Cardiovascular Risk Factors in Childhood and Adulthood and Cardiovascular Disease in Middle Age.

Importance: Recent evidence suggests that childhood levels of serum lipids, blood pressure, body mass index (BMI), and smoking contribute to adult risk of cardiovascular disease (CVD). Evidence is lacking on whether this is independent of adult risk levels. Objective: To quantify direct and indirect effects of childhood risk factors on adult CVD via adulthood risk factors using mediation analysis, and to quantify their relative importance during different life-course stages using a life-course approach. Design, Setting, and Participants: This prospective cohort study followed participants from the US, Finland, and Australia from childhood (1970s-1990s) until 2019, with data on CVD risk factors in childhood and adulthood. Longitudinal childhood and adulthood risk factors were summarized to describe BMI, lipids, and blood pressure cumulatively. Childhood and adulthood smoking were assessed with questionnaires. Data analysis was performed May 2022 to August 2023. Main Outcomes and Measures: The primary outcomes were fatal and nonfatal cardiovascular events in adulthood. Mediation analysis was used to estimate the direct and indirect effects of the childhood risk factors with CVD events, reported as incidence rate ratios (RRs) and 95% CIs. Results: A total of 10 634 participants (4506 male participants [42.4%]; mean [SD] age at childhood visit, 13.3 [3.0] years; mean [SD] age at adulthood visit, 32.3 [6.0] years) were included in the cohort. The mean (SD) age at CVD event or censoring was 49.2 (7.0) years. The median (IQR) follow-up time was 23.6 (18.7-30.2) years. Childhood risk factors, (low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC], triglycerides, systolic blood pressure [SBP], smoking, BMI, and a combined score of these) were associated with CVD. BMI (direct effect for incidence RR per 1 SD unit, 1.18; 95% CI, 1.05-1.34) and LDL-C (direct effect incidence RR, 1.16; 95% CI, 1.01-1.34) in particular were found to play an important role via direct pathways, whereas the indirect effects were larger for TC, triglycerides, SBP, and the combined score. Childhood smoking only affected CVD via adulthood smoking. Life-course models confirmed that for the risk of CVD, childhood BMI plays nearly as important role as adulthood BMI, whereas for the other risk factors and the combined score, adulthood was the more important period. Conclusions and Relevance: In this cohort study of 10 634 participants, childhood risk factors were found to be associated both directly and indirectly to adult CVD, with the largest direct effect seen for BMI and LDL-C. These findings suggest that intervention for childhood risk factors, in particular BMI, is warranted to reduce incidence of adult CVD as it cannot be fully mitigated by risk factor management in adulthood.

Non-High-Density Lipoprotein Cholesterol Levels From Childhood to Adulthood and Cardiovascular Disease Events.

Importance: Elevated non-high-density lipoprotein cholesterol (non-HDL-C; a recommended measure of lipid-related cardiovascular risk) is common in children and increases risk of adult cardiovascular disease (CVD). Whether resolution of elevated childhood non-HDL-C levels by adulthood is associated with reduced risk of clinical CVD events is unknown. Objective: To examine the associations of non-HDL-C status between childhood and adulthood with incident CVD events. Design, Setting, and Participants: Individual participant data from 6 prospective cohorts of children (mean age at baseline, 10.7 years) in the US and Finland. Recruitment took place between 1970 and 1996, with a final follow-up in 2019. Exposures: Child (age 3-19 years) and adult (age 20-40 years) non-HDL-C age- and sex-specific z scores and categories according to clinical guideline-recommended cutoffs for dyslipidemia. Main Outcomes and Measures: Incident fatal and nonfatal CVD events adjudicated by medical records. Results: Over a mean length of follow-up of 8.9 years after age 40 years, 147 CVD events occurred among 5121 participants (60% women; 15% Black). Both childhood and adult non-HDL-C levels were associated with increased risk of CVD events (hazard ratio [HR], 1.42 [95% CI, 1.18-1.70] and HR, 1.50 [95% CI, 1.26-1.78] for a 1-unit increase in z score, respectively), but the association for childhood non-HDL-C was reduced when adjusted for adult levels (HR, 1.12 [95% CI, 0.89-1.41]). A complementary analysis showed that both childhood non-HDL-C levels and the change between childhood and adulthood were independently associated with the outcome, suggesting that from a preventive perspective, both childhood non-HDL-C levels and the change into adulthood are informative. Compared with those whose non-HDL-C levels remained within the guideline-recommended range in childhood and adulthood, participants who had incident non-HDL-C dyslipidemia from childhood to adulthood and those with persistent dyslipidemia had increased risks of CVD events (HR, 2.17 [95% CI, 1.00-4.69] and HR, 5.17 [95% CI, 2.80-9.56], respectively). Individuals who had dyslipidemic non-HDL-C in childhood but whose non-HDL-C levels were within the guideline-recommended range in adulthood did not have a significantly increased risk (HR, 1.13 [95% CI, 0.50-2.56]). Conclusions and Relevance: Individuals with persistent non-HDL-C dyslipidemia from childhood to adulthood had an increased risk of CVD events, but those in whom dyslipidemic non-HDL-C levels resolve by adulthood have similar risk to individuals who were never dyslipidemic. These findings suggest that interventions to prevent and reduce elevated childhood non-HDL-C levels may help prevent premature CVD.

Impact of Hematopoietic Cell Transplantation on Cardiovascular Risk Factors and Insulin Sensitivity.

The use of hematopoietic cell transplantation (HCT) for treating malignant conditions in children has increased over the past five decades, leading to a growing population of long-term survivors.This population of childhood HCT survivors faces increased risks of adverse medical effects due to cancer treatments, including adverse cardiovascular disease (CVD) risk factors such as metabolic syndrome, insulin resistance. but the impact of exposure to HCT preparative conditioning regimen has not been clearly delineated. These risk factors, including obesity, dyslipidemia, hypertension, and insulin resistance (IR), are significant contributors to premature cardiovascular disease and represent a leading cause of non-relapse deaths in childhood cancer and HCT survivors. This study aimed to assess the early development of CVD risk factors and their relationship to insulin resistance in a large population of pediatric and young adult HCT survivors of childhood hematologic malignancies. The study compared their cardiovascular risk profiles, insulin resistance (measured by euglycemic hyperinsulinemic clamp studies), and body composition (determined by dual X-ray absorptiometry - DXA) with a cohort of sibling controls. We enrolled 151 HCT recipients (26.36 ±0.90 years at study enrollment; time since HCT of 2.6-31.5 years) and 92 sibling controls to complete at cardiovascular risk assessment including insulin sensitivity by hyperinsulinemic euglycemic clamp, anthropometry, body composition by dual X-ray absorptiometry, blood pressure, and serum biomarkers. We used linear models to test for mean differences in all continuous outcomes between survivors and siblings, accounting for intra-family correlations with generalized estimating equations. Recipients of HCT were found to have lower insulin sensitivity and more likely to have adverse CVD risk factors in comparison to their healthy siblings. Significantly higher percent fat mass and visceral adipose tissue, and significantly lower lean body mass were noted in HCT recipients than sibling controls despite having a similar body mass index between the two groups. Total body irradiation in the conditioning regimen was one of the strongest factors associated with lower insulin sensitivity, dyslipidemia and abnormal body composition leading to sarcopenic obesity. This study reveals that pediatric and young adult HCT survivors are more insulin resistant and have a higher prevalence of adverse cardiovascular risk factors compared to sibling controls. The presence of cardiovascular risk factors at a relatively young age raises concerns about an escalating trajectory of cardiovascular disease in this population. Therefore, regular monitoring of HCT survivors for cardiometabolic risk factors and early intervention will be crucial for preventing cardiovascular-related complications in the future. The findings underscore the importance of survivorship care for pediatric and young adult HCT survivors, with a focus on managing cardiovascular risk factors and promoting a healthy lifestyle to mitigate long-term adverse effects. Early identification and targeted interventions can significantly improve the long-term health outcomes of this vulnerable population, reducing the burden of cardiovascular disease and related complications.

Childhood Non-HDL Cholesterol and LDL Cholesterol and Adult Atherosclerotic Cardiovascular Events.

BACKGROUND: Although low-density lipoprotein cholesterol (LDL-C) remains the primary cholesterol target in clinical practice in children and adults, non-high-density lipoprotein cholesterol (non-HDL-C) has been suggested as a more accurate measure of atherosclerotic cardiovascular disease (ASCVD) risk. We examined the associations of childhood non-HDL-C and LDL-C levels with adult ASCVD events and determined whether non-HDL-C has better utility than LDL-C in predicting adult ASCVD events. METHODS: This prospective cohort study included 21 126 participants from the i3C Consortium (International Childhood Cardiovascular Cohorts). Proportional hazards regressions were used to estimate the risk for incident fatal and fatal/nonfatal ASCVD events associated with childhood non-HDL-C and LDL-C levels (age- and sex-specific z scores; concordant/discordant categories defined by guideline-recommended cutoffs), adjusted for sex, Black race, cohort, age at and calendar year of child measurement, body mass index, and systolic blood pressure. Predictive utility was determined by the C index. RESULTS: After an average follow-up of 35 years, 153 fatal ASCVD events occurred in 21 126 participants (mean age at childhood visits, 11.9 years), and 352 fatal/nonfatal ASCVD events occurred in a subset of 11 296 participants who could be evaluated for this outcome. Childhood non-HDL-C and LDL-C levels were each associated with higher risk of fatal and fatal/nonfatal ASCVD events (hazard ratio ranged from 1.27 [95% CI, 1.14-1.41] to 1.35 [95% CI, 1.13-1.60] per unit increase in the risk factor z score). Non-HDL-C had better discriminative utility than LDL-C (difference in C index, 0.0054 [95% CI, 0.0006-0.0102] and 0.0038 [95% CI, 0.0008-0.0068] for fatal and fatal/nonfatal events, respectively). The discordant group with elevated non-HDL-C and normal LDL-C had a higher risk of ASCVD events compared with the concordant group with normal non-HDL-C and LDL-C (fatal events: hazard ratio, 1.90 [95% CI, 0.98-3.70]; fatal/nonfatal events: hazard ratio, 1.94 [95% CI, 1.23-3.06]). CONCLUSIONS: Childhood non-HDL-C and LDL-C levels are associated with ASCVD events in midlife. Non-HDL-C is better than LDL-C in predicting adult ASCVD events, particularly among individuals who had normal LDL-C but elevated non-HDL-C. These findings suggest that both non-HDL-C and LDL-C are useful in identifying children at higher risk of ASCVD events, but non-HDL-C may provide added prognostic information when it is discordantly higher than the corresponding LDL-C and has the practical advantage of being determined without a fasting sample.

Blood Pressure in Children in the 21st Century: What Do We Know and Where Do We Go From Here?

The association between hypertension in adulthood and cardiovascular morbidity and death is well known. Based on that association, a diagnosis of elevated blood pressure in children has been clinically interpreted as early cardiovascular disease. The objective of this review is to discuss historical data and new research on the relationship between elevated blood pressure and early preclinical and later adult cardiovascular disease. After summarizing the evidence, we will address the gaps in knowledge around Pediatric hypertension in an effort to stimulate research into the important role that control of blood pressure in youth may play in preventing adult cardiovascular disease.

Childhood Cardiovascular Risk Factors and Adult Cardiovascular Events.

BACKGROUND: Childhood cardiovascular risk factors predict subclinical adult cardiovascular disease, but links to clinical events are unclear. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).

Obesity during childhood is associated with higher cancer mortality rate during adulthood: the i3C Consortium.

BACKGROUND: In high-income countries, cancer is the leading cause of death among middle-aged adults. Prospective data on the effects of childhood risk exposures on subsequent cancer mortality are scarce. METHODS: We examined whether childhood body mass index (BMI), blood pressure, glucose and lipid levels were associated with adult cancer mortality, using data from 21,012 children enrolled aged 3-19 years in seven prospective cohort studies from the U.S., Australia, and Finland that have followed participants from childhood into adulthood. Cancer mortality (cancer as a primary or secondary cause of death) was captured using registries. RESULTS: 354 cancer deaths occurred over the follow-up. In age-, sex, and cohort-adjusted analyses, childhood BMI (Hazard ratio [HR], 1.13; 95% confidence interval [CI] 1.03-1.24 per 1-SD increase) and childhood glucose (HR 1.22; 95%CI 1.01-1.47 per 1-SD increase), were associated with subsequent cancer mortality. In a multivariable analysis adjusted for age, sex, cohort, and childhood measures of fasting glucose, total cholesterol, triglycerides, and systolic blood pressure, childhood BMI remained as an independent predictor of subsequent cancer mortality (HR, 1.24; 95%CI, 1.03-1.49). The association of childhood BMI and subsequent cancer mortality persisted after adjustment for adulthood BMI (HR for childhood BMI, 1.35; 95%CI 1.12-1.63). CONCLUSIONS: Higher childhood BMI was independently associated with increased overall cancer mortality.

Childhood BMI and Fasting Glucose and Insulin Predict Adult Type 2 Diabetes: The International Childhood Cardiovascular Cohort (i3C) Consortium.

OBJECTIVE: To examine childhood BMI, fasting glucose, and insulin in relation to incident adult type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: We used data from the International Childhood Cardiovascular Cohort (i3C) Consortium. Data included childhood (age 3-19 years) measurements obtained during the 1970s-1990s; a health questionnaire, including self-report of adult T2DM (occurrence age, medication use) obtained at mean age 40 years; and a medical diagnosis registry (Finland). RESULTS: The sample included 6,738 participants. Of these, 436 (6.5%) reported onset of T2DM between ages 20 and 59 (mean 40.8) years, and 86% of them reported use of a confirmed antidiabetic medication. BMI and glucose (age and sex standardized) were associated with incident T2DM after adjustment for cohort, country, sex, race, age, and calendar year of measurement. Increasing levels of childhood BMI and glucose were related to an incrementally increased risk of T2DM beginning at age 30 years, beginning at cut points <95th percentile for BMI and <100 mg/dL for glucose. Insulin was positively associated with adult T2DM after adjustment for BMI and glucose and added to T2DM discrimination. CONCLUSIONS: Childhood BMI and glucose are predictors of adult T2DM at levels previously considered to be within the normal range. These easy-to-apply measurements are appealing from a clinical perspective. Fasting insulin has the potential to be an additional predictor.

Childhood/Adolescent Smoking and Adult Smoking and Cessation: The International Childhood Cardiovascular Cohort (i3C) Consortium.

Background Despite declining US adolescent smoking prevalence from 40% among 12th graders in 1995 to around 10% in 2018, adolescent smoking is still a significant problem. Using the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes 7 international cohorts recruited in childhood and followed into adulthood, the present study was designed to confirm the important relation between adolescent smoking and daily adult smoking and present new data on adult smoking into the forties and comparison of smoking in the United States, Finland, and Australia. Methods and Results Childhood smoking experience during ages 6 to 19 in the 1970s and 1980s was classifiable in 6687 i3C participants who also provided smoking status in their twenties and forties through 2011-2018. Prevalence of daily smoking in their twenties was directly related to degree of smoking during adolescence and inversely related to the age at which that smoking experience occurred (P trend, <0.001). Similar patterns were observed for prediction of smoking during age forties. Among the 2465 smokers in their twenties, cessation by their forties was generally inverse to degree of smoking in ages 6 to 19 (P trend, <0.001). Prevalence of smoking during adolescence and adulthood was similar among US, Finnish, and Australian participants. Conclusions These long-term follow-up data show that smoking intensity increased throughout adolescence. Prevalence of adult smoking and cessation by the forties were both correlated with levels of childhood smoking intensity. These data lend support to preventive strategies designed to reduce, delay, or eliminate any youth access to cigarettes.

Clinical Decision Support for Recognizing and Managing Hypertensive Blood Pressure in Youth: No Significant Impact on Medical Costs.

OBJECTIVE: To evaluate economic costs from the health system perspective of an electronic health record-based clinical decision support (CDS) tool, TeenBP, designed to assist in the recognition and management of hypertension in youth. METHODS: Twenty primary care clinics within an integrated health system were randomized to the TeenBP CDS or usual care (UC), with patient enrollment from 4/15/14 to 4/14/16. The 12-month change in standardized medical care costs for insured patients aged 10 to 17 years without prior hypertension were calculated for each study arm. The primary analysis compared patients with ≥1 visit with blood pressure (BP) ≥95th percentile (isolated hypertensive BP), and secondary analyses compared patients with ≥3 visits within one year with BP ≥95th percentile (incident hypertension). Generalized estimating equation models estimated the difference-in-differences in costs between groups over time. RESULTS: Among 925 insured patients with an isolated hypertensive BP, the pre-to-post change in overall costs averaged $22 more for TeenBP CDS versus UC patients over 12 months, but this difference was not statistically significant (P = .723). Among 159 insured patients with incident hypertension, the pre-to-post change in overall costs over 12 months was higher by $227 per person on average for TeenBP CDS versus UC patients, but this difference also was not statistically significant (P = .313). CONCLUSIONS: The TeenBP CDS intervention was previously found to significantly improve identification and management of hypertensive BP in youth, and in this study, we find that this tool did not significantly increase care costs in its first 12 months of clinical use.

Longitudinal Changes in Weight Status from Childhood and Adolescence to Adulthood.

OBJECTIVES: To study the change in body mass index (BMI) from childhood and adolescence and development of obesity into adulthood. STUDY DESIGN: 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). RESULTS: 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. CONCLUSIONS: 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.

Predicting overweight and obesity in young adulthood from childhood body-mass index: comparison of cutoffs derived from longitudinal and cross-sectional data.

BACKGROUND: Historically, cutoff points for childhood and adolescent overweight and obesity have been based on population-specific percentiles derived from cross-sectional data. To obtain cutoff points that might better predict overweight and obesity in young adulthood, we examined the association between childhood body-mass index (BMI) and young adulthood BMI status in a longitudinal cohort. METHODS: In this study, we used data from the International Childhood Cardiovascular Cohort (i3C) Consortium (which included seven childhood cohorts from the USA, Australia, and Finland) to establish childhood overweight and obesity cutoff points that best predict BMI status at the age of 18 years. We included 3779 children who were followed up from 1970 onwards, and had at least one childhood BMI measurement between ages 6 years and 17 years and a BMI measurement specifically at age 18 years. We used logistic regression to assess the association between BMI in childhood and young adulthood obesity. We used the area under the receiver operating characteristic curve (AUROC) to assess the ability of fitted models to discriminate between different BMI status groups in young adulthood. The cutoff points were then compared with those defined by the International Obesity Task Force (IOTF), which used cross-sectional data, and tested for sensitivity and specificity in a separate, independent, longitudinal sample (from the Special Turku Coronary Risk Factor Intervention Project [STRIP] study) with BMI measurements available from both childhood and adulthood. FINDINGS: The cutoff points derived from the longitudinal i3C Consortium data were lower than the IOTF cutoff points. Consequently, a larger proportion of participants in the STRIP study was classified as overweight or obese when using the i3C cutoff points than when using the IOTF cutoff points. Especially for obesity, i3C cutoff points were significantly better at identifying those who would become obese later in life. In the independent sample, the AUROC values for overweight ranged from 0·75 (95% CI 0·70-0·80) to 0·88 (0·84-0·93) for the i3C cutoff points, and the corresponding values for the IOTF cutoff points ranged from 0·69 (0·62-0·75) to 0·87 (0·82-0·92). For obesity, the AUROC values ranged from 0·84 (0·75-0·93) to 0·90 (0·82-0·98) for the i3C cutoff points and 0·57 (0·49-0·66) to 0·76 (0·65-0·88) for IOTF cutoff points. INTERPRETATION: The childhood BMI cutoff points obtained from the i3C Consortium longitudinal data can better predict risk of overweight and obesity in young adulthood than can standards that are currently used based on cross-sectional data. Such cutoff points should help to more accurately identify children at risk of adult overweight or obesity. FUNDING: None.

Impact of updated pediatric hypertension guidelines on progression from elevated blood pressure to hypertension in a community-based primary care population.

In 2017, definitions for pediatric hypertension were updated. A threshold of 130/80 mm Hg was introduced for stage 1 hypertension in adolescents, and children with obesity were removed from the reference population, lowering the 95th percentile, compared to the 2004 Fourth Report. The impact of these changes on care for youth with elevated blood pressure has not been well described. The objective of this study was to compare the 2017 and 2004 criteria for hypertension, evaluating how they impact estimates of risks for elevated blood pressure to progress to hypertension. Data came from youth 10-17 years of age with ≥2 elevated blood pressure measurements (≥90th percentile or ≥120/80 mm Hg) between 04/15/2014 and 04/14/2016 and three additional measurements over two subsequent years. Blood pressures were recorded in primary care practices within a large health system, as part of routine care. Rates of incident hypertension following persistent elevated blood pressure based on the 2017 guidelines vs the 2004 Fourth Report were compared. We found, among 2025 youth with persistent elevated blood pressure, 46% were female and mean age was 14.6 years. Over 2 years of follow-up, progression to hypertension occurred in 5.9% using the 2017 guidelines vs 1.1% using 2004 Fourth Report definitions. Using the 2017 criteria, progression was most common in older youth and those with obesity. In conclusion, for most youth, elevated blood pressure does not progress to hypertension within 2 years. However, progression from elevated blood pressure to hypertension was more than 5-fold greater when applying the 2017 guidelines compared to the older 2004 Fourth Report criteria.

The International Childhood Cardiovascular Cohort (i3C) consortium outcomes study of childhood cardiovascular risk factors and adult cardiovascular morbidity and mortality: Design and recruitment.

Although it is widely thought that childhood levels of cardiovascular (CV) risk factors are related to adult CV disease, longitudinal data directly linking the two are lacking. This paper describes the design and organization of the International Childhood Cardiovascular Cohort Consortium Outcomes Study (i3C Outcomes), the first longitudinal cohort study designed to locate adults with detailed, repeated, childhood biological, physical, and socioeconomic measurements and a harmonized database. I3C Outcomes uses a Heart Health Survey (HHS) to obtain information on adult CV endpoints, using mail, email, telephone, and clinic visits in the United States (U.S.) and Australia and a national health database in Finland. Microsoft Access, REsearch Data Capture (REDCap) (U.S.), LimeSurvey (Australia), and Medidata™ Rave data systems are used to collect, transfer and organize data. Self-reported CV events are adjudicated via hospital and doctor-released medical records. After the first two study years, participants (N = 10,968) were more likely to be female (56% vs. 48%), non-Hispanic white (90% vs. 80%), and older (10.4 ±â€¯3.8 years vs. 9.4 ±â€¯3.3 years) at their initial childhood study visit than the currently non-recruited cohort members. Over 48% of cohort members seen during both adulthood and childhood have been found and recruited, to date, vs. 5% of those not seen since childhood. Self-reported prevalences were 0.7% Type 1 Diabetes, 7.5% Type 2 Diabetes, 33% hypertension, and 12.8% CV event. 32% of CV events were judged to be true. I3C Outcomes is uniquely able to establish evidence-based guidelines for child health care and to clarify relations to adult CV disease.

Associations of sex, age and adiposity in endothelium-independent dilation in children.

OBJECTIVE: To examine the association of age, sex, and obesity status on endothelial-independent dilation (EID) among children and adolescents. STUDY DESIGN: This study examined 264 children (143 males) between 8 to 18 years old (mean ± SD: age = 14.3 ± 2.7 years). Endothelial-independent dilation was assessed via ultrasound imaging of the brachial artery following administration of 0.3 milligrams of sublingual nitroglycerin. A one-way analysis of variance with Bonferroni post hoc comparisons assessed sex-differences in percent peak EID dilation (EID%-peak) and EID area under the curve (EID%-AUC), while analysis of covariance (ANCOVA) adjusted for race, age, body mass index percentile (BMI-percentile), and brachial artery diameter. Multiple linear regression evaluated the association of sex, age, BMI-percentile, percent body fat (%BF), and brachial artery diameter on EID. RESULTS: Prior to adjustment, EID%-peak was significantly higher among females than males (mean ± SE: 26.9 ± 0.5% versus 22.9 ± 0.6%, p < 0.001, respectively); similar findings for EID%-AUC (4214% ± 105%·s versus 3398% ± 97%·s, p < 0.001) were observed. After adjusting for covariates, EID%-AUC remained consistent (p = 0.03) while EID%-peak was not significantly different between sexes (p = 0.21). EID%-peak was significantly higher among normal weight compared to obese participants (p = 0.04), while no differences were observed between obesity status after adjustment for brachial artery diameter (p = 0.64). Both unadjusted (p = 0.16) and adjusted EID%-AUC (p = 0.24) was not significantly different between obesity status. BMI-percentile was not associated with EID%-peak (p = 0.76) or EID%-AUC (p = 0.30). Additionally, %BF was not associated with EID%-peak (p = 0.56) or EID%-AUC (p = 0.15). After adjusting for brachial artery diameter, BMI-percentile, and age, males had lower EID%-AUC (p = 0.03) and lower but not significant EID%-peak (p = 0.21). SIGNIFICANCE: Vascular smooth muscle function was significantly lower among male children and adolescents, which is suggestive that impaired EID and increased cardiovascular disease risk among males may begin in childhood. Interestingly, obesity status and BMI-percentile was not associated with EID in children and adolescents after adjusting for brachial artery diameter.

Association Between Carotid Intima Media Thickness, Age, and Cardiovascular Risk Factors in Children and Adolescents.

BACKGROUND: Measures of carotid intima media thickness (cIMT) in adults are correlated with adiposity and the metabolic syndrome (MetS) and predict cardiovascular (CV) events. Relations in children are not as well studied. Our objective was to determine the relations of cIMT with body mass index (BMI) and CV risk score in children. METHODS: The study included 291 children (158 M/133 F) 6-18 years of age (140 aged 6-11/151 aged 12-18) with measurements of height, weight, waist circumference; fasting lipids, glucose, insulin, and cIMT. A CV risk cluster score was developed from sum of the z-scores of the five MetS components (waist circumference, blood pressure, serum triglycerides, high-density lipoprotein cholesterol, and insulin). Partial Pearson correlation coefficients were adjusted for age, sex, and race. RESULTS: There was no significant age difference in cIMT from 6 to 18 years of age. BMI and CV risk score were significantly correlated (P < 0.0001), and both were correlated with cIMT (r = 0.14, P = 0.02 and r = 0.16, P = 0.006, respectively). Slight age-related differences in associations of cIMT with CV risk score and BMI were explained by unusual values in a few children. CONCLUSIONS: These cross-sectional data in normal children show that cIMT was stable from childhood into adolescence. However, both BMI and CV risk score had small, but significant positive correlations with cIMT. Therefore, maintaining normal levels of adiposity and other risk variables may be useful in preventing early changes associated with preclinical atherosclerosis.

Clinical Decision Support for Recognition and Management of Hypertension: A Randomized Trial.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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 (P ≤ .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 (P = .001 and .046, respectively). Only 1% of patients were prescribed an antihypertensive medication within 6 months of developing hypertension. CONCLUSIONS: The CDS had a significant, beneficial effect on the recognition of hypertension, with a moderate increase in guideline-adherent management.

Predicting Hypertension Among Children With Incident Elevated Blood Pressure.

OBJECTIVE: To develop a model to predict hypertension risk among children with incident elevated blood pressure (BP); to test the external validity of the model. METHODS: A retrospective cohort study was conducted in 3 organizations: Kaiser Permanente Colorado was the model derivation site; HealthPartners of Minnesota and Kaiser Permanente Northern California served as external validation sites. During study years 2006 through 2012, all children aged 3 through 17 years with incident elevated BP in an outpatient setting were identified. The predictor variables were demographic and clinical characteristics collected during routine care. Cox proportional hazards regression was used to predict subsequent hypertension, and diagnostic statistics were used to assess model performance. RESULTS: Among 5598 subjects at the derivation site with incident elevated BP, 160 (2.9%) developed hypertension during the study period. Eight characteristics were used to predict hypertension risk: age, sex, race, BP preceding incident elevated BP, body mass index percentile, systolic BP percentile, diastolic BP percentile, and clinical setting of the incident elevated BP. At the derivation site, the model discriminated well between those at higher versus lower risk of hypertension (c-statistic = 0.77). At external validation sites, the observed risk of hypertension was higher than the predicted risk, and the model showed poor discrimination (c-statistic ranged from 0.64 to 0.67). CONCLUSIONS: Among children with incident elevated BP, a risk model demonstrated good internal validity with respect to predicting subsequent hypertension. However, the risk model did not perform well at 2 external validation sites, which might limit transportability to other settings.

The Carotid Intima-Media Thickness and Arterial Stiffness of Pediatric Mucopolysaccharidosis Patients Are Increased Compared to Both Pediatric and Adult Controls.

Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but cardiovascular disease causes mortality in a significant percentage of survivors. Markers must be developed to predict MPS cardiac risk and monitor efficacy of investigational therapies.MPS patients underwent carotid artery ultrasonography from which carotid intima-media thickness (cIMT) and three measures of arterial stiffness were calculated: carotid artery distensibility (cCSD), compliance (cCSC), and incremental elastic modulus (cIEM). MPS carotid measurements were compared to corresponding data from pediatric and adult healthy cohorts. 33 MPS patients (17 MPS I, 9 MPS II, 4 MPS IIIA, and 3 MPS VI; mean age 12.5 ± 4.7 years), 560 pediatric controls (age 13.1 ± 4.0 years), and 554 adult controls (age 39.2 ± 2.2 years) were studied. Age and sex-adjusted aggregate MPS cIMT (0.56 ± 0.05 mm) was significantly greater than both pediatric (+0.12 mm; 95% CI +0.10 to +0.14 mm) and adult (+0.10 mm; 95% CI +0.06 to +0.14 mm) control cohorts; similar findings were observed for all MPS subtypes. Mean MPS cIMT approximated the 80th percentile of the adult cohort cIMT. MPS patients also demonstrated significantly increased adjusted arterial stiffness measurements, evidenced by reduced cCSD, cCSC, and increased cIEM, compared to pediatric and adult control cohorts. Regardless of treatment, MPS patients demonstrate increased cIMT and arterial stiffness compared to healthy pediatric and adult controls. These data suggest that relatively young MPS patients demonstrate a "structural vascular age" of at least 40 years old.