Daiji Nagayama

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.

Evaluation of Blood Pressure Control using a New Arterial Stiffness Parameter, Cardio-ankle Vascular Index (CAVI)

Arterial stiffness has been known to be a surrogate marker of arteriosclerosis, and also of vascular function. Pulse wave velocity (PWV) had been the most popular index and was known to be a predictor of cardiovascular events. But, it depends on blood pressure at measuring time. To overcome this problem, cardio-ankle vascular index (CAVI) is developed. CAVI is derived from stiffness parameter β by Hayashi, and the equation of Bramwell-Hill, and is independent from blood pressure at a measuring time. Then, CAVI might reflect the proper change of arterial wall by antihypertensive agents. CAVI shows high value with aging and in many arteriosclerotic diseases and is also high in persons with main coronary risk factors. Furthermore, CAVI is decreased by an administration of α1 blocker, doxazosin for 2-4 hours, Those results suggested that CAVI reflected the arterial stiffness composed of organic components and of smooth muscle cell contracture. Angiotensin II receptor blocker, olmesartan decreased CAVI much more than that of calcium channel antagonist, amlodipine, even though the rates of decreased blood pressure were almost same. CAVI might differentiate the blood pressure-lowering agents from the point of the effects on proper arterial stiffness. This paper reviewed the principle and rationale of CAVI, and the possibilities of clinical applications, especially in the studies of hypertension.

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.

Resveratrol Ameliorates Arterial Stiffness Assessed by Cardio-Ankle Vascular Index in Patients With Type 2 Diabetes Mellitus

Resveratrol has been reported to have potent anti-atherosclerotic effects in animal studies. However, there are few interventional studies in human patients with atherosclerogenic diseases. The cardio-ankle vascular index (CAVI) reflects arterial stiffness and is a clinical surrogate marker of atherosclerosis. The aim of the present study was to investigate the effect of resveratrol on arterial stiffness assessed by CAVI in patients with type 2 diabetes mellitus (T2DM).In this double-blind, randomized, placebo-controlled study, 50 patients with T2DM received supplement of a 100mg resveratrol tablet (total resveratrol: oligo-stilbene 27.97 mg/100 mg/day) or placebo daily for 12 weeks. CAVI was assessed at baseline and the end of study. Body weight (BW), blood pressure (BP), glucose and lipid metabolic parameters, and diacron-reactive oxygen metabolites (d-ROMs; an oxidative stress marker) were also measured.Resveratrol supplementation decreased systolic BP (-5.5 ± 13.0 mmHg), d-ROMs (-25.6 ± 41.8 U.CARR), and CAVI (-0.4 ± 0.7) significantly (P < 0.05) and decreased BW (-0.8 ± 2.1 kg, P = 0.083) and body mass index (-0.5 ± 0.8 kg/m2, P = 0.092) slightly compared to baseline, while there were no significant changes in the placebo group. Decreases in CAVI and d-ROMs were significantly greater in the resveratrol group than in the placebo group. Multivariate logistic regression analysis identified resveratrol supplementation as an independent predictor for a CAVI decrease of more than 0.5.In conclusion, 12-week resveratrol supplementation may improve arterial stiffness and reduce oxidative stress in patients with T2DM. Resveratrol may be beneficial in preventing the development of atherosclerosis induced by diabetes. However, a large-scale cohort study is required to validate the present findings.

The Role of Monitoring Arterial Stiffness with Cardio-Ankle Vascular Index in the Control of Lifestyle-Related Diseases

Arteriosclerosis is a major contributor to cardiovascular diseases. One of the difficulties in controlling those diseases is the lack of a suitable indicator of arteriosclerosis or arterial injury in routine clinical practice. Arterial stiffness was supposed to be one of the monitoring indexes of arteriosclerosis. Cardio-ankle vascular index (CAVI) is reflecting the stiffness of the arterial tree from the origin of the aorta to the ankle, and one of the features of CAVI is independency from blood pressure at a measuring time. When doxazosin, an α1-adrenergic blocker, was administered, CAVI decreased, indicating that arterial stiffness is composed of both organic stiffness and functional stiffness, which reflects the contraction of arterial smooth muscle. CAVI shows a high value with aging and in many arteriosclerotic diseases, and is also high in persons possessing main coronary risk factors such as diabetes mellitus, metabolic syndrome, hypertension and smoking. Furthermore, when the most of those risk factors were controlled by proper methods, CAVI improved. Furthermore, the co-relationship between CAVI and heart function was demonstrated during treatment of heart failure. This paper reviews the principle and rationale of CAVI, and discusses the meaning of monitoring CAVI in following up so-called lifestyle-related diseases and cardiac dysfunction in routine clinical practice.

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.

Effects of serotonin on expression of the LDL receptor family member LR11 and 7-ketocholesterol-induced apoptosis in human vascular smooth muscle cells.

Serotonin (5-HT) is a known mitogen for vascular smooth muscle cells (VSMCs). The dedifferentiation and proliferation/apoptosis of VSMCs in the arterial intima represent one of the atherosclerotic changes. LR11, a member of low-density lipoprotein receptor family, may contribute to the proliferation of VSMCs in neointimal hyperplasia. We conducted an in vitro study to investigate whether 5-HT is involved in LR11 expression in human VSMCs and apoptosis of VSMCs induced by 7-ketocholesterol (7KCHO), an oxysterol that destabilizes plaque. 5-HT enhanced the proliferation of VSMCs, and this effect was abolished by sarpogrelate, a selective 5-HT2A receptor antagonist. Sarpogrelate also inhibited the 5-HT-enhanced LR11 mRNA expression in VSMCs. Furthermore, 5-HT suppressed the 7KCHO-induced apoptosis of VSMCs via caspase-3/7-dependent pathway. These findings provide new insights on the changes in the differentiation stage of VSMCs mediated by 5-HT.

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.