[show abstract][hide abstract] ABSTRACT: Atherosclerotic cardiovascular diseases are the leading causes of morbidity and mortality worldwide. We have previously shown that arachidonate 15-lipoxygenase B (ALOX15B) is highly expressed in atherosclerotic carotid plaques, and elucidation of mechanisms downstream of activated lipoxygenases may be relevant to our understanding of the genesis of atherosclerotic diseases. We examined 120 carotid plaques from patients with symptomatic carotid artery stenosis and showed that the extent of ALOX15B staining was significantly increased in carotid plaques with thrombosis. Impedance aggregometry analyses showed that the ALOX15B enzyme products 15-HETE and 15-HPETE increased platelet aggregation. By using a calibrated automatic thrombin assay, we showed that the ALOX15B products also increased both peak levels of thrombin and the total endogenous thrombin potential. Moreover, platelet aggregation was increased by addition of cell lysates from ischemic human macrophages, whereas platelet aggregation was reduced after knockdown of ALOX15B in human macrophages. Our data show that ALOX15B expression in human carotid plaques is associated with thrombus formation and that enzyme products of ALOX15B increase platelet aggregation and thrombin generation. We therefore propose that activated ALOX15B in macrophages may play a role in the induction of atherothrombotic events by increasing platelet aggregation and thrombin generation.
PLoS ONE 01/2014; 9(2):e88546. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: We investigated whether serum concentrations of apolipoprotein (apo) B and apoA-I and the apoB/apoA-I ratio provided predictive information on myocardial infarction (MI) and ischemic stroke during 13 years of follow-up in a group of initially clinically healthy 58-year-old men, free from previous cardiovascular disease, diabetes, other established disease, or treatment with cardiovascular drugs. Multivariate logistic regression analysis showed that the apoB/apoA-I ratio and apoB were significant and independent determinants of MI (exponentiation of the B coefficient [Exp(β)] 3.1, 95% confidence interval [CI] 1.6-6.3, P = .001, Exp(β) 2.8, 95% CI 1.1-7.7, P = .045, respectively). The area under the receiver-operating characteristics curve as a relative measure of test efficiency was highest and significant for both apoB/apoA-I ratio and apoB (area under the curve = 0.75, P < .001). In conclusion, the apoB/apoA-I ratio and apoB are independent risk factors for MI and has the highest efficiencies for predicting MI in initially healthy middle-aged men.
[show abstract][hide abstract] ABSTRACT: Type 2 diabetes (T2D) is a result of complex gene-environment interactions, and several risk factors have been identified, including age, family history, diet, sedentary lifestyle and obesity. Statistical models that combine known risk factors for T2D can partly identify individuals at high risk of developing the disease. However, these studies have so far indicated that human genetics contributes little to the models, whereas socio-demographic and environmental factors have greater influence. Recent evidence suggests the importance of the gut microbiota as an environmental factor, and an altered gut microbiota has been linked to metabolic diseases including obesity, diabetes and cardiovascular disease. Here we use shotgun sequencing to characterize the faecal metagenome of 145 European women with normal, impaired or diabetic glucose control. We observe compositional and functional alterations in the metagenomes of women with T2D, and develop a mathematical model based on metagenomic profiles that identified T2D with high accuracy. We applied this model to women with impaired glucose tolerance, and show that it can identify women who have a diabetes-like metabolism. Furthermore, glucose control and medication were unlikely to have major confounding effects. We also applied our model to a recently described Chinese cohort and show that the discriminant metagenomic markers for T2D differ between the European and Chinese cohorts. Therefore, metagenomic predictive tools for T2D should be specific for the age and geographical location of the populations studied.
[show abstract][hide abstract] ABSTRACT: OBJECTIVES: Contrast-enhanced ultrasonography (CEUS) has been used to assess the vascularisation of carotid plaques. Our aim was to develop and validate a standardised semi-automated method for CEUS examination of plaques, and test if the technique could be used to identify vulnerable plaques. METHODS: Study participants were a mixed population of symptomatic and asymptomatic subjects, selected if they had a plaque with height >2.5 mm and <10% acoustic shadowing. Participants received a bolus of ultrasound contrast agent and a 90-s cine-loop was captured. A Contrast Quantification Program (CQP) was developed and trained to identify extent of contrast uptake after motion correction and application of a noise reduction algorithm. The technique was validated by comparing CQP values with visual assessment of contrast uptake. CQP values were also compared with plaque echogenicity and history of clinical events. RESULTS: CQP values correlated with a visual, 5-scale classification of contrast uptake by two blinded, experienced sonographers. Repeated contrast injections showed high reproducibility. Participants with a history of ipsilateral stroke/TIA had significantly higher CQP values than asymptomatic participants. CONCLUSION: We present a reproducible, semi-automatic method to identify vascularisation of carotid plaques, which could be used in prospective studies to determine the clinical value of plaque vascularisation.
European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery 04/2013; · 2.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cadmium exposure has been found to be associated with atherosclerotic plaques in the carotid arteries and with circulating levels of the proatherogenic intercellular adhesion molecule-1 (ICAM-1). The research questions were (1) if blood and urinary cadmium levels are associated with low ankle-brachial index (ABI) as a measure of peripheral artery disease in a longitudinal study and (2) if ICAM-1 mediates proatherogenic effects of cadmium exposure.
A prospective, observational cohort study with a 5-year follow-up and an experimental study of cultured human aortic endothelial cells exposed to cadmium.
Research unit at a university hospital.
A cohort of 64-year-old women (n=489) recruited by stratified sampling of similarly sized groups with normal, impaired and diabetic glucose tolerance as assessed in a population-based screening examination. PRIMARY AND SECONDARY OUTCOME MEASURES: ABI (ratio of the systolic blood pressures in the tibial and brachial arteries ≤0.9 in any artery) in relation to cadmium exposure; ICAM-1 concentrations in the cell culture medium after cadmium incubation.
High (tertile 3 vs 1) concentrations of blood (B-Cd) or creatine-adjusted urinary cadmium (U-Cd) at baseline were found to predict low ABI after adjustment for smoking and other cardiovascular risk factors at baseline. For U-Cd the OR was 2.5 (95% CI 1.1 to 5.8). After exclusion of participants with ultrasound-assessed femoral atherosclerosis at baseline the OR for U-Cd was unchanged, and for B-Cd it was 3.7 (95% CI 1.05 to 13.3). Inclusion of serum ICAM-1 levels did not affect the cadmium-related ORs in multivariate analyses. The experimental study did not show any cadmium-induced increase of the production of ICAM-1 from human endothelial cells.
Cadmium exposure was associated with future peripheral artery disease, supporting the concept that cadmium exposure in the population has proatherogenic effects, although ICAM-1 mediated effects do not seem to be involved.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Cadmium is a wide-spread pollutant. Observational studies suggest associations between cadmium and prevalence of type 2 diabetes. Experimental studies indicate that cadmium may cause impaired insulin production. OBJECTIVES: To examine whether cadmium exposure is associated with impaired glucose tolerance and type 2 diabetes and impaired pancreatic beta-cell function. METHODS: Oral glucose tolerance tests were used in a screening examination of 64-year old women (n=2595) to identify all with diabetes, impaired (IGT) and normal (NGT) glucose tolerance. Random samples of women with type 2 diabetes (n=215), IGT (n=207) and NGT (n=194) were recruited in a cross-sectional examination including measurement of pancreatic insulin production (acute insulin response) and insulin sensitivity (homeostasis model assessment). Cadmium concentrations were measured in blood and urine. A follow-up examination was performed after 5.4 years with assessment of new cases with diabetes or impaired glucose tolerance. RESULTS: At baseline, neither blood nor urinary cadmium concentrations showed any statistically significant differences between women with type 2 diabetes, IGT or NGT. The prospective analysis included 68 cases with incident diabetes, 58 with IGT and 118 women with NGT and no associations with cadmium levels at baseline were observed. Blood and urinary cadmium at baseline were not associated with insulin production, blood glucose, HbA1c, or changes in HbA1c during follow-up. CONCLUSIONS: This is the first study of cadmium and diabetes with detailed data on pancreatic beta-cell function, insulin sensitivity and glucose tolerance. Cadmium exposure was not associated with increased risk of type 2 diabetes or IGT.
Environmental Research 12/2012; · 3.24 Impact Factor
[show abstract][hide abstract] ABSTRACT: Abstract Background: The metabolic syndrome is a global health problem and is associated with subsequent development of cardiovascular disease (CVD). However, data are scarce concerning prospective association of the syndrome and CVD in populations free of diabetes and previous CVD that also is free of all cardiovascular drugs. The aim of this study was to assess the risk of cardiovascular events due to the metabolic syndrome in a population-based cohort of initially healthy, low-risk, and medication-free 58-year-old Swedish men during 13-years of follow-up. Methods: From a total population sample of 1728 subjects, a stratified and randomly selected group of 391 subjects was included. The metabolic syndrome was defined according to the National Cholesterol Education Program. Cardiovascular events and cause of death were investigated by contact with the Centre of Epidemiology at the National Board of Health and Welfare. Results: The metabolic syndrome increased the risk of cardiovascular events with a hazard ratio of 2.1 [95% confidence interval (CI) 1.3-3.4], P=0.003. When adjusted for the factors of leisure-time physical activity, smoking habits, alcohol intake, and low-density lipoprotein cholesterol (LDL-C), the hazard ratio was 2.0 (95% CI 1.1-3.4), P=0.016. Conclusion: In a 13-year follow-up in initially healthy men, the metabolic syndrome increases the risk of cardiovascular events by two-fold. This risk was maintained also after adjustment for lifestyle factors.
[show abstract][hide abstract] ABSTRACT: OBJECTIVES: There is currently widespread exposure to the toxic metal cadmium through the diet as well as through smoking, and it has been suggested that cadmium exposure may increase the risk of cardiovascular disease. Here we examined whether cadmium exposure is associated with prevalence and growth of atherosclerotic plaques in the carotid arteries. DESIGN AND SUBJECTS: The analyses were performed in a screening-based cohort of 64-year-old Caucasian women with stratified, random selection to groups with normal glucose tolerance, impaired glucose tolerance and diabetes (n = 599). We measured cadmium concentrations in blood and urine at baseline. In addition, we performed ultrasound examination to determine the prevalence and area of atherosclerotic plaques in the carotid arteries and assessed smoking history and other cardiovascular risk factors at baseline and at a follow-up examination after a mean of 5.4 years. RESULTS: At baseline, blood cadmium levels were associated with increased risk of plaque and a large plaque area after adjustment for confounders. In women who had never smoked, blood cadmium levels correlated positively with plaque area at baseline. The occurrence of large plaques and the change in plaque area at follow-up were associated with blood and creatinine-corrected urinary cadmium concentrations at baseline after adjustment for confounders. Blood and urine cadmium levels added information to established cardiovascular risk factors in predicting progress of atherosclerosis. CONCLUSIONS: We have shown that cadmium levels in blood and urine are independent factors associated with the development of atherosclerotic plaques at baseline as well as prospectively. This novel observation emphasizes the need to consider cadmium as a pro-atherogenic pollutant.
Journal of Internal Medicine 07/2012; · 6.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Current Swedish guidelines recommend that carotid endarterectomy should be performed within 14 days of a qualifying neurological event, but it is not clear if very urgent surgery after an event is associated with increased perioperative risk. The aim of this study was to determine how the time between the event and carotid endarterectomy affects the procedural risk of mortality and stroke.
We prospectively analyzed data on all patients who underwent carotid endarterectomies for symptomatic carotid stenosis between May 12, 2008, and May 31, 2011, with records in the Swedish Vascular Registry (Swedvasc). Patients were divided according to time between the qualifying event and surgery (0-2 days, 3-7 days, 8-14 days, 15-180 days). Stroke rate and mortality at 30 days postsurgery were determined.
We analyzed data for 2596 patients and found that the combined mortality and stroke rate for patients treated 0 to 2 days after qualifying event was 11.5% (17 of 148) versus 3.6% (29 of 804), 4.0% (27 of 677), and 5.4% (52 of 967) for the groups treated at 3 to 7 days, 8 to 14 days, and 15 to 180 days, respectively. In a multivariate analysis, time was an independent risk factor for perioperative complications: patients treated at 0 to 2 days had a relative OR of 4.24 (CI, 2.07-8.70; P<0.001) compared with the reference 3- to 7-day group.
In this study of patients treated for symptomatic carotid disease, it was safe to perform surgery as early as Day 3 after a qualifying neurological event in contrast to patients treated within 0 to 2 days, which has a significantly increased perioperative risk.
[show abstract][hide abstract] ABSTRACT: Atherosclerotic lesions are characterized by lipid-loaded macrophages (foam cells) and hypoxic regions. Although it is well established that foam cells are produced by uptake of cholesterol from oxidized LDL, we previously showed that hypoxia also promotes foam cell formation even in the absence of exogenous lipids. The hypoxia-induced lipid accumulation results from increased triglyceride biosynthesis but the exact mechanism is unknown. Our aim was to investigate the importance of glucose in promoting hypoxia-induced de novo lipid synthesis in human macrophages. In the absence of exogenous lipids, extracellular glucose promoted the accumulation of Oil Red O-stained lipid droplets in human monocyte-derived macrophages in a concentration-dependent manner. Lipid droplet accumulation was higher in macrophages exposed to hypoxia at all assessed concentrations of glucose. Importantly, triglyceride synthesis from glucose was increased in hypoxic macrophages. GLUT3 was highly expressed in macrophage-rich and hypoxic regions of human carotid atherosclerotic plaques and in macrophages isolated from these plaques. In human monocyte-derived macrophages, hypoxia increased expression of both GLUT3 mRNA and protein, and knockdown of GLUT3 with siRNA significantly reduced both glucose uptake and lipid droplet accumulation. In conclusion, we have shown that hypoxia-induced increases in glucose uptake through GLUT3 are important for lipid synthesis in macrophages, and may contribute to foam cell formation in hypoxic regions of atherosclerotic lesions.
PLoS ONE 01/2012; 7(8):e42360. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Male ApoE(-/-) mice were exposed to SDR-stress during 12 weeks, 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.
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.
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.
[show abstract][hide abstract] ABSTRACT: Circulating C-reactive protein (CRP), reflective of systemic chronic low-grade inflammation, is a marker associated with cardiovascular disease (CVD). One of the mechanisms through which physical activity might promote cardiovascular health is by preventing changes in inflammation biomarkers, such as CRP. The present study examined the association of self-reported physical activity with an inflammation biomarker, high-sensitivity CRP (hs-CRP), in a population-based cohort of clinically healthy 58-year-old men. Compared with a sedentary lifestyle both moderate (1.81 [0.94-3.69] vs 1.28 [0.55-2.90] mg/L; P < .05) and vigorous physical activity (1.81 [0.94-3.69] vs 0.88 [0.42-1.81] mg/L; P < .001) were associated with decrease in hs-CRP levels. In summary, we identified an association between self-reported leisure time physical activity and hs-CRP in a cross-sectional study of healthy 58-year-old men, with decreased levels of CRP by increased intensities of physical activity.
[show abstract][hide abstract] ABSTRACT: The metabolic syndrome (MetS) is characterized by a cluster of factors that confer an increased risk of cardiovascular morbidity as well as mortality. It is established that physical activity (PA) has a protective role in cardiovascular morbidity and mortality, mainly through favorable effects on traditional risk factors such as body mass and blood pressure. We assessed the prevalence of MetS in a population-based sample of 64-year-old women with impaired glucose tolerance (IGT) with respect to leisure-time PA (LTPA). The results showed an inverse linear association (P < .05) between LTPA and MetS in this group. In conclusion, this study suggests that an increased PA level has an important role in preventing MetS in women with IGT.
[show abstract][hide abstract] ABSTRACT: Increased vascularization is considered an important contributing factor for plaque vulnerability. Microvascular proliferative disease in patients with diabetes results in renal damage and visual loss. We assessed the hypothesis that vascularization in carotid atherosclerotic tissue is increased in diabetic patients, especially in the critical shoulder regions of the plaque.
Carotid endarterectomy specimens, clinical data, and blood samples were collected from patients with symptomatic carotid artery stenosis (median 85 days after clinical event) and pharmacologic treatment for diabetes (n = 26) or no diabetes (n = 85). Plaques were fixed in formalin and transverse tissue sections prepared. Histopathology and immunohistochemistry were performed for detection of endothelial cells (anti-CD34), macrophages (anti-CD68), vascular endothelial growth factor (VEGF), and its receptor (VEGFR-2). Neovascularization was assessed as CD34(+) neovessel density in the entire section area and by the presence or absence of CD34(+) vessels in the shoulder and cap regions of the plaques.
The patient groups did not differ significantly in neovascularization in the entire transverse sections (2.0 vs 2.1 vessels/mm(2); P = .61) or in the fibrous cap (52% of the patients in both groups; P = .95). Neovascularization of the plaque shoulder regions was observed in 52% of the diabetic patients and in 26% of the nondiabetic patients (P = .028). VEGF-stained areas were similar in the two patient groups (0.4% and 0.2% of shoulder area; P = .61). Patients with diabetes had more VEGFR-2 (1.0% vs 0.2% of shoulder area; P < .016) and less CD68 staining (0.4% vs 3.6% of shoulder area; P < .008). Time from clinical event to surgery was positively associated with neovascularization of the plaque shoulder regions (≤90 days, 18% of patients; >90 days, 50% of patients; P = .002), independently of diabetes status.
Diabetes was associated with increased vascularization of the shoulder regions in patients with symptomatic carotid atherosclerotic plaques. This was accompanied by increased expression of VEGFR-2. The increased vascularization of the plaque shoulder regions may help explain why patients with diabetes are at increased risk of atherosclerotic complications.
Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 07/2011; 54(5):1324-1331.e5. · 3.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: The metabolic syndrome (MetS) is characterized by a constellation of factors that confer an increased risk for cardiovascular morbidity and mortality. It is well-known that physical activity (PA) has a protective role on cardiovascular morbidity and mortality, mainly through its favorable effects on traditional risk factors such as body mass and blood pressure (BP). We assessed the prevalence of MetS in a population-based sample of 58-year-old men with respect to leisure-time PA and also to occupational PA. The results showed an inverse linear association (P < .05) between leisure time physical activity (LTPA) and MetS in this group. In conclusion, this study suggests that PA has an important role in controlling MetS.
[show abstract][hide abstract] ABSTRACT: To examine how serum adiponectin levels predict the incidence of type 2 diabetes, from different prediabetic states, in relation to insulin sensitivity and β-cell function during 5.5 years of follow-up.
In a population-based cohort of 64-year-old Caucasian women, we assessed glucose tolerance, insulin sensitivity as homeostasis model assessment, insulin secretion as acute insulin response, lifestyle factors and serum concentrations of adiponectin and high-sensitivity C-reactive protein. After 5.5 years of follow-up, 167 women with normal glucose tolerance (NGT) and 174 with impaired glucose tolerance (IGT) at baseline were re-examined and incidence of diabetes was assessed.
A total of 69 new cases of diabetes were detected during follow-up. Diabetes incidence was independently predicted by low levels of serum adiponectin, insulin resistance and insulin secretion, cigarette smoking, impaired fasting glucose (IFG) and IGT at baseline. Serum adiponectin below 11.54 g L(-1) was associated with an odds ratio of 3.6 (95% confidence interval 1.4-8.6) for future type 2 diabetes. At baseline, a high serum adiponectin concentration correlated positively with high levels of insulin sensitivity and insulin secretion. Women with incident diabetes had lower serum adiponectin levels in the NGT, IFG and IGT groups at baseline compared to those who did not develop diabetes during follow-up.
Low adiponectin concentrations were associated with future diabetes independently of insulin secretion and sensitivity, as well as IGT, IFG, smoking and abdominal obesity.
Journal of Internal Medicine 12/2010; 269(6):636-43. · 6.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: We examined whether high-sensitivity C-reactive protein (hsCRP) ≥2.0 mg/L was associated with increased intima-media thickness (IMT), plaque burden, and plaque echolucency in carotid arteries. Women (n = 635) from a population sample of 64-year-old females with varying degrees of glucose tolerance underwent risk factor assessment, measurement of hsCRP, and ultrasound examinations of the carotid arteries. Participants with hsCRP levels ≥2.0 mg/L had elevated carotid bulb IMT independently of other cardiovascular risk factors compared with those with hsCRP <2.0 mg/L. The participants with plaques in the highhsCRP group had larger total plaque area compared to those with plaque in the lower hsCRP group. Plaque echolucency did not differ between groups. High-sensitivity CRP levels ≥2.0 mg/L were accompanied by elevated IMT in the carotid bulbs independently of other cardiovascular risk factors. Total plaque area was larger among women with plaques in the high hsCRP group versus the lower hsCRP group.