Carotid artery intima-media thickness and elasticity in relation to glucose tolerance.

The association between diabetes and subclinical atherosclerosis is well established. The effect of non-diabetic glucose intolerance on early atherosclerosis is not as straightforward, and the data regarding sex-related differences in this matter are limited. Therefore, our aim was to investigate these associations in men and women separately. We studied 1,304 Finnish men and women over 45 years of age who participated in the Finnish Health 2000 Survey. Ultrasonically determined carotid artery intima-media thickness and elasticity were used as markers of early atherosclerosis. Glucose tolerance was categorized according to the American Diabetes Association criteria for diabetes mellitus. Age-adjusted means for carotid artery intima-media thickness and elasticity indices were significantly (P < 0.05) associated with glucose tolerance status in both sexes. There was a trend of increasing early atherosclerosis with the worsening of glucose tolerance in men and women. These associations were weakened in both sexes after further adjustments for other cardiovascular risk factors. In women, but not in men, significant (P < 0.05) associations between glucose tolerance status and carotid artery elasticity were seen even after these further adjustments. Diabetes and non-diabetic glucose intolerance are associated with increased early carotid atherosclerosis compared with normal glucose tolerance in both sexes. Our results suggest that women with glucose intolerance may be in greater risk than men.

Periodontal infection and subclinical atherosclerosis: the role of high-density lipoprotein as a modifying factor.

BACKGROUND: Periodontitis is suggested to enhance the process of vascular inflammation leading to atherosclerosis. The purpose was to study the relation between periodontal infection and subclinical atherosclerosis, and whether this relation is dependent on high-density lipoprotein (HDL) cholesterol levels. METHODS: A secondary analysis of the data of a diabetic study, confined to 60 dentate subjects who underwent clinical examinations in 1990-1992 and in 1996-1998, was carried out. Ultrasonographic measurements of carotid, aortic and femoral atherosclerosis were performed in 2000. RESULTS: No consistent association was found between the presence of periodontal pockets and subclinical atherosclerosis in the total population, but a fairly strong association was found among subjects with a low HDL level, whereas in subjects with a high HDL level, an opposing and less consistent association was found. Product terms indicating a possible modification by HDL were statistically significant (at p=0.05 level) for total plaques with all cut-off values, for plaques in carotid arteries with cut-off values 1.2-1.4 and for intima-media thickness with cut-off values of 1.1-1.2, but not for aorta plaques. CONCLUSIONS: HDL levels or factors closely associated with HDL levels appear to modify the association between periodontal infection and certain parameters of subclinical atherosclerosis.

Acromial shape in asymptomatic subjects: a study of 305 shoulders in different age groups.

BACKGROUND: It has been reported that acromial morphology and age have an independent association with rotator cuff pathology. In a recent study, we found the acromial angle of patients with stage III impingement syndrome (tear in the rotator cuff, according to the Neer classification of shoulder impingement syndrome) to be significantly greater than the acromial angle of their age-matched healthy controls. PURPOSE: To find out if acromial shape also changes, i.e., becomes more curved with age, in shoulders without any rotator cuff problems or previous shoulder surgery. MATERIAL AND METHODS: Standard supraspinatus outlet view (SOV) was obtained from both shoulders of healthy persons with no shoulder-related problems or previous shoulder surgery (n = 305; 36 SOVs for subjects aged 21-30 years, 60 for 31-40 years, 67 for 41-50 years, 52 for 51-60 years, 48 for 61-70 years, and 42 for over 71 years of age). Acromial angle, tilt, and the type of the acromion were evaluated. RESULTS: There were no statistically significant differences in the evaluated morphological parameters between the different age groups. CONCLUSION: Our results suggest that the shape of the acromion does not change with age in individuals who do not have any rotator cuff pathology. According to our results, the changes in acromial morphology seem to be similar in each age group.

Variation in the vascular endothelial growth factor gene, carotid intima-media thickness and the risk of acute myocardial infarction.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor, but its role in atherogenesis is still unclear. Our goal was to study whether three variants of the VEGF gene, previously associated with VEGF production, are linked to atherosclerosis defined as carotid intima-media thickness (IMT) and as the risk of acute myocardial infarction (AMI). MATERIAL AND METHODS: Three VEGF gene single nucleotide polymorphisms (SNPs) (-2578A>C rs699947, -634C>G rs2010963 and +936C>T rs3025039) were genotyped in 516 control subjects of the OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort and in 251 survivors of AMI. In the OPERA cohort, the genotyped SNPs were analysed for their association with IMT. The SNPs were also analysed for their association with the risk of AMI, a complication of advanced atherosclerosis. In addition, haplotype frequencies and their associated effects on IMT and on the risk of AMI were estimated. RESULTS: None of the single genotyped polymorphisms was significantly associated with overall IMT or with the risk of AMI. However, the haplotype CCC was associated with higher overall IMT without plaques in women (p = 0.01, haplotypic effect +0.03 mm), the haplotype CCT with higher IMT without plaques in the internal carotid artery in men (p = 0.001, +0.11), while the haplotype AGT was associated with reduced AMI risk (p = 0.015, OR = 0.46). CONCLUSIONS: Variation in the VEGF gene is weakly associated with IMT and the risk of AMI, but the effect can only be observed when the information of the SNPs is combined by constructing haplotypes.

Plasma interleukin-5 levels are related to antibodies binding to oxidized low-density lipoprotein and to decreased subclinical atherosclerosis.

OBJECTIVES: This study's aim was to assess the role of interleukin (IL)-5 in modulating the levels of antibodies binding to oxidized low-density lipoprotein (OxLDL) in human atherosclerosis. BACKGROUND: Various pro- and anti-inflammatory cytokines have been implicated in atherogenesis, and recent findings in mice indicate that the cytokine IL-5 plays a protective role in atherosclerosis in part via the induction of antibodies binding to OxLDL. METHODS: Plasma IL-5 levels and antibody titers to 2 most commonly used models of OxLDL (copper OxLDL and malondialdehyde-modified LDL) were measured in 1,011 Finnish middle-aged subjects with chemiluminescent enzyme-linked immunosorbent assay. Intima-media thickness (IMT) was assessed ultrasonographically from the internal carotid artery, the bifurcation, and the common carotid artery. RESULTS: There was a significant positive association between plasma IL-5 levels and antibody titers to copper OxLDL (p = 0.010 and p = 0.044, immunoglobin [Ig] M and G, respectively) and IgM to malondialdehyde-modified LDL (p < 0.001) in the association analysis performed between different IL-5 quartiles. Furthermore, plasma IL-5 levels were found to be inversely associated with bifurcational IMT, and even after adjustments for traditional risk factors of atherosclerosis (age, gender, smoking, systolic blood pressure, LDL, and body mass index), IL-5 remained an independent determinant of the mean bifurcational IMT (p = 0.010). CONCLUSIONS: Our data demonstrate that plasma IL-5 levels are related to the plasma levels of antibodies binding to OxLDL and to decreased subclinical atherosclerosis in humans. These results are in line with earlier findings in murine atherosclerosis and indicate for the first time that IL-5 may play a role in human atherosclerosis.

Interactions between ghrelin, leptin and IGF-I affect metabolic syndrome and early atherosclerosis.

BACKGROUND: High leptin and low ghrelin are associated with the metabolic syndrome (MS). AIMS AND METHODS: Ghrelin, leptin (RIA kits), and insulin-like growth factor I (IGF-I) (ELISA kit) concentrations of the population-based cohort of 1045 subjects and their interactions with metabolic parameters were analysed. Intima-media thickness (IMT) was measured with carotid ultrasound. RESULTS: The interaction between leptin and ghrelin on the MS was significant (P = 0.011). An additive effect of high leptin and low ghrelin on metabolic disturbances was observed: low ghrelin concentration (adjusted for age and sex) (P < 0.001) was associated with the MS and type 2 diabetes in the highest but not in the lower leptin quartiles. In the highest leptin quartile, ghrelin concentrations decreased linearly when the number of International Diabetes Federation MS criteria met (P < 0.01) increased. Ghrelin-leptin relation was independently associated with carotid IMT (P < 0.005). The independent positive association (P < 0.01) between the plasma ghrelin quartile and the carotid IMT was evident in the lowest IGF-I quartile. CONCLUSIONS: Low ghrelin is associated with MS and type 2 diabetes in the presence of insulin and leptin resistance. Ghrelin-leptin relation is associated with early atherosclerosis. The interaction between IGF-I and ghrelin modifies the association of ghrelin with early atherosclerosis.

High plasma resistin level is associated with enhanced highly sensitive C-reactive protein and leukocytes.

OBJECTIVES: Resistin is a newly described hormone with a suggested role in insulin resistance. In humans, inflammatory cells seem to be the major source of resistin. The aim of this study was to find out whether plasma resistin concentration associates with carotid artery atherosclerosis and the risk factors of atherosclerosis. METHODS: Plasma resistin concentrations were measured in 525 Finnish middle-aged subjects among our population-based cohort. Intima-media thickness was measured from the internal carotid artery, the bifurcation enlargement, and the common carotid artery. RESULTS: Among all the subjects, the median resistin concentration was 7.07 ng/ml (interquartile range, 5.82-8.84), women having higher levels than men (P < 0.001) with median values of 7.56 ng/ml (6.18-9.19) and 6.67 ng/ml (5.63-8.31), respectively. Resistin level correlated negatively with mean intima-media thickness, internal carotid artery, and common carotid artery, but the association did not remain significant after adjustments. Plasma resistin concentration was associated positively with leukocytes (P < 0.001), highly sensitive C-reactive protein (P = 0.009), and IGF binding protein 1 (P < 0.001), but not with plasma insulin or glucose levels in analysis of covariance after adjustments for age, sex, and body mass index. CONCLUSIONS: The results imply that inflammatory factors are more important in the determination of plasma resistin concentration than plasma insulin or glucose values. Resistin is associated with proatherogenic inflammatory markers but not independently with early atherosclerosis.

IGF-I concentrations are positively associated with carotid artery atherosclerosis in women.

BACKGROUND: Alterations in the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis are associated with increased cardiovascular morbidity and mortality, but previous studies have yielded conflicting results. In addition, the T1169A polymorphism in the GH1 gene has been associated with IGF-I levels. AIMS: To investigate whether IGF-I concentrations and the T1169A polymorphism of the GH1 gene are associated with cardiovascular risk factors and the intima media thickness (IMT) of the carotid artery. METHODS: Fasting plasma IGF-I concentrations (n=1008) were measured in a large population-based OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort. Genotype variants were determined by the restriction fragment length polymorphism method. RESULTS: Low IGF-I concentrations associated with several cardiovascular risk factors including age, adiposity, and high triglyceride, fasting insulin and C-reactive protein concentrations in the analysis of all subjects. In the multivariate models, however, IGF-I concentrations were positively associated with the mean IMT of women (ss=0.127, P=0.009) whereas the association in men was weaker and negative (ss=-0.088, P=0.034). The 1169A allele was associated with low low-density lipoprotein cholesterol in both sexes and with low systolic blood pressure levels in women. CONCLUSIONS: IGF-I concentrations were associated with several traditional cardiovascular risk factors. The observed gender difference in the association between IGF-I concentrations and carotid artery atherosclerosis warrants further study. The GH1 1169A allele may be associated with a favourable metabolic profile.

Associations of microalbuminuria and blood pressure with carotid, aortic and femoral atheromatous plaques in elderly Finns.

AIMS: To evaluate the possible associations of microalbuminuria (MA) and blood pressure (BP) with the ultrasonographic manifestations of carotid, aortic and femoral atherosclerosis in 65-year-old Finns. METHODS: Ultrasonographic measurements were performed on 54 diabetic subjects, 97 subjects with impaired glucose tolerance (IGT) and 57 normoglycemic subjects (NGT). Urinary albumin and creatinine concentrations were measured from an early morning spot urine sample, and the urinary albumin-to-creatinine ratio (ACR) of > or = 2.5 mg/mmol in men and > or = 3.5 mg/mmol in women was used as a measure of MA. Hypertension was defined as either a systolic BP of > or = 160 mmHg or a diastolic BP of > or = 95 mmHg or being on antihypertensive medication. RESULTS: Eighteen subjects were microalbuminuric and 176 subjects normoalbuminuric. MA was associated with diabetes mellitus and high systolic and diastolic BP. The subjects were divided into two groups according to the median total number of carotid, aortic and femoral plaques: > or = 9 versus 0-8 plaques. A high number of plaques were associated with hypertension, male gender, smoking and MA. When the study subjects were stratified according to hypertension, it turned out that MA was associated with a high number of plaques in hypertensive, but not in nonhypertensive subjects. According to the results of logistic regression analysis with a high number of plaques as the dependent variable, the unadjusted OR for smoking was 6.0 (95% CI 2.4-15.3) in hypertensive subjects. Microalbuminuria was of borderline statistical significance (OR 4.5, 95% CI 0.9-22.9). After adjustment for systolic blood pressure and fasting glucose concentration, the OR for microalbuminuria was reduced to 3.3 (95% CI 0.6-18.4).

Paraoxonase-1 gene Leu-Met55 and Gln-Arg192 polymorphisms are not associated with carotid artery atherosclerosis in a population-based cohort.

BACKGROUND: Paraoxonase-1 (PON1) is an enzyme that prevents low-density lipoprotein (LDL) oxidation. The role of polymorphisms of PON1 determining early atherosclerotic changes is currently unclear. DESIGN: Cross sectional cohort study. METHODS: Nine hundred and ninety-nine subjects from a population-based cohort were screened. Intima-media thickness (IMT) was measured by ultrasonography. Leu-Met55 and Gln-Arg192 polymorphism were determined. RESULTS: No association between PON1 genotypes and IMT was found. This finding remained after adjusting for confounding factors. CONCLUSIONS: The PON1 Leu-Met55 and Gln-Arg192 polymorphisms are not major risk factors for atherosclerosis in the general Caucasian population.

Serum androgen levels and testicular structure during pubertal maturation in male subjects with epilepsy.

PURPOSE: To evaluate reproductive endocrine function in boys and young men with epilepsy taking an antiepileptic drug in a population-based, controlled study. METHODS: Seventy patients and 70 controls matched for age and pubertal stage participated in this study. Twenty-eight patients were taking carbamazepine (CBZ); five, lamotrigine (LTG); 12, oxcarbazepine (OXC); and 25, valproate (VPA) as monotherapy for epilepsy. All subjects were examined clinically, and their medical histories were obtained. Serum reproductive hormone and sex hormone-binding globulin concentrations were measured, and testicular ultrasonography was performed. RESULTS: Serum testosterone levels were within the normal range in young male patients with epilepsy. However, the patients taking VPA had high serum androstenedione levels at all pubertal stages. In prepuberty, their serum androstenedione values were already approximately fivefold compared with the values of the controls (8.7 nM; SD, 4.0 vs. 1.8 nM, SD, 1.0; p < 0.0003), and they were elevated in 64% of the VPA-treated patients compared with none of the other patients, p = 0.0006. Serum sex hormone-binding globulin levels were increased, and serum dehydroepiandrosterone sulfate concentrations decreased in the pubertal patients taking CBZ. The mean testicular volumes did not differ between the patients and the controls. CONCLUSIONS: CBZ and VPA, but not LTG and OXC, are associated with changes in serum sex-hormone levels in boys and young men with epilepsy. However, the long-term health consequences of these reproductive endocrine changes during pubertal development remain to be established.

Immunoglobulin M type of autoantibodies to oxidized low-density lipoprotein has an inverse relation to carotid artery atherosclerosis.

BACKGROUND: Lipoprotein oxidation plays an important part in atherogenesis. Autoantibodies to oxidation-specific epitopes of LDL occur in plasma and atherosclerotic lesions of humans and animals. The potential role of these autoantibodies in atherogenesis still remains unsolved. We studied the relationship between different isotypes of autoantibodies to copper-oxidized LDL and malondialdehyde-modified LDL (MDA-LDL) and carotid artery intima-media thickness (IMT) in a population-based cohort of 1022 middle-aged men and women. In addition, we studied the relation of C-reactive protein (CRP) to IMT. METHODS AND RESULTS: The levels of IgM, IgG, and IgG2 autoantibodies binding to MDA-LDL and copper-oxidized LDL were determined in plasma samples by chemiluminescence-based ELISA. IMT and the number of plaques were measured ultrasonographically. The subjects were divided into tertiles for antibody titers. We found an inverse association between IMT and IgM autoantibody titers to MDA-LDL that remained statistically significant after adjusting for age, gender, LDL cholesterol, systolic blood pressure, CRP, and smoking. CRP was not independently associated with IMT. CONCLUSIONS: These results show that IgM autoantibodies to MDA-LDL have an inverse association with carotid atherosclerosis. The possible implications of this finding are discussed.

The signal sequence polymorphism of the MnSOD gene is associated with the degree of carotid atherosclerosis.

Redox-state of the cells of vascular walls is an important determinant of atherosclerosis. Manganese superoxide dismutase (MnSOD) is an essential anti-oxidant enzyme working in mitochondria of mammalian cells. A potentially functional amino acid polymorphism (Ala16Val) has been described in the signal sequence of the enzyme. The aim of the current study was to test whether the signal sequence polymorphism of the MnSOD would be associated with the degree of carotid atherosclerosis. The polymorphism was genotyped in a sample of 989 middle-aged hypertensive and control subjects. Carotid atherosclerosis was quantified as intima-media thickness (IMT) by ultrasound. The signal sequence polymorphism was found to be a minor determinant of carotid IMT explaining 1.3% of the overall variation, the Val allele associated with the higher IMT. In women, a significant interaction with plasma levels of low-density lipoprotein (LDL) cholesterol was detected, since LDL cholesterol levels were positively correlated with carotid IMT only in the carriers of the Val allele and the Val allele was associated with higher IMT only in the subjects with highest plasma levels of LDL cholesterol. In conclusion, the signal sequence polymorphism of the MnSOD gene is a minor determinant of carotid IMT pointing out the importance of redox-balance in the atherogenesis.

Apolipoprotein E polymorphism affects carotid artery atherosclerosis in smoking hypertensive men.

OBJECTIVE: Smoking is a risk factor for increased carotid artery intima-media thickness (IMT). The apolipoprotein E (apoE) 4 allele has been associated with cardiovascular diseases, but the role of apoE in regard to intima-media thickness (IMT) has remained controversial. The objective was to investigate whether there is some gene-environment interaction between smoking and apoE polymorphism. DESIGN Cross-sectional case-control study. METHODS: IMTs of 511 hypertensive and control men were measured ultrasonographically and the apoE genotypes were determined. Genotypes with the 4 allele were pooled into one group and the genotypes without it into another. RESULTS: A significant interaction between the 4 allele and smoking affecting IMT was observed among the hypertensive smokers, as assessed by analysis of covariance. The mean carotid IMT was significantly greater (1.01 versus 0.90 mm, P = 0.003) in the 4 carriers than in the subjects without 4 among the hypertensive smokers. The number of plaques was also significantly higher. No differences were found in the other subjects (hypertensive non-smokers or controls). Linear regression analysis indicated that the 4 allele was an independent determinant of IMT in the hypertensive smokers but not in the other subjects. The estimated average effect of the 4 allele on the mean IMT in the hypertensive smokers was 0.088 mm (P < 0.001). In the oldest age group, the interaction of smoking and 4 was also seen in the control subjects. CONCLUSION: The findings suggest that the 4 carriers are particularly susceptible to the atherogenic effects of smoking. This interaction is particularly clear in hypertensive subjects.

Low insulin sensitivity measured by both quantitative insulin sensitivity check index and homeostasis model assessment method as a risk factor of increased intima-media thickness of the carotid artery.

The present study evaluated the association of ultrasonographic manifestations of carotid atherosclerosis with glucose status, various components of the insulin resistance syndrome, and insulin sensitivity measured by a novel quantitative insulin sensitivity check index (QUICKI = 1/[log(I0) + log (G0)]). Carotid ultrasonographic measurements were performed on 54 diabetic subjects, 97 subjects with impaired glucose tolerance and 57 normoglycemic subjects. QUICKI and insulin resistance measured by a HOMA (homeostasis model assessment) method had a high negative correlation (r = -0.995, P < 0.001). QUICKI was lower in diabetic subjects (0.319 +/- 0.022) than in subjects with impaired glucose tolerance (0.334 +/- 0.027) or normoglycemia (0.335 +/- 0.022, P = 0.002). There was an increasing trend in the mean and maximal intima-media thickness (IMT) of the common carotid artery (CCA) with worsening of glucose status. The maximal IMT of the CCA correlated inversely with QUICKI (r = -0.158, P = 0.027). The prevalence of severe CCA atherosclerosis (maximal IMT of the CCA > or = 1.2 mm) was 41% in men and 16% in women (P < 0.001). It was also associated with a long (> or =26 yr) smoking history. The prevalence of severe CCA atherosclerosis was 11% in the highest QUICKI tertile, 36% in the middle tertile, and 33% in the lowest tertile (P = 0.002). Systolic blood pressure was higher and high-density lipoprotein cholesterol lower in subjects with severe CCA atherosclerosis, compared with those without it. In multiple regression analysis, the adjusted odds ratio for severe CCA atherosclerosis was 5.7 (95% confidence interval, 2.2-15.1) in subjects in the two lowest tertiles of QUICKI, compared with those in the highest tertile.

General practitioner's skills to perform limited goal-oriented abdominal US examinations after one month of intensive training.

A training program of "limited goal-oriented abdominal sonography" for general practitioners (GPs) was planned, set up and tested. After 1 month of intensive training (about 100 examinations), four test subjects succeeded in technically performing examinations in four patients out of five patients, and were able to rule out or exclude fluid collections, aortic aneurysms and common gallbladder disease.