Childhood cardiovascular risk factors predict subclinical adult cardiovascular disease, but links to clinical events are unclear.
In a prospective cohort study involving participants in the ...International Childhood Cardiovascular Cohort (i3C) Consortium, we evaluated whether childhood risk factors (at the ages of 3 to 19 years) were associated with cardiovascular events in adulthood after a mean follow-up of 35 years. Body-mass index, systolic blood pressure, total cholesterol level, triglyceride level, and youth smoking were analyzed with the use of i3C-derived age- and sex-specific z scores and with a combined-risk z score that was calculated as the unweighted mean of the five risk z scores. An algebraically comparable adult combined-risk z score (before any cardiovascular event) was analyzed jointly with the childhood risk factors. Study outcomes were fatal cardiovascular events and fatal or nonfatal cardiovascular events, and analyses were performed after multiple imputation with the use of proportional-hazards regression.
In the analysis of 319 fatal cardiovascular events that occurred among 38,589 participants (49.7% male and 15.0% Black; mean ±SD age at childhood visits, 11.8±3.1 years), the hazard ratios for a fatal cardiovascular event in adulthood ranged from 1.30 (95% confidence interval CI, 1.14 to 1.47) per unit increase in the z score for total cholesterol level to 1.61 (95% CI, 1.21 to 2.13) for youth smoking (yes vs. no). The hazard ratio for a fatal cardiovascular event with respect to the combined-risk z score was 2.71 (95% CI, 2.23 to 3.29) per unit increase. The hazard ratios and their 95% confidence intervals in the analyses of fatal cardiovascular events were similar to those in the analyses of 779 fatal or nonfatal cardiovascular events that occurred among 20,656 participants who could be evaluated for this outcome. In the analysis of 115 fatal cardiovascular events that occurred in a subgroup of 13,401 participants (31.0±5.6 years of age at the adult measurement) who had data on adult risk factors, the adjusted hazard ratio with respect to the childhood combined-risk z score was 3.54 (95% CI, 2.57 to 4.87) per unit increase, and the mutually adjusted hazard ratio with respect to the change in the combined-risk z score from childhood to adulthood was 2.88 (95% CI, 2.06 to 4.05) per unit increase. The results were similar in the analysis of 524 fatal or nonfatal cardiovascular events.
In this prospective cohort study, childhood risk factors and the change in the combined-risk z score between childhood and adulthood were associated with cardiovascular events in midlife. (Funded by the National Institutes of Health.).
Nephropathy and retinopathy remain important complications of type 1 diabetes. It is unclear whether their progression is slowed by early administration of drugs that block the renin-angiotensin ...system.
We conducted a multicenter, controlled trial involving 285 normotensive patients with type 1 diabetes and normoalbuminuria and who were randomly assigned to receive losartan (100 mg daily), enalapril (20 mg daily), or placebo and followed for 5 years. The primary end point was a change in the fraction of glomerular volume occupied by mesangium in kidney-biopsy specimens. The retinopathy end point was a progression on a retinopathy severity scale of two steps or more. Intention-to-treat analysis was performed with the use of linear regression and logistic-regression models.
A total of 90% and 82% of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year period did not differ significantly between the placebo group (0.016 units) and the enalapril group (0.005, P=0.38) or the losartan group (0.026, P=0.26), nor were there significant treatment benefits for other biopsy-assessed renal structural variables. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group; the incidence was higher with losartan (17%, P=0.01 by the log-rank test) but not with enalapril (4%, P=0.96 by the log-rank test). As compared with placebo, the odds of retinopathy progression by two steps or more was reduced by 65% with enalapril (odds ratio, 0.35; 95% confidence interval CI, 0.14 to 0.85) and by 70% with losartan (odds ratio, 0.30; 95% CI, 0.12 to 0.73), independently of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo.
Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy. (ClinicalTrials.gov number, NCT00143949.)
To examine the association of BMI percentile and change in BMI percentile to change in blood pressure (BP) percentile and development of hypertension (HTN).
This retrospective cohort included 101 606 ...subjects age 3 to 17 years from 3 health systems across the United States. Height, weight, and BPs were extracted from electronic health records, and BMI and BP percentiles were computed with the appropriate age, gender, and height charts. Mixed linear regression estimated change in BP percentile, and proportional hazards regression was used to estimate risk of incident HTN associated with BMI percentile and change in BMI percentile.
The largest increases in BP percentile were observed among children and adolescents who became obese or maintained obesity. Over a median 3.1 years of follow-up, 0.3% of subjects developed HTN. Obese children ages 3 to 11 had twofold increased risk of developing HTN compared with healthy weight children. Obese children and adolescents had a twofold increased risk of developing HTN, and severely obese children had a more than fourfold increased risk. Compared with those who maintained a healthy weight, children and adolescents who became obese or maintained obesity had a more than threefold increased risk of incident HTN.
We observed a strong, statistically significant association between increasing BMI percentile and increases in BP percentile, with risk of incident HTN associated primarily with obesity. The adverse impact of weight gain and obesity in this cohort over a short period underscores the early need for effective strategies for prevention of overweight and obesity.
Objective To determine the associations of adiposity and insulin resistance with measures of vascular structure and function in children. Study design A cross-sectional study included 252 children ...(age 15.1 ± 2.4 years; body mass index percentile 68.2 ± 26.5%; Tanner 2-5). Measurements of body fat percentage were obtained with dual-energy X-ray absorptiometry and visceral adipose tissue (VAT) with computed tomography. Insulin resistance was measured with hyperinsulinemic euglycemic clamp. Vascular measurements for endothelial function (brachial artery flow-mediated dilation FMD), vascular structure (carotid intima-media thickness cIMT), vascular stiffness (carotid incremental elastic modulus), and pulse wave velocity were analyzed by tertiles of adiposity and insulin resistance. Additional analyses with ANCOVA and linear regression were adjusted for Tanner, sex, race, and family relationship; FMD was also adjusted for baseline artery diameter. Results FMD was positively associated with high adiposity (body mass index, body fat percentage, and VAT) ( P < .01 all). Insulin resistance was not associated with FMD. cIMT was significantly, positively related to obesity, VAT, and insulin resistance ( P < .05 all). No differences in carotid incremental elastic modulus and pulse wave velocity were observed in relation to adiposity or insulin resistance. Conclusions The findings suggest that adiposity is associated with higher FMD, and insulin resistance and VAT are associated with higher cIMT in children. Further research is needed to clarify the progression of these relations.
The objective of this study was to describe longitudinal relations of serum total free fatty acids (FFAs) to insulin resistance (IR) and cardiovascular (CV) risk factors from adolescence into ...adulthood. The cohort included participants in a longitudinal study of obesity and IR with complete data, including anthropometric measures, FFAs, IR measured by euglycemic clamp, blood pressure, fasting serum lipids, and insulin at mean 15 and 22 years of age (n = 207) and their parents (n = 272). FFAs and IR were not significantly related at mean 15 years of age but were significantly related at mean age 22 years. FFA did not relate to BMI at either age. FFA at 15 years of age estimated IR at 22 years of age. In parents (mean age 51 years), FFA was significantly correlated with BMI, percent body fat, systolic blood pressure, LDL, and IR. Associations with all risk factors except IR in parents were attenuated by adjustment for BMI. Most 22 years of age correlations with parents were higher than corresponding 15 years of age correlations. This study finds that FFA is associated with IR starting in young adulthood. The relation between FFA and CV risk factors does not become significant until later adulthood. The results support a significant impact of early metabolic dysfunction on later CV risk.
To study the change in body mass index (BMI) from childhood and adolescence and development of obesity into adulthood.
We performed a longitudinal study of 480 individuals (49% male; 67% white) with ...height and weight measures in childhood (mean age 7 years), repeated in adolescence (mean age 16 years) and adulthood (mean age 39 years). Weight status in childhood was defined as low normal weight (0-<50 BMI percentile); high normal weight (50-<85 BMI percentile); overweight (85-<95 BMI percentile); obese (≥95 BMI percentile). Adult weight status was defined as normal weight (18.5-<25 kg/m2); overweight (25-<30 kg/m2); obese (>30 kg/m2).
Adult obesity (%) increased with weight status in childhood (low normal weight 17%; high normal weight 40%; overweight 59%; obesity 85%) and similarly with adolescence. Children in a lower category in adolescence than in childhood had lower risk of having adult obesity than did those who maintained their childhood category. Among adults with obesity, 59% (111 out of 187) were normal weight as children, with 75% (83 out of 111) from the high normal weight children; and 50% of adults with obesity were normal weight (n = 94/187) as adolescents, with 84% (81 out of 94) from the high normal weight adolescents. Only 6% of 143 normal weight adults had either overweight (n = 9) or obesity (n = 0) during childhood.
This study shows the high risk for adult obesity in children and adolescents who have overweight or obesity. A majority of adults with obesity had a 50-85 BMI percentile as children. Those who did not move to higher weight status between childhood and adolescence had lower probability of adult obesity.
Blood pressure (BP) tracking (maintaining a BP percentile) across life is not well defined but is important in predicting which children will become hypertensive adults. We computed BP tracking in ...subjects with BP measured in childhood and adulthood and performed logistic regression to determine the ability of childhood BP to predict adult hypertension (N=5035, 46.7 years, 74.2% white, 17.7% black; 39.6% male). Prevalence of hypertension was 29%. Correlations between systolic BP for child and adolescent were r=0.48; for adolescent and young adult were r=0.40, and for child and young adult were r=0.24 (all P<0.0001). Participants self-reporting adult hypertension were less likely to be white (38.7% black, 27.6% white, 20.9% other; P<0.0001) and female (26.4% females, 32.9% male, P<0.0001). Participants with adult hypertension were more likely to have higher BP and adiposity by age 10 years and abnormal lipids and glucose by age 16 years. There was a graded increase in the frequency of self-reported adult hypertension across the BP change groups, even within the persistently normotensive group (X
<0.0001) from 19% in children with a systolic BP% persistently below the median to 80% for individuals with elevated BP in both childhood and adolescence. Although our precision to predict which individual child is at risk of adult BP-related cardiovascular disease is weak, an increase in systolic BP and body mass index percentile from childhood to adolescence should signal a need for lifestyle intervention to prevent future sustained hypertension-related cardiovascular disease.
Insulin resistance is associated with obesity but mechanisms controlling this relationship in humans are not fully understood. Studies in animal models suggest a linkage between adipose reactive ...oxygen species (ROS) and insulin resistance. ROS oxidize cellular lipids to produce a variety of lipid hydroperoxides that in turn generate reactive lipid aldehydes that covalently modify cellular proteins in a process termed carbonylation. Mammalian cells defend against reactive lipid aldehydes and protein carbonylation by glutathionylation using glutathione‐S‐transferase A4 (GSTA4) or carbonyl reduction/oxidation via reductases and/or dehydrogenases. Insulin resistance in mice is linked to ROS production and increased level of protein carbonylation, mitochondrial dysfunction, decreased insulin‐stimulated glucose transport, and altered adipokine secretion. To assess protein carbonylation and insulin resistance in humans, eight healthy participants underwent subcutaneous fat biopsy from the periumbilical region for protein analysis and frequently sampled intravenous glucose tolerance testing to measure insulin sensitivity. Soluble proteins from adipose tissue were analyzed using two‐dimensional gel electrophoresis and the major carbonylated proteins identified as the adipocyte and epithelial fatty acid‐binding proteins. The level of protein carbonylation was directly correlated with adiposity and serum free fatty acids (FFAs). These results suggest that in human obesity oxidative stress is linked to protein carbonylation and such events may contribute to the development of insulin resistance.
Although blood pressure (BP) is routinely measured in outpatient visits, elevated BP and hypertension are often not recognized. We evaluated whether an electronic health record-linked clinical ...decision support (CDS) tool could improve the recognition and management of hypertension in adolescents.
We randomly assigned 20 primary care clinics within an integrated care system to CDS or usual care. At intervention sites, the CDS displayed BPs and percentiles, identified incident hypertension on the basis of current or previous BPs, and offered tailored order sets. The recognition of hypertension was identified by an automated review of diagnoses and problem lists and a manual review of clinical notes, antihypertensive medication prescriptions, and diagnostic testing. Generalized linear mixed models were used to test the effect of the intervention.
Among 31 579 patients 10 to 17 years old with a clinic visit over a 2-year period, 522 (1.7%) had incident hypertension. Within 6 months of meeting criteria, providers recognized hypertension in 54.9% of patients in CDS clinics and 21.3% of patients in usual care (
≤ .001). Clinical recognition was most often achieved through visit diagnoses or documentation in the clinical note. Within 6 months of developing incident hypertension, 17.1% of CDS subjects were referred to dieticians or weight loss or exercise programs, and 9.4% had additional hypertension workup versus 3.9% and 4.2%, respectively (
= .001 and .046, respectively). Only 1% of patients were prescribed an antihypertensive medication within 6 months of developing hypertension.
The CDS had a significant, beneficial effect on the recognition of hypertension, with a moderate increase in guideline-adherent management.
Objective: Emerging data indicate that insulin resistance is common among children and adolescents and is related to cardiometabolic risk, therefore requiring consideration early in life. However, ...there is still confusion on how to define insulin resistance, how to measure it, what its risk factors are, and whether there are effective strategies to prevent and treat it. A consensus conference was organized in order to clarify these points.
Participants: The consensus was internationally supported by all the major scientific societies in pediatric endocrinology and 37 participants.
Evidence: An independent and systematic search of the literature was conducted to identify key articles relating to insulin resistance in children.
Consensus Process: The conference was divided into five themes and working groups: background and definition; methods of measurement and screening; risk factors and consequences; prevention; and treatment. Each group selected key issues, searched the literature, and developed a draft document. During a 3-d meeting, these papers were debated and finalized by each group before presenting them to the full forum for further discussion and agreement.
Conclusions: Given the current childhood obesity epidemic, insulin resistance in children is an important issue confronting health care professionals. There are no clear criteria to define insulin resistance in children, and surrogate markers such as fasting insulin are poor measures of insulin sensitivity. Based on current screening criteria and methodology, there is no justification for screening children for insulin resistance. Lifestyle interventions including diet and exercise can improve insulin sensitivity, whereas drugs should be implemented only in selected cases.
This consensus provides an evidence-based summary of the current knowledge on insulin resistance in children, particularly on definition, risk factors, consequences, methods of measurement, prevention, and treatment.
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