Increased prevalence of vulnerable atherosclerotic plaques and low levels of natural IgM antibodies against phosphorylcholine in patients with systemic lupus erythematosus

The role of inflammation in the development of atherosclerosis is now accepted and a focus of many studies because of its complex mechanisms. The risk of cardiovascular disease (CVD) and atherosclerosis is reported to be increased in systemic lupus erythematosus (SLE), especially in the group of young women. The introduction of statins in the 1990’s lowered considerably the morbidity and mortality in CVD. In the last decade, research efforts were concentrated on the immunological mechanisms of atherosclerosis and on the possibility to influence these mechanisms. Our group recently reported a negative association between natural IgM-antibodies against phosphorylcholine (IgM anti-PC) and CVD outcome in the general population. Potential mechanisms considered include anti-inflammatory properties and inhibition of uptake of oxidized low density lipoprotein (oxLDL) in macrophages. The objective herein was to study mechanisms of atherosclerosis in SLE and the relation to traditional and non-traditional risk factors in an SLE cohort, in comparison with an age and sex matched control group. As systemic endothelial dysfunction is one of the earliest signs of atherosclerosis in the general population, we also assessed skin microvascular endothelial function in SLE patients and controls. A total of 114 patients with SLE were compared with 122 age and sex-matched population-based controls. Common carotid intima-media thickness (IMT), calculated intima-media area (cIMa) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded according to echogenicity. Anti-PC was assessed by enzyme-linked immunosorbent assay (ELISA). Endothelial function in skin was tested with local application of acetylcholine (ACh) and any concomitant increase in skin perfusion was measured with Laser Doppler Fluxmetry (LDF) in 84 of the SLE-patients and 81 of the age- and sex-matched controls. Incidence of hypertension, presence of insulin resistance (determined by homeostasis model assessment of insulin resistance, HOMA-IR) and the levels of triglycerides and C-reactive protein (CRP) were increased in the SLE patients, while smoking, cholesterol and high density lipoprotein (HDL) did not differ from controls. Low levels of IgM anti-PC were more common in the SLE patients than in the controls. IMT and cIMa did not differ significantly between groups. However, plaques were more often found in the SLE patients. Age, LDL and IgM anti-PC were independently associated with plaque occurrence in the SLE patients. Furthermore, in the left carotid arteries echolucent plaques were more prevalent in SLE when compared to controls. There were no significant differences in skin microvascular endothelial function between SLE patients and controls. In the SLE group, endothelial function did not vary in relation to presence of skin manifestations, Raynaud’s phenomenon, nephritis or plaque occurrence. In SLE patients with CVD, however, endothelial function was impaired. Conclusion: Plaque occurrence in the carotid arteries was increased in SLE and was independently associated with age, LDL and low anti-PC levels. Vulnerable plaques were more common in SLE than in controls. Anti-PC could be a novel risk marker for atherosclerosis with therapeutic potential in SLE. Skin microvascular endothelial function was associated with CVD but not with early signs of atherosclerosis in SLE-patients. The endothelial function was not different in SLE-patients, as compared to controls

Chromosome 1p13 genetic variants antagonize the risk of myocardial infarction associated with high ApoB serum levels

PMCID: PMC3480949This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

The interaction between coagulation factor 2 receptor and interleukin 6 haplotypes increases the risk of myocardial infarction in men.

The aim of the study was to investigate if the interaction between the coagulation factor 2 receptor (F2R) and the interleukin 6 (IL6) haplotypes modulates the risk of myocardial infarction (MI) in the Stockholm Heart Epidemiology Program (SHEEP). Seven SNPs at the F2R locus and three SNPs at the IL6 locus were genotyped. Haplotypes and haplotype pairs (IL6*F2R) were generated. A logistic regression analysis was performed to analyze the association of the haplotypes and haplotype pairs with the MI risk. Presence of an interaction between the two haplotypes in each haplotype pair was calculated using two different methods: the statistical, on a multiplicative scale, which includes the cross product of the two factors into the logistic regression model; the biological, on an additive scale, which evaluates the relative risk associated with the joint presence of both factors. The ratio between the observed and the predicted effect of the joint exposure, the synergy index (S), indicates the presence of a synergy (S>1) or of an antagonism (S<1). None of the haplotypes within the two loci was associated with the risk of MI. Out of 22 different haplotype pairs, the haplotype pair 17 GGG*ADGTCCT was associated with an increased risk of MI with an OR (95%CI) of 1.58 (1.05-2.41) (p = 0.02) in the crude and an OR of 1.72 (1.11-2.67) (p = 0.01) in the adjusted analysis. We observed the presence of an interaction on a multiplicative scale with an OR (95%CI) of 2.24 (1.27-3.95) (p = 0.005) and a slight interactive effect between the two haplotypes on an additive scale with an OR (95%CI) of 1.56 (1.02-2.37) (p = 0.03) and S of 1.66 (0.89-31). In conclusion, our results support the hypothesis that the interaction between these two functionally related genes may influence the risk of MI and suggest new mechanisms involved in the genetic susceptibility to MI

The metabolic syndrome and ECG detected left ventricular hypertrophy--influences from IGF-1 and IGF-binding protein-1.

BACKGROUND AND AIMS: The metabolic syndrome (MetS) is associated with an increased risk for left ventricular hypertrophy (LVH) and cardiovascular mortality. The aim of this study was to investigate potential influences from insulin-like growth factor-1 (IGF-1) and IGF binding protein-1 (IGFBP-1) on the relationship between the MetS and LVH, also taking into account the role of physical activity (PA), use of oestrogen and gender. METHODS AND RESULTS: In a population-based cross-sectional study of 60-year-old men (n = 1822) and women (n = 2049) participants underwent physical examination and laboratory tests, including electrocardiography (ECG), and completed an extensive questionnaire. Women showed higher levels of IGFBP-1 than men (37.0 vs. 28.0 µg/l, p < 0.001), and women with LVH had lower levels of IGFBP-1 than women without LVH (31.0 µg/l vs. 37.0 µg/l, p < 0.001). Furthermore, women with low levels of IGFBP-1 had a significantly increased risk of having LVH (crude OR ≈ 2.5). When stratifying for PA and oestrogen, respectively, a weaker association between IGFBP-1 and LVH was demonstrated in physically active men and women, compared to inactive individuals, as well as in women using oestrogen, compared to non-users. CONCLUSION: In a representative sample of 60-year-old Swedish men and women, the main findings were higher levels of IGFBP-1 in women than in men; lower levels of IGFBP-1 in women with LVH, compared to women without LVH; and an increased risk of having LVH in women with low levels of IGFBP-1. The association between IGFBP-1 and LVH was diminished in physically active men and women, as well as in women using oestrogen

Antibodies against native and oxidized cardiolipin and phosphatidylserine and phosphorylcholine in atherosclerosis development.

BACKGROUND: Antibodies against cardiolipin and phosphatidylserine (anti-CL and anti-PS) are associated with thrombosis. In contrast, we determined that IgM antibodies against oxidized CL and PS (OxCL and OxPS) and phosphorylcholine (anti-PC) could be protection markers for cardiovascular disease (CVD). METHODS: 226 individuals with established hypertension (diastolic pressure>95 mmHg) from the European Lacidipine Study on Atherosclerosis. Antibodies were tested by ELISA. As a surrogate measure of atherosclerosis, the mean of the maximum intima-media thicknesses (IMT) in the far walls of common carotids and bifurcations was determined by ultrasonography at the time of inclusion and 4 years following inclusion. RESULTS: Increases in IMT measures at follow-up were significantly less common in subjects which at baseline had high IgM anti-OxPS and anti-PC at above 75th percentile: OR 0,45, CI (0,23-0,86) and OR 0.37, CI (0,19-0,71), p = 0.0137 respectively and above 90th percentile: OR 0.32, CI (0,12-0,84) and OR 0.39, CI (0,15-1.00), p = 0.050 and OR 0,22, CI (0,08-0,59) p = 0,0029. IgM anti-OxCL was negatively associated with IMT increases (OR, 0.32, CI (0,12-0,84), p = 0231). There were no associations for IgM anti-PS or anti-CL. Anti-PC, as determined herein by a commercial ELISA, was strongly associated with data from our previously published in house ELISA (R = 0,87; p<0,0001).) Anti-PC was also a risk marker at low levels (below 25th percentile; OR = 2,37 (1,16-4,82), p = 0,0177). CONCLUSIONS: High levels of IgM anti-OxPS and anti-OxCL, but not traditional anti-phospholipid antibodies (anti-PS and anti-CL), are associated with protection against atherosclerosis development. In addition, low IgM anti-PC was a risk marker but high a protection marker

Antibodies against malondialdehyde among 60-year-olds: prediction of cardiovascular disease

Abstract Malondialdehyde (MDA) is generated in oxidized LDL. It forms covalent protein adducts, and is recognized by antibodies (anti-MDA). We previously studied IgM anti-MDA, and here we focus on IgG, IgG1 and IgG2 anti-MDA in predicting cardiovascular disease (CVD). We determined, by ELISA, anti-MDA in a 7-year follow-up of 60-year-old men and women from Stockholm County (2039 men, 2193 women). We identified 210 incident CVD cases (defined as new events of myocardial infarction (MI), and hospitalization for angina pectoris) and ischemic stroke, and 620 age- and sex-matched controls. IgG anti-MDA was not associated with CVD. Median values only differed significantly for IgG1 anti-MDA among men, with lower levels among cases than controls (p = 0.039). High IgG1 anti-MDA (above 75th percentile) was inversely associated with CVD risk after adjustment for smoking, body mass index, type 2 diabetes, hyperlipidemia, and hypertension, (OR and 95% CI: 0.59; 0.40–0.89). After stratification by sex, this association emerged in men (OR and 95% CI: 0.46; 0.27–0.77), but not in women. IgG2 anti-MDA were associated with protection in the whole group and among men though weaker than IgG1 anti-MDA. IgG2 anti-MDA above the 75th percentile was associated with an increased risk of MI/angina in women (OR and 95% CI: 2.57; (1.08–6.16)). IgG1 and less so IgG2 anti-MDA are protection markers for CVD and MI/angina in the whole group and among men. However, IgG2 anti-MDA was a risk marker for MI/angina among women. These findings could have implications for both prediction and therapy