In 1996, adiponectin was reported to be the most abundant transcript in adipose tissue. Animal studies revealed that administering adiponectin improves insulin resistance and blood glucose levels and inhibits atherosclerosis. In the present article, we review the significance of measuring serum high-molecular-weight (HMW) adiponectin levels in human subjects.
Our cross-sectional studies revealed that the serum HMW adiponectin concentration was 1.9 times higher in healthy Japanese females than males and had a strong positive correlation with HDL-cholesterol but a negative correlation with BMI and the homeostasis model assessment insulin resistance index (HOMA-IR). They also indicated that the serum HMW adiponectin concentration had a stronger association with HOMA-IR and metabolic syndrome than the total adiponectin concentration.
Our longitudinal study, a 6-year follow-up of Japanese men, suggested that a decreased level of HMW adiponectin is a predictor of progression to metabolic syndrome. In another intervention study, lifestyle modification for 3 months induced a decrease in BMI and waist circumference and an increase in serum HMW adiponectin but not the total adiponectin level in 16 Japanese males with metabolic syndrome.
Administering thiazolidinediones to diabetic patients increased the serum HMW adiponectin concentration 3 fold and improved glucose and lipid profiles and blood pressure. Some people may inherit a lower serum concentration of adiponectin, and have a higher risk of developing cardiovascular diseases.
It is suggested that HMW adiponectin is a useful marker for the evaluation and care of subjects with metabolic syndrome and related disorders.

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Aim: Smoking has been established as a major risk factor for cardiovascular disease. It causes oxidative stress and sub-clinical inflammation, which undermine the antioxidant defense system of the body. We reasoned that natural antioxidant defense systems may be compromised in smokers. To this end, we examined whether haptoglobin (Hp), a potent antioxidant, is impacted negatively by smoking.
Methods: Study participants consisted of 121 current smokers and 105 healthy non-smokers without diabetes and without blood smear-positive P. falciparum. Smokers were defined as individuals who smoke at least 1 cigarette a week and are current smokers (occasional and regular). Baseline demographics, hematological indices, lipid profiles, blood pressure, lactate dehydrogenase activity and haptoglobin phenotypes were determined.
Results: Ahaptoglobinemia was found to be highly overrepresented in smokers (odds ratio (OR)=3.1, 95% confidence interval (CI)=1.5-6.5, p=0.002). This observation was not attributed to intravascular hemolysis. Hp2-2 phenotype was found to be under represented in smokers (OR=0.53, 95% CI=0.28-0.99, p=0.05). Smoking was confirmed to augment hypertension (diastolic blood pressure (DBP) and systolic blood pressure (SBP) in male smokers (p=0.0001). Interestingly, however, this appeared not to be related to lipid metabolism, as HDL was elevated (p=0.0007) while LDL was decreased (p=0.004) in smokers within the study population.
Conclusion: We conclude that smoking is a risk factor for ahaptoglobinemia, which will impact negatively on anti-oxidant defenses and augment pro-oxidative stress effects.

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Aim: Nutritional parameters, such as B-vitamins, have not been studied for an association with low-density lipoprotein (LDL) particle size. The present study explored whether serum vitamin levels, including folate and vitamin B-12, could be associated with LDL particle size.
Methods: Using a randomly selected population of 255 hospital workers, we collected detailed lipid profiles, including triglyceride (TG), high-density lipoprotein (HDL) cholesterol, and LDL particle sizes. The peak particle size of LDL was measured by density gradient ultracentrifugation and a pore gradient lipoprotein system. Serum folate and vitamin B-12 levels were measured about 1 year later and analyzed. Carotid intima-media thickness (IMT) and hepatic steatosis were diagnosed ultrasonographically, and metabolic syndrome was diagnosed using ATP III criteria.
Results: LDL peak particle size was significantly correlated with carotid mean IMT (r=-0.16, p=0.010). Serum folate levels were significantly and positively correlated with HDL cholesterol and negatively with TG, although the latter showed borderline significance. With increasing serum folate levels, the LDL peak particle size showed a gradual independent increase, even when adjusted for age, sex, hepatic steatosis, metabolic syndrome, and the TG/HDL cholesterol ratio.
Conclusion: Folate may act to enhance LDL particle size. Future clinical and research work should include a study of the safe application and manipulation of folate levels in order to control LDL particle size.

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Aim: A sedentary lifestyle with insufficient exercise is associated with cardiovascular disease. Previous studies have demonstrated that endurance exercise benefits atherosclerosis and cardiovascular disorders; however, the mechanisms by which physical activity, such as voluntary exercise (Ex), produces these effects are not fully understood.
Methods and Results: Eight-week-old male apolipoprotein (ApoE)-deficient mice were fed a standard diet (STD) or high fat diet (HFD) for 10 weeks. The HFD+Ex group mice performed Ex on a running wheel for 10 weeks. No significant differences in lipid profiles were observed between the HFD and HFD+Ex groups. Although changes in body and brown adipose tissue weights were comparable between the HFD and HFD+Ex groups, white adipose tissue weight was significantly lower in the HFD+Ex group than in the HFD group. The areas of atherosclerotic lesions in the aortic sinus and thoracoabdominal aorta were significantly reduced in the HFD+Ex group than in the HFD group (p<0.001). There was a strong negative correlation between atherosclerotic areas and the mean running distance per day in the HFD+Ex group (r=-0.90, p=0.01). Endothelial function was significantly preserved in the HFD+Ex group (p<0.05). Serum interleukin-6 and macrophage chemoattractant protein-1 levels were significantly lower and those of adiponectin were significantly higher in the HFD+Ex group than in the HFD group (p<0.05).
Conclusions: These results suggest that Ex ameliorates the progression of endothelial dysfunction and atherosclerotic lesion formation through anti-inflammatory effects, despite continued consumption of HFD.

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Aim: The accumulation of Visceral fat is known to precede metabolic disorders and atherosclerosis. This study aimed to determine the relationships between body mass index (BMI), waist circumference (WC), estimated visceral fat area (eVFA) measured by bioelectrical impedance analysis (BIA), and obesity-related cardiovascular risk factors.
Methods: The study population was 2,870 middle-aged Japanese employees (males/females=2,322/ 548), who had undergone a health check-up.
Results: In the receiver operating characteristic (ROC) curve, the cutoff levels yielding maximal sensitivity plus specificity for predicting the prevalence of ≥ 2 risks were, 24.5 kg/m² for BMI, 84.6 cm for WC, and 111 cm² for eVFA in males, and 23.6 kg/m², 81.5 cm, and 67 cm² in females. The average number of risk factors was over 1.0 in those with a BMI ≥ 25 kg/m² and with a WC ≥ 85 cm for males, ≥ 28 kg/m² and ≥ 95 cm respectively for females, and those with an eVFA ≥ 100 cm² for both males and females. In males, it was around 1.0 with cutoff levels of BMI, WC, and eVFA from the ROC curve. However, in females, it was around 0.6, because the prevalence of subjects with obesity and multiple risks was very low.
Conclusions: These results suggested that the cutoff level for visceral fat reduction should be set based on an absolute value of risk factors, rather than a calculated value. In regular health check-up, it may be useful to set an absolute cutoff value for eVFA at 100 cm² as criteria to screen for multiple obesity-related cardiovascular risk factors.

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Aim: Changes in indexes of obesity, such as waist circumference (WC) and body mass index (BMI), may influence some glucose metabolism-related parameters in both obese and non-obese subjects. We have investigated the impact of changes in WC and in BMI on data related to glucose metabolism over a one-year period.
Methods: Data from 3213 individuals (2014 men, 1199 women) who underwent a general health screening two years running and were not taking antidiabetic medication were analyzed.
Results: In men, percent changes in WC (%dWC) and BMI (%dBMI) were both significantly correlated with percent changes in fasting glucose (%dFG), in hemoglobin A_1C (%dHbA_1C), and in HOMA-IR (%dHOMA-IR). In women, these relationships were not significant except for the relationship between %dBMI and %dHOMA-IR. In a multivariate linear regression analysis using age, %dBMI, and %dWC as independent variables, %dBMI, but not %dWC, was found to be an independent predictor of %dHOMA-IR in both genders. Furthermore, in men, %dBMI was also an independent factor predicting %dFG and %dHbA_1C.
Conclusion: During the one-year period, a reduction in BMI, and thus weight loss, was found to be associated with the improvement of insulin sensitivity, especially in men. A reduction in WC was also associated with an improvement in insulin sensitivity in men; however, this relationship did not remain significant after controlling for changes in BMI.

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Aim: We investigated the effects of simvastatin on markers of inflammation, oxidative stress and endothelial cell apoptosis in hyperlipidemic endstage renal disease patients on chronic hemodialysis (HD).
Methods: In 25 hyperlipidemic HD patients who received 10 mg of simvastatin for 6 months and another 25 controls, the extended lipid profile and serum hsIL-6, MCP-1, sICAM-1, sVCAM-1, and sE-selectin, plasma oxLDL, and serum sFas and sFasL levels were determined at baseline, 3 months and 6 months. In 18 patients of the simvastatin group, the expression of CD14, CD16, CD62L and CD64 on monocyfes was determined with flow cytometry.
Result: Simvastatin treatment resulted in significant reductions in serum lipid levels at 3 months and beyond, compared to at baseline. Moreover, at 6 months, simvastatin caused a significant reduction in CRP (p < 0.001), which correlated to the decrease in total and LDL cholesterol levels, as well as a significant reduction in IL-6 (p=0.001), sICAM-1 (p < 0.001), sVCAM-1 (p < 0.001), oxLDL (p=0.001), sFas (p=0.02) and CD14 expression (p < 0.001), compared to baseline values. No significant changes in the controls were noticed during the study.
Conclusion: In conclusion, in hyperlipidemic HD patients, simvastatin treatment resulted in a significant reduction in markers of endothelial dysfunction, inflammation, oxidative stress, endothelial cell apoptosis and peripheral blood monocyte stimulation. The reduction in CRP appears to be related to the lipid-lowering effects of simvastatin.

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Aim: Nitroglycerin-mediated vasodilatation (NMD) provides insight into the NTG-induced bioactivity of smooth muscle. It is plausible that in dysfunctional smooth muscle cells, the response to nitroglycerin may become blunted. The relationship between impaired brachial artery NMD and subsequent cardiovascular events is not well established.
Methods: We examined brachial artery flow-mediated dilatation (FMD) and NMD using ultrasound in 93 subjects (71±7 years, including 26 with peripheral artery disease (PAD), 37 with aortic aneurysms, 10 with PAD complicated with aneurysms, and 20 without evident arterial disease). Brachial artery responses to hyperemia and nitroglycerin were measured every minute after cuff deflation and nitroglycerin administration. Time courses of vasodilatation were assessed and maximal FMD and NMD were measured.
Results: The time courses in response to NTG were sigmoidal and maximal diameter reached 7.2±1.6 minutes after NTG was administered sublingually. The mean FMD was 2.3±2.0% and the mean NMD was 17.6±7.1%. Subjects were prospectively followed for an average of 47±13 months. Eighteen subjects had an event during follow-up; events included myocardial infarction (five), unstable angina pectoris (four), stroke (two), aortic dissection (one), ruptured aortic aneurysm (three), symptomatic abdominal aortic aneurysm (two), and lower limb ischemia requiring revascularization (one). NMD and FMD were significantly lower in subjects with events than in those without an event. In a Cox proportional-hazards model, lower FMD as well as lower NMD independently predicted future cardiovascular events.
Conclusion: Brachial artery nitroglycerin-mediated vasodilatation may add information to conventional risk stratification.

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Aim: The risk index for atherosclerotic cardiovascular diseases in the Japanese metabolic syndrome-focused health checkup program was changed from total cholesterol (TC) to low-density lipoprotein cholesterol (LDL-C). We discuss the validity of this change with respect to standardization.
Methods: The beta-quantification procedure of the Centers for Disease Control and Prevention (CDC) uses the LDL-C reference value as a target. Clinical laboratories and commercial manufactur-ers use homogeneous LDL-C methods for standardization. (A) For clinical laboratories, LDL-C in 648 samples requested from 108 hospitals was analyzed. (B) Manufacturers participated in the CDC/Cholesterol Reference Method Laboratory Network LDL-C standardization protocol. The standard-ization was conducted with a performance follow-up for the 10-year period from 1998 to 2008 at 2-year intervals, 6 times.
Results: (A) In clinical laboratories, acceptable LDL-C levels within ±4% of the CDC's criteria re-mained 70.4%, 456 of 648 subjects. Negative maximum bias deviating from the LDL-C target value was -35.8%, -52.5 mg/dL, and positive maximum bias was +24.5%, +32.3 mg/dL. (B) For man-ufacturers, the standardization achievement rate of the analytical reagent/instrument/calibrator sys-tem in the last four standardizations from 2002 to 2008 remained on average 66.6%, far lower than the level required.
Conclusions: The standardization achievement rate of homogeneous LDL-C methods was much low-er than that of TC. TC should still be used as a risk index for atherosclerotic cardiovascular diseases. The standardization achievement rate of homogeneous LDL-C should be maintained at 100%, at least using samples with normal lipoprotein profiles. The accuracy and specificity of LDL-C should be further improved before practical and clinical use.

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Aim: Pulse wave velocity (PWV), an estimate of arterial stiffness, is an important predictor of cardiovascular risk. The aim of this study was to investigate the relationship between lipoprotein subclasses and brachial-ankle PWV (baPWV).
Methods: A total of 131 apparently healthy Japanese men without a history of cardiovascular disease were divided into two groups: normal glucose metabolism (n =87) and impaired glucose metabolism (n =44). Cholesterol concentrations of major lipoproteins and their subclasses were determined by HPLC with gel permeation columns.
Results: In the normal glucose metabolism group, age, systolic blood pressure, and diastolic pressure were associated with increased baPWV, and a stepwise multiple linear regression analysis revealed that age (p =0.022) and systolic blood pressure (p < 0.001) were significantly independent determinants of baPWV. In the impaired glucose metabolism group, age (p =0.002), very small LDL cholesterol (p =0.012), systolic blood pressure (p =0.021), and the fasting plasma glucose concentration (p =0.038) were identified as independent determinants of baPWV, although a univariate analysis revealed significant relationships of several plasma lipid compositions or species to baPWV.
Conclusions: In addition to aging, hypertension and glucose levels, very small LDL cholesterol levels appear to play an important role in the development of arterial stiffness in men with impaired glucose metabolism.

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Aim: The aim of this study was to investigate whether peripheral arterial disease (PAD) is predictive of disability and whether the relationship between PAD and disability can be fully explained by baseline physical functions.
Methods: We followed for five years 783 Japanese aged 70 years or older without a disability at baseline in 2003. We defined participants certificed as requiring long-term care as having incident disability. The hazard ratio (HR) and 95% confidence interval (95% CI) for incident disability were calculated using the Cox proportional hazards model.
Results: After adjusting for possible confounders other than physical function, the HR of incident disability among participants with PAD was 1.86 (95%CI: 1.06 to 3.26).Although the risk was attenuated (HR=1.63, 95%CI: 0.92 to 2.86) after adding baseline physical function as a covariate, the HR was still high. Furthermore, the relation was not statistically significant, but the group with higher physical function and PAD also had a higher HR of incident disability than those who had higher physical function without PAD.
Conclusion: PAD is an important predictor of disability even if the level of baseline physical function is high.

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Familial lecithin: cholesterol acyltransferase (LCAT) deficiency is an autosomal recessive disorder characterized by corneal opacity, hemolytic anemia, proteinuria, and a low serum level of high-density lipoprotein cholesterol (HDL-C). Also, LCAT activity is remarkably decreased or absent.
A 57-year-old Japanese man presented with corneal opacity, proteinuria, and a very low serum level of HDL-C. His LCAT activity was too low to measure. From clinical observations and results of examinations, we suspected LCAT deficiency. We performed a kidney biopsy and gene analysis.
Light microscopy revealed the vacuolation of glomerular capillary tufts. Electron microscopy revealed small deposits in the glomerular basement membrane (GBM), extracellular matrix, and vascular endothelial cells.
We identified a homozygous C to T point mutation at nucleotide 501 (g.501 C>T) of exon 4 at codon 140, resulting in an arginine (Arg) to cysteine (Cys) amino acid substitution (A140C) in the patient.
These findings were characteristic of LCAT deficiency, which was confirmed to be due to a mutation that has only been reported in Japan.

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