Bone mineral density and carotid atherosclerosis in systemic lupus erythematosus: a controlled cross-sectional study.

INTRODUCTION: As osteoporosis is reported to be associated with atherosclerosis in the general population we examined the relationship between bone mass and carotid measurements in patients with systemic lupus erythematosus (SLE) and controls, and possible links between them in SLE. METHODS: In a cross-sectional study, 111 SLE-patient were compared with 111 age- and sex-matched controls, mean age 48.7(12.9) years, 89% were women, of which 51% postmenopausal. Carotid intima media thickness (cIMT), carotid plaque occurrence and echogenicity were determined by B-mode ultrasound and bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). RESULTS: BMD and cIMT were inversely associated both in patients and controls. Patients, but not controls, with carotid plaque had higher cIMT at low BMD than at normal BMD, p = 0.010. Logistic regression indicated more than doubled odds ratio (OR) of carotid plaque in patients, particularly in post-menopausal women, than in controls in relation to all BMD measurements. For low BMD at hip, significant increased OR for echolucent plaque was shown for patients compared with controls. In patients, significant impact of age, body mass index, smoking, systolic blood pressure, blood lipids, diabetes mellitus, impaired renal function, low levels of complement C3 and C4, history of nephritis, SLE-damage index and ever use of antimalarial was found for association between BMD and higher cIMT and carotid plaque. In multivariate regression, low C4 was independent contributor to association between total BMD and upper cIMT tertile, accounted for OR (95% confidence interval) of 3.2 (1.03-10.01), and also for association with bilateral carotid plaque, OR of 4.8 (1.03-22.66). The contribution of low C4 for the association between BMD and carotid atherosclerosis was enhanced within the second and third tertiles of total BMD. CONCLUSION: This study is the first to demonstrate inverse association between BMD and carotid measurements in both SLE-patients and controls. Our results suggest that SLE-patients may suffer higher burden of (sub)clinical atherosclerotic disease, especially presence of both echolucent and echogenic plaque, than controls with the same bone mineral status. Low complement C4 seems to play an important role in earlier development of carotid atherosclerosis already within (sub)normal ranges of total BMD in patients.

C-reactive protein in relation to early atherosclerosis and periodontitis.

Periodontitis may affect atherosclerosis via the chronic inflammation. We investigated high-sensitivity C-reactive protein (hsCRP) in relation to early vascular atherosclerotic changes in non-symptomatic subjects with and without long-term periodontitis. Carotid ultrasonography with calculation of common carotid artery intima-media area (cIMA) was performed, and hsCRP and atherosclerosis risk factors were analysed in randomly chosen 93 patients with periodontitis and 41 controls. The relationship between hsCRP, cIMA and atherosclerosis risk factors was evaluated with multiple logistic regression analysis. Women displayed lower hsCRP (p < 0.05) and higher serum HDL (p < 0.001) than men. In all patients with periodontitis, cIMA values were higher than in controls. Periodontitis appeared to be a major predictor for increased cIMA (odds ratio, 3.82; 95% confidence interval, 1.19-12.26). Neither of these factors was significantly associated with hsCRP which thus appeared not sensitive enough to be a marker for periodontitis or atherosclerosis. Hence, irrespective of low hsCRP levels, periodontitis appeared to increase the risk for atherosclerosis.

Longitudinal levels of apolipoproteins and antibodies against phosphorylcholine are independently associated with carotid artery atherosclerosis 5 years after rheumatoid arthritis onset--a prospective cohort study.

OBJECTIVE: RA is associated with premature atherosclerosis. Here, we determined the associations of apolipoproteins and immunoglobulin M (IgM) antibodies against phosphorylcholine (anti-PC) with carotid artery atherosclerosis in a prospective cohort of patients with early RA. METHODS: In all 114 patients, age 50.6 (11.2) years, 68.4% women, with recent RA (<12 months after symptoms onset) were included and assessed at 0, 3, 12, 24 and 60 months after RA diagnosis. At the same time points, apolipoproteins were determined by immunoturbidimetry, and IgM anti-PC by ELISA. Carotid intima-media thickness (cIMT) (common carotid) and occurrence of plaques (common, internal and external carotids) were the principal study outcomes, which were examined with high-resolution B-mode ultrasonography after 5 years of RA disease. Mixed linear modelling and generalized estimating equations (GEEs) were used for longitudinal statistical analyses. RESULTS: Multivariate regression analyses showed that age, male gender, smoking (ever) and history of cardiovascular disease (CVD), hypertension or diabetes mellitus, but no other baseline variables, had independent associations with cIMT (P < 0.05). Plaque detection was positively associated with age and smoking (ever). After adjustment, a longitudinal approach demonstrated an independent negative prediction of cIMT by apoA1 (P = 0.047), but a positive by apoB/apoA1 ratio (P = 0.030). Higher levels of pro-atherogenic apolipoproteins over time, apoB and apoB/apoA1 ratio, and low anti-PC tertile were independently associated with enhanced detection of bilateral carotid plaque (P = 0.002, 0.026 and 0.000, respectively). Both baseline and longitudinal levels of inflammatory/disease-related factors failed to show significant associations with the study outcomes. CONCLUSION: Apolipoproteins and anti-PC may have independent roles in subclinical atherosclerosis in patients with RA.

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

INTRODUCTION: The risk of cardiovascular disease (CVD) and atherosclerosis is reported to be increased in systemic lupus erythematosus (SLE). We recently reported a negative association between natural IgM-antibodies against phosphorylcholine (anti-PC) in the general population, high anti-PC levels leading to decreased atherosclerosis development and low levels to increased risk of CVD. Potential mechanisms include anti-inflammatory properties and inhibition of uptake of oxidized low density lipoprotein (LDL) in macrophages. The objective herein was to study atherosclerosis in SLE in detail and in relation to traditional and non-traditional risk factors. METHODS: 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 as a surrogate measure of atherosclerosis. Plaques were graded according to echogenicity and grouped as 1 to 4, with 1 being echoluscent, and considered most vulnerable. Anti-PC was studied by ELISA. RESULTS: Hypertension, triglycerides and insulin resistance (determined by homeostasis model assessment of insulin resistance) and C-reactive protein (CRP) were increased in SLE (P < 0.01) while smoking, LDL, high density lipoprotein (HDL) did not differ between groups. Low levels of anti-PC IgM (lowest tertile) were more common in SLE patients than in controls (P = 0.0022). IMT and cIMa did not differ significantly between groups. However, plaques were more often found in SLE patients (P = 0.029). Age, LDL and IgM anti-PC (lowest tertile) were independently associated with plaque occurrence in SLE. Further, in the left carotid arteries echoluscent plaques (grade 1) were more prevalent in SLE as compared to controls (P < 0.016). CONCLUSIONS: Plaque occurrence in the carotid arteries is increased in SLE and is independently associated with age, LDL and low anti-PC levels. Vulnerable plaques were more common in SLE. Anti-PC could be a novel risk marker also with a therapeutic potential in SLE.

The optimal cuff width for measuring toe blood pressure.

To determine the optimal cuff width for measuring toe blood pressure in patients with lower limb ischemia, this experimental prospective study examined 20 patients with symptoms of peripheral arterial disease referred for vascular examination or vascular surgery. Toe blood pressure was measured hydrostatically by the pole test using cuffs of different widths. Pole test reflects the true physiological blood pressure value and was the reference method. Blood pressures obtained using the cuffs were related to this value and to patients' toe circumference. With the 2.5-cm cuff, the patients had a mean pole test toe blood pressure of 28 mm Hg (range, 6-55 mm Hg). Compared with pole test results, the toe blood pressure was 15.6 mm Hg (95% confidence interval [CI], 8-23 mm Hg) higher when measured using the 2.0-cm cuff (P < .001) and 4.5 mm Hg (95% CI, 0-9 mm Hg) higher when measured using the 2.5-cm cuff (P = .07). Using the 1.5-cm and 3.0-cm cuffs, the differences were 27.0 mm Hg (95% CI, 13-43 mm Hg) and -2.0 mm Hg (95% CI, -11 to 8 mm Hg), respectively. The cuff width greatly affects the obtained toe blood pressure value, and larger cuffs correspond better to the hydrostatic pressure. For clinical use and as a reporting standard, we propose that toe blood pressure measurements should be made using a 2.5-cm-wide cuff.

Duplex ultrasonography is an efficient diagnostic tool for the detection of moderate to severe internal carotid artery stenosis.

BACKGROUND: The aim of this prospective national multicentre study with 10 participating university and county hospitals was to establish the diagnostic accuracy of carotid duplex sonography in the identification of >or=70% internal carotid artery (ICA) stenosis defined according to European Carotid Surgery Trial (ECST) criteria. METHODS: In 134 patients, aged 69 +/- 9 years, ICA stenoses were identified by routine carotid duplex ultrasonography, confirmed angiographically within 2 months, and graded according to ESCT criteria. The accuracy of carotid duplex to detect ICA stenosis >or=70% was assessed using receiver operating characteristic (ROC) analysis with carotid angiography as a reference. RESULTS: Measurement of peak systolic velocity in ICA (PSV(ICA)) identified ICA stenosis >or=70% with high diagnostic accuracy that was Doppler angle dependent resulting in different optimal PSV(ICA) cut points within the angle range 0 degrees -49 degrees (1 x 7 m s(-1)) and 50 degrees -62 degrees (2 x 3 m s(-1)). The diagnostic discrimination was significantly better when narrow Doppler angles (0 degrees -49 degrees ) were used (P<0 x 01) providing the sensitivity of 98 +/- 2% and specificity of 94 +/- 4%. DISCUSSION: Ultrasound duplex technique identifies moderate to severe (>or=70%) ICA stenoses (ECST criteria) with high degree of accuracy that can be further improved by the use of Doppler angle specific optimal PSV(ICA) cut points.

Increased leukotriene concentrations in gingival crevicular fluid from subjects with periodontal disease and atherosclerosis.

Recent studies indicate that periodontal disease is associated with the development of early atherosclerotic lesions in the carotid artery. Since inflammation is a key feature in both atherosclerosis and periodontal disease, a common mediator of the two diseases could be anticipated. Leukotrienes are lipid-derived inflammatory mediators recently implicated in the pathogenesis of atherosclerosis and previously shown to be produced in periodontitis. The aim of the present study was to detect leukotrienes in gingival crevicular fluid (GCF) from subjects with atherosclerosis. Carotid ultrasonography and oral clinical examination were performed in 19 periodontitis patients and 16 healthy subjects. Atherosclerotic plaques were detected on ultrasound examination in 13 subjects with periodontis, and in 5 of the healthy subjects. Elevated concentrations of leukotriene B(4) and cysteinyl-leukotrienes were detected in GCF from subjects with a high dental plaque index (PLI>0.3), supporting an increased leukotriene formation in periodontitis. In addition, subjects with atherosclerotic plaques had significantly elevated concentrations of cysteinyl-leukotrienes in their GCF as compared with subjects without a visible plaque. Finally, the increased cysteinyl-leukotriene concentrations in GCF from atherosclerotic subjects were observed also when sub groups of periodontis patients and healthy subjects were compared separately. In summary, increased GCF concentrations of cysteinyl-leukotrienes were correlated to measures of both periodontitis and atherosclerosis. These results suggest that increased leukotriene formation may represent a possible link between periodontitis and atherosclerosis and a risk factor marker for both diseases.

Low fetuin-A levels are associated with cardiovascular death: Impact of variations in the gene encoding fetuin.

BACKGROUND: Vascular calcification is common among end-stage renal disease (ESRD) patients and a central characteristic of the atherosclerotic cardiovascular disease observed in dialysis patients. Fetuin-A, a circulating calcium-regulatory glycoprotein that inhibits vascular calcification, is associated with inflammation and outcome in dialysis patients. In the present study, we evaluated the association between fetuin-A, clinical phenotype, and outcome, as well as the impact of fetuin gene (AHSG) polymorphisms on the protein product and outcome. METHODS: In a cohort of 258 (161 males) ESRD patients starting renal replacement therapy [glomerular filtration rate (GFR) 6.8 +/- 0.2 mL/min] aged 52 +/- 1 years the following parameters were studied: presence of malnutrition (subjective global assessment), comorbidity [diabetes mellitus and clinical manifest cardiovascular disease (CVD)], carotid plaques (N= 101), hs-CRP, fetuin-A, S-albumin, interleukin (IL)-6, and single nucleotide polymorphisms (SNPs) in the AHSG gene (N= 215) at amino acid positions Thr248Met (C-->T), Thr256Ser (C-->G), Asp276Asn (G-->A), and Arg317Cys (C-->T). RESULTS: Both all-cause (P < 0.001) and cardiovascular (P < 0.001) mortality were associated with low fetuin-A levels independently of age, smoking, diabetes, S-albumin, CVD, and inflammation (CRP > or =10 mg/L). Inflamed (0.199 vs. 0.247 g/L; P < 0.01) and malnourished (0.207 vs. 0.262 g/L; P < 0.05) patients had significantly lower median fetuin-A than noninflamed and well-nourished ESRD patients, respectively. In a logistic regression model (N= 101), fetuin-A was significantly (P < 0.05) associated with the presence of carotid plaques independently of age, CVD, diabetes, S-albumin, gender, and inflammation. Significant correlations were observed between fetuin-A and both S-albumin (Rho = 0.30; P < 0.0001) and IL-6 (Rho =-0.21; P < 0.01). Patients with the AHSG 256Ser allele had lower serum fetuin-A levels, and higher all-cause and cardiovascular mortality rate if they were inflamed. CONCLUSION: The present study shows that a low fetuin-A level is associated with malnutrition, inflammation, and atherosclerosis (carotid plaques), as well as with increased cardiovascular and all-cause mortality. Because the present study demonstrates an effect of variations in the AHSG gene on both circulating fetuin-A levels and outcome, this indicates that ESRD patients with the AHSG 256Ser allele are at risk of accelerated vascular calcification.

Early carotid atherosclerosis in subjects with periodontal diseases.

BACKGROUND AND PURPOSE: There is growing experimental evidence implicating chronic inflammation/infection as an atherosclerotic risk factor. In this study, the involvement of periodontal disease in the development of early atherosclerotic vascular lesions has been evaluated. METHODS: In randomly chosen 82 patients with periodontal disease and 31 periodontally healthy individuals subjected to a clinical oral examination in 1985, atherosclerotic risk factor analysis and carotid ultrasonography was performed during reexamination 16 years later. Common carotid artery intima-media thickness (IMT) and lumen diameter were measured and intima-media area (cIMA) was calculated. The relationship between IMT and cIMA as dependent variables and periodontal disease, age, gender, body mass index, heredity for atherosclerosis, diabetes mellitus, hypertension, plasma cholesterol, smoking, and education as independent variables was evaluated in a multiple logistic regression model. RESULTS: The mean values of IMT and cIMA were significantly higher in patients with periodontal disease than in controls, both at the right (P<0.01 and P<0.001, respectively) and left side (P<0.001 for both variables). When the means of the bilateral measurements of these 2 ultrasonographic variables were tested, multiple logistic regression analysis identified periodontal disease as a principal independent predictor of the common carotid artery cIMA (odds ratio [OR], 5.20; P=0.003) and IMT (OR, 4.64; P=0.004). CONCLUSIONS: The present results indicate that periodontal disease is associated with the development of early atherosclerotic carotid lesions.

Micro- and macrocirculatory effects of apheresis in patients with familial hyperlipidemia.

High lipid levels have been shown to coexist with a disturbed vascular endothelial function. Thus, acute lipid lowering could be expected to improve vascular reactivity. Patients with familial hyperlipidemia (FH) have substantial and rapid decreases in lipid levels after low-density lipoprotein apheresis. Thus, an opportunity exists to study acute effects of lipid lowering on vascular reactivity. Flow mediated vasodilation (FMD) is commonly used to assess endothelial function in conduit vessels, whereas vital capillary microscopy during the post-reactive hyperemia (PRH) phase is used to assess response at the microvascular level. It is not known whether endothelial dysfunction is a general phenomenon in all kinds of vessels or if there are differences between micro- and macrovessels. In the present study, we were not able to demonstrate an improved vascular response after acute lipid lowering in FH patients. This was true both in the microcirculation (PRH) and in the conduit vessels (FMD). However, the two methods gave concordant results, demonstrating disturbed vascular reactivity in the patients as compared with healthy subjects. We have found no previous report with parallel assessments at the microcirculatory and macrocirculatory levels.

[Recommendations by the Swedish Quality Board for Carotid Surgery. Ultrasound good preoperative method for evaluating degree of carotid stenosis]. / Rekommendationer från Svenska kvalitetskommittén för karotiskirurgi. Ultraljud bra preoperativ metod för gradering av karotisstenos.

The estimated degree of carotid stenosis is decisive for the selection of patients who would benefit from surgical treatment. Carotid thrombendarterectomy is recommended in patients with symptomatic > or = 80 procent internal carotid artery stenosis (ECST method). Many vascular centers now often rely entirely on duplex ultrasonography to select the patients for carotid surgery. The results of a recently published Swedish multicenter study (Jogestrand et al., Eur J Vasc Endovasc Surg 2002; 23:510-8) demonstrate that certain technical aspects of the ultrasound examination are of importance for the estimation of the degree of stenosis. Based on these results, the Swedish Quality Board for Carotid Surgery recommends the use of Doppler angle range specific cut off points for the peak systolic velocity in the internal carotid artery for identification of high-grade internal carotid artery stenosis: These cut off points are > or = 2.1 m/s for insonation angles of 0-49 degrees and > or = 3.2 m/s for angles 50-60 degrees. The angle of insonation should be kept as small as possible and should always be stated in the investigators report.

Elevated interleukin-6 predicts progressive carotid artery atherosclerosis in dialysis patients: association with Chlamydia pneumoniae seropositivity.

The cardiovascular mortality rate is unacceptably high in patients with end-stage renal disease (ESRD), which suggests an accelerated atherogenic process. The cause(s) of the accelerated atherogenesis in ESRD patients are not known, though recent studies suggest that persistent infection, such as Chlamydia pneumoniae, and proinflammatory cytokines may contribute. Forty-five ESRD patients (26 men) aged 51 +/- 2 years was studied at a time-point close to start of dialysis treatment and again after about 12 months of dialysis treatment. By using noninvasive B-mode ultrasonography, we evaluated changes in a surrogate marker of atherosclerosis, calculated intima media (cIM) area, in the common carotid artery. C-reactive protein (CRP), S-albumin, and interleukin-6 (IL-6) assessed the presence of an inflammatory reaction. We also measured C pneumoniae antibodies by microimmunofluorescence, nutritional status by subjective global assessment, lipid parameters, smoking habits, and the presence of comorbidity close to the start of dialysis. No significant changes in the prevalence of carotid plaques or the mean cIM area were observed during the first 12 months of dialysis. However, because some patients showed marked increases in the cIM area during only 12 months of dialysis we divided the patients into 2 groups: 23 nonprogressors ((delta)cIM area -2.7 +/- 0.4 mm2) and 22 progressors ((delta)cIM area 3.6 +/- 0.7 mm2). Sex, age, body mass index, comorbidity, blood lipid levels, S-albumin, and CRP levels did not differ significantly between the 2 groups. On the other hand, progressors had a significantly elevated basal median level of IL-6 (5.7 versus 3.1 pg/mL; P < 0.05) and an increased prevalence of positive (> or 1/64) immunoglobulin (Ig) A antichlamydia antibodies (59% versus 17%; P < 0.01) compared with nonprogressors. A significant positive (R = 0.41; P < 0.01) correlation was found between Log IL-6 and changes in the cIM area during 12 months of dialysis. In a stepwise multiple regression model, Log IL-6 did predict, independently (P < 0.01) of traditional risk factors and C pneumoniae antibodies, changes in the cIM area. These data suggest that a persistent chlamydial infection stimulates IL-6 levels, which in turn may be involved in the pathogenesis of accelerated carotid atherosclerosis in dialysis patients.