| 1. |
- Nordin Fredrikson, Gunilla, et al.
(författare)
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Identification of autoantibodies in human plasma recognizing an apoB-100 LDL receptor binding site peptide
- 2006
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Ingår i: Journal of Lipid Research. - 1539-7262 .- 0022-2275. ; 47:9, s. 2049-2054
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to test the hypothesis that autoantibodies recognize amino acid sequences in the LDL receptor binding region of apolipoprotein B-100 (apoB-100). Autoantibodies against an unmodified or malondialdehyde (MDA)-modified LDL receptor binding site peptide were determined by ELISA in baseline plasma samples of 78 cases with coronary events and 149 matched controls recruited from the prospective Malmo Diet Cancer Study. IgG and IgM recognizing this peptide were detected in all subjects but did not differ between cases and controls. Inverse associations were observed between IgG against the native binding site and plasma oxidized LDL (r = -0.21, P < 0.005), but there were no significant associations with total or LDL cholesterol levels. In univariate analyses, inverse associations were found between baseline carotid intima-media thickness and IgG against the MDA-modified binding site (r = -0.14, P < 0.05), but this association was lost when controlling for other major cardiovascular risk factors. Specificity studies demonstrated that the binding of autoantibodies to these sequences could be inhibited by oxidized but not by native LDL. Autoantibodies recognizing the LDL receptor binding site in apoB-100 are frequently expressed. Their association with plasma oxidized LDL suggests that they have been generated in response to breakdown products of LDL oxidation, but their influence on cholesterol metabolism and the development of atherosclerosis appears limited.
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| 2. |
- Nilsson, Peter, et al.
(författare)
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The enigma of increased non-cancer mortality after weight loss in healthy men who are overweight or obese.
- 2002
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 252:1, s. 70-78
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To study effects on non-cancer mortality of observational weight loss in middle-aged men stratified for body mass index (BMI), taking a wide range of possible confounders into account. Design. Prospective, population based study. Setting. Male population of Malmö, Sweden. Participants. In all 5722 men were screened twice with a mean time interval of 6 years in Malmö, southern Sweden. They were classified according to BMI category at baseline (<21, 22-25, overweight: 26-30, and obesity: 30+ kg m-2) and weight change category until second screening (weight stable men defined as having a baseline BMI ± 0.1 kg m-2 year-1 at follow-up re-screening). Main outcome measures. Non-cancer mortality calculated from national registers during 16 years of follow-up after the second screening. Data from the first year of follow-up were excluded to avoid bias by mortality caused by subclinical disease at re-screening. Results. The relative risk (RR; 95% CI) for non-cancer mortality during follow-up was higher in men with decreasing BMI in all subgroups: RR 2.64 (1.46-4.71, baseline BMI <21 kg m-2), 1.39 (0.98-1.95, baseline BMI 22-25 kg m-2), and 1.71 (1.18-2.47, baseline BMI 26+ kg m-2), using BMI-stable men as reference group. Correspondingly, the non-cancer mortality was also higher in men with increasing BMI, but only in the obese group (baseline BMI 26+ kg m-2) with RR 1.86 (1.31-2.65). In a subanalysis, nonsmoking obese (30+ kg m-2) men with decreased BMI had an increased non-cancer mortality compared with BMI-stable obese men (Fischer's test: P=0.001). The mortality risk for nonsmoking overweight men who increased their BMI compared with BMI-stable men was also significant (P=0.006), but not in corresponding obese men (P=0.094). Conclusions. Weight loss in self-reported healthy but overweight middle-aged men, without serious disease, is associated with an increased non-cancer mortality, which seems even more pronounced in obese, nonsmoking men, as compared with corresponding but weight-stable men. The explanation for these observational findings is still enigmatic but could hypothetically be because of premature ageing effects causing so-called weight loss of involution.
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| 3. |
- Norinder, A, et al.
(författare)
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Costs for screening, intervention and hospital treatment generated by the Malmö Preventive Project: a large-scale community screening programme.
- 2002
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 251:1, s. 44-52
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The purpose of this study was to estimate retrospectively the costs of health care resources used in the Malmö Preventive Project, Sweden and estimate the costs of in-patient care that were avoided because of early intervention. SETTING AND SUBJECTS: A large-scale community intervention programme was conducted from 1974 to 1992 in Malmö, Sweden with the aim of reducing morbidity and mortality of cardiovascular diseases (CVD), alcohol related illnesses, and breast cancer. Between 1974 and 1992, 33 336 male and female subjects were screened for hypertension, hyperlipidaemia, type-2 diabetes and alcohol abuse. Intervention programmes that included life-style modifications, follow-up visits with physicians and nurses and drug therapy were offered to about 25% of screened subjects. METHODS: Recruitment costs were generated through out the screening period. Intervention costs were estimated for 5 years after screening. Excess in-patient care costs were estimated by subtracting hospital consumption for an unscreened, matched cohort from that of the screened cohort over follow-up periods of 13-19 years. Intervention and excess in-patient care costs were estimated until 1996. RESULTS: The net expenditures for recruitment and intervention was SEK253 million and saved costs for in-patient care of SEK143 millions (1998 prices). Considering the opportunity cost of the resources used in the study, the net cost rises to about SEK200 millions. CONCLUSIONS: The results suggest that only part of the intervention costs were offset by reduction in future morbidity health care costs. This is in line with results from prospective analyses of other primary prevention programmes.
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| 4. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 5. |
- Zetterqvist, Anna, et al.
(författare)
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Inhibition of nuclear factor of activated T-cells (NFAT) suppresses accelerated atherosclerosis in diabetic mice.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis.
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| 6. |
- Gustavsson, Carin, et al.
(författare)
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Vascular cellular adhesion molecule-1 (VCAM-1) expression in mice retinal vessels is affected by both hyperglycemia and hyperlipidemia.
- 2010
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Inflammation has been proposed to be important in the pathogenesis of diabetic retinopathy. An early feature of inflammation is the release of cytokines leading to increased expression of endothelial activation markers such as vascular cellular adhesion molecule-1 (VCAM-1). Here we investigated the impact of diabetes and dyslipidemia on VCAM-1 expression in mouse retinal vessels, as well as the potential role of tumor necrosis factor-α (TNFα). METHODOLOGY/PRINCIPAL FINDINGS: Expression of VCAM-1 was examined by confocal immunofluorescence microscopy in vessels of wild type (wt), hyperlipidemic (ApoE(-/-)) and TNFα deficient (TNFα(-/-), ApoE(-/-)/TNFα(-/-)) mice. Eight weeks of streptozotocin-induced diabetes resulted in increased VCAM-1 in wt mice, predominantly in small vessels (<10 µm). Diabetic wt mice had higher total retinal TNFα, IL-6 and IL-1β mRNA than controls; as well as higher soluble VCAM-1 (sVCAM-1) in plasma. Lack of TNFα increased higher basal VCAM-1 protein and sVCAM-1, but failed to up-regulate IL-6 and IL-1β mRNA and VCAM-1 protein in response to diabetes. Basal VCAM-1 expression was higher in ApoE(-/-) than in wt mice and both VCAM-1 mRNA and protein levels were further increased by high fat diet. These changes correlated to plasma cholesterol, LDL- and HDL-cholesterol, but not to triglycerides levels. Diabetes, despite further increasing plasma cholesterol in ApoE(-/-) mice, had no effects on VCAM-1 protein expression or on sVCAM-1. However, it increased ICAM-1 mRNA expression in retinal vessels, which correlated to plasma triglycerides. CONCLUSIONS/SIGNIFICANCE: Hyperglycemia triggers an inflammatory response in the retina of normolipidemic mice and up-regulation of VCAM-1 in retinal vessels. Hypercholesterolemia effectively promotes VCAM-1 expression without evident stimulation of inflammation. Diabetes-induced endothelial activation in ApoE(-/-) mice seems driven by elevated plasma triglycerides but not by cholesterol. Results also suggest a complex role for TNFα in the regulation of VCAM-1 expression, being protective under basal conditions but pro-inflammatory in response to diabetes.
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| 7. |
- Lind, Lars, et al.
(författare)
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The plasma protein profile and cardiovascular risk differ between intima-media thickness of the common carotid artery and the bulb : A meta-analysis and a longitudinal evaluation
- 2020
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Ingår i: Atherosclerosis. - : ELSEVIER IRELAND LTD. - 0021-9150 .- 1879-1484. ; 295, s. 25-30
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Genetic loci associated with CHD show different relationships with intima-media thickness in the common carotid artery (IMT-CCA) and in the bulb (IMT-bulb). We evaluated if IMT-CCA and IMT-bulb differ also with respect to circulating protein profiles and risk of incident atherosclerotic disease.Methods: In three Swedish cohorts (MDC, IMPROVE, PIVUS, total n > 7000), IMT-CCA and IMT-bulb were assessed by ultrasound at baseline, and 86 cardiovascular-related proteins were analyzed. In the PIVUS study only, IMT-CCA and IMT-bulb were investigated in relation to incident atherosclerotic disease over 10 years of follow-up.Results: In a meta-analysis of the analysis performed separately in the cohorts, three proteins, matrix metalloproteinase-12 (MMP-12), hepatocyte growth factor (HGF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), were associated with IMT-CCA when adjusted for traditional cardiovascular risk factors. Five proteins were associated with IMT-bulb (MMP-12, growth/differentiation factor 15 (GDF-15), osteoprotegerin, growth hormone and renin). Following adjustment for cardiovascular risk factors, IMT-bulb was significantly more closely related to incident stroke or myocardial infarction (total number of cases, 111) than IMT-CCA in the PIVUS study (HR 1.51 for 1 SD, 95%CI 1.21-1.87, p < 0.001 vs HR 1.17, 95%CI 0.93-1.47, p = 0.16). MMP-12 levels were related to this combined end-point (HR 1.30, 95%CI 1.08-1.56, p = 0.0061).Conclusions: Elevated levels of MMP-12 were associated with both IMT-CCA and IMT-bulb, but other proteins were significantly related to IMT in only one of these locations. The finding that IMT-bulb was more closely related to incident atherosclerotic disease than IMT-CCA emphasizes a difference between these measurements of IMT.
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| 8. |
- Borné, Yan, et al.
(författare)
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Biomarkers of blood cadmium and incidence of cardiovascular events in non-smokers: results from a population-based proteomics study
- 2019
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Ingår i: Clinical Proteomics. - : Springer Science and Business Media LLC. - 1542-6416 .- 1559-0275. ; 16:21
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCadmium is a toxic metal with multiple adverse health effects, including risk of cardiovascular disease (CVD). The mechanistic link between cadmium and CVD is unclear. Our aim was to examine the associations between blood cadmium (B-Cd) and 88 potential protein biomarkers of CVD.MethodsB-Cd and 88 plasma proteins were measured in a community-based prospective cohort, the Malmo Diet and Cancer study. The primary analysis was performed in never smokers (n=1725). Multiple linear regression was used with adjustments for age and sex, and correction for multiple comparisons using the false discovery rate method. Proteins significantly associated with B-Cd were replicated in long-term former smokers (n=782). Significant proteins were then studied in relation to incidence of CVD (i.e., coronary events or ischemic stroke) in never smokers.ResultsFifteen proteins were associated with B-Cd in never smokers. Eight of them were replicated in long-term former smokers. Kidney injury molecule-1, fibroblast growth factor-23 (FGF23), tumor necrosis factor receptor-2, matrix metalloproteinase-12, cathepsin L1, urokinase plasminogen activator receptor, C-C motif chemokine-3 (CCL3), and chemokine (C-X3-C motif) ligand-1 were associated with B-Cd both in never smokers and long-term former smokers. Except for CCL3 and FGF23, these proteins were also significantly associated with incidence of CVD.ConclusionsB-Cd in non-smokers was associated with eight potential plasma biomarkers of CVD and kidney injury. The results suggest pathways for the associations between B-Cd and CVD and kidney injury.
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| 9. |
- Berglund, Lisa, et al.
(författare)
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Nuclear Factor of Activated T Cells Regulates Osteopontin Expression in Arterial Smooth Muscle in Response to Diabetes-Induced Hyperglycemia
- 2010
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Ingår i: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY. - Baltimore : Lippincott Williams & Wilkins. - 1079-5642. ; 30, s. 154-218
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Tidskriftsartikel (refereegranskat)abstract
- Objective-Hyperglycemia is a recognized risk factor for cardiovascular disease in diabetes. Recently, we reported that high glucose activates the Ca2+/calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in arteries ex vivo. Here, we sought to determine whether hyperglycemia activates NFAT in vivo and whether this leads to vascular complications. Methods and Results-An intraperitoneal glucose-tolerance test in mice increased NFATc3 nuclear accumulation in vascular smooth muscle. Streptozotocin-induced diabetes resulted in increased NFATc3 transcriptional activity in arteries of NFAT-luciferase transgenic mice. Two NFAT-responsive sequences in the osteopontin (OPN) promoter were identified. This proinflammatory cytokine has been shown to exacerbate atherosclerosis and restenosis. Activation of NFAT resulted in increased OPN mRNA and protein in native arteries. Glucose-induced OPN expression was prevented by the ectonucleotidase apyrase, suggesting a mechanism involving the release of extracellular nucleotides. The calcineurin inhibitor cyclosporin A or the novel NFAT blocker A-285222 prevented glucose-induced OPN expression. Furthermore, diabetes resulted in higher OPN expression, which was significantly decreased by in vivo treatment with A-285222 for 4 weeks or prevented in arteries from NFATc3(-/-) mice. Conclusions-These results identify a glucose-sensitive transcription pathway in vivo, revealing a novel molecular mechanism that may underlie vascular complications of diabetes.
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| 10. |
- Gränsbo, Klas, et al.
(författare)
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Cardiovascular and Cancer Mortality in Very Elderly Post-Myocardial Infarction Patients Receiving Statin Treatment
- 2010
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 55:13, s. 1362-1369
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The purpose of this study was to determine whether statin treatment is effective and safe in very elderly (80 years and older) acute myocardial infarction (AMI) patients. Background Elderly individuals constitute an increasing percentage of patients admitted to hospitals for AMI. Despite that these patients have a higher mortality risk, the application of evidence-based medicine remains much lower than for younger patients. Methods We included all patients 80 years and older who were admitted with the diagnosis of AMI in the Register of Information and Knowledge About Swedish Heart Intensive Care Admissions between 1999 and 2003 (n = 21,410). Of these, complete covariate and follow-up data were available for 14,907 patients (study population A). To limit the bias related comorbidity on statin therapy, we also performed analyses excluding patients who died within 14 days of the acute event (study population B) and all patients who died within 365 days (study population C). A propensity score was used to adjust for initial differences between treatment groups. Results All-cause mortality was significantly lower in patients receiving statin treatment at discharge in study population A (relative risk: 0.55, 95% confidence interval: 0.51 to 0.59), in study population B (relative risk: 0.65; 95% confidence interval: 0.60 to 0.71), and in study population C (relative risk: 0.66; 95% confidence interval: 0.59 to 0.76). Similar observations were made for cardiovascular mortality as well as for AMI mortality. There was no increase in cancer mortality in statin-treated patients. Conclusions Statin treatment is associated with lower cardiovascular mortality in very elderly post-infarction patients without increasing the risk of the development of cancer.
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