Johannes Hulthe

Circulating Oxidized LDL Is Associated With Subclinical Atherosclerosis Development and Inflammatory Cytokines (AIR Study)

Objective—Circulating oxidized LDL (Ox-LDL) is associated with clinical manifestations of atherosclerosis. However, no previous study has examined the relationship between subclinical atherosclerosis and Ox-LDL. The aims of the present study were to investigate the relationship between clinically silent ultrasound-assessed atherosclerotic changes in the carotid and femoral arteries and Ox-LDL and to explore the relationship between Ox-LDL, C-reactive protein, and the inflammatory cytokines interleukin-6 and tumor necrosis factor-&agr;. Methods and Results—The study group (n=391) consisted of clinically healthy, 58-year-old men recruited from the general population. Ox-LDL was measured by using a specific monoclonal antibody, mAb-4E6. The results showed that Ox-LDL was related to intima-media thickness and plaque occurrence in the carotid and femoral arteries. In addition, Ox-LDL was associated with tumor necrosis factor-&agr; and C-reactive protein. Circulating Ox-LDL was also associated with LDL cholesterol but not with blood pressure or smoking. When adjusting for other risk factors, both LDL cholesterol and Ox-LDL seemed to be independent predictors of plaque occurrence in the carotid and femoral arteries (odds ratios for quintile 5 versus quintile 1 were 2.17, P =0.049 and 2.25, P =0.050, for LDL cholesterol and Ox-LDL, respectively). Conclusions—Ox-LDL was associated with both subclinical atherosclerosis and inflammatory variables, supporting the concept that oxidatively modified LDL may play a major role in atherosclerosis development, although no causality can be shown in this cross-sectional study.

The Metabolic Syndrome, LDL Particle Size, and Atherosclerosis The Atherosclerosis and Insulin Resistance (AIR) Study

An operative definition of the metabolic syndrome has been suggested by a working group associated with the World Health Organization in 1998. The aim of this study was to examine whether small, low density lipoprotein (LDL) particle size was associated with the metabolic syndrome and with subclinical atherosclerosis as measured by ultrasound in the carotid and femoral arteries. The study was performed in a population-based sample of clinically healthy men (N=391), all 58 years old and not undergoing any treatment with cardiovascular drugs. Exclusion criteria were cardiovascular or other clinically overt diseases or continuous medication with cardiovascular drugs. The results showed that subjects characterized by the metabolic syndrome (n=62) had a thicker mean intima-media complex (IMT) in both the carotid and femoral arteries (0.86 versus 0.77 mm, P <0.001, and 1.03 versus 1.00 mm, P =0.022, respectively) and also lower mean values for LDL particle size (25.78 versus 26.80 nm, respectively, P <0.001) compared with subjects with no risk factors (n=77). The group with the metabolic syndrome (n=62) also had higher mean values for serum cholesterol and heart rate. In the whole study group (N=391), there were significant but weak negative relationships between small LDL particle size, increasing IMT, and increasing cross-sectional intima-media area of the carotid and femoral arteries and also negative relationships between LDL particle size and plaque occurrence and size in the carotid and femoral arteries. In summary, this is the first large-scale study to demonstrate a relationship between the clustering of risk factors that constitute the metabolic syndrome and a small LDL particle size pattern and the occurrence of preclinical atherosclerosis in the carotid and femoral arteries, as assessed by the ultrasound technique, in healthy 58-year-old men recruited from the general population.

Atherosclerotic Changes in the Carotid Artery Bulb as Measured by B-Mode Ultrasound Are Associated With the Extent of Coronary Atherosclerosis

BACKGROUND AND PURPOSE Ultrasound is increasingly used to measure atherosclerotic development in carotid and femoral arteries. The aim of this study was to investigate the relationship between coronary atherosclerosis as measured by quantitative angiography and peripheral atherosclerosis as measured by ultrasound in three different arterial regions. METHODS Patients (n = 32) with at least two coronary segments with visible signs of atherosclerosis as defined in a computer-assisted analysis of coronary angiograms were also examined with B-mode ultrasound. The extent of coronary atherosclerosis was expressed as the average diameter stenosis of coronary segments, and peripheral atherosclerosis was defined as intima-media thickness (IMT) and plaque occurrence in the common carotid artery, the carotid bulb, and the common femoral artery. RESULTS The results showed a significant correlation between the ultrasound measurement of IMT of the carotid bulb and diameter stenosis of the included coronary segments (r = .68, P = .01) and of carotid plaques and diameter stenosis (P < .001). The correlation between common carotid IMT and diameter stenosis of included coronary segments was not statistically significant (r = .31, NS). There were no significant relationships between common femoral IMT or femoral plaques and diameter stenosis of included coronary segments. CONCLUSIONS Although this study is small, it points to a very important aspect of ultrasound measurements of atherosclerosis: measurements performed in the common carotid artery or the femoral artery may not relate to coronary atherosclerosis in the same way as measurements performed in the carotid bulb. The findings underline the importance of measuring IMT not only in the common carotid artery but also in the carotid bulb and present data separately. These results have to be confirmed in a larger-scale study.

Low adipocyte-derived plasma protein adiponectin concentrations are associated with the metabolic syndrome and small dense low-density lipoprotein particles: atherosclerosis and insulin resistance study.

Circulating plasma adiponectin, an adipocyte-derived protein, has been shown to be decreased in obese subjects as well as in patients with type 2 diabetes and also in subjects who do not have diabetes, but are insulin resistant. We assessed the relationship between plasma levels of adiponectin, the metabolic syndrome and the occurrence of small dense LDL particles (pattern B) in 101 clinically healthy middle-aged subjects recruited from the general population. Low adiponectin levels were associated with the metabolic syndrome and low-density lipoprotein (LDL) particle size (r =.55, P <.001). The relationship between adiponectin and LDL particle size remained in a multiple regression model, in which adiponectin and total body fat explained 30% of the variability in LDL particle size. Furthermore, subjects in the lowest tertile of adiponectin had an increased risk of having pattern B (risk odds ratio [ROR] = 5.6). Because this was a cross-sectional study, no conclusions can be drawn about causality. This is the first population-based study in man demonstrating a relationship between small dense LDL particles and adiponectin.

Circulating oxidized low‐density lipoprotein (LDL) is associated with risk factors of the metabolic syndrome and LDL size in clinically healthy 58‐year‐old men (AIR study)

Abstract. Sigurdardottir V, Fagerberg B, Hulthe J (Sahlgrenska University Hospital, Göteborg University, Gothenburg, Sweden). Circulating oxidized low‐density lipoprotein (LDL) is associated with risk factors of the metabolic syndrome and LDL size in clinically healthy 58‐year‐old men (AIR study). J Intern Med 2002; 252: 440–447.

Serum matrix metalloproteinase-3 concentration is influenced by MMP-3 )1612 5A/6A promoter genotype and associated with myocardial infarction

Objectives.  Matrix metalloproteinase‐3 (MMP‐3) is implicated in the formation of atherosclerotic plaques, and the MMP‐3 −1612 5A/6A polymorphism is associated with myocardial infarction (MI) and stable coronary artery disease (CAD). The present study examined whether the −1612 5A/6A polymorphism in the promoter region of the MMP‐3 gene influences serum concentrations of MMP‐3 and whether serum concentrations of MMP‐3 are related to extent of coronary atherosclerosis and risk of MI.

Oxidized low-density lipoprotein in plasma is a prognostic marker of subclinical atherosclerosis development in clinically healthy men

Objective.  To investigate the association between plasma oxidized low‐density lipoprotein (OxLDL) and the progress of clinically silent atherosclerosis, as measured by ultrasound in the carotid arteries.

Apolipoprotein B/Apolipoprotein A-I in Relation to the Metabolic Syndrome and Change in Carotid Artery Intima-Media Thickness During 3 Years in Middle-Aged Men

Background and Purpose— The apolipoprotein B (apoB)/apolipoprotein A-I (apoA-I) ratio is a measure of the relationship between different lipoprotein particles and a powerful predictor of coronary death. The aim was to examine whether apoB/apoA-I was associated with the metabolic syndrome (MetS) at baseline and also with the future change in carotid artery intima-media thickness (IMT). Methods— In 313 58-year-old men, carotid artery IMT was measured bilaterally by high-resolution B-mode ultrasound at baseline and after 3 years of follow-up. Serum apolipoprotein concentrations and the components of MetS were measured at study entry. Results— ApoB/apoA-I showed statistically significant associations with body mass index, waist-to-hip ratio, high-density lipoprotein (HDL) cholesterol, triglycerides, low-density lipoprotein (LDL) particle size, insulin, and diastolic blood pressure. Two thirds of the patients with MetS had high apoB/apoA-I ratios (>0.90) compared with one third of those without the syndrome (P<0.001). The IMT change was associated with apoB, total cholesterol, LDL cholesterol, triglycerides, and inversely with HDL cholesterol and LDL particle size at entry, and there was a strong colinearity between these variables. The subjects with apoB/apoA-I above the first tertile (0.74) had a 20-μm-higher (95% CI, 7 to 33) annual increase in IMT compared with those below this level after adjustment for blood pressure and smoking. Conclusions— The apoB/apoA-I ratio was strongly associated with MetS and its components at baseline. ApoB/apoA-I at baseline was related to the change in carotid artery IMT during 3 years of follow-up. There was a strong colinearity between apoB/apoA and the atherogenic lipids.

Antibodies to Oxidized LDL in Relation to Intima-Media Thickness in Carotid and Femoral Arteries in 58-Year-Old Subjectively Clinically Healthy Men

Abstract—Antibody (Ab) titers to oxidized low density lipoprotein (OxLDL) have been found to be independent predictors of the progression of carotid atherosclerosis. Ab titers against OxLDL may be related to the entire burden of atherosclerosis in the vascular tree or, more specifically, to the disease process in different arterial regions. Therefore, the aim of the present study was to investigate the relationship between IgG and IgM titers to modified LDL and intima-media thickness (IMT) in the carotid and femoral arteries in subjectively clinically healthy 58-year-old men. IMT was measured by ultrasound, and Ab titers to modified LDL were measured by ELISA. The results showed that the common carotid artery IMT was associated with elevated titers of IgG-OxLDL Ab and independently with systolic blood pressure, smoking, and body mass index. The femoral artery IMT showed a negative correlation to IgM-OxLDL Ab and independent associations with smoking, systolic blood pressure, and total cholesterol. To summarize, in 58-year-old subjectively clinically healthy men recruited from the general population, there was a positive association between IgG-OxLDL Ab and IMT in the common carotid artery and a negative association between IgM-OxLDL Ab and IMT in the common femoral artery. However, these associations were not independent of other risk factors.

Antibodies to Oxidized LDL in Relation to Carotid Atherosclerosis, Cell Adhesion Molecules, and Phospholipase A2

Abstract —The role of the humoral immune response to oxidized low density lipoprotein (Ox-LDL) in atherogenesis is unclear and available studies are contradictory. The aims of the present study were (1) to compare antibody titers to modified LDL in a group of patients with hypercholesterolemia (n=102) with those in matched controls (n=102), (2) to analyze whether these titers were related to atherosclerosis development as measured by ultrasound, and (3) to analyze whether these titers were related to soluble cell adhesion molecules and secretory type II phospholipase A2 in plasma. The results showed that male patients with hypercholesterolemia had lower immunoglobulin G (IgG) titers compared with those in healthy controls. In the control group, there was an inverse correlation between intima-media thickness of the carotid artery bulb and IgM titers against Ox-LDL and malondialdehyde-LDL (r =−0.35, P =0.001; and r =−0.31, P =0.003, respectively). In the patient group, however, only weak associations were seen. IgG titers were positively associated with soluble intercellular adhesion molecule-1, soluble E-selectin, and secretory type II phospholipase A2. Taken together, the results of this study support the concept that the humoral immune response against Ox-LDL may be protective in early atherosclerosis. The pattern, however, is complex, and the role of the immune response may differ in different patient groups as well as at different stages of the disease.