Noriko Ban

Improvement of cardio‐ankle vascular index by glimepiride in type 2 diabetic patients

Aims:  Glimepiride, a third generation sulfonylurea (SU), is known to have extrapancreatic effects, but its vascular effect is unclear. We investigated the efficacy of glimepiride in improving arterial stiffness assessed by cardio‐ankle vascular index (CAVI) in type 2 diabetic patients, compared with glibenclamide, a conventional SU.

Effects of body weight reduction on cardio-ankle vascular index (CAVI)

OBJECTIVE Obesity is associated with type 2 diabetes, dyslipidemia and hypertension, contributing to atherogenesis. Weight reduction is the fundamental therapy for obesity. Recently, a novel arterial stiffness parameter called cardio-ankle vascular index (CAVI) has been developed. We hypothesized that CAVI may be a candidate marker of increased vascular stiffness in obese patients. The aim of this study is to investigate the effect of weight reduction on CAVI. SUBJECTS AND METHODS Using CAVI as an indicator, we assessed the changes in arterial stiffness in 47 obese Japanese subjects (aged 46 ± 13 years) who underwent a 12-week weight reduction program consisting of a calorie restriction diet (20-25 kcal/day) and exercise therapy. Visceral fat area (VFA) was evaluated by CT. RESULTS At baseline, CAVI correlated positively with age (r = 0.70), blood pressure (r = 0.23), VFA (r = 0.26) and HbA1c (r = 0.39). After 12 weeks of weight reduction, mean BMI decreased from 33.3 ± 7.5 to 30.7 ± 6.4 kg/m(2) (p < 0.0001), and mean CAVI decreased from 8.3 to 7.9 (p < 0.01). The change in VFA correlated positively with change in CAVI in subjects with decrease in CAVI (r = 0.47). Furthermore, change in VFA was a significant independent predictor for change in CAVI. No significant correlation was observed between change in CAVI and clinical variables such as BMI, HbA1c and lipids. CONCLUSION This study demonstrated that CAVI decreased after weight reduction, and was associated with a decrease in VFA. CAVI reduction maybe a marker of improved vascular stiffness after weight reduction in subjects with visceral adiposity.

Improvement of postprandial hyperglycemia and arterial stiffness upon switching from premixed human insulin 30/70 to biphasic insulin aspart 30/70

Postprandial hyperglycemia is known to be associated with increasing cardiovascular mortality in type 2 diabetes mellitus patients. Cardio-ankle vascular index (CAVI) reflects arterial stiffness and is more useful for predicting coronary atherosclerosis than intima-media thickness. Premixed human insulin 30/70 (BHI30) containing rapid-acting insulin has been used conventionally as a biphasic insulin. Recently, a biphasic insulin analogue preparation, biphasic insulin aspart 30/70 (BIAsp30), containing ultrarapid-acting insulin has been approved and expected to improve postprandial hyperglycemia. The aim of this study was to clarify the effects of switching the biphasic insulin from BHI30 to BIAsp30 on arterial stiffness in type 2 diabetes mellitus patients. Twenty-six type 2 diabetes mellitus patients (glycosylated hemoglobin >6.5%) who were already receiving biphasic insulin therapy with BHI30 twice daily were observed for 3 months. Afterward, BHI30 was switched to BIAsp30. At 3 months after switching, relative mobility of the peak of LDL fraction decreased significantly (from 0.3462 ± 0.041 to 0.3356 ± 0.035, P < .01); and CAVI also decreased significantly (from 9.77 ± 1.11 to 9.35 ± 1.17 m/s, P < .005). A significant negative correlation was observed between the change in CAVI and change in 1,5-anhydroglucitol (1,5-AG) (r = -0.3929, P < .05). A stronger correlation between change in CAVI and change in 1,5-AG was observed in the subgroup of patients whose 1,5-AG levels were elevated after switching (r = -0.6261, P < .05) compared with all subjects. These results suggest that switching biphasic insulin from BHI30 to BIAsp30 improves arterial stiffness, and the improvement of arterial stiffness may be associated with improvement of postprandial hyperglycemia.

Determination of serum 7-ketocholesterol concentrations and their relationships with coronary multiple risks in diabetes mellitus

Oxysterols have cytotoxic effects and contribute to the development of atherosclerosis. To examine association between 7-ketocholesterol and diabetes mellitus, and other coronary risk factors, we developed a reliable quantitative method to measure serum 7-ketocholesterol (s-7KCHO) and studied s-7KCHO in patients with type 2 diabetes mellitus (T2DM). The s-7KCHO was detected by gas chromatography-mass spectrometry assay. The s-7KCHO was significantly higher in patients with T2DM (n=137, 33.8 ng/ml) compared to non-diabetic healthy subjects (n=89, 16.1 ng/ml). Patients with T2DM were divided into two groups with two or more than two risk factors (defined as multiple risk factors group) and with zero or one risk factor (non-multiple risk factors group). The s-7KCHO was significantly higher in multiple risk factors group (39.5 ng/ml) compared to non-multiple risk factors (30.1 ng/ml). Among patients with multiple risk factors group, s-7KCHO was significantly higher in patients with high low-density lipoprotein cholesterol (LDL-C) levels (45.1+/-5.9 ng/ml) compared to those with normal LDL-C levels (35.3+/-7.0 ng/ml). Furthermore, s-7KCHO increased according to the number of concurrent coronary risk factors. These results suggest that serum 7-ketocholesterol levels may depend on the multiple risk factors and serum LDL-C levels.

Cardio-Ankle Vascular Index is Independently Associated with Future Cardiovascular Events in Outpatients with Metabolic Disorders

AIM We investigated whether cardio-ankle vascular index (CAVI), an arterial stiffness marker, independently predicts future cardiovascular events in subjects with metabolic disorders. METHODS 1562 outpatients underwent CAVI between April 2004 and March 2006 at Toho University, Sakura Medical Center in Chiba, Japan. Patients who already had cardiovascular events at baseline, patients with low ankle brachial index (＜0.9), and patients with atrial fibrillation were excluded. After exclusion, 1080 subjects with metabolic disorders including diabetes mellitus, hypertension and dyslipidemia were screened and followed prospectively. RESULTS Eventually, 1003 subjects (92.9% of 1,080 subjects) followed until March 2012 (follow-up duration 6.7±1.6 years) were analyzed. During the observation period, 90 subjects had new-onset myocardial infarction or angina pectoris confirmed by angiography. All subjects were stratified into quartiles by baseline CAVI (Q1: CAVI ≤8.27, Q2: CAVI 8.28-9.19, Q3: CAVI 9.20-10.08, Q4: CAVI ≥10.09). Age, male ratio and future cardiovascular events increased as CAVI quartile became higher. In Cox proportional hazards regression analysis, the factors independently associated with higher risk of future cardiovascular events were every 1.0 increment of CAVI [hazard ratio (HR) 1.126, p= 0.039], male gender (HR 2.276, p=0.001), smoking (HR 1.846, p=0.007), diabetes mellitus (HR 1.702,p=0.020), and hypertension (HR 1.682, p=0.023). CONCLUSION In individuals with metabolic disorders, CAVI was a predictor of future cardiovascular events, independent of traditional coronary risk factors. CAVI is a potentially valuable tool to identify persons likely to benefit from more intensive therapeutic approaches.

High serum uric acid is associated with increased cardio-ankle vascular index (CAVI) in healthy Japanese subjects: A cross-sectional study

OBJECTIVE To investigate the association of serum uric acid (SUA) with arterial stiffness assessed by cardio-ankle vascular index (CAVI). METHODS We analyzed the cross-sectional data from 27,360 healthy Japanese subjects (12,910 males and 14,450 females) aged between 20 and 74 years without a past history of heart disease, stroke, hypertension, diabetes, nephritis or gout. We investigated whether SUA was independently associated with CAVI in a gender-specific manner. RESULTS BMI, CAVI, systolic/diastolic BP, GOT, GPT, γ-GTP, triglyceride (TG), creatinine and SUA were higher and HDL-C was lower in males than in females. Next, they were stratified by SUA into 3 groups: lower tertile (T1), middle tertile (T2) and upper tertile (T3) and by gender. CAVI increased progressive with increasing SUA tertile, after adjusting for age, BMI and systolic BP (sBP) identified in multiple regression analysis for CAVI. Multivariate analysis showed that the odds ratios (95% CI) relative to T1 for high CAVI (≥90(th) percentile) were 1.233 (0.928-1.638) in T2 and 1.352 (1.031-1.773) in T3 for males, and 1.133 (0.984-1.303) in T2 and 1.361 (1.098-1.687) in T3 for females, after adjusting for confounders. Furthermore, increase in adjusted CAVI was observed in a lower SUA range in females compared to that observed in males. CONCLUSION We demonstrated an independent correlation between SUA and CAVI, and observed gender difference in the SUA range for increase in CAVI. These results may suggest the need to set different target SUA levels for men and women in anti-hyperuricemic treatment for atherosclerosis prevention.

Pioglitazone improves the cardio-ankle vascular index in patients with type 2 diabetes mellitus treated with metformin

Background Type 2 diabetes is known to be associated with elevated cardiovascular mortality. Pioglitazone improves blood pressure (BP) and pulse wave velocity (PWV), which is an arterial stiffness parameter. Arterial stiffness is closely associated with cardiovascular disease. However, PWV is correlated with BP. The cardio-ankle vascular index (CAVI) reflects arterial stiffness independent of BP. Pioglitazone improves PWV but reduces blood pressure. The aim of this study was to re-evaluate the effect of pioglitazone on arterial stiffness with CAVI. Methods Sixty patients with type 2 diabetes mellitus and already on 500 mg/day of metformin received add-on therapy of pioglitazone 15 mg/day or glimepiride 1 mg/day for 6 months, during which time changes in their metabolic parameters and CAVI were observed. Results After 6 months of treatment, both pioglitazone (n=30) and glimepiride (n=30) improved fasting blood glucose and glycated hemoglobin. The changes in fasting blood glucose and glycated hemoglobin between the two groups were greater in the pioglitazone group. Systolic and diastolic BP was decreased in both groups, with no significant between-group differences. Only pioglitazone increased serum adiponectin levels, and the change in adiponectin between the pioglitazone and glimepiride groups was significantly different. CAVI was decreased significantly by pioglitazone but remained unchanged after treatment with glimepiride. The change in CAVI between the two groups was significantly different. Conclusion These results suggest that pioglitazone improves CAVI, a BP-independent arterial stiffness parameter, in patients with type 2 diabetes mellitus treated with metformin.

Resveratrol attenuates triglyceride accumulation associated with upregulation of Sirt1 and lipoprotein lipase in 3T3-L1 adipocytes

Aim We aimed to investigate the effect of resveratrol (Rsv) on expression of genes regulating triglyceride (TG) accumulation and consumption in differentiated 3T3-L1 preadipocytes. Methods 3T3-L1 preadipocytes were cultured in DMEM supplemented with 10% fetal calf serum. Upon reaching confluence, cells were induced to differentiate for 4 days, cultured for 10 days for TG accumulation, and then incubated with Rsv (0, 25 or 50 μM) for 3 days. TG accumulation was analyzed by Oil Red-O staining. To understand how Rsv regulates TG accumulation and consumption, changes in gene and protein expressions of several factors associated with free fatty acid (FFA) uptake and β-oxidation were investigated by real-time RT-PCR and Western blot. For further elucidation of underlying mechanisms, we also investigated gene expressions using Sirtuin1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) siRNA. Results Rsv dose dependently enhanced Sirt1 expression and reduced TG accumulation. Rsv-induced reduction of TG accumulation was abolished by inhibition of Sirt1 and PGC1α. Rsv also enhanced expressions of genes involved in FFA uptake [peroxisome proliferator-activated receptor-gamma (PPARγ) and lipoprotein lipase] and in β-oxidation regulation [PGC1-α and carnitine palmitoyl-transferase 1a (CPT1a)]. All these effects were abolished by Sirt1 inhibition. Conclusion The present results suggest that Rsv may augment synthesis and oxidation of fatty acid, and possibly increases energy utilization efficiency in adipocytes through activation of Sirt1. The present study may provide meaningful evidence supporting the efficacy of Rsv in the treatment of obesity.

Inverse relationship of cardioankle vascular index with BMI in healthy Japanese subjects: a cross-sectional study

Objective The objective of this study is to investigate the association of body mass index (BMI) with arterial stiffness assessed by cardioankle vascular index (CAVI). Subjects and methods A retrospective cross-sectional study was conducted in 23,257 healthy Japanese subjects (12,729 men and 10,528 women, aged 47.1 ± 12.5 years, BMI 22.9 ± 3.4 kg/m2) who underwent health screening between 2004 and 2006 in Japan. Exclusion criteria were current medication use and a past history of cardiovascular disease, hypertension, stroke, diabetes, and nephritis. Results Male subjects showed significantly higher BMI, CAVI, and triglycerides and lower high-density lipoprotein (HDL)-cholesterol compared with female subjects. Next, the subjects were divided into tertiles of BMI: lower, middle, and upper, in a gender-specific manner. After adjusting for confounders including age, systolic blood pressure, and HDL-cholesterol identified by multiple regression analysis, the mean CAVI decreased progressively as BMI tertile increased in both genders. Furthermore, a negative inverse relationship between BMI and adjusted CAVI was observed throughout the BMI distribution. Multivariate logistic regression model for contributors of high CAVI (≥90th percentile) identified obesity (odds ratios (95% confidence interval): 0.804 (0.720–0.899)], older age [15.6 (14.0–17.4)], male gender [2.26 (2.03–2.51)], hypertension [2.28 (2.06–2.54)], impaired fasting glucose [1.17 (1.01–1.37)], and low HDL-cholesterol [0.843 (0.669–1.06)] as independent factors. Conclusion We demonstrated an inverse relationship between CAVI and BMI in healthy Japanese subjects, suggesting that systemic accumulation of adipose tissue per se may lead to a linear decrease of arterial stiffness in nonobese and obese subjects without metabolic disorders.

Os 10-04 Inverse Relationship Between Cardio-ankle Vascular Index (cavi) And Body Mass Index In Healthy Japanese Subjects: A Cross-sectional Study

Objective: To investigate the association of body mass index (BMI) with cardio-ankle vascular index (CAVI). Design and Method: We analyzed cross-sectional data from 23,257 healthy Japanese subjects (12,729 males and 10528 females) without past history of heart disease, hypertension, stroke, diabetes and nephritis between 20 and 74 (47.1 ± 12.5) years of age who underwent health screening during 2004 to 2006 in Japan. Results: Male showed markedly higher BMI, CAVI, TG and lower HDL-C. Next, BMI was divided into 3 groups of lower, middle and upper tertile in a gender-specific manner. After adjusting for confounders including age, systolic BP, HDL-C and Non-HDL-C extracted in multiple regression analysis for CAVI, the mean values of CAVI decreased gradually by BMI tertile in both genders. Furthermore, the negative gradient of BMI with adjusted CAVI was seemed constantly throughout. Multivariate logistic regression model demonstrated that the odds ratios (95% CIs) for high CAVI (≥ 90th percentile) were 0.801 (0.716 – 0.897) in Obesity, 15.1 (13.5 – 16.9) in Elderly, 2.28 (2.06 – 2.54) in Male, 2.21 (1.97 – 2.47) in Hypertension, 3.29 (2.81 – 3.86) in Low-HDL-C and 1.06 (0.845 – 1.32) in Impaired fasting glucose. Conclusions: We demonstrated the inverse relationship between BMI and CAVI, which revealed that systemic accumulation of adipose tissue, itself, might lead to the decrease of arterial stiffness linearly.OBJECTIVE To investigate the association of body mass index (BMI) with cardio-ankle vascular index (CAVI). DESIGN AND METHOD We analyzed cross-sectional data from 23,257 healthy Japanese subjects (12,729 males and 10528 females) without past history of heart disease, hypertension, stroke, diabetes and nephritis between 20 and 74 (47.1 ± 12.5) years of age who underwent health screening during 2004 to 2006 in Japan. RESULTS Male showed markedly higher BMI, CAVI, TG and lower HDL-C. Next, BMI was divided into 3 groups of lower, middle and upper tertile in a gender-specific manner. After adjusting for confounders including age, systolic BP, HDL-C and Non-HDL-C extracted in multiple regression analysis for CAVI, the mean values of CAVI decreased gradually by BMI tertile in both genders. Furthermore, the negative gradient of BMI with adjusted CAVI was seemed constantly throughout. Multivariate logistic regression model demonstrated that the odds ratios (95% CIs) for high CAVI (≥ 90th percentile) were 0.801 (0.716 - 0.897) in Obesity, 15.1 (13.5 - 16.9) in Elderly, 2.28 (2.06 - 2.54) in Male, 2.21 (1.97 - 2.47) in Hypertension, 3.29 (2.81 - 3.86) in Low-HDL-C and 1.06 (0.845 - 1.32) in Impaired fasting glucose. CONCLUSIONS We demonstrated the inverse relationship between BMI and CAVI, which revealed that systemic accumulation of adipose tissue, itself, might lead to the decrease of arterial stiffness linearly.