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Background Dyslipidemia is associated with kidney function decline (KFD), although the non-linear relationship of lipid parameters to KFD has not been fully elucidated. We aimed to determine the detailed relationship of baseline lipid parameters with KFD, considering the mediation of arterial stiffness. Methods A total of 27864 urban residents with estimated glomerular filtration rate (eGFR)≥60 ml/min/1.73m2 at baseline, who participated in a median of 3 (range 2 to 8) consecutive annual health examinations were studied. Arterial stiffness was assessed by cardio-ankle vascular index (CAVI). KFD was defined as development of eGFR below 60 ml/min/1.73m2. Results During the study period, 1837 participants (6.6%) developed KFD. Receiver-operating-characteristic analysis determined that the cutoff values independently associated with KFD are 123 mg/dL for low-density lipoprotein cholesterol (LDL-C) [AUC (95% CI): 0.570 (0.557−0.583)], 65 mg/dL for high-density lipoprotein cholesterol (HDL-C) [0.552 (0.539−0.566)], 82 mg/dL for triglycerides (TG) [0.606 (0.593−0.618)] and 1.28 for TG/HDL-C ratio [0.600 (0.587−0.612)]. These cut-offs were independently associated with KFD in Cox analysis. Regarding the contribution of each lipid parameter to KFD, a linear relationship was observed for both TG and TG/HDL-C, and a U-shaped relationship for HDL-C. A adjusted mediating effect of CAVI on the relationship of TG or TG/HDL-C ratio with KFD was observed (Mediating rate: 2.9% in TG, 2.5% in TG/HDL-C ratio). Regarding the association to KFD, a linear relationship was observed for both TG and TG/HDL-C, a U-shaped relationship for HDL-C. A mediating effect of CAVI on the relationship of TG or TG/HDL-C ratio with KFD was observed after adjustment for confounders. Conclusions TG and TG/HDL-C ratio related linearly to KFD and was partially mediated by CAVI. A U-shaped relationship was observed between HDL-C and RFD risk. LDL-C showed no significant association. Further study should investigate whether intensive TG-lowering treatment prevents KFD via decreasing CAVI.

Aim To clarify the mechanism by which pitavastatin reduced cardiovascular (CV) events more effectively than atorvastatin in the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP), the changes in (Δ) non-heparinized serum level of lipoprotein lipase mass (LPL mass) during administration of the respective statins were investigated. Methods From TOHO-LIP data, 223 hypercholesterolemic patients with any CV risks followed at Toho University Sakura Medical Center were analyzed. The patients were randomized to pitavastatin (2 mg/day) group (n=107) or atorvastatin (10 mg/day) group (n=116), and followed for 240 weeks. In this subgroup study, the primary and secondary end points were the same as those in TOHO-LIP, and 3-point major adverse cardiovascular events (3P-MACE) was added. The relationship between ΔLPL mass during the first year and the incidences of each end point was analyzed. Results The lipid-lowering effect was not different between the two statins. Cumulative 240-week incidence of each end point was significantly lower in pitavastatin group (primary: 1.9% vs. 10.3%, secondary: 4.7% vs. 18.1%, 3P-MACE: 0.9% vs. 6.9%). Mean LPL mass (64.9 to 69.0 ng/mL) and eGFR (70.1 to 73.6 ml/min/1.73m2) increased in pitavastatin group, but not in atorvastatin group during the first year. Cox proportional-hazards model revealed that ΔLPL mass (1 ng/mL or 1SD) contributed to almost all end points. Conclusions Pitavastatin administration reduced CV events more efficaciously than atorvastatin despite similar LDL cholesterol-lowering effect of the two statins. Increased LPL mass during the first year by pitavastatin treatment may be associated with this efficacy.

Kouichi Murakami,1 Emi Inayama,1 Yukiko Itoh,1 Shoji Tuchiya,1 Masashi Iwasaki,2 Nobuko Tamura,1 Toshihiko Suzuki,3 Noriko Iwai,1 Junji Utino,4 Motoyuki Masai,4 Daiji Nagayama,5,6 Kohji Shirai4,6 1Seijinaki Mihama Narita Clinic, Narita City, Chiba, 286-0041, Japan; 2Seijinkai Mihama Katori Clinic, Katori City, Chiba, 287-0041, Japan; 3Seijinkai Mihama Sakura Clinic, Sakura City, Chiba, 285-0841, Japan; 4Seijinkai Mihama Hospital, Chiba City, Chiba, 261-0013, Japan; 5Nagayama Clinic, Oyama City, Tochigi, 323-0032, Japan; 6Sakura Hospital, School of Medicine Toho University, Sakura City, Chiba, 285-8741, JapanCorrespondence: Daiji NagayamaNagayama Clinic, 2-12-22, Tenjin-Cho, Oyama City, Tochigi, 323-0032, JapanTel/Fax +81-285-22-0219Email deverlast96071@gmail.comAim: Mortality rate of maintenance hemodialysis patients is known to be high. Cardio-ankle vascular index (CAVI) is an index reflecting the proper stiffness of the arterial tree from the origin of the aorta to the ankle. We aimed to clarify the utility of CAVI as a predictor of mortality in hemodialysis patients. The roles of age and nutritional conditions on survival were also examined.Methods: We followed 242 patients undergoing hemodialysis for 6 consecutive years. Data from 209 patients (mean age was 60 ± 11 years) excluding those with ankle-brachial index < 0.90 were then analyzed. CAVI and heart to ankle pulse wave velocity (haPWV) were measured using Vasera 1500.Results: Thirty-eight hemodialysis patients who died during the 6-year period had higher age, cardiothoracic ratio (CTR), CAVI, and haPWV, and lower diastolic blood pressure, albumin, phosphate, and calcium phosphate product. The Kaplan–Meier curves for cumulative survival among the tertile groups showed that the mortality rate was higher in the highest tertile (T3) compared to T1/T2 for both CAVI and haPWV. Receiver operating characteristic (ROC) analysis revealed that CAVI had better discriminatory power for all-cause mortality compared to haPWV. In the Cox-proportional hazards analyses, 1 SD increase in both parameters contributed independently to all-cause mortality [CAVI: HR 1.595 (95% CI 1.108– 2.297), haPWV: HR 1.695 (95% CI 1.185– 2.425)], as well as age and CTR. Both parameters above the cut-offs estimated in the ROC analysis (CAVI ≥ 9.2, haPWV ≥ 8.9) also had independent contributions to mortality.Conclusion: Through the 6 consecutive years of follow-up in 209 HD patients, increased CAVI might represent a major modifiable risk factor for all-cause mortality. Further research is needed to examine whether CAVI-lowering interventions contribute to improved prognosis.Keywords: hemodialysis patient, mortality, cardio-ankle vascular index, phosphorus

Background Abdominal obesity as a risk factor for diagnosing metabolic syndrome (MetS) is conventionally evaluated using waist circumference (WC), although WC does not necessarily reflect visceral adiposity. Objective To examine whether replacing WC with “A Body Shape Index (ABSI)”, an abdominal obesity index calculated by dividing WC by an allometric regression of weight and height, in MetS diagnosis is useful for predicting renal function decline. Subjects/Methods In total, 5438 Japanese urban residents (median age 48 years) who participated in a public health screening program for 4 consecutive years were enrolled. Systemic arterial stiffness was assessed by cardio-ankle vascular index (CAVI). The predictability of the new-onset renal function decline (eGFR 2) by replacing high WC with high ABSI (ABSI ≥ 0.080) was examined using three sets of MetS diagnostic criteria: Japanese, IDF and NCEP-ATPIII. Results In Japanese and NCEP-ATPIII criteria, MetS diagnosed using ABSI (ABSI-MetS) was associated with significantly higher age-adjusted CAVI compared to non-MetS, whereas MetS diagnosed using WC (WC-MetS) showed no association. Kaplan–Meier analysis of the rate of new-onset renal function decline over 4 years (total 8.7%) showed remarkable higher rate in subjects with ABSI-MetS than in those without (log-rank test p p = 0.014–0.617). In gender-specific Cox-proportional hazards analyses including age, proteinuria, and treatments of metabolic disorders as confounders, ABSI-MetS (Japanese criteria for both sexes, IDF criteria for men) contributed independently to the new-onset renal function decline. Of these, the contribution of IDF ABSI-MetS disappeared after adjustment by high CAVI in the subsequent analysis. Conclusion In this study, replacing WC with ABSI in MetS diagnostic criteria more efficiently predicted subjects at risk of renal function decline and arterial stiffening.

Background Presepsin is a diagnostic and prognostic biomarker of both bacterial infection and sepsis; however, elevated presepsin levels have also been observed without sepsis. We conducted several analyses to evaluate the clinical laboratory parameters affecting presepsin levels. Method We analyzed the association between sequential organ failure assessment (SOFA) scores and plasma presepsin levels and then analyzed clinical laboratory parameters in 567 patients with univariate and multivariate regression analysis and analysis of covariance (ANCOVA). We also determined presepsin in the bile of 11 patients and examined the presepsin immunostaining in liver. Results Spearman’s rank correlation analysis with loge change revealed that presepsin levels were closely associated with loge-transformed SOFA score (ρ = 0.541), alkaline phosphatase (ALP); (ρ = 0.454) and gamma-glutamyl transferase; (ρ = 0.505). Multivariate regression analysis revealed that loge-transformed SOFA score (β-coefficient = 0.316), ALP level (β-coefficient = 0.380), and creatinine level (β-coefficient = 0.290) independently and significantly affected loge presepsin levels. ANCOVA revealed that presepsin levels were significantly higher in patients with hepatobiliary disease. Patients who presented with dilatation of the bile ducts and elevated ALP levels or total bilirubin levels exhibited high presepsin levels in the bile. Presepsin production in liver Kupffer cells was also confirmed by immunostaining. Conclusion Presepsin levels is correlated with the elevation of biliary enzymes in patients without renal dysfunction or sepsis. Additionally, presepsin exists with high concentrations in the bile and is positive in Kupffer cells.

Aim: In the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP), a multicenter randomized controlled trial, pitavastatin significantly reduced cardiovascular (CV) events compared to atorvastatin in patients with hypercholesterolemia. To investigate the mechanism by which pitavastatin preferentially prevents CV events, we investigated the relationship between CV events and cardio-ankle vascular index (CAVI) using the TOHO-LIP database. Methods: For the subgroup analysis, we selected patients from a single center, Toho University Sakura Medical Center. After excluding those who had CV events at baseline or during the first year, 254 patients were enrolled. The primary end point was the same as that of TOHO-LIP, and three-point major cardiac adverse events (3P-MACE) was added as secondary end point. Results: The cumulative 5-year incidence of 3P-MACE (pitavastatin 1.6%, atorvastatin 6.1%, P =0.038) was significantly lower in pitavastatin group (2 mg/day) than in atorvastatin group (10 mg/day). CAVI significantly decreased only in pitavastatin group during the first year (9.50–9.34, P =0.042), while the change in low-density lipoprotein cholesterol (LDL-C) did not differ between the two groups. The change in CAVI during the first year positively correlated with 3P-MACE and tended to be an independent predictor of 3P-MACE in Cox proportional hazards model (hazard ratio, 1.736; P =0.079). The annual change in CAVI throughout the observation period was significantly higher in subjects with CV events compared to those without. Conclusions: In this subgroup analysis, the reduction in CV events tended to be associated with the CAVI-lowering effect of pitavastatin, which was independent of the LDL-C-lowering effect.

Kazuhiro Shimizu,1 Mao Takahashi,1 Shuji Sato,1 Atsuhito Saiki,1 Daiji Nagayama,1,2 Takashi Hitsumoto,3 Akira Takahara,4 Kohji Shirai1,5 1Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba, Japan; 2Department of Internal Medicine, Nagayama Clinic, Oyama, Tochigi, Japan; 3Hitsumoto Medical Clinic, Shimonoseki, Yamaguchi, Japan; 4Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, Japan; 5Department of Internal Medicine, Seijinkai Mihama Hospital, Chiba, Chiba, JapanCorrespondence: Kazuhiro Shimizu, Department of Internal Medicine, Toho University Sakura Medical Center, 561-4 Shimoshizu, Sakura, Chiba, 285-8741, Japan, Tel +81-43-462-8811, Fax +81-43-462-8820, Email k432@sakura.med.toho-u.ac.jpAbstract: Predictive factors for vascular events have not been established. The vasculature of the atheroma is supplied by penetration of the vasa vasorum through the smooth muscle cell layer from the adventitia. Smooth muscle cell contraction induces compression of the vasa vasorum, resulting in ischemia in intimal atheromatous lesions. Cardio-ankle vascular index (CAVI) has become known as an index of arterial stiffness of the arterial tree from the origin of the aorta to the ankle. CAVI reflects the progress of arteriosclerosis, and a rapid rise in CAVI indicates arterial smooth muscle cell contraction. We hypothesized that rapidly increased arterial stiffness evaluated by CAVI may be a predictor of impending cardiovascular events.Keywords: arterial stiffness, stress, plaque rupture, CAVI

Background: Most comparisons of arterial stiffness\ud between ethnic groups focus on pulse wave velocity. This\ud study used the cardio-ankle vascular index (CAVI) in\ud European compared to Japanese individuals to investigate\ud how cardiovascular risk factors affect arterial aging across\ud geographic regions.\ud Methods: Four hundred and ninety-four European and\ud 1044 Japanese individuals underwent measurements of\ud CAVI, blood pressure and information on cardiovascular\ud risk factors. Both datasets included individuals with 0–5\ud cardiovascular risk factors.\ud Results: Average CAVI was higher in the Japanese than\ud the European group in every age category, with significant\ud differences up to 75 years for males and 85 for females.\ud The correlation of CAVI with age, controlled for\ud cardiovascular risk factors, was slightly higher in Japanese\ud females (r¼0.594 vs. Europeans r¼0.542) but much\ud higher in European males (r¼0.710 vs. Japanese\ud r¼0.511). There was a significant correlation between\ud CAVI and total cardiovascular risk factors in the Japanese\ud (r¼0.141, P

Daiji Nagayama,1,2 Atsuhito Saiki,2 Kohji Shirai3 1Department of Internal Medicine, Nagayama Clinic, Tochigi, Japan; 2Center of Diabetes, Endocrine and Metabolism, Toho University Sakura Medical Center, Chiba, Japan; 3Department of Internal Medicine, Mihama Hospital, Chiba, JapanCorrespondence: Daiji NagayamaDepartment of Internal Medicine, Nagayama Clinic, 2-12-22, Tenjin-Cho, Oyama-City, Tochigi, 323-0032, JapanTel/Fax +81-285-22-0219Email deverlast96071@gmail.comAbstract: The significance of statin treatment for the reduction of cardiovascular (CV) disease has been reported, whereas other reports have also described anti-cancer properties associated with the class effect of statins. However, the differences in anti-cancer effect of various types of statins have rarely been examined. Pitavastatin is a statin with a different chemical structure and pharmacokinetics from other statins, and the mechanism of the specific anti-cancer effect of pitavastatin has been reported in in vivo therapeutic models. We previously revealed that pitavastatin therapy was superior to atorvastatin therapy in the prevention of CV events, despite similar LDL-cholesterol-lowering effect in the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP). Furthermore, in subgroup analysis of the TOHO-LIP study, cumulative 240-week incidence of new cancer cases tended to be lower in the pitavastatin group compared to the atorvastatin group [0.32% (1/312) vs 1.94% (6/310), log-rank P=0.051]. This finding might reveal the superiority of pitavastatin to prevent carcinogenesis. The molecular mechanism by which pitavastatin suppresses the incidence of any-organ cancer is gradually elucidated, and new combination of cancer treatments with pitavastatin will be developed in the future to further enhance the anti-cancer activity and reduce the side effects.Keywords: pitavastatin, anti-cancer effect, TOHO-LIP

The relative usefulness of arterial stiffness parameters on renal function remains controversial. This study aimed to compare the predictive ability of three arterial stiffness parameters at baseline; cardio-ankle vascular index (CAVI), heart-ankle pulse wave velocity (haPWV) and CAVI 0 , a variant of CAVI that theoretically excludes dependence on blood pressure, for renal function decline in Japanese general population.A total of 27 864 Japanese urban residents without renal impairment at baseline who participated in two to eight consecutive (mean 3.5 ± 1.7 times) annual health examinations were studied.During the study period, 6.6% of participants developed renal function decline (estimated glomerular filtration rate60 ml/min per 1.73 m 2 ), all of whom had relatively high values in all arterial stiffness parameters. In receiver-operating characteristic curve analysis, the discriminatory power for renal function decline showed a decreasing trend of CAVI to haPWV to CAVI 0 (C-statistic: 0.740 vs. 0.734 vs. 0.726). The cut-offs were CAVI 8.0, haPWV 7.23 and CAVI 0 11.6. In Cox-proportional hazards analysis for increase of each parameter above cut-off or by 1 standard deviation (SD) adjusted for two models of confounders, only CAVI always contributed significantly to renal function decline. Restricted cubic spline regression analysis suggested that CAVI most accurately reflected the risk of renal function decline.Increase in arterial stiffness parameters, especially CAVI, may represent a major modifiable risk factor for renal function decline in the general population. Further research is needed to examine whether CAVI-lowering interventions contribute to the prevention of chronic kidney disease.

Obesity has been known to relate to various diseases and metabolic disorders. Since the implication of body shape has been mentioned, obesity can be divided into visceral obesity and subcutaneous obesity. The former is considered the upstream pathophysiology of metabolic syndrome (MetS), and has been emphasized worldwide for the prevention of cardiovascular diseases in the last quarter century. However, some prospective studies have shown that cardiovascular mortality and morbidity are not necessarily higher in patients with MetS compared to those without. Recently, cardio-ankle vascular index (CAVI) has been established as an indicator of arteriosclerosis. This parameter is independent of blood pressure at the measuring time, and reflects systemic arterial stiffness from the aortic origin to the ankle. However, since CAVI is not necessarily high in MetS patients, attempts have been made to clarify this unexpected phenomenon. In several studies, CAVI was found to correlate negatively with body mass index (BMI), and also with waist circumference (WC) which is a widely used representative visceral obesity index. On the other hand, a body shape index (ABSI) is also a visceral obesity index designed to be minimally associated with BMI, and is calculated by dividing WC by an allometric regression of weight and height. Replacing high WC with high ABSI in MetS diagnosis promoted the identification of MetS patients with increased CAVI in cross-sectional studies on Japanese and Korean populations. Additionally, the incidence of MetS diagnosed using high ABSI was associated with significant increase in CAVI after 1 year of observation. Enhanced predictive ability for renal function decline by replacing WC with ABSI in MetS diagnosis was also observed in a longitudinal study in Japanese urban residents. These findings suggest that MetS diagnosis using high ABSI instead of high WC as a visceral obesity index needs to be reconsidered. However, further research is desirable on Caucasian, whose body shape differs slightly from that of Asians.

Kazuhiro Shimizu,1 Mao Takahashi,1 Shuji Sato,1 Atsuhito Saiki,1 Daiji Nagayama,1 Masashi Harada,2 Chikao Miyazaki,2 Akira Takahara,3 Kohji Shirai1 1Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba, Japan; 2Department of Neurosurgery, Toho University Omori Medical Center, Omori, Tokyo, Japan; 3Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, JapanCorrespondence: Kohji ShiraiDepartment of Internal Medicine, Toho University Sakura Medical Center, 561-4 Shimoshizu, Sakura City, Chiba, 285-8741, JapanTel +81-43-462-8811Fax +81-43-462-8820Email kshirai@kb3.so-net.ne.jpAbstract: Cardiovascular diseases have been recognized as the main cause of death all over the world. Recently, the established cardio-ankle vascular index (CAVI) has become known as an index of arterial stiffness of the arterial tree from the origin of the aorta to the ankle. CAVI reflects the progress of arteriosclerosis, and a rapid rise in CAVI indicates arterial smooth muscle cell contraction. Considering the vasculature of the atheroma where vasa vasorum penetrates the smooth muscle cell layer and supplies blood to the intimal atheromatous lesion, a rapid rise of CAVI means “choked” atheroma. Thus, we proposed a “smooth muscle cell contraction” hypothesis of plaque rupture.Keywords: arterial stiffness, atherosclerosis, smooth muscle cell contraction, CAVI

AIM: The J-SMART study was the first national survey of Japanese patients undergoing laparoscopic sleeve gastrectomy (LSG). We performed a subgroup analysis of J-SMART focusing on the differences in patient background and diabetes remission between patients with BMI 32–34.9 kg/m(2) and those with higher BMI. METHODS: In this multi-institutional retrospective study at 10 certified bariatric institutions, 203 Japanese with type 2 diabetes (T2D) and BMI of 32 kg/m(2) or higher were analyzed (mean age: 49.2 years, BMI: 43.8 kg/m(2), HbA1c: 7.6%). Patients were stratified into five groups according to preoperative BMI. RESULTS: Background characteristics in BMI 32.0–34.9 group were higher adjusted HbA1c, higher visceral/subcutaneous fat area ratio, higher prevalence of diabetic retinopathy, higher frequency of insulin use and lower serum C-peptide. Although 2-year percent total weight loss (21.7%) and diabetes complete remission (CR) rate (52.4%) were lower in BMI 32.0–34.9 group, diabetes improvement rate was 81.0%, and the decrease in HbA1c and number of antidiabetic drugs were comparable or greater than those with higher BMI. Higher BMI and no insulin use were significant independent predictors of diabetes CR. No significant independent predictor was identified for diabetes improvement. CONCLUSION: The patients with 32–34.9 kg/m(2) were characterized by more severe visceral obesity, T2D and the complications, and lower intrinsic insulin secretion capacity. LSG should be considered as a treatment option for patients with BMI 32–34.9 kg/m(2), to improve diabetes control.

Objective: The aim of this study was to investigate the association of the maximum lifetime body mass index (max BMI) with hemodialysis initiation and comorbidities in Japanese hemodialysis patients. Methods: In a retrospective cross-sectional study on 724 hemodialysis patients, max BMI, age at hemodialysis initiation, and comorbidities including sleep apnea syndrome, cerebro-cardiovascular diseases, and proliferative diabetic retinopathy (PDR) were analyzed. Early hemodialysis initiation was defined as age Result: Diabetes patients showed a higher max BMI and prevalence of atherosclerotic diseases than nondiabetes patients, despite almost the same age at hemodialysis initiation. Patients with early hemodialysis initiation showed higher male ratio, prevalence of PDR, and max BMI than those with later initiation, despite almost equal prevalence of diabetes. Receiver-operating characteristic curve analysis determined a max BMI of 28.4 kg/m2 as a reliable cutoff value for predicting early hemodialysis initiation, and this parameter was identified as an independent predictor of early hemodialysis initiation using bivariate logistic regression analysis. Vitrectomy for PDR also tended to contribute independently to early hemodialysis initiation. Conclusion: A high max BMI contributed to early hemodialysis initiation independent of diabetes. Furthermore, PDR was associated with a high max BMI and early hemodialysis initiation. These results suggest that weight reduction in young chronic kidney disease patients with obesity may prevent hemodialysis and blindness.

Introduction: We previously reported that preoperative serum insulin-like growth factor-1 (IGF-1) is a predictor of total weight loss percentage (%TWL) after laparoscopic sleeve gastrectomy (LSG). IGF-1 may suppress muscle loss after surgery. IGF-1 almost accurately reflects the growth hormone (GH) secretion status, and GH has lipolytic effects. Therefore, IGF-1 may influence both the maintenance of skeletal muscle and the reduction of adipose tissue after LSG. The identification of the relationship between preoperative serum IGF-1 and body composition changes after LSG can help in understanding the pathophysiology of obesity. Methods: We retrospectively reviewed 72 patients with obesity who underwent LSG and were followed up for 12 months. We analyzed the relationship between preoperative serum IGF-1 levels and body composition changes after LSG. A multiple regression model was used. Results: LSG led to a significant reduction in body weight. Both body fat mass and skeletal muscle mass decreased after LSG. Preoperative serum IGF-1 levels significantly correlated with %TWL, changes in skeletal muscle mass, and body fat mass after LSG. The multiple regression model showed that preoperative serum IGF-1 levels were related to decreased body fat mass and maintaining skeletal muscle mass after LSG. Discussion/Conclusion: Preoperative IGF-1 measurement helps predict not only successful weight loss but also decreases body fat mass and maintains skeletal muscle mass after LSG.

Introduction The main pathophysiology of sepsis is considered to be circulation crisis with an imbalance of vasodilation and vasoconstriction mechanisms, which contributes to multiple organ failure. However, sepsis-induced hemodynamic changes have not been fully validated by novel arterial stiffness parameter. The aim of this study was to clarify the acute vascular alteration and hemodynamic change in sepsis using cardio-ankle-vascular index (CAVI). Methods Twenty-one Japanese patients (14 males and 7 females, age 62.8 ± 19.0 years) with sepsis were recruited. CAVI was measured before and 1-week after sepsis treatment. Results The leading underlying cause of sepsis was pyelonephritis, followed by pneumonia, lung abscess, hepatic abscess and cholecystitis. All subjects recovered from sepsis. Analysis of all subjects showed a significant increase in CAVI after 1-week treatment (7.9 ± 2.4 to 9.6 ± 1.8, P < 0.001), but no significant change in blood pressure (BP) was observed. Significant correlations were observed for all combinations among the change in CAVI, systolic BP and ln[procalcitonin (PCT)], respectively. Additionally, in subjects with PCT at presentation ≥2.0 ng/mL, the increase in CAVI after treatment was significantly greater compared to those with PCT < 2.0 ng/mL (2.4 ± 1.6 vs 1.1 ± 0.9, P = 0.037). Discussion CAVI may reflect sepsis-induced vascular alteration which is not indicated by BP change, and is associated with sepsis severity. These findings suggest the usefulness of CAVI in the management of circulatory failure in sepsis patients.

Introduction: Laparoscopic sleeve gastrectomy (LSG) significantly increases high-density lipoprotein cholesterol (HDL-C) and lipoprotein lipase (LPL) in pre-heparin serum (pre-heparin LPL levels). LPL is a regulator of serum triglyceride (TG) and HDL-C production; this may be the mechanism for HDL-C increase after LSG. This study aimed to elucidate the mechanism of increase in HDL-C levels by examining the relationship between changes in serum HDL-C levels and LPL after LSG. Methods: We retrospectively reviewed 104 obese patients, who underwent LSG and were followed up for 12 months. We analyzed the relationship between changes in serum HDL-C levels and various clinical parameters after LSG. Results: A significant decrease was observed in the patients’ BMI and serum TG levels after LSG. Conversely, HDL-C levels and pre-heparin LPL levels were significantly increased after LSG. Simple linear regression showed that changes in HDL-C levels were significantly correlated with total weight loss percentage, change in TG levels, abdominal fat areas, and pre-heparin LPL levels. Additionally, the multiple regression model revealed that a decrease in TG levels and an increase in pre-heparin LPL levels were correlated with increased HDL-C levels after LSG. Discussion/Conclusion: These results show that a decrease in TG levels and an increase in LPL are mechanisms for increased HDL-C levels after LSG.

Background: Abdominal obesity as a risk factor for diagnosing metabolic syndrome (MetS) is conventionally evaluated using waist circumference (WC), although WC does not necessarily reflect visceral adiposity. We aimed to examine whether replacing WC with “A Body Shape Index (ABSI)”, an abdominal obesity index, in MetS diagnosis is useful for predicting renal function decline (RFD). Methods: A retrospective cohort study was conducted in 5438 Japanese urban residents (median age 48 years) who participated in a public health screening program for 4 consecutive years. Systemic arterial stiffness was assessed by cardio-ankle vascular index (CAVI), and high CAVI was defined as CAVI ≥ 9.0. The predictability of the occurrence of RFD (eGFR < 60 mL/min/1.73m 2 ) by replacing high WC with high ABSI (ABSI ≥ 0.080) was examined using three sets of MetS diagnostic criteria: Japanese, International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII). Results: In Japanese and NCEP-ATPIII criteria, MetS diagnosed using ABSI (ABSI-MetS) was associated with significantly higher age-adjusted CAVI compared to non-MetS, whereas MetS diagnosed using WC (WC-MetS) showed no association. Kaplan-Meier analysis of the rate of new-onset RFD over 4 years (total 8.7%) showed remarkable higher rate in subjects with ABSIMetS than in those without (log-rank test p Conclusion: In this study, replacing WC with ABSI in MetS diagnostic criteria more efficiently predicted subjects at risk of RFD and arterial stiffening. Further studies are needed to confirm whether MetS diagnosed using ABSI also predicts CVD.

Introduction: In patients with severe obesity, albuminuria can be improved by both conventional medical therapy and bariatric surgery. The purpose of this study was to compare the impact of weight loss achieved through conventional medical therapy or laparoscopic sleeve gastrectomy (LSG) on albuminuria in Japanese subjects with severe obesity and identify the factors involved. Methods: We retrospectively evaluated the clinical characteristics including the urinary albumin/creatinine ratio (UACR) of 340 consecutive subjects with a body mass index ≥35 who received LSG (n = 242) or medical therapy (n = 98) between 2010 and 2018 and were followed for at least 12 months. Results: The baseline of the UACR was not different between the 2 groups. At the 12-month follow-up, total weight loss (TWL) and decreases in glycosylated hemoglobin (HbA1c) and loge UACR were greater in the LSG group than in the medical therapy group (body weight; −35.7 kg vs. −8.0 kg, p < 0.001, HbA1c; −1.4% vs. −0.7%, p < 0.001, loge UACR; −0.3 vs. 0.9, p < 0.001). The rate of complete remission of diabetes was significantly higher in the LSG group than in the medical therapy group. At 12 and 36 months (n = 111 in the medical therapy group, n = 56 in the LSG group at 36 months), loge UACR increased in the medical therapy group, while it remained unchanged or decreased in the LSG group. In subjects with microalbuminuria and macroalbuminuria, changes in the loge UACR correlated with percent total body weight loss (%TWL) in both groups at 12 months. Percent TWL contributed independently to the change in the loge UACR, irrespective of whether LSG was performed. In receiver-operating characteristic analysis, a weight loss of 7.8% predicted a decrease in the UACR (∆UACR Conclusion: Our analysis suggests that albuminuria may increase over time if only medical therapy is continued. To improve albuminuria, weight loss may be more important than whether LSG is performed.

Aim Cardio-ankle vascular index (CAVI) reflects arterial stiffness and has been established as a useful surrogate marker of atherosclerosis. Contrary to the abundant data indicating slower progression of atherosclerosis with statins, studies on fibrates remain scarce. The aim of this study was thus to clarify the effect of bezafibrate on CAVI as well as on oxidative stress. Methods A randomized, open-label, controlled study was performed. 66 hypertriglyceridemic patients with type 2 diabetes were assigned to two groups: bezafibrate (400 mg/day) group and eicosapentaenoic acid (EPA 1.8 g/day) group. Patients were administered the respective treatment for 12 weeks. CAVI, glycolipid metabolic parameters, and diacron-reactive oxygen metabolites (d-ROMs) were evaluated before and after the study period. Results Serum triglycerides (TG), remnant-like particle cholesterol (RLP-C), fasting plasma glucose, HbA1c and d-ROMs decreased, while HDL-cholesterol increased significantly in the bezafibrate group but did not change in the EPA group. The decreases in TG, RLP-C, HbA1c and d-ROMs were significantly greater in the bezafibrate group than in the EPA group. CAVI decreased significantly only in the bezafibrate group and the decrease was significantly greater in bezafibrate group than in EPA group. Simple regression analysis showed no significant relationship between the change in CAVI and changes in other variables. Multivariate logistic regression analysis identified high baseline CAVI, low HDL-cholesterol level, and bezafibrate administration as significant independent predictors of CAVI decrease. Conclusion Bezafibrate treatment ameliorates arterial stiffness accompanied by improvement of glycolipid metabolism and oxidative stress. These effects potentially have important beneficial health consequences in hypertriglyceridemic patients with type 2 diabetes.

Introduction Sodium-dependent glucose transporter-2 (SGLT2) inhibitors such as dapagliflozin induce weight loss, but the mechanism is thought to involve loss of both body fat and skeletal muscle mass. The decrease in skeletal muscle mass may lead to worsening of insulin resistance in type 2 diabetes patients. On the other hand, formula diet (FD) is a low-calorie food containing low carbohydrates, low fat, and sufficient protein, vitamins, and minerals to support a healthy and balanced diet, and is used for the treatment of obesity or diabetes. Therefore, we examine whether the protein supplementation is superior to the fat supplementation in metabolic improvement of the poorly controlled type 2 diabetes patients treated with SGLT2 inhibitor. We compare the therapeutic effects using two types of FD; a high protein FD and a high fat FD. Patients are prescribed dapagliflozin and replacement of one of three meals with FD. We compare high protein FD and high fat FD with respect to improvement of glycemic control while maintaining skeletal muscle mass. Methods We conduct a prospective, multicenter, double-blinded, randomized, controlled, investigator-initiated clinical trial. Patients who satisfy the eligibility criteria will be randomized to two groups (1:1) and prescribed 5 mg of dapagliflozin once daily together with a high protein FD or high fat FD (same number of calories) to replace one of three meals a day (one meal with FD only and two normal meals). The observation period for both groups is 24 weeks. The primary endpoint is the change in HbA1c. Planned Outcomes This study is ongoing and scheduled to complete in June 2019. The findings of this study will be disseminated through peer-reviewed publications and conference presentations. Trial Registration University Hospital Medical Information Network (UMIN) 000024580. Funding This study was carried out under contract with the specified nonprofit corporation Hokkaido Institute of Health Sciences, based on a grant from AstraZeneca Co., Ltd. and Ono Pharmaceutical Co., Ltd. for an investigator-initiated clinical trial. The authors funded the journals article processing charges.

Objective To clarify that the new index of abdominal obesity, a body shape index (ABSI), is associated with obesity-related metabolic disorders and arterial stiffness. Materials We analyzed the cross-sectional data from 62,514 Japanese subjects (mean age 44.4 years, mean body mass index (BMI) 22.2 kg/m2) without a past history of cardiovascular disease, stroke, or treatment for obesity-related metabolic disorders. Methods Various body adiposity indices including BMI, waist circumference (WC), and ABSI were evaluated for abilities to indicate metabolic disorders and arterial stiffness assessed by cardio-ankle vascular index (CAVI). Results WC, WC/height ratio, and WC/BMI ratio correlated with BMI regardless of gender or obesity, whereas ABSI hardly correlated with BMI. ROC analyses demonstrated that ABSI had the highest discriminatory power in predicting high CAVI (≥ 90th percentile) compared to other body adiposity indices, and the cut-off value was 0.080. Increases in ABSI as well as BMI reflected severity of metabolic disorders. After adjusting for confounders identified by multiple regression analysis, adjusted CAVI correlated positively with ABSI, whereas an inverted relationship was observed between adjusted CAVI and BMI. Additionally, the contribution of high ABSI (≥ 0.080) for high CAVI was independent of gender, age, obesity, and obesity-related metabolic disorders in the multivariate logistic regression model. Conclusion ABSI is an easily calculated index of abdominal obesity which reflects metabolic disorders and systemic arterial stiffening, and may be useful in primary health screening even without any medical equipment for visceral fat quantification.

Aim: To investigate the associations of conventional lipid parameters with arterial stiffness assessed by cardio — ankle vascular index (CAVI). 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, body mass index (BMI) 22.9 ± 3.4 kg/m2) who underwent health screening between 2004 and 2006 in Japan. Results: Male subjects had significantly higher BMI, CAVI and triglycerides (TG), and lower high-density lipoprotein cholesterol (HDL-C) compared to female subjects. After adjusting for confounders, including gender, age, systolic blood pressure and BMI identified by multiple regression analysis, adjusted CAVI was lower in normolipidemic than in dyslipidemic subjects. Among dyslipidemic subjects, those with hypertriglyceridemia had higher adjusted CAVI. A trend test detected linear relations between adjusted CAVI and all the conventional lipid parameters throughout the entire range of serum levels. After adjusting for confounders, logistic regression models showed that all lipid parameters contributed independently to high CAVI (≥ 90th percentile). Receiver–operating–characteristic analysis determined reliable cut-off values of 93 mg/dl for TG (area under the curve, AUC = 0.735), 114 mg/dl for low-density lipoprotein cholesterol (AUC = 0.614) and 63 mg/dl for HDL-C (AUC= 0.728) in predicting high CAVI. These cut-off values were confirmed to independently predict high CAVI in a bivariate logistic regression model. Conclusion: The present study demonstrated independent contribution of conventional lipid parameters to CAVI, indicating a possible association of lipid parameters with early vascular damage.

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.

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.

Introduction The main pathophysiology of sepsis is considered to be circulation crisis with an imbalance of vasodilation and vasoconstriction mechanisms, which contributes to multiple organ failure. However, sepsis-induced hemodynamic changes have not been fully validated by novel arterial stiffness parameter. The aim of this study was to clarify the acute vascular alteration and hemodynamic change in sepsis using cardio-ankle-vascular index (CAVI). Methods Twenty-one Japanese patients (14 males and 7 females, age 62.8 ± 19.0 years) with sepsis were recruited. CAVI was measured before and 1-week after sepsis treatment. Results The leading underlying cause of sepsis was pyelonephritis, followed by pneumonia, lung abscess, hepatic abscess and cholecystitis. All subjects recovered from sepsis. Analysis of all subjects showed a significant increase in CAVI after 1-week treatment (7.9 ± 2.4 to 9.6 ± 1.8, P < 0.001), but no significant change in blood pressure (BP) was observed. Significant correlations were observed for all combinations among the change in CAVI, systolic BP and ln[procalcitonin (PCT)], respectively. Additionally, in subjects with PCT at presentation ≥2.0 ng/mL, the increase in CAVI after treatment was significantly greater compared to those with PCT < 2.0 ng/mL (2.4 ± 1.6 vs 1.1 ± 0.9, P = 0.037). Discussion CAVI may reflect sepsis-induced vascular alteration which is not indicated by BP change, and is associated with sepsis severity. These findings suggest the usefulness of CAVI in the management of circulatory failure in sepsis patients.

Background There has been no report about outcome of pitavastatin versus atorvastatin therapy in high-risk patients with hypercholesterolemia. Methods Hypercholesterolemic patients with one or more risk factors for atherosclerotic diseases (n = 664, age = 65, male = 54%, diabetes = 76%, primary prevention = 74%) were randomized to receive pitavastatin 2 mg/day (n = 332) or atorvastatin 10 mg/day (n = 332). Follow-up period was 240 weeks. The primary end point was a composite of cardiovascular death, sudden death of unknown origin, nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, or heart failure requiring hospitalization. The secondary end point was a composite of the primary end point plus clinically indicated coronary revascularization for stable angina. Results The mean low-density lipoprotein cholesterol (LDL-C) level at baseline was 149 mg/dL. The mean LDL-C levels at 1 year were 95 mg/dL in the pitavastatin group and 94 mg/dL in the atorvastatin group. There were no differences in LDL-C levels between both groups, however, pitavastatin significantly reduced the risk of the primary end point, compared to atorvastatin (pitavastatin = 2.9% and atorvastatin = 8.1%, HR, 0.366; 95% CI 0.170–0.787; P = 0.01 by multivariate Cox regression) as well as the risk of the secondary end point (pitavastatin = 4.5% and atorvastatin = 12.9%, HR = 0.350; 95%CI = 0.189–0.645, P = 0.001). The results for the primary and secondary end points were consistent across several prespecified subgroups. There were no differences in incidence of adverse events between the statins. Conclusion Pitavastatin therapy compared with atorvastatin more may prevent cardiovascular events in hypercholesterolemic patients with one or more risk factors for atherosclerotic diseases despite similar effects on LDL-C levels.

Statins have been reported to increase the plasma concentration of arachidonic acid (AA), an omega-6 long chain polyunsaturated fatty acid (LCPUFA) in several clinical studies indicating that statins affect the endogenous synthesis of LCUFAs. In the present study, we investigated the roles of the intrinsic mevalonate cascade and Rho-dependent pathway in LCPUFA synthesis, especially focusing on fatty acid desaturases (Fads) 2, using the human hepatocellular carcinoma cell line HepG2. Cell number and the activity of caspase-3 and 7 (caspase-3/7) was measured using a commercial kit. Gene expression was analyzed by quantitative real-time PCR. Protein expression was detected by Western blot analysis. Atorvastatin decreased cell viability and increased caspase-3/7 activity in a dose-dependent manner. At lower concentrations, atorvastatin stimulated both mRNA and protein expression of Fads2, and increased mRNA expression of FADS1 and ELVOL5. Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), but not cholesterol, fully reversed atorvastatin-induced upregulation of Fads2, and mevalonate-effected reversal was inhibited by treatment with the Rho-associated protein kinase inhibitor Y-27632. These data clearly demonstrated that in human HepG2 cells, statins affect the endogenous synthesis of LCPUFAs by regulation of not only Fads2, but also Fads1 and Elovl5, through the GGPP-dependent Rho kinase pathway.

Measurement of arterial stiffness in routine medical practice is important to assess the progression of arteriosclerosis. So far, many parameters have been proposed to quantitatively represent arterial stiffness. Among these, pulse wave velocity (PWV) has been most frequently applied to clinical medicine because those could be measured simply and non-invasively. PWV had established the usefulness of measuring arterial wall stiffness. However, PWV essentially depends on blood pressure at the time of measurement. Therefore, PWV is not appropriate as a parameter for the evaluation of arterial stiffness, particularly for the studies involving blood pressure changes.On the other hand, stiffness parameter β is an index reflecting arterial stiffness without the influence of blood pressure. Recently, this parameter has been applied to develop a new arterial stiffness index called cardio-ankle vascular index (CAVI). Therefore, CAVI does not depend on blood pressure changes during the measurements; CAVI could represent the stiffness of the arterial tree from the origin of the aorta to the ankle.Many clinical studies obtained from CAVI are being accumulated. CAVI showed high value in arteriosclerotic diseases, such as coronary artery diseases, cerebral infarction, and chronic kidney diseases, and also in majority of people with various coronary risk factors. The improvement of those risk factors decreased CAVI. Furthermore, the role of CAVI as a predictor of cardio-vascular events was reported recently.We review the clinical studies on CAVI and discuss the clinical usefulness of CAVI as a candidate surrogate end-point marker for cardiovascular disease.

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.

Aims: To investigate the association of metabolic parameters including hemoglobin glycation index (HGI, observed HbA1c – predicted HbA1c) with systemic arterial stiffness assessed by cardio-ankle vascular index (CAVI). Subjects: We analyzed the cross-sectional data from 22,696 subjects (mean age 48.0 years, mean FPG 88 mg/dL, mean HbA1c 5.5%) with or without past history of metabolic disorders including diabetes. Results: Men had higher body mass index (BMI), CAVI, blood pressure (BP), FPG, HbA1c, total cholesterol and triglyceride; and lower age, HGI and HDL-cholesterol. After stratifying subjects into HGI quartiles, the highest quartile (Q4) group showed higher age, female ratio, and frequencies of obesity, hypertension, diabetes, and dyslipidemia. Furthermore, bivariate logistic regression model revealed that the Q4 of HGI was a significant predictor of high CAVI (⩾9.0) independent of the presence of diabetes. Conclusion: High HGI is associated with systemic arterial stiffening independent of hyperglycemia. This index is therefore expected to be not only a predictor of hypoglycemia, but also a therapeutic guide for atherosclerosis.