Association between fast-migrating low-density lipoprotein subfraction as characterized by capillary isotachophoresis and intima-media thickness of carotid artery.

BACKGROUND: A mildly modified LDL subfraction that is characterized by an increased negative charge exists in plasma. This electronegative LDL separated by ion-exchange chromatography has been shown to be inflammatory and its proportion is increased in patients with hyperlipidemia and diabetes mellitus. The present study examined the association between the level of fast (f)-migrating LDL subfraction characterized by capillary isotachophoresis (cITP) and carotid-artery intima-media thickness (CA-IMT). METHODS AND RESULTS: This study included 469 subjects who underwent a physical examination. CA-IMT was determined by high-resolution B-model ultrasonoraphy. Levels of charge-based LDL subfractions were measured by cITP on a Beckman P/ACE MDQ system. An increased serum LDL-C level and cITP fLDL level were associated with increased CA-IMT after adjusting for age. The extent of the associations between cITP fLDL and CA-IMT and between LDL-C and CA-IMT were similar as assessed by a receiver-operating characteristic curve analysis. LDL-C, triglyceride, and remnant-like particle cholesterol levels were independently correlated with cITP fLDL, and the LDL-C level had the strongest correlation with cITP fLDL. The association between the cITP fLDL level and CA-IMT was significant in the high LDL-C stratum but not in the low stratum, indicating that it is modified by the LDL-C level. The high-LDL-C-high-fLDL group had the highest relative risk for a high CA-IMT among the groups with each combination of LDL-C and cITP fLDL level. CONCLUSION: The cITP fLDL level was associated with CA-IMT and its combination with the LDL-C level is a stronger indicator for a high CA-IMT.

Pravastatin improves insulin resistance in dyslipidemic patients.

To evaluate the effect of pravastatin on both lipid and glucose metabolism, twenty-two consecutive dyslipidemic patients treated with pravastatin at 10 mg/day for one year were enrolled in this study. The meal test, which consisted of 115 g of cookies (energy 560 kcal; glucose 75 g; protein 7 g; fat 24 g), was conducted before and after one year of treatment. Insulin resistance was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR), by the area under the IRI curve (AUC-IRI), and by the formula AUC-IRI x AUC-PG. After one year of treatment with pravastatin, the plasma glucose (PG), immunoreactive insulin (IRI) and C-peptide levels were unchanged after fasting and at 120 minutes after the meal test; however, PG, IRI and C-peptide levels at 60 minutes after the meal were all significantly decreased from baseline (p < 0.05). AUC-IRI and AUC-IRI x AUC-PG were also significantly decreased (p < 0.05). HOMA-IR was reduced by 26.8%, but the reduction was not significant. The triglyceride (TG) level was decreased after fasting and increased at 60 and 120 minutes after the meal test, but not significantly. This study demonstrated that pravastatin not only reduced serum lipids, but also improved the glucose metabolism, including insulin resistance, of dyslipidemic patients.

The influence of lifestyle modification on carotid artery intima-media thickness in a suburban Japanese population.

To evaluate the influence of lifestyle modification with and without lipid-lowering drug therapy on the carotid arterial wall, we did a 2 year prospective ultrasound study of carotid intima-media thickness (IMT) in 1390 male and female residents of a suburban Japanese town. According to total cholesterol (TC) level at baseline, subjects were classified into a lifestyle modification alone group (TC >/= 220 mg/dl, n = 437), a lifestyle modification with lipid-lowering drug group (TC >/= 220 mg/dl, n = 159), and a control group (TC < 220 mg/dl, n = 794). After 2 years of follow-up, both sexes of both treatment groups showed significant reductions of TC, low-density lipoprotein cholesterol (LDL-C), and IMT, although TC continued over 220 mg/dl in some subjects in the lifestyle modification group. The reduction of TC and LDL-C was significantly higher in the lifestyle modification with lipid-lowering drug group than in the lifestyle modification alone group. Although the IMT reduction was not statistically different between the treatment groups of either sex, the reduction of IMT was greater in the lifestyle modification with lipid-lowering drug group than in the lifestyle modification alone group. Our results indicate that comprehensive lifestyle modification can reduce carotid IMT in the general population, with or without the use of lipid-lowering drugs and that cholesterol reduction is of benefit even when TC level remain above the recommended level.

Carotid atherosclerosis and cardiovascular risk factors: a comparison of residents of a rural area of Okinawa with residents of a typical suburban area of Fukuoka, Japan.

Areas of Japan are known worldwide for the longevity of their residents. Okinawa has the highest longevity in Japan and a low rate of death due to cardiovascular disease. We investigated carotid atherosclerotic (CA) risk factors in islands of I city in Okinawa prefecture and compared them with K town, a suburban area of Fukuoka prefecture in Kyushu, to determine the relationship between cardiovascular risk factors and carotid atherosclerosis. We investigated conventional cardiovascular risk factors in 1078 I city residents (375 men, mean age 63.7 and 703 women, mean age 60.0) in 2000 and 2364 K town residents (676 men, mean age 57.1 and 1688 women, mean age 53.0) in 1999. Carotid atherosclerosis was assessed by mean intima-media thickness (IMT) by B-mode ultrasound. The mean IMT was significantly lower in the residents of I city than in those of K town (P < 0.05). Total cholesterol (TC) and low-density-lipoprotein cholesterol (LDL-C) levels and smoking rate were also lower in I city than in K town. Body mass index (BMI) and triglyceride (TG) level were higher in I city than in K town. In I city, multiple regression analysis found independent relationships between carotid atherosclerosis and age, sex (male), hypertension, LDL cholesterol, high-density-lipoprotein cholesterol (HDL-C), and diabetes. The lower mean IMT is probably related to a lower lifetime burden of atherosclerotic risk factors, which may in turn be related to the longevity of Okinawa residents. BMI was not a cardiovascular risk factor, although LDL cholesterol was a common important risk factor.

Association of Chlamydia pneumoniae antibody with the cholesterol-lowering effect of statins.

To investigate the association between Chlamydia pneumoniae (C. pneumoniae) infection and atherosclerosis, we compared the effect of lipid-lowering drugs on carotid intima-media thickness (IMT) between patients who were positive and negative for C. pneumoniae antibodies. A total of 165 asymptomatic hypercholesterolemic patients were randomized to probucol (500 mg per day, n = 82) or pravastatin (10 mg per day, n = 83) and followed for 2 years. The 2-year change of IMT in the common carotid artery was the primary endpoint, while mean IMT change and major cardiovascular events were secondary endpoints. C. pneumoniae antibodies (IgA and IgG) were measured by enzyme-linked immunosorbent assay. The 50 patients without C. pneumoniae antibodies showed significant reduction of IMT progression (-19%), while no significant change of IMT was noted in the 115 antibody-positive patients (-6%). Significant inverse associations were found between the reduction of IMT progression and the C. pneumoniae IgA- and IgG-antibody index (P < 0.01 and 0.01, respectively). No significant differences in the reduction of serum total-cholesterol and LDL-cholesterol were found between antibody-positive and -negative patients. There was no significant difference of efficacy between probucol and pravastatin. These observations suggest that C. pneumoniae infection reduces the effect of lipid-lowering therapy on carotid atherosclerosis and that this organism may play a role in the progression of atherosclerosis.

Carotid artery lesions and atherosclerotic risk factors in Japanese hemodialysis patients.

To determine the prevalence and severity of carotid artery lesions and which risk factors might be responsible for atherosclerosis in end-stage renal disease (ESRD) patients, we tested for carotid atherosclerosis (CA) by ultrasonography and compared the CA prevalence with well-known or suspected atherosclerotic risk factors in 226 hemodialysis (HD) patients and 2410 healthy residents of Japan. The CA prevalence was higher in the HD patients than in the healthy residents. Univariate analysis showed that HD patients with CA had a higher frequency of diabetes mellitus and left ventricular hypertrophy, and were significantly older, had significantly higher systolic blood pressure and pulse pressure, and lower albumin levels than those without. Multivariate analysis showed that age, pulse pressure, phosphorus, duration of HD, and diabetes mellitus were independent, significant predictors for CA in the HD patients. Neither Chlamydia pneumoniae seropositivity nor elevated homocysteine level was independently, significantly associated with CA. Our results suggest that HD patients had more advanced CA than the healthy residents. CA in the HD patients may be associated not only with several conventional risk factors but also with non-conventional risk factors such as phosphorus and the HD procedure itself.

Chlamydia pneumoniae seropositivity and early carotid atherosclerosis in a suburban Japanese population.

To evaluate the association between Chlamydia pneumoniae (C. pneumoniae) infection and carotid atherosclerosis (CA), we investigated CA assessed by carotid B-mode ultrasound and known or suspected atherosclerotic risk factors including C. pneumoniae IgG and IgA antibodies in 2410 residents (mean age 54.5+/-13.6 years, 697 men) of a suburban Japanese town. CA was found in 30.1% of men and in 14.0% of women, IgG in 59.4% and in 51.4%, and IgA in 36.9% and in 32.4%, respectively. In univariate analysis, most conventional atherosclerotic risk factors and IgA antibody were significantly associated with CA in both sexes, but not IgG. In multivariate logistic regression analysis, independent risk factors for CA were confirmed with age and triglycerides (TG) in men and age, systolic blood pressure, pack-years of smoking, and low-density lipoprotein cholesterol (LDL-C) in women, but not IgG and IgA in either sex. These results do not support C. pneumoniae infection as an important risk factor for CA in this Japanese population.

Increased frequency of IFN-gamma-producing peripheral CD8+ T cells with memory-phenotype in patients with chronic hepatitis C.

To identify the capacity for cytokine production and the phenotypic characteristics of peripheral CD8(+) T cells in patients with chronic hepatitis C, 31 patients with chronic hepatitis C and 22 healthy controls were studied at the single cell level by three-color flow cytometry. Whole blood was stained with surface CD8, intracellular interferon-gamma (IFN-gamma), and interleukin-4 (IL-4), surface CD8, CD28, and intracellular IFN-gamma after stimulation with PMA plus ionomycin, and then surface CD8, CD45RA, and CD28. IFN-gamma-producing peripheral CD8(+) T cells were found frequently in patients than in controls (P < 0.05), whereas IL-4-producing peripheral CD8(+) T cells were not. Although the frequency of peripheral CD28(+)CD8(+) and CD28(-)CD8(+) T cells in patients was not different from that of controls, CD28(+)CD8(+) T cells exceeded CD28(-)CD8(+) T cells in the capacity for IFN-gamma-production after mitogenic stimulation (P < 0.01). In a more detailed analysis of the CD28(+)CD8(+) T cells, CD45RA(-)CD28(+)CD8(+) T cells, defined phenotypically as memory cells, were found frequently in patients than in controls (P < 0.05). There were no significant correlations between the frequency of IFN-gamma-producing peripheral CD8(+) T cells and hepatitis C virus RNA level or serum alanine aminotransferase level in patients. These data suggest that functionally T cytotoxic type 1 and memory CD8(+) T cells are predominant in the peripheral blood of chronic hepatitis C patients and that such activated CD8(+) T cells are associated with liver damage.

Effects of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia. Fukuoka Atherosclerosis Trial (FAST).

OBJECTIVES: This study investigated the effect of reducing serum lipids on carotid artery intima-media thickness (IMT) in asymptomatic patients with hypercholesterolemia from Fukuoka, Japan. BACKGROUND: Carotid atherosclerosis is a strong, independent predictor of morbidity and mortality in patients with coronary heart disease (CHD). METHODS: A total of 246 asymptomatic hypercholesterolemic patients (mean age 66 years) were randomized to receive either probucol (500 mg/day, n = 82) or pravastatin (10 mg/day, n = 83) or to enter a control group (diet alone, n = 81); they were followed for two years. The change in IMT in the common carotid artery was the primary end point measure, and the incidence of major cardiovascular events was the secondary measure. RESULTS: Over the two-year period, serum low-density lipoprotein (LDL) cholesterol was significantly reduced in the pravastatin group (36%), the probucol group (29%) and the control group (12%) (p < 0.0001, p < 0.0001 and p < 0.05, respectively). After two years, the probucol and pravastatin groups showed a significant reduction in IMT (-13.9% and -13.9% and p < 0.01 and p < 0.01, respectively), but there was significant IMT thickening (23.2%; p < 0.05) in the control group. Probucol reduced the rate of IMT increase, independently of its reduction of LDL or high-density lipoprotein cholesterol. Moreover, there was a significantly lower incidence of cardiac events in the probucol group (2.4%) than in the control group (13.6%) (p = 0.0136). CONCLUSIONS: Probucol reduced cholesterol levels and stabilized plaque, leading to a lower incidence of cardiac events in these hypercholesterolemic patients.