An Alternative Approach to Determining Metabolic Syndrome Component Cutoffs in Children and Adolescents Using Segmental Regression Analysis.

Background: The prevalence of metabolic syndrome is increasing in children and adolescents. Although some diagnostic criteria for metabolic syndrome exist, further research is needed to determine appropriate age-, sex-, and race-specific cutoffs for each component. Methods and Results: Health examinations were conducted in 1,679 children aged 6-15 years in 9 regions of Japan. Participants were divided into 3 age groups for each sex: 6-8, 9-11, and 12-15 years. For metabolic syndrome components in each group, inverse cumulative percentile graphs were drawn and approximated by 3 regression lines using segmented regression analysis. The intersection of each regression line was defined as the breakpoint, and the measured value corresponding to the breakpoint percentile as the breakpoint value. Breakpoint values for waist circumference were age dependent at approximately 60, 70, and 80 cm for ages 6-8, 9-11, and 12-15 years, respectively. Breakpoint values for blood pressure were age- and/or sex dependent, while those for triglycerides, high-density lipoprotein cholesterol, and fasting blood glucose were neither age nor sex dependent. Based on these results, we proposed new cutoffs for diagnosing metabolic syndrome in Japanese children and adolescents. Conclusions: Breakpoint values obtained by segmented regression analysis on inverse cumulative percentile graphs can be useful for determining metabolic syndrome component cutoffs in children and adolescents.

Developmental trajectories at a high risk for childhood overweight/obesity.

BACKGROUND: The associations between developmental patterns (trajectories) in children and maternal factors have been widely investigated, but paternal effects on these trajectories are unclear. This study aimed to determine child and parental factors involved in developmental trajectories at high risk for causing adverse cardiovascular (CV) profiles in children. METHODS: We analyzed longitudinal anthropometric data from birth to the present and CV profiles of 1,832 healthy volunteers (51% girls) aged 3-15 years who participated in a nationwide study between July 2012 and January 2014. Six trajectory latent class growth models were developed using body mass index z- scores. Predictors for being in developmental trajectories at high risk for causing adverse CV profiles were determined by multivariate regression analysis. RESULTS: The mean±standard deviation number of anthropometric data points was 12±3 for both boys and girls. Among the six trajectories, the infantile onset and continual increase groups had significantly worse levels of many CV profiles than those in the remaining groups. Paternal overweight/obesity was an independent predictor for boys being in the infantile onset group and for girls being in the continual increase group. Additionally, maternal pre-pregnancy overweight/obesity in boys and maternal excessive gestational weight gain in girls were independent predictors for being in the infantile onset group. Having no sibling in boys and an older maternal age were independent predictors for being in the continual increase group. CONCLUSIONS: Interventions to prevent childhood obesity should include strategies that focus on fathers and mothers as well as those that focus on children with certain types of familial background.

Impact of lifestyles of adolescents and their parents on cardiovascular risk factors in adolescents.

AIM: The aim of this study was to determine the impact of the lifestyles of adolescents and their parents on the levels of cardiovascular (CV) risk factors in the adolescents. METHODS: A total of 755 volunteers (331 male, 424 female) aged 15 to 18 years were included. Abdominal obesity, hypertension, elevated triglyceride levels, decreased high density lipoprotein-cholesterol levels, and hyperglycemia were considered to be CV risk factors. Self-reported lifestyle, including participation in school-based extracurricular (EC) physical activities, time spent on physical activity or watching television (TV), and average daily food intake were assessed. Parental information on weight status and lifestyle was also obtained. RESULTS: Multivariate regression analyses showed that participation in EC physical activities, time spent watching TV, regular breakfast consumption, total energy intake, fiber intake per 1,000 Kcal, and parental BMI were independently associated with the levels of one or more CV risk factors in adolescents. Among these, participation in EC physical activities had a profound effect on adolescent CV risk factor levels. The risk of male adolescent obesity was associated with paternal obesity, but not with maternal obesity. Conversely, the risk of female adolescent obesity was associated with maternal obesity but not with paternal obesity. CONCLUSIONS: Participation in EC physical activities may be the first-line approach for adolescents to maintain favorable CV risk factor levels. An association between paternal or maternal obesity and adolescent obesity differs between adolescent genders in Japan; thus, approaches focusing on parents should take the gender of the adolescent into consideration.

Impact of having one cardiovascular risk factor on other cardiovascular risk factor levels in adolescents.

AIM: Little is known about the impact of having one cardiovascular (CV) risk factor on the levels of other CV risk factors in the general adolescent population. We hypothesized that when adolescents have one CV risk factor, the levels of other CV risk factors worsen simultaneously. METHODS: Subjects consisted of 1,257 healthy adolescent volunteers (549 males and 708 females) aged 15-18 years. Abdominal obesity, hypertension, raised triglyceride levels, decreased HDL-cholesterol levels and hyperglycemia were used as CV risk factors. Homeostasis assessment of insulin resistance (HOMA-IR) was used as a surrogate marker of insulin resistance. Levels of four biomarkers, leptin, adiponectin, high-sensitive C-reactive protein, and desacyl-ghrelin, were also determined. Cut-offs for gender-specific individual CV risk factor levels were based on the 90th (or 10th) percentile values of the subjects in the present study. RESULTS: The levels of all CV risk factors and HOMA-IR significantly and simultaneously worsened when adolescents had one CV risk factor in both genders. Having any one CV risk factor indicated the development of other CV risk factors in adolescents; in particular, we found that the development of abdominal obesity in male subjects had a harmful effect on the levels of other CV risk factors and was associated with the worsening of all four biomarkers examined. CONCLUSIONS: It is important to determine the presence or absence of these CV risk factors before and/or during adolescence, because having one CV risk factor indicates the start of an accumulation of CV risk factors in the general adolescent population.

Visceral fat accumulation in Japanese high school students and related atherosclerotic risk factors.

AIM: To investigate the factors that influence visceral fat accumulation in adolescence, we performed a medical examination of high school students and assessed abdominal fat thickness and fatty change of the liver. METHODS: A cohort of 374 Japanese high school students aged 15-16 years (193 boys and 181 girls) in public high schools in Chiba prefecture were enrolled. Anthropometric parameters, blood cell count, blood chemistry and adipocytokine levels were measured. Preperitoneal fat thickness (PFT) and echoic contrast of the liver were measured by ultrasonography. RESULTS: Anthropometric parameters, systolic blood pressure, blood cell count, ALT, AST, FBS, gamma-GTP, HDL-C, LpL, UA, adiponectin, resistin and leptin levels differed between sexes. Multivariate regression analysis revealed that leptin was the most appropriate marker for PFT in both sexes (p<0.0001). Visceral obesity, categorized as PFT exceeding 8 mm, was observed in 9.6% of all students. Boys with visceral obesity showed apparent liver dysfunction, hyperlipidemia, hyperinsulinemia, and high leptin and low adiponectin levels. Overall, 16.6% of boys and 30.4% of girls showed hepatorenal echo contrast positivity. Boys with visceral obesity and fatty liver had more risk factors for atherosclerosis. CONCLUSIONS: Physical examination of high school students is important for early detection of atherosclerosis.

Multicenter collaborative randomized parallel group comparative study of pitavastatin and atorvastatin in Japanese hypercholesterolemic patients: collaborative study on hypercholesterolemia drug intervention and their benefits for atherosclerosis prevention (CHIBA study).

AIMS: To compare the efficacy and safety of pitavastatin and atorvastatin in Japanese patients with hypercholesterolemia. METHODS AND RESULTS: Japanese patients with total cholesterol (TC) > or = 220 mg/dL were randomized to receive pitavastatin 2 mg (n=126) or atorvastatin 10 mg (n=125) for 12 weeks. The primary endpoint was percent change from baseline in non-HDL-C level after 12 weeks of treatment. Reduction of non-HDL-C by pitavastatin treatment (39.0%, P=0.456 vs. atorvastatin) was non-inferior to that by atorvastatin (40.3%). Both pitavastatin and atorvastatin also significantly reduced LDL-C by 42.6% and 44.1%, TC by 29.7% and 31.1%, and TG by 17.3% and 10.7%, respectively, at 12 weeks without intergroup differences. HDL-C showed a significant increase at 12 weeks with pitavastatin treatment (3.2%, P=0.033 vs. baseline) but not with atorvastatin treatment (1.7%, P=0.221 vs. baseline). Waist circumference, body weight and BMI were significantly correlated with percent reduction of non-HDL-C in the atorvastatin group, whereas pitavastatin showed consistent reduction of non-HDL-C regardless of the body size. In patients with metabolic syndrome, LDL-C was reduced significantly more in patients receiving pitavastatin when compared with those receiving atorvastatin. AST, ALT and gammaGTP increased significantly in patients receiving atorvastatin but not in those receiving pitavastatin. Both treatments were well tolerated. CONCLUSION: Pitavastatin 2 mg and atorvastatin 10 mg are equally effective in improving the lipid profile and were well tolerated in Japanese patients with hypercholesterolemia.

Prognosis of hypercholesterolemic patients taking pravastatin for five years: the Chiba Lipid Intervention Program (CLIP) Study.

The Chiba Lipid Intervention Program (CLIP) Study was designed to clarify the prognosis of Japanese hypercholesterolemic patients taking pravastatin for 5 years. Hypercholesterolemic patients (n = 2,529) with a total cholesterol level > or = 220 mg/dl and without histories of ischemic coronary heart disease and/or cerebral infarction were administered pravastatin (10-20 mg/day). Among them, 2,131 took pravastatin fully (Pravastatin-continued group), and 398 discontinued the treatment (Discontinued group). The baseline total cholesterol level was 264.3 +/- 34.7 mg/dl (mean +/- standard deviation). The mean reduction rates of total cholesterol and low-density lipoprotein (LDL) cholesterol were 18.0% and 27.2%, respectively. Mild and moderate adverse events occurred in 86 cases (3.6%). Serious adverse events were not observed. Death rates of the pravastatin-continued group and of the discontinued group were 2.6 and 16.0/1,000 persons/year, respectively. Cardiac events (fatal and nonfatal myocardial infarction, cardiac death, angina pectoris) in all, occurred in 35 patients (incidence rate = 2.77/1,000 persons/year). In the pravastatin continued group, 9 causes of fatal and nonfatal myocardial infarction occurred (0.84/1,000 persons/year), whereas in the discontinued group, 4 cases occurred (2.06/1,000 persons/ year). The risk ratio for cardiac events was correlated with the number of risks. In the low-risk group (< or = 1 risk), decreased rates of LDL-cholesterol were less in the cardiac event group than the non-cardiac event group (LDL-cholesterol; 16% vs 25%, p = 0.04). These results suggested the following; 1) Pravastatin maintained a cholesterol lowering effect long-term without serious complications. 2) Pravastatin administration might reduce the mortality rate and myocardial infarction. 3) The combination of multiple risks is a strong factor for a cardiac event in addition to hypercholesterolemia.

A case of hyperlipidemia with homozygous apolipoprotein E5 (Glu3-->Lys).

In this study, we present clinical feature of a novel case with homozygous apolipoprotein (apo) E5. The patient was a 53-year-old Japanese woman. She was from a small island off the coast of Kagoshima Prefecture, Japan. Her parents were first degree cousins. No corneal opacification, xanthomatosis, lymphadenopathy, or hepatosplenomegaly was observed. There have been no signs of clinically overt atherosclerosis to date. Her serum total cholesterol, triglycerides (TG) and high-density lipoprotein (HDL)-cholesterol levels were 11.6, 6.1 and 1.2 mmol/l, respectively, and apo A-I, A-II, B, C-II, C-III and E levels were 121, 34.8, 269, 10.4, 25.7 and 10.3 mg/dl, respectively. Serum lipoprotein profile analyzed by agarose gel electrophoresis and differential staining revealed markedly increased cholesterol and TG in both beta and prebeta-migrated lipoproteins, whereas alpha-migrated lipoprotein showed decreased cholesterol. Her apo E isoform analyzed by isoelectric focusing (IEF) was found to be homozygous apo E5. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis of her apo E and lipoprotein lipase (LPL) genes revealed that she had a homozygous apo E (Glu3-->Lys) and heterozygous LPL variant Ser447 to Ter. Her son and daughter, both of whom had hyperlipidemia, were found to have apo E3/5 phenotype. Direct sequencing analysis of her apo E gene confirmed a homozygous one nucleotide change: G to A at nucleotide position of 2836 in the exon 3, resulting in Glu3-->Lys mutation. This is the first report of lipids and lipoprotein profiles in patients with homozygous apo E5 (Glu3-->Lys).

Single LDL apheresis improves serum remnant-like particle-cholesterol, C-reactive protein, and malondialdehyde-modified-low-density lipoprotein concentrations in Japanese hypercholesterolemic subjects.

BACKGROUND: Single low-density lipoprotein (LDL)-apheresis may affect serum remnant-like particle-cholesterol (RLP-C), C-reactive protein (CRP) and malondialdehyde-modified (MDA)-LDL concentrations. SUBJECTS AND METHODS: Six subjects with hypercholesterolemia (five men, one woman) were involved in this study. Mean age and body mass index of the study subjects were 58+/-3.1 years and 23.6+/-2.07 kg/m(2), respectively. Five of the subjects were diagnosed as heterozygous familial hypercholesterolemia (FH) because of having both marked hypercholesterolemia and Achilles tendon xanthomas. LDL apheresis was introduced and continued using a dextran sulfate cellulose adsorption column technique every 2 weeks. Serum RLP-C was measured using an immunoaffinity mixed gel containing anti-apolipoprotein A-I and anti-apolipoprotein B monoclonal antibody. Serum CRP was measured by latex-enhanced assay. Serum MDA-LDL was measured using monoclonal antibody against MDA-LDL (ML25). RESULTS: Combined treatment in the steady state pre-treatment yielded a total, LDL- and HDL-cholesterol, and TG concentrations of 5.39+/-0.81, 3.82+/-1.03, 1.24+/-0.29 and 0.92+/-0.43 mmol/l, respectively, and a post-treatment total, LDL- and HDL-cholesterol and TG concentrations of 2.79+/-0.37 (-48%, p<0.001), 1.63+/-0.29 (-57%, p<0.001), 1.18+/-0.26 (-5%, NS) and 0.23+/-0.11 mmol/l (-75%, p<0.001), respectively. Serum RLP-C and CRP concentrations showed a substantial reduction [-73%, p<0.05 for RLP-C; -56%, p<0.05 for CRP] during this procedure. In addition, LDL apheresis was found to also cause a marked reduction in serum MDA-LDL concentration (-61%, p<0.05). CONCLUSION: LDL-apheresis is an effective treatment for removing atherogenic factors RLP-C, CRP and MDA-LDL from sera.