 285.0±74.9μmol/l, p=0.03) and type 2 diabetes mellitus prevalence (13.6% vs. 4.7%, p=0.019). Binary logistic regression analysis revealed that only hypertension indices and HR associated independently with TOD.Conclusions: TOD is highly prevalent in patients with RA and associates independently with hypertension, arterial stiffness and heart rate. Further prospective studies are needed to confirm these findings and examine the role of beta-blockers in this particular population.

Physical activity, the Framingham risk score and risk of coronary heart disease in men and women of the EPIC-Norfolk study

2009-09-23

Abstract: Objective: Test the hypothesis that considering leisure-time and work-related physical activity habits in addition to the Framingham risk score (FRS) would result into better classification of coronary heart disease (CHD) risk than FRS alone.Methods: Prospective, population-based study of 9564 men and 12165 women aged 45–79 years followed for an average of 11.4 years. A modified FRS which takes into account physical activity (evaluated using a validated lifestyle questionnaire taking into account leisure-time and work-related physical activity) was computed.Results: During follow-up, 2191 CHD events occurred. Among 3369 men who were classified as intermediate risk (event rate of 12.4%) according to the FRS, 413 were reclassified into the low-risk category and 279 were reclassified into the high-risk category after modification of the FRS. After reclassification of these men, CHD event rate was of 5.3% and 18.6%, respectively for men classified at low and high CHD risk. Among 4766 women initially classified as intermediate risk (event rate of 8.4%), 1282 were reclassified into the low-risk category whereas 1071 women were reclassified into the high-risk category. After reclassification of these women, CHD event rate was of 6.8% and 12.2%, respectively for women classified at low and high CHD risk.Conclusions: Results of the present study suggest that asking simple questions about leisure-time and work-related physical activity which can be rapidly obtained by any physician at no cost could be helpful in the estimation of patients’ CHD risk.

Serum albumin levels predict vascular dysfunction with paradoxical pathogenesis in healthy individuals

2009-10-12

Abstract: Background: Serum albumin is affected by both nutritional status and inflammation. It is, therefore, thought to be highly linked with pathogenesis of vascular dysfunction.Methods: Cross-sectional data from 2091 individuals aged 23–87, who underwent a general health examination, were analyzed. First, we investigated the association between serum albumin level and vascular functions, as assessed by brachial-ankle pulse-wave velocity (PWV). Then, we evaluated the prevalence of hyperglycemia (fasting blood sugar ≥100mg/dl), metabolic syndrome as determined by NCEP criteria, and inflammation (CRP ≥0.4mg/dl), across tertiles of albumin levels.Results: In a multivariate regression model, a U-shaped relationship between serum albumin and PWV was statistically significant when albumin level was treated as a continuous variable in g/dl and centered at 4.4g/dl (quadratic term P-value=0.006). The highest tertile of albumin level (4.6–5.4g/dl) was associated with increased odds ratios for hyperglycemia of 1.35 (1.07–1.70) compared to the middle tertile (4.4–4.5g/dl), whereas the lowest tertile (3.3–4.3g/dl) was associated with reduced odds ratios for hyperglycemia of 0.80 (0.65–0.99). The highest tertile was also associated with increased odds ratios for metabolic syndrome of 1.30 (0.96–1.76) compared to the middle tertile, whereas the lowest tertile was associated with reduced odds ratios of 0.70 (0.51–0.95).Furthermore, the lowest tertile was associated with increased prevalence of inflammation with an adjusted odds ratio of 1.85 (1.15–2.97).Conclusions: The current results demonstrate that extremes of serum albumin levels are linked to vascular dysfunction among healthy individuals. Furthermore, serum albumin is paradoxically linked to vascular disease under conditions both of overnutrition and of malnutrition and inflammation complex.

Serum selenium and prognosis in cardiovascular disease: results from the AtheroGene study

2009-10-19

Abstract: Objective: Experimental data suggest a protective role of the essential trace element selenium against cardiovascular disease (CVD), whereas epidemiological data remains controversial. We aimed to investigate the impact of serum selenium concentration in patients presenting with stable angina pectoris (SAP) or acute coronary syndrome (ACS) on long term prognosis.Methods: Baseline selenium concentration was measured in 1731 individuals (852 with SAP, and 879 with ACS). During a median follow-up of 6.1 years, 190 individuals died from cardiovascular causes.Results: In those ACS patients who subsequently died of cardiac causes, selenium levels were lower compared to survivors (61.0μg/L versus 71.5μg/L; P<0.0001). In a fully adjusted model, patients in the highest tertile of selenium concentration had a hazard ratio of 0.38 (95% CI: 0.16–0.91; P=0.03) as compared with those in the lowest. No association between selenium levels and cardiovascular outcome was observed in SAP.Conclusions: Low selenium concentration was associated with future cardiovascular death in patients with ACS.

Platelet activation and inflammatory response in patients with non-dipper hypertension

2009-09-27

Abstract: Objective: Non-dipper hypertensives had about three times the risk of atherosclerotic events than hypertensives whose blood pressure was >10% lower at night compared to daytime (dippers). Platelet activation and inflammatory response may derive from most atherosclerotic events. Mean platelet volume (MPV) is a determinant of platelet activation and high sensitive C-reactive protein (hs-CRP) is the best candidate assay to identify and monitor the inflammatory response. We aimed to determine whether MPV and hs-CRP levels are elevated in non-dipper patients compared to dippers and healthy controls. In addition, we tried to find out if MPV and CRP are related to each other or not in non-dipper hypertensives.Method: The total 126 patients study group included 86 patients with hypertension and 40 healthy subjects (16 male, mean age; 51±4) as control. Ambulatory blood pressure monitoring was performed for all patients. Hypertensive patients were divided into two groups; 46 dipper patients (18 male, mean age; 50±9) and 40 non-dipper patients (17 male, mean age; 53±11). Clinical baseline characteristics were similar between groups. We measured mean platelet volume in a blood sample collected in EDTA tubes and high-sensitive CRP was measured by using BN2 model nephlometer.Results: Non-dipper patients demonstrated higher levels of MPV compared to dippers and normotensives (9.72±0.52 fl vs 9.38±0.33 fl and 8.92±0.42 fl, p<0.05, respectively). High-sensitive CRP levels were also significantly higher in non-dippers compared to dippers and normotensives (4.9±1.7mg/l vs 3.8±1.5mg/l and 2.7±0.8mg/l, p<0.05, respectively). There was significant positive correlation between MPV and CRP levels (p=0.002, r=0.482) in non-dipper hypertensives.Conclusion: Our results suggest that patients with non-dipping tend to have increased platelet activation and inflammatory response. Increased platelet activation and inflammatory response could contribute to increase the atherosclerotic risk in non-dipper patients compared to dippers.

Bone mineral density and atherosclerosis: The Multi-Ethnic Study of Atherosclerosis, Abdominal Aortic Calcium Study

2009-10-12

Abstract: Context: Molecular and cell biology studies have demonstrated an association between bone and arterial wall disease, but the significance of a population-level association is less clear and potentially confounded by inability to account for shared risk factors.Objective: To test population-level associations between atherosclerosis types and bone integrity.Main outcome measures: Volumetric trabecular lumbar bone mineral density (vBMD), ankle-brachial index (ABI), intima-media thickness (IMT) of the common carotid (CCA-IMT) and internal carotid (ICA-IMT) arteries, and carotid plaque echogenicity.Design, setting and participants: A random subset of participants from the Multi-Ethnic Study of Atherosclerosis (MESA) assessed between 2002 and 2005.Results: 904 post-menopausal female (62.4 years; 62% non-white; 12% ABI <1; 17% CCA-IMT >1mm; 33% ICA-IMT >1mm) and 929 male (61.4 years; 58% non-white; 6% ABI <1; 25% CCA-IMT >1mm; 40% ICA-IMT >1mm) were included. In serial, sex-specific regression models adjusting for age, ethnicity, body mass index, dyslipidemia, hypertension, smoking, alcohol consumption, diabetes, homocysteine, interleukin-6, sex hormones, and renal function, lower vBMD was associated with lower ABI in men (p for trend <0.01) and greater ICA-IMT in men (p for trend <0.02). CCA-IMT was not associated with vBMD in men or women. Carotid plaque echogenicity was independently associated with lower vBMD in both men (trend p=0.01) and women (trend p<0.04). In all models, adjustment did not materially affect results.Conclusions: Lower vBMD is independently associated with structural and functional measures of atherosclerosis in men and with more advanced and calcified carotid atherosclerotic plaques in both sexes.

Triglycerides and non-high-density lipoprotein cholesterol and the incidence of cardiovascular disease in an urban Japanese cohort: The Suita study

2009-10-05

Abstract: Objective: The impact of elevated triglycerides (TG) and non-high density lipoprotein cholesterol (non-HDLC) on the incidence of stroke and myocardial infarction (MI) has not been well evaluated in Asian populations such as in Japan, which have a lower incidence of myocardial infarction, but a higher risk of stroke than Western populations.Methods: The authors conducted an 11.7-year prospective study ending in 2005 of 5098 Japanese aged 30–79 living in an urban population, initially free of stroke or MI. The relationship between serum lipids and the risk for stroke and MI was determined by dividing the participants into four groups stratified by the combination of serum levels of TG and non-HDLC. The cut-off value was 1.7mmol/L for TG and 4.9mmol/L for non-HDLC.Results and conclusion: The total person-years were 59,774 (27,461 for men and 32,313 for women). During the follow-up period, there were 113 cases of MI and 180 of stoke (with 116 cerebral infarctions). Compared with the low TG/low non-HDLC group, the hazard ratio (95% confidence interval) for MI in the high TG/high non-HDLC group was 2.55 (1.53–4.24) after adjustment for other cardiovascular risk factors. The hazard ratio for cerebral infarction in the high TG alone group was 1.63 (1.03–2.56); however, the risk of cerebral infarction was not significantly increased in the other groups. High serum levels of TG and non-HDLC are both important targets for the prevention of cardiovascular disease in Japan.

NT-proBNP is associated with coronary heart disease risk in healthy older women but fails to enhance prediction beyond established risk factors: Results from the British Women's Heart and Health Study

2009-10-08

Abstract: Objective: Limited evidence suggests NT-proBNP improves prediction of coronary heart disease (CHD) events but further data are needed, especially in people without pre-existing CHD and in women.Methods: We measured NT-proBNP in serum from 162 women with incident CHD events and 1226 controls (60–79 years) in a case–control study nested within the prospective British Women's Heart and Health Study. All cases and controls were free from CHD at baseline. We related NT-proBNP to CHD event risk, and determined to what extent NT-proBNP enhanced CHD risk prediction beyond established risk factors.Results: The odds ratio for CHD per 1 standard deviation increase in logeNT-proBNP was 1.37 (95% CI: 1.13–1.68) in analyses adjusted for established CHD risk factors, social class, CRP and insulin. However, addition of logeNT-proBNP did not improve the discrimination of a prediction model including age, social class, smoking, physical activity, lipids, fasting glucose, waist:hip ratio, hypertension, statin and aspirin use, nor a standard Framingham risk score model; area under the receiver operator curve for the former model increased from 0.676 to 0.687 on inclusion of NT-proBNP (p=0.3). Furthermore, adding NT-proBNP did not improve calibration of a prediction model containing established risk factors, nor did inclusion more appropriately re-classify participants in relation to their final outcome. Findings were similar (independent associations, but no prediction improvement) for fasting insulin and CRP.Conclusion: These results caution against use of NT-proBNP for CHD risk prediction in healthy women and suggest a need for larger studies in both genders to resolve outstanding uncertainties.

Plasma cystatin C for prediction of 1-year cardiac events in Mediterranean patients with non-ST elevation acute coronary syndrome

2009-10-12

Abstract: Objective: Evaluation of renal function (RF) is important for management of patients with non-ST elevation acute coronary syndrome (NSTE-ACS). Cystatin C, a sensitive marker of RF, appears to be also a marker of cardiovascular risk. Little is known regarding its predictive role in NSTE-ACS patients.Methods: We assessed 525 patients taking part in the “Systemic Inflammation Evaluation in patients with NSTE-ACS” (SIESTA) study. Patients were subdivided in quartiles according to cystatin C plasma concentrations (mg/L), i.e., Q1<0.81; Q2=0.81–0.92; Q3=0.93–1.10; Q4≥1.11. Glomerular filtration rate (eGFR) was estimated using the modification of diet in renal disease (MDRD) equation. The study end-point was the composite of cardiac death, non-fatal myocardial infarction and unstable angina at 1-year follow up.Results: Few patients (0.8%) had severely impaired RF (MDRD<30ml/min/1.73m2). 157 patients reached (30%) the study end-point. Patients in Q3 and Q4 showed a higher cumulative probability of cardiac events compared to patients in the lowest quartile. On multivariable analysis, patients in Q3 and Q4 had an increased incidence of cardiac events (adjusted HR=1.57 95%CI 1.04–2.49; p=0.036). Patients with TIMI risk score ≥3 or in-hospital heart failure were also at higher risk for acute cardiac events. Conventional markers of RF, i.e., serum creatinine and eGRF, were not predictors for the study end-point.Conclusions: Increased levels of cystatin C were an independent predictor of cardiac events at 1-year follow up in this contemporary series of Mediterranean patients with NSTE-ACS.

Corrigendum to “Studies of the human aortic intima by a direct quantitative assay of mutant alleles in the mitochondrial genome” [Atherosclerosis 204 (2009) 184–190]

2009-09-25

The author(s) regret that Dr. A. Orekhov's surname appeared incorrectly in the original article. The author(s) would like to apologise for any inconvenience this may have caused to the readers of the journal.