Lena Bokemark

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.

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.

Carotid and femoral atherosclerosis, cardiovascular risk factors and C-reactive protein in relation to smokeless tobacco use or smoking in 58-year-old men

Abstract. Wallenfeldt K, Hulthe J, Bokemark L, Wikstrand J, Fagerberg B (Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden). Carotid and femoral atherosclerosis, cardiovascular risk factors and C‐reactive protein in relation to smokeless tobacco use or smoking in 58‐year‐old men. J Intern Med 2001; 250: 492–501.

Insulin resistance and intima–media thickness in the carotid and femoral arteries of clinically healthy 58‐year‐old men. The Atherosclerosis and Insulin Resistance Study (AIR)

Abstract. Bokemark L, Wikstrand J, Attvall S, Hulthe J, Wedel H, Fagerberg B (Sahlgrenska University Hospital, and the Nordic School of Public Health, Göteborg, Sweden). Insulin resistance and intima–media thickness in the carotid and femoral arteries of clinically healthy 58‐year‐old men. The Atherosclerosis and Insulin Resistance Study (AIR). J Intern Med 2001; 249: 59–67.

Insulin, insulin propeptides and intima-media thickness in the carotid artery in 58-year-old clinically healthy men. The Atherosclerosis and Insulin Resistance study (AIR).

Aims To examine the relationship between specific (intact) insulin, insulin propeptides and subclinical atherosclerosis.

Endothelium‐dependent flow‐mediated vasodilatation, insulin resistance and the metabolic syndrome in 60‐year‐old men

Objectives.  To evaluate the endothelium‐dependent flow‐mediated vasodilatation (FMD) in the brachial artery and to study the relationship to insulin sensitivity and to the metabolic syndrome in 60‐year‐old clinically healthy men.

The euglycemic hyperinsulinemic clamp examination: variability and reproducibility

The aim was to examine the reproducibility of the euglycemic hyperinsulinemic clamp method. From a random population sample of 60-year-old clinically healthy men, 32 subjects with varying degrees of insulin sensitivity were recruited. Conventional 2-h clamp examinations were carried out at an interval of 2 weeks. Insulin was infused intravenously (priming for 10 min and thereafter 1.0 mU/kg body wt/min). Glucose was infused concomitantly aiming at a whole blood glucose of 5 mmol/L. The glucose infusion rate (GIR) was adjusted for body weight or fat free mass (FFM), the latter measured with dual-energy X-ray absorptiometry. During the ®nal hour of each examination (60 ± 120 min) the mean whole blood glucose concentrations were 5.06¡0.15 and 5.09¡ 0.17 mmol/L, respectively. Of the different time intervals studied, the glucose infusion rate during the ®nal hour (GIR60 ± 120) showed the highest correlation and lowest coef®cient of variation (GIR60 ± 120 adjusted by FFM: r~0.70, coef®cient of variation~14.7%). Adjustment of GIR for weight instead of FFM underestimated insulin sensitivity in obese men. GIR60 ± 120 adjusted for FFM tended to increase during the second examination. The measurement error was constant across all GIR. In summary, the euglycemic hyperinsulinemic clamp method has a coef®cient of variation around 15%. The glucose infusion rate should be adjusted for fat free mass.The aim was to examine the reproducibility of the euglycemic hyperinsulinemic clamp method. From a random population sample of 60-year-old clinically healthy men, 32 subjects with varying degrees of insulin sensitivity were recruited. Conventional 2-h clamp examinations were carried out at an interval of 2 weeks. Insulin was infused intravenously (priming for 10 min and thereafter 1.0 mU/kg body wt/min). Glucose was infused concomitantly aiming at a whole blood glucose of 5 mmol/L. The glucose infusion rate (GIR) was adjusted for body weight or fat free mass (FFM), the latter measured with dual-energy X-ray absorptiometry. During the final hour of each examination (60-120 min) the mean whole blood glucose concentrations were 5.06+/-0.15 and 5.09+/-0.17 mmol/L, respectively. Of the different time intervals studied, the glucose infusion rate during the final hour (GIR60-120) showed the highest correlation and lowest coefficient of variation (GIR60-120 adjusted by FFM: r=0.70, coefficient of variation=14.7%). Adjustment of GIR for weight instead of FFM underestimated insulin sensitivity in obese men. GIR60-120 adjusted for FFM tended to increase during the second examination. The measurement error was constant across all GIR. In summary, the euglycemic hyperinsulinemic clamp method has a coefficient of variation around 15%. The glucose infusion rate should be adjusted for fat free mass.

Computerized measurement of LDL particle size in human serum: Reproducibility studies and evaluation of LDL particle size in relation to metabolic variables and the occurrence of atherosclerosis

OBJECTIVES The main aims of the present research project were to develop and evaluate a new software program for evaluation of LDL particle size applied to the gradient gel electrophoresis methodology without the use of previous ultracentrifugation, and to investigate the relationships among LDL particle size, metabolic variables and atherosclerosis, as measured by ultrasound, in subjects with different degrees of insulin resistance. METHODS LDL particle size was determined by polyacrylamide gradient gel electrophoresis. RESULTS Coefficient of variation for between-assay experiments was 0.3% (r = 0.99) for measurement of LDL peak particle size. LDL peak particle size was negatively correlated to serum triglycerides, apolipoprotein B, fasting insulin, BMI and diastolic blood pressure and positively correlated to HDL. Furthermore, subjects with moderate to large plaques in the carotid artery had smaller LDL particles compared to subjects without plaques. CONCLUSIONS This project resulted in a highly reproducible, computerized method for the analysis of LDL particle size. The data suggest that it is possible to assess LDL particle size in serum without the use of previous ultra-centrifugation. LDL particle size was associated with metabolic variables and the occurrence of moderate to large plaques in the carotid artery.

The Effect of Statins on Acute and Long-Term Outcome After Ischemic Stroke in the Elderly

BACKGROUND Although treatment with statins has produced beneficial effects when used as secondary prevention, its primary protective role is still somewhat controversial. Moreover, few studies have evaluated the effect of statins in older patients with stroke. OBJECTIVE The aim was to investigate whether treatment with statins decreases stroke severity and/or improves survival and outcome after stroke in an older population. METHODS We investigated the association between previous statin use and stroke severity (National Institutes of Health Stroke Scale [NIHSS]), as well as the effect of poststroke statin treatment on 12-month functional outcome (modified Rankin Scale [mRS] score) in 799 patients (mean age, 78 years), with acute ischemic stroke. The effect of statin treatment on survival was examined using the Cox proportional hazard model, after adjusting for relevant covariates. RESULTS Statins did not decrease stroke severity and did not improve 30-day survival. However, both the 12-month survival (hazard ratio = 0.33; 95% CI, 0.20-to 0.54; P < 0.001) and the 12-month functional outcome (odds ratio = 2.09; 95% CI, 1.25-3.52; P = 0.005) were significantly better in the group treated with statins. CONCLUSIONS Significantly better survival and functional outcome were noted with poststroke statins at the end of the 12-month follow-up period. Statins seem to provide beneficial effects for the long-term functional outcome and survival in the elderly.