Influence Of Metabolic Status On Incident Hypertension In Obese Children:a Prospective Population-based Cohort Study

Background:Obesity in children and adolescence has increased at an alarming rate in both developed and developing countries in recent decades and has become a major public healthy and social problem. In China, along with the rapid economic growth, the prevalence of general obesity and abdominal obesity increased significantly from 6.1% to 13.1% and 4.9% to 11.7% over the past 17 years, respectively. Data from the physical fitness and health research of Chinese school students showed that the prevalence of childhood obesity has rapidly increased from 0.2% in 1985 to 8.1% in 2010.Obesity is strongly associated with long-term morbidity and mortality. Moreover, obese children are more likely to be accompanied with cardiovascular risk factors such as hypertension, dyslipidaemia and metabolic syndrome. Additionally, overweight during in childhood and adolescence is also a risk factor for adult obesity, hypertension and even mortality. However, not all obese subjects are at a similar risk for obesity-related metabolic abnormalities. Extensive individual heterogeneity exists in obese populations, and combining obesity with metabolic health components yields a spectrum of obesity phenotypes. One of the most intriguing phenotypes in this regard is the metabolically healthy obesity (MHO) and controversies on the benign nature of this phenotype regarding future morbidity and mortality.The metabolically healthy obese (MHO), despite presenting as obesity, seems to be protected from obesity-related metabolica abnormalities. Moreover, MHO individuals might not benefit from energy restriction and exercise interventions. The current obesity epidemic and its related health problem calls for targeted interventions that take into account different subtypes of obesity, rather than uniform "one size fits all" strategies that ignore the large degree of heterogeneity among obese individuals. Therefore, there are potential benefits of distinguishing MHO from metabolically unhealthy obese individuals who are more likely to require early pharmacological treatment and lifestyle interventions. Another phenotype, termed metabolically unhealthy normal-weight (MUNW) phenotype, presents normal weight with an abnormal metabolic profile. Several studies found that MUMW individuals showed increased hypertension and cardiovascular disease (CVD) risk, and had higher risk for heart failure compared with MHO individuals. Hence, identifying these subpopulations might have clinical significance in terms of prevention cadivascular metabolic dieases.Conflicting evidence regarding the risk of CVD associated with the MHO and MUNW phenotypes exist. The potential mechanism involved the different definitions, age, race/ethnicity as well as period of follow-up. In addition, the current CVD metabolic risk factors such as metabolic syndrome or insulin resistance might not be sufficient to demonstrate the complete range of metabolic abnormalities in MHO individuals, and additional metabolic risk factors, including inflammation, uric acid(UA) as well as apolipoprotein, might explain the positive relationship MHO and CVD outcomes. Leptin, adiponectin, leptin/adiponectin ratio, have been observed to be informative biomarkers for obesity, metabolic syndrome (MS), Type 2 diabetes or CVD in children and adolescents. However, it is unknown whether these adipokines as additional components of MS might be effective indicators for an increased CVD risk in MHO individuals.Hypertension is one of the most important predictors of CVD mortality. Many epidemiological studies have indicated that adult hypertension begins at childhood. More and more evidence have demonstrated that hypertension is common in children and adolescence and has the potential long-term harm to their health. Obesity is the most strongest and indepent risk factor for hypertension in children. The prevalence of adult hypertension and related CVD has increased in recent years along with the increased trends in children obesity. Thus, identifying the association of MHO and MUNW phenotypes with the risk of hypertension might partially explain the inconsistent results regarding the risk of CVD events or mortality. Observations on the relationship between the MHO and MUNW phenotypes and the risk of cardiovascular events have been made in adult populations. However, no longtitudinal studies have addressed the effects of MHO and MUNW phenotypes on the risk of developing hypertension in children and adolescents.Given that the MHO phenotype starts in childhood and continues into adulthood and a rapidly increasing prevalence of obesity and hypertension in children and adolescents in China. Hence, understanding epidemiology, determinants as well as the health consequences associated with MHO and MUNW phenotypes have public health and clinical significance in terms of management and theraphy strategies for obesity and obesity-related diseases.Objective:1) To examine the prevalence and clinical characteristics of body size phenotypes and the association beween obesity phenotype and blood pressure in children.2) To explore the role of body size phenotypes in predicting the risk of incident hypertension using data from a cohort study of children.3) To compare the levels of adipokines among different body size phenotype and determine the potential role in the association between obesity phenotype and hypertension in children.Methods:Subjects were recuited from the Beijing Child and Adolescent Metabolic Syndrome Study (BCAMS). The target population of BCAMS was children, aged 6-18 years, who lived in Beijing with their parents or guardians at least for 6 months. A stratified, randomly cluster sampling design was used to select subjects in 8 urbans and 10 suburbs stratified by 18 administrative districts (countries) in Beijing. Four out of eight urban districts and three out of seven rural districts were selected. A total of 22 primary schools (children aged 6-12 years) and 7 high schools (children aged 13-18 years) in those seven districts were randomly selected. A representative sample of 19 593 children aged 6-18 years who had complete information of physical assessment and finger capillary blood tests were retrieved from BCAMS data files. Further, a total of 5 053 children who had taken venipuncture blood samples were selected as the baseline population by un-radomly from the sample of 19 593 chilren. In total,2 661 children, who were still at school were followed up in December 2010. A total of 2 189 children, after excluding children who had hypertension, were followed up, and 1 184 children participated in the final exammiation. The rate of follow-up was 54.1%.All the participants completed a detailed standard questionnaire including demographic information, birth information, lifestyle, parents’ education and cardiovascular disease history. Anthropometric measurements including height, weight, waist circumference (WC) and fat mass percentage (FMP) were obtained using standardized techniques. Clinic and laboratory measurement included blood pressure, pubertal development, fasting blood glucose, lipid spectrum, insulin and adipokines.We used the BMI to define normal weight, overweight and obesity (age- and gender-specific BMI cutoffs were as recommended by the Working Group on Obesity in China, WGOC) in children aged 7-18 years. The age-and gender-specific 85th and 95th BMI percentile from the Growth Charts proposed by US Center for Disease Control and Prevention in 2000 was used to define overweight and obesity in children aged 6 years. Abdominal obesity was defined as WC≥90th percentile for age and sex. Hypertension was defined at baseline if the SBP and (or) DBP were equal to or greater than the 95th percentile for age and gender in children aged 6-17 years. SBP≥140mmHg and (or) DBP≥90mmHg to define hypertension in adults.Metabolic abnormalities were defined by metabolic syndrome components or insulin resistance. According to the National Cholesterol Education Program(NCEP III), participants meeting at least 2 of the following 5 criteria qualify as having the metabolic syndrome:1) central obesity defined as waist circumference≥90th percentile for age and sex; 2) elevated SBP and/or DBP≥90th percentile for age and sex; 3) hypertriglyceridemia, defined as triglyceride levels≥1.24 mmol/L; 4) low serum HDL cholesterol defined as≤1.03 mmol/L; and 5) impaired fasting glucose defined as≥5.6 mmol/L. IR was defined as a HOMA-IR>3.0.By combination BMI and metabolic status, all subjects were classified into six body size phenotypes:metabolically healthy normal weight, metabolically healthy overweight, MHO, MUNW, metabolically unhealthy overweight and metabolically unhealthy obese.The statistical analyses were performed using SPSS20.0 (SPSS, Inc., Chicago, Illinois) with statistical significance set at P<0.05. The statistic methods used in this research including variance (ANOVA), a Bonferroni post hoc comparison test, the chi-squared test and multivariate logistic regression models.Results:1. Prevalence and clinic characteristic of body size phenotype1)The prevalence of MUNW, MHO and metabolically unhealthy obesity phenotype, in the whole study population, were 2.9%,15.5% and 32.2%, respectively.The prevalence of normal weight insulin-resistance phenotype, obese insulin-sensitive phenotype and obese insulin-resistance phenotype in the entire population were 1.4%, 35.2% and 13.3%, respectively. The MUNW phenotype and normal weight insulin-resistance phenotype represented 7.6% and 3.7% of the normal weight population, respectively.2) BMI, WC, fat mass percentile, Triglycerides, LDL-cholesterol,blood pressure, and fasting glucose were higher in metabolically unhealthy obesity phenotype, while HDL-cholesterol was higher in MHO phenotype (all,P<0.05). Individuals in the obese insulin-sensitive phenotype were younger, had lower BMI, WC, fat mass percentile, blood pressure, Triglycerides, fasting glucose and fasting insulin, as well as had a higher HDL-cholesterol than in insulin-resistance phenotype(all,P<0.05).2. Association between body size phenotype and blood pressure1) The blood pressure levels, regaredless of metabolic status, increased with BMI. The MHO phenotype had higher blood pressure levels (SBP:108±12mmHg; DBP:71±9 mmHg) than metabolically healthy normal weight phenotype(SBP:99±11mmHg; DBP:63±9 mmHg) (P<0.05). The ability of MHO phenotypes on the risk for hypertension was 2.74(95%CI,1.52～4.93) times than metabolically healthy normal weight phenotype.The hypertension risk of metabolically unhealthy obesity phenotype was signigicantly higher than that of MHO phenotype. The MUNW obesity was not associated with the incidence of hypertension.2) Blood pressure levels in obese insulin-resistance individuals(SBP:112±11mmHg; DBP:72±8 mmHg) were significantly higher than in obese insulin-sesitive individuals (SBP:96±7mmHg; DBP:59±7 mmHg),P<0.05.The ability of obese insulin-sesitive phenotype on the risk for hypertension was 4.05 (95%CI,2.40-6.76) times than normal weight insulin-sesitive phenotype.3. The role of body size phenotypes in predicting the risk of incident hypertension1) The cumulative 6-year hypertension incidence was higher with higher BMI categories, irrespective of the presence of metabolic abnormality. The hypertension incidence was higher in obese individuals, compared with overweight and normal weight indiciduals.2) Compared with metabolically healthy normal weight individuals, metabolically healthy overweight and MHO individuals showed higher risk of hypertension, ORs were 2.07(95%CI,1.12-3.84) and 6.03(95%CI,3.84-9.44), respectively. The risk of hypertension in obese insulin-sesitive individuals than that in normal weight insulin-sesitive individuals (OR=4.94,95%CI=2.95-8.26). Both MUNW and normal weight insulin-resistance individuals were not related to hypertension incidence.4. Association of adipokins and body size phenotype and the risk of hypertension1) MHO individuals had higher leptin (10.67 ug/L vs 1.13 ug/L), leptin/adiponectin ratio(0.95 vs 0.06) and lower adiponectin(12.06 ug/L vs 15.62 ug/L) levels than metabolically healthy normal weight individuals(all, P<0.05). Compared with metabolically healthy normal weight individuals, the prevalence of high leptin (43.2% vs 2.0%), lower adiponectin(27.5% vs 15.4%) and high leptin/adiponectin ratio (41.3% vs 3.3%) in MHO individuals was higher than those in metabolically healthy normal weight individuals (all, P<0.01).2) The hypertension incidence was not only elevated in MHO combined with low adiponectin individuals (OR=7.30,95%CI= 3.08-17.36), high leptin individuals (OR= 5.49,95%CI=2.69-11.20) and high leptin/adiponectin ratio (OR=6.53,95% CI=3.19-13.33), but also higher in MHO individuals.Conclusions:1) The MHO phenotype and obese insulin-sesitive phenotype are common in Chinese children. MHO phenotype display lower BMI, waist circumference, fat mass percentile and more favorable metabolic profile.2) Body weight appeared to play a more important role in the elevalted SBP, DBP and the development of hypertension in Chinese children than metabolic risk factors.In same weight status, the incidence of hypertension was higher in metabolically unhealthy individuals than that in metabolically healthy individuals.3) The risk of hypertension was both elevated in MHO individuals. The MUNW phenotype and metabolically unhealthy non-abdominal obese was not significantly associated with the incidence hypertension. Thus, MHO phenotype was not a benign condition. The potential benefits of differentiating the MHO and MUNW phenotypes among children and adolescents in clinical practice appear limited.4) The elevated levels of leptin, leptin/adiponectin and reduced levels of adiponectin among MHO individuals could contribute to the increased hypertension risk observed in long-term studies. It is important to define "metabolically healthy" by non-traditional cardiovascular metabolic risk fators in clinical practice and research.